WorldWideScience

Sample records for human genomic region

  1. Human-mouse comparative genomics: successes and failures to reveal functional regions of the human genome

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    Pennacchio, Len A.; Baroukh, Nadine; Rubin, Edward M.

    2003-05-15

    Deciphering the genetic code embedded within the human genome remains a significant challenge despite the human genome consortium's recent success at defining its linear sequence (Lander et al. 2001; Venter et al. 2001). While useful strategies exist to identify a large percentage of protein encoding regions, efforts to accurately define functional sequences in the remaining {approx}97 percent of the genome lag. Our primary interest has been to utilize the evolutionary relationship and the universal nature of genomic sequence information in vertebrates to reveal functional elements in the human genome. This has been achieved through the combined use of vertebrate comparative genomics to pinpoint highly conserved sequences as candidates for biological activity and transgenic mouse studies to address the functionality of defined human DNA fragments. Accordingly, we describe strategies and insights into functional sequences in the human genome through the use of comparative genomics coupled wit h functional studies in the mouse.

  2. Analysis of Human Accelerated DNA Regions Using Archaic Hominin Genomes

    Science.gov (United States)

    Burbano, Hernán A.; Green, Richard E.; Maricic, Tomislav; Lalueza-Fox, Carles; de la Rasilla, Marco; Rosas, Antonio; Kelso, Janet; Pollard, Katherine S.; Lachmann, Michael; Pääbo, Svante

    2012-01-01

    Several previous comparisons of the human genome with other primate and vertebrate genomes identified genomic regions that are highly conserved in vertebrate evolution but fast-evolving on the human lineage. These human accelerated regions (HARs) may be regions of past adaptive evolution in humans. Alternatively, they may be the result of non-adaptive processes, such as biased gene conversion. We captured and sequenced DNA from a collection of previously published HARs using DNA from an Iberian Neandertal. Combining these new data with shotgun sequence from the Neandertal and Denisova draft genomes, we determine at least one archaic hominin allele for 84% of all positions within HARs. We find that 8% of HAR substitutions are not observed in the archaic hominins and are thus recent in the sense that the derived allele had not come to fixation in the common ancestor of modern humans and archaic hominins. Further, we find that recent substitutions in HARs tend to have come to fixation faster than substitutions elsewhere in the genome and that substitutions in HARs tend to cluster in time, consistent with an episodic rather than a clock-like process underlying HAR evolution. Our catalog of sequence changes in HARs will help prioritize them for functional studies of genomic elements potentially responsible for modern human adaptations. PMID:22412940

  3. Forces shaping the fastest evolving regions in the human genome.

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    Katherine S Pollard

    2006-10-01

    Full Text Available Comparative genomics allow us to search the human genome for segments that were extensively changed in the last approximately 5 million years since divergence from our common ancestor with chimpanzee, but are highly conserved in other species and thus are likely to be functional. We found 202 genomic elements that are highly conserved in vertebrates but show evidence of significantly accelerated substitution rates in human. These are mostly in non-coding DNA, often near genes associated with transcription and DNA binding. Resequencing confirmed that the five most accelerated elements are dramatically changed in human but not in other primates, with seven times more substitutions in human than in chimp. The accelerated elements, and in particular the top five, show a strong bias for adenine and thymine to guanine and cytosine nucleotide changes and are disproportionately located in high recombination and high guanine and cytosine content environments near telomeres, suggesting either biased gene conversion or isochore selection. In addition, there is some evidence of directional selection in the regions containing the two most accelerated regions. A combination of evolutionary forces has contributed to accelerated evolution of the fastest evolving elements in the human genome.

  4. Linkage disequilibrium of evolutionarily conserved regions in the human genome

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    Johnson Todd A

    2006-12-01

    Full Text Available Abstract Background The strong linkage disequilibrium (LD recently found in genic or exonic regions of the human genome demonstrated that LD can be increased by evolutionary mechanisms that select for functionally important loci. This suggests that LD might be stronger in regions conserved among species than in non-conserved regions, since regions exposed to natural selection tend to be conserved. To assess this hypothesis, we used genome-wide polymorphism data from the HapMap project and investigated LD within DNA sequences conserved between the human and mouse genomes. Results Unexpectedly, we observed that LD was significantly weaker in conserved regions than in non-conserved regions. To investigate why, we examined sequence features that may distort the relationship between LD and conserved regions. We found that interspersed repeats, and not other sequence features, were associated with the weak LD tendency in conserved regions. To appropriately understand the relationship between LD and conserved regions, we removed the effect of repetitive elements and found that the high degree of sequence conservation was strongly associated with strong LD in coding regions but not with that in non-coding regions. Conclusion Our work demonstrates that the degree of sequence conservation does not simply increase LD as predicted by the hypothesis. Rather, it implies that purifying selection changes the polymorphic patterns of coding sequences but has little influence on the patterns of functional units such as regulatory elements present in non-coding regions, since the former are generally restricted by the constraint of maintaining a functional protein product across multiple exons while the latter may exist more as individually isolated units.

  5. Chromosome region-specific libraries for human genome analysis

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    Kao, Fa-Ten.

    1991-01-01

    We have made important progress since the beginning of the current grant year. We have further developed the microdissection and PCR- assisted microcloning techniques using the linker-adaptor method. We have critically evaluated the microdissection libraries constructed by this microtechnology and proved that they are of high quality. We further demonstrated that these microdissection clones are useful in identifying corresponding YAC clones for a thousand-fold expansion of the genomic coverage and for contig construction. We are also improving the technique of cloning the dissected fragments in test tube by the TDT method. We are applying both of these PCR cloning technique to human chromosomes 2 and 5 to construct region-specific libraries for physical mapping purposes of LLNL and LANL. Finally, we are exploring efficient procedures to use unique sequence microclones to isolate cDNA clones from defined chromosomal regions as valuable resources for identifying expressed gene sequences in the human genome. We believe that we are making important progress under the auspices of this DOE human genome program grant and we will continue to make significant contributions in the coming year. 4 refs., 4 figs.

  6. Forces shaping the fastest evolving regions in the human genome

    DEFF Research Database (Denmark)

    Pollard, Katherine S; Salama, Sofie R; King, Bryan;

    2006-01-01

    Comparative genomics allow us to search the human genome for segments that were extensively changed in the last approximately 5 million years since divergence from our common ancestor with chimpanzee, but are highly conserved in other species and thus are likely to be functional. We found 202 gen...... contributed to accelerated evolution of the fastest evolving elements in the human genome.......Comparative genomics allow us to search the human genome for segments that were extensively changed in the last approximately 5 million years since divergence from our common ancestor with chimpanzee, but are highly conserved in other species and thus are likely to be functional. We found 202...... genomic elements that are highly conserved in vertebrates but show evidence of significantly accelerated substitution rates in human. These are mostly in non-coding DNA, often near genes associated with transcription and DNA binding. Resequencing confirmed that the five most accelerated elements...

  7. Computational Comparison of Human Genomic Sequence Assemblies for a Region of Chromosome 4

    OpenAIRE

    Semple, Colin; Stewart W. Morris; Porteous, David J.; Evans, Kathryn L.

    2002-01-01

    Much of the available human genomic sequence data exist in a fragmentary draft state following the completion of the initial high-volume sequencing performed by the International Human Genome Sequencing Consortium (IHGSC) and Celera Genomics (CG). We compared six draft genome assemblies over a region of chromosome 4p (D4S394–D4S403), two consecutive releases by the IHGSC at University of California, Santa Cruz (UCSC), two consecutive releases from the National Centre for Biotechnology Informa...

  8. Comparative Genomic Analyses of the Human NPHP1 Locus Reveal Complex Genomic Architecture and Its Regional Evolution in Primates.

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    Bo Yuan

    2015-12-01

    Full Text Available Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM# 256100 is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region where low copy repeats (LCRs are abundant. Loss of function of NPHP1 is responsible for approximately 85% of the NPHP1 cases-about 80% of such individuals carry a large recurrent homozygous NPHP1 deletion that occurs via nonallelic homologous recombination (NAHR between two flanking directly oriented ~45 kb LCRs. Published data revealed a non-pathogenic inversion polymorphism involving the NPHP1 gene flanked by two inverted ~358 kb LCRs. Using optical mapping and array-comparative genomic hybridization, we identified three potential novel structural variant (SV haplotypes at the NPHP1 locus that may protect a haploid genome from the NPHP1 deletion. Inter-species comparative genomic analyses among primate genomes revealed massive genomic changes during evolution. The aggregated data suggest that dynamic genomic rearrangements occurred historically within the NPHP1 locus and generated SV haplotypes observed in the human population today, which may confer differential susceptibility to genomic instability and the NPHP1 deletion within a personal genome. Our study documents diverse SV haplotypes at a complex LCR-laden human genomic region. Comparative analyses provide a model for how this complex region arose during primate evolution, and studies among humans suggest that intra-species polymorphism may potentially modulate an individual's susceptibility to acquiring disease-associated alleles.

  9. DNA sequence comparative analysis of the 3pter-p26 region of human genome

    Institute of Scientific and Technical Information of China (English)

    LUO; Chunqing; LI; Yan; ZHANG; Xiaowei; ZHANG; Yilin; ZHAN

    2005-01-01

    Most proterminal regions of human chromosomes are GC-rich and gene-rich. Chromosome 3p is an exception. Its proterminal region is GC-poor, and likely to lose heterozygosity, thus causing a number of fatal diseases. Except one gap left in the telomeric position, the proterminal region of human chromosome 3p has been completely sequenced. The detailed sequence analysis showed: (i) the GC content of this region was 38.5%, being the lowest among all the human proterminal regions; (ii) this region contained 20 known genes and 22 predicted genes, with an average gene size of 97.5 kb. The previously mapped gene Cntn3 was not found in this region, but instead located in the 74 Mb position of human chromosome 3p; (iii) the interspersed repeats of this region were more active than the average level of the whole human genome, especially (TA)n, the content of which was twice the genome average; (iv) this region had a conserved synteny extending from 104.1 Mb to 112.4 Mb on the mouse chromosome 6, which was 8% larger in size, not in accordance with the whole genome comparison, probably because the 3pter-p26 region was more likely to lose neocleitides and its mouse synteny had more active interspersed repeats.

  10. Identifying Human Genome-Wide CNV, LOH and UPD by Targeted Sequencing of Selected Regions.

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    Wei Li

    Full Text Available Copy-number variations (CNV, loss of heterozygosity (LOH, and uniparental disomy (UPD are large genomic aberrations leading to many common inherited diseases, cancers, and other complex diseases. An integrated tool to identify these aberrations is essential in understanding diseases and in designing clinical interventions. Previous discovery methods based on whole-genome sequencing (WGS require very high depth of coverage on the whole genome scale, and are cost-wise inefficient. Another approach, whole exome genome sequencing (WEGS, is limited to discovering variations within exons. Thus, we are lacking efficient methods to detect genomic aberrations on the whole genome scale using next-generation sequencing technology. Here we present a method to identify genome-wide CNV, LOH and UPD for the human genome via selectively sequencing a small portion of genome termed Selected Target Regions (SeTRs. In our experiments, the SeTRs are covered by 99.73%~99.95% with sufficient depth. Our developed bioinformatics pipeline calls genome-wide CNVs with high confidence, revealing 8 credible events of LOH and 3 UPD events larger than 5M from 15 individual samples. We demonstrate that genome-wide CNV, LOH and UPD can be detected using a cost-effective SeTRs sequencing approach, and that LOH and UPD can be identified using just a sample grouping technique, without using a matched sample or familial information.

  11. Identifying Human Genome-Wide CNV, LOH and UPD by Targeted Sequencing of Selected Regions.

    Science.gov (United States)

    Wang, Yu; Li, Wei; Xia, Yingying; Wang, Chongzhi; Tang, Y Tom; Guo, Wenying; Li, Jinliang; Zhao, Xia; Sun, Yepeng; Hu, Juan; Zhen, Hefu; Zhang, Xiandong; Chen, Chao; Shi, Yujian; Li, Lin; Cao, Hongzhi; Du, Hongli; Li, Jian

    2014-01-01

    Copy-number variations (CNV), loss of heterozygosity (LOH), and uniparental disomy (UPD) are large genomic aberrations leading to many common inherited diseases, cancers, and other complex diseases. An integrated tool to identify these aberrations is essential in understanding diseases and in designing clinical interventions. Previous discovery methods based on whole-genome sequencing (WGS) require very high depth of coverage on the whole genome scale, and are cost-wise inefficient. Another approach, whole exome genome sequencing (WEGS), is limited to discovering variations within exons. Thus, we are lacking efficient methods to detect genomic aberrations on the whole genome scale using next-generation sequencing technology. Here we present a method to identify genome-wide CNV, LOH and UPD for the human genome via selectively sequencing a small portion of genome termed Selected Target Regions (SeTRs). In our experiments, the SeTRs are covered by 99.73%~99.95% with sufficient depth. Our developed bioinformatics pipeline calls genome-wide CNVs with high confidence, revealing 8 credible events of LOH and 3 UPD events larger than 5M from 15 individual samples. We demonstrate that genome-wide CNV, LOH and UPD can be detected using a cost-effective SeTRs sequencing approach, and that LOH and UPD can be identified using just a sample grouping technique, without using a matched sample or familial information.

  12. Structure-infectivity analysis of the human rhinovirus genomic RNA 3' non-coding region.

    OpenAIRE

    1996-01-01

    The specific recognition of genomic positive strand RNAS as templates for the synthesis of intermediate negative strands by the picornavirus replication machinery is presumably mediated by cis-acting sequences within the genomic RNA 3' non-coding region (NCR). A structure-infectivity analysis was conducted on the 44 nt human rhinovirus 14 (HRV14) 3' NCR to identify the primary sequence and/or secondary structure determinants required for viral replication. Using biochemical RNA secondary stru...

  13. Short interspersed transposable elements (SINEs) are excluded from imprinted regions in the human genome.

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    Greally, John M

    2002-01-08

    To test whether regions undergoing genomic imprinting have unique genomic characteristics, imprinted and nonimprinted human loci were compared for nucleotide and retroelement composition. Maternally and paternally expressed subgroups of imprinted genes were found to differ in terms of guanine and cytosine, CpG, and retroelement content, indicating a segregation into distinct genomic compartments. Imprinted regions have been normally permissive to L1 long interspersed transposable element retroposition during mammalian evolution but universally and significantly lack short interspersed transposable elements (SINEs). The primate-specific Alu SINEs, as well as the more ancient mammalian-wide interspersed repeat SINEs, are found at significantly low densities in imprinted regions. The latter paleogenomic signature indicates that the sequence characteristics of currently imprinted regions existed before the mammalian radiation. Transitions from imprinted to nonimprinted genomic regions in cis are characterized by a sharp inflection in SINE content, demonstrating that this genomic characteristic can help predict the presence and extent of regions undergoing imprinting. During primate evolution, SINE accumulation in imprinted regions occurred at a decreased rate compared with control loci. The constraint on SINE accumulation in imprinted regions may be mediated by an active selection process. This selection could be because of SINEs attracting and spreading methylation, as has been found at other loci. Methylation-induced silencing could lead to deleterious consequences at imprinted loci, where inactivation of one allele is already established, and expression is often essential for embryonic growth and survival.

  14. Genomic Regions Associated With Interspecies Communication in Dogs Contain Genes Related to Human Social Disorders

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    Persson, Mia E.; Wright, Dominic; Roth, Lina S. V.; Batakis, Petros; Jensen, Per

    2016-01-01

    Unlike their wolf ancestors, dogs have unique social skills for communicating and cooperating with humans. Previously, significant heritabilities for human-directed social behaviors have been found in laboratory beagles. Here, a Genome-Wide Association Study identified two genomic regions associated with dog’s human-directed social behaviors. We recorded the propensity of laboratory beagles, bred, kept and handled under standardized conditions, to initiate physical interactions with a human during an unsolvable problem-task, and 190 individuals were genotyped with an HD Canine SNP-chip. One genetic marker on chromosome 26 within the SEZ6L gene was significantly associated with time spent close to, and in physical contact with, the human. Two suggestive markers on chromosome 26, located within the ARVCF gene, were also associated with human contact seeking. Strikingly, four additional genes present in the same linkage blocks affect social abilities in humans, e.g., SEZ6L has been associated with autism and COMT affects aggression in adolescents with ADHD. This is, to our knowledge, the first genome-wide study presenting candidate genomic regions for dog sociability and inter-species communication. These results advance our understanding of dog domestication and raise the use of the dog as a novel model system for human social disorders. PMID:27685260

  15. Genomic Regions Associated With Interspecies Communication in Dogs Contain Genes Related to Human Social Disorders.

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    Persson, Mia E; Wright, Dominic; Roth, Lina S V; Batakis, Petros; Jensen, Per

    2016-09-29

    Unlike their wolf ancestors, dogs have unique social skills for communicating and cooperating with humans. Previously, significant heritabilities for human-directed social behaviors have been found in laboratory beagles. Here, a Genome-Wide Association Study identified two genomic regions associated with dog's human-directed social behaviors. We recorded the propensity of laboratory beagles, bred, kept and handled under standardized conditions, to initiate physical interactions with a human during an unsolvable problem-task, and 190 individuals were genotyped with an HD Canine SNP-chip. One genetic marker on chromosome 26 within the SEZ6L gene was significantly associated with time spent close to, and in physical contact with, the human. Two suggestive markers on chromosome 26, located within the ARVCF gene, were also associated with human contact seeking. Strikingly, four additional genes present in the same linkage blocks affect social abilities in humans, e.g., SEZ6L has been associated with autism and COMT affects aggression in adolescents with ADHD. This is, to our knowledge, the first genome-wide study presenting candidate genomic regions for dog sociability and inter-species communication. These results advance our understanding of dog domestication and raise the use of the dog as a novel model system for human social disorders.

  16. Identification and analysis of genomic regions with large between-population differentiation in humans.

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    Myles, S; Tang, K; Somel, M; Green, R E; Kelso, J; Stoneking, M

    2008-01-01

    The primary aim of genetic association and linkage studies is to identify genetic variants that contribute to phenotypic variation within human populations. Since the overwhelming majority of human genetic variation is found within populations, these methods are expected to be effective and can likely be extrapolated from one human population to another. However, they may lack power in detecting the genetic variants that contribute to phenotypes that differ greatly between human populations. Phenotypes that show large differences between populations are expected to be associated with genomic regions exhibiting large allele frequency differences between populations. Thus, from genome-wide polymorphism data genomic regions with large allele frequency differences between populations can be identified, and evaluated as candidates for large between-population phenotypic differences. Here we use allele frequency data from approximately 1.5 million SNPs from three human populations, and present an algorithm that identifies genomic regions containing SNPs with extreme Fst. We demonstrate that our candidate regions have reduced heterozygosity in Europeans and Chinese relative to African-Americans, and are likely enriched with genes that have experienced positive natural selection. We identify genes that are likely responsible for phenotypes known to differ dramatically between human populations and present several candidates worthy of future investigation. Our list of high Fst genomic regions is a first step in identifying the genetic variants that contribute to large phenotypic differences between populations, many of which have likely experienced positive natural selection. Our approach based on between population differences can compliment traditional within population linkage and association studies to uncover novel genotype-phenotype relationships.

  17. CpG islands undermethylation in human genomic regions under selective pressure.

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    Sergio Cocozza

    Full Text Available DNA methylation at CpG islands (CGIs is one of the most intensively studied epigenetic mechanisms. It is fundamental for cellular differentiation and control of transcriptional potential. DNA methylation is involved also in several processes that are central to evolutionary biology, including phenotypic plasticity and evolvability. In this study, we explored the relationship between CpG islands methylation and signatures of selective pressure in Homo Sapiens, using a computational biology approach. By analyzing methylation data of 25 cell lines from the Encyclopedia of DNA Elements (ENCODE Consortium, we compared the DNA methylation of CpG islands in genomic regions under selective pressure with the methylation of CpG islands in the remaining part of the genome. To define genomic regions under selective pressure, we used three different methods, each oriented to provide distinct information about selective events. Independently of the method and of the cell type used, we found evidences of undermethylation of CGIs in human genomic regions under selective pressure. Additionally, by analyzing SNP frequency in CpG islands, we demonstrated that CpG islands in regions under selective pressure show lower genetic variation. Our findings suggest that the CpG islands in regions under selective pressure seem to be somehow more "protected" from methylation when compared with other regions of the genome.

  18. Read clouds uncover variation in complex regions of the human genome.

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    Bishara, Alex; Liu, Yuling; Weng, Ziming; Kashef-Haghighi, Dorna; Newburger, Daniel E; West, Robert; Sidow, Arend; Batzoglou, Serafim

    2015-10-01

    Although an increasing amount of human genetic variation is being identified and recorded, determining variants within repeated sequences of the human genome remains a challenge. Most population and genome-wide association studies have therefore been unable to consider variation in these regions. Core to the problem is the lack of a sequencing technology that produces reads with sufficient length and accuracy to enable unique mapping. Here, we present a novel methodology of using read clouds, obtained by accurate short-read sequencing of DNA derived from long fragment libraries, to confidently align short reads within repeat regions and enable accurate variant discovery. Our novel algorithm, Random Field Aligner (RFA), captures the relationships among the short reads governed by the long read process via a Markov Random Field. We utilized a modified version of the Illumina TruSeq synthetic long-read protocol, which yielded shallow-sequenced read clouds. We test RFA through extensive simulations and apply it to discover variants on the NA12878 human sample, for which shallow TruSeq read cloud sequencing data are available, and on an invasive breast carcinoma genome that we sequenced using the same method. We demonstrate that RFA facilitates accurate recovery of variation in 155 Mb of the human genome, including 94% of 67 Mb of segmental duplication sequence and 96% of 11 Mb of transcribed sequence, that are currently hidden from short-read technologies.

  19. Thousands of corresponding human and mouse genomic regions unalignable in primary sequence contain common RNA structure

    DEFF Research Database (Denmark)

    Torarinsson, Elfar; Sawera, Milena; Havgaard, Jakob Hull

    2006-01-01

    been investigated. Owing to the limitations in computational methods, comparative genomics has been lacking the ability to compare such nonconserved sequence regions for conserved structural RNA elements. We have investigated the presence of structural RNA elements by conducting a local structural...... alignment, using FOLDALIGN, on a subset of these 100,000 corresponding regions and estimate that 1800 contain common RNA structures. Comparing our results with the recent mapping of transcribed fragments (transfrags) in human, we find that high-scoring candidates are twice as likely to be found in regions...... expressed non-coding RNA sequences not alignable in primary sequence....

  20. A hybrid neural network system for prediction and recognition of promoter regions in human genome

    Institute of Scientific and Technical Information of China (English)

    CHEN Chuan-bo; LI Tao

    2005-01-01

    This paper proposes a high specificity and sensitivity algorithm called PromPredictor for recognizing promoter regions in the human genome. PromPredictor extracts compositional features and CpG islands information from genomic sequence,feeding these features as input for a hybrid neural network system (HNN) and then applies the HNN for prediction. It combines a novel promoter recognition model, coding theory, feature selection and dimensionality reduction with machine learning algorithm.Evaluation on Human chromosome 22 was ~66% in sensitivity and ~48% in specificity. Comparison with two other systems revealed that our method had superior sensitivity and specificity in predicting promoter regions. PromPredictor is written in MATLAB and requires Matlab to run. PromPredictor is freely available at http://www.whtelecom.com/Prompredictor.htm.

  1. Mitochondrial Genome Analyses Suggest Multiple Trichuris Species in Humans, Baboons, and Pigs from Different Geographical Regions.

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    Mohamed B F Hawash

    Full Text Available The whipworms Trichuris trichiura and Trichuris suis are two parasitic nematodes of humans and pigs, respectively. Although whipworms in human and non-human primates historically have been referred to as T. trichiura, recent reports suggest that several Trichuris spp. are found in primates.We sequenced and annotated complete mitochondrial genomes of Trichuris recovered from a human in Uganda, an olive baboon in the US, a hamadryas baboon in Denmark, and two pigs from Denmark and Uganda. Comparative analyses using other published mitochondrial genomes of Trichuris recovered from a human and a porcine host in China and from a françois' leaf-monkey (China were performed, including phylogenetic analyses and pairwise genetic and amino acid distances. Genetic and protein distances between human Trichuris in Uganda and China were high (~19% and 15%, respectively suggesting that they represented different species. Trichuris from the olive baboon in US was genetically related to human Trichuris in China, while the other from the hamadryas baboon in Denmark was nearly identical to human Trichuris from Uganda. Baboon-derived Trichuris was genetically distinct from Trichuris from françois' leaf monkey, suggesting multiple whipworm species circulating among non-human primates. The genetic and protein distances between pig Trichuris from Denmark and other regions were roughly 9% and 6%, respectively, while Chinese and Ugandan whipworms were more closely related.Our results indicate that Trichuris species infecting humans and pigs are phylogenetically distinct across geographical regions, which might have important implications for the implementation of suitable and effective control strategies in different regions. Moreover, we provide support for the hypothesis that Trichuris infecting primates represents a complex of cryptic species with some species being able to infect both humans and non-human primates.

  2. A Compendium of Chromatin Contact Maps Reveals Spatially Active Regions in the Human Genome.

    Science.gov (United States)

    Schmitt, Anthony D; Hu, Ming; Jung, Inkyung; Xu, Zheng; Qiu, Yunjiang; Tan, Catherine L; Li, Yun; Lin, Shin; Lin, Yiing; Barr, Cathy L; Ren, Bing

    2016-11-15

    The three-dimensional configuration of DNA is integral to all nuclear processes in eukaryotes, yet our knowledge of the chromosome architecture is still limited. Genome-wide chromosome conformation capture studies have uncovered features of chromatin organization in cultured cells, but genome architecture in human tissues has yet to be explored. Here, we report the most comprehensive survey to date of chromatin organization in human tissues. Through integrative analysis of chromatin contact maps in 21 primary human tissues and cell types, we find topologically associating domains highly conserved in different tissues. We also discover genomic regions that exhibit unusually high levels of local chromatin interactions. These frequently interacting regions (FIREs) are enriched for super-enhancers and are near tissue-specifically expressed genes. They display strong tissue-specificity in local chromatin interactions. Additionally, FIRE formation is partially dependent on CTCF and the Cohesin complex. We further show that FIREs can help annotate the function of non-coding sequence variants. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Identification of the human chromosomal region containing the iridogoniodysgenesis anomaly locus by genomic-mismatch scanning.

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    Mirzayans, F; Mears, A J; Guo, S W; Pearce, W G; Walter, M A

    1997-01-01

    Genome-mismatch scanning (GMS) is a new method of linkage analysis that rapidly isolates regions of identity between two genomes. DNA molecules from regions of identity by descent from two relatives are isolated based on their ability to form extended mismatch-free heteroduplexes. We have applied this rapid technology to identify the chromosomal region shared by two fifth-degree cousins with autosomal dominant iridogoniodysgenesis anomaly (IGDA), a rare ocular neurocristopathy. Markers on the short arm of human chromosome 6p were recovered, consistent with the results of conventional linkage analysis conducted in parallel, indicating linkage of IGDA to 6p25. Control markers tested on a second human chromosome were not recovered. A GMS error rate of approximately 11% was observed, well within an acceptable range for a rapid, first screening approach, especially since GMS results would be confirmed by family analysis with selected markers from the putative region of identity by descent. These results demonstrate not only the value of this technique in the rapid mapping of human genetic traits, but the first application of GMS to a multicellular organism. Images Figure 2 PMID:9245991

  4. Structured RNAs in the ENCODE selected regions of the human genome

    DEFF Research Database (Denmark)

    Washietl, Stefan; Pedersen, Jakob Skou; Korbel, Jan O

    2007-01-01

    characteristic signals in primary sequence, comparative approaches evaluating evolutionary conservation of structures are most promising. We have used three recently introduced programs based on either phylogenetic-stochastic context-free grammar (EvoFold) or energy directed folding (RNAz and AlifoldZ), yielding......Functional RNA structures play an important role both in the context of noncoding RNA transcripts as well as regulatory elements in mRNAs. Here we present a computational study to detect functional RNA structures within the ENCODE regions of the human genome. Since structural RNAs in general lack...... and EvoFold, and an additional 239 RNAz or EvoFold predictions are supported by the (more stringent) AlifoldZ algorithm. Five hundred seventy RNAz structure predictions fall into regions that show signs of selection pressure also on the sequence level (i.e., conserved elements). More than 700 predictions...

  5. Genomic and network patterns of schizophrenia genetic variation in human evolutionary accelerated regions.

    Science.gov (United States)

    Xu, Ke; Schadt, Eric E; Pollard, Katherine S; Roussos, Panos; Dudley, Joel T

    2015-05-01

    The population persistence of schizophrenia despite associated reductions in fitness and fecundity suggests that the genetic basis of schizophrenia has a complex evolutionary history. A recent meta-analysis of schizophrenia genome-wide association studies offers novel opportunities for assessment of the evolutionary trajectories of schizophrenia-associated loci. In this study, we hypothesize that components of the genetic architecture of schizophrenia are attributable to human lineage-specific evolution. Our results suggest that schizophrenia-associated loci enrich in genes near previously identified human accelerated regions (HARs). Specifically, we find that genes near HARs conserved in nonhuman primates (pHARs) are enriched for schizophrenia-associated loci, and that pHAR-associated schizophrenia genes are under stronger selective pressure than other schizophrenia genes and other pHAR-associated genes. We further evaluate pHAR-associated schizophrenia genes in regulatory network contexts to investigate associated molecular functions and mechanisms. We find that pHAR-associated schizophrenia genes significantly enrich in a GABA-related coexpression module that was previously found to be differentially regulated in schizophrenia affected individuals versus healthy controls. In another two independent networks constructed from gene expression profiles from prefrontal cortex samples, we find that pHAR-associated schizophrenia genes are located in more central positions and their average path lengths to the other nodes are significantly shorter than those of other schizophrenia genes. Together, our results suggest that HARs are associated with potentially important functional roles in the genetic architecture of schizophrenia.

  6. Mitochondrial genome analyses suggest multiple Trichuris species in humans, baboons, and pigs from different geographical regions

    DEFF Research Database (Denmark)

    Hawash, Mohamed B. F.; Andersen, Lee O.; Gasser, Robin B.;

    2015-01-01

    BACKGROUND: The whipworms Trichuris trichiura and Trichuris suis are two parasitic nematodes of humans and pigs, respectively. Although whipworms in human and non-human primates historically have been referred to as T. trichiura, recent reports suggest that several Trichuris spp. are found...... in primates. METHODS AND FINDINGS: We sequenced and annotated complete mitochondrial genomes of Trichuris recovered from a human in Uganda, an olive baboon in the US, a hamadryas baboon in Denmark, and two pigs from Denmark and Uganda. Comparative analyses using other published mitochondrial genomes...... of Trichuris recovered from a human and a porcine host in China and from a françois' leaf-monkey (China) were performed, including phylogenetic analyses and pairwise genetic and amino acid distances. Genetic and protein distances between human Trichuris in Uganda and China were high (~19% and 15%, respectively...

  7. Genomic and Network Patterns of Schizophrenia Genetic Variation in Human Evolutionary Accelerated Regions

    OpenAIRE

    Xu, Ke; Schadt, Eric E.; Pollard, Katherine S.; Roussos, Panos; Joel T Dudley

    2015-01-01

    The population persistence of schizophrenia despite associated reductions in fitness and fecundity suggests that the genetic basis of schizophrenia has a complex evolutionary history. A recent meta-analysis of schizophrenia genome-wide association studies offers novel opportunities for assessment of the evolutionary trajectories of schizophrenia-associated loci. In this study, we hypothesize that components of the genetic architecture of schizophrenia are attributable to human lineage-specifi...

  8. Genomic and Network Patterns of Schizophrenia Genetic Variation in Human Evolutionary Accelerated Regions

    OpenAIRE

    Xu, Ke; Schadt, Eric E.; Pollard, Katherine S.; Roussos, Panos; Dudley, Joel T

    2015-01-01

    The population persistence of schizophrenia despite associated reductions in fitness and fecundity suggests that the genetic basis of schizophrenia has a complex evolutionary history. A recent meta-analysis of schizophrenia genome-wide association studies offers novel opportunities for assessment of the evolutionary trajectories of schizophrenia-associated loci. In this study, we hypothesize that components of the genetic architecture of schizophrenia are attributable to human lineage-specifi...

  9. Thousands of corresponding human and mouse genomic regions unalignable in primary sequence contain common RNA structure

    DEFF Research Database (Denmark)

    Torarinsson, Elfar; Sawera, Milena; Havgaard, Jakob Hull

    2006-01-01

    overlapped by transfrags than regions that are not overlapped by transfrags. To verify the coexpression between predicted candidates in human and mouse, we conducted expression studies by RT-PCR and Northern blotting on mouse candidates, which overlap with transfrags on human chromosome 20. RT-PCR results...... confirmed expression of 32 out of 36 candidates, whereas Northern blots confirmed four out of 12 candidates. Furthermore, many RT-PCR results indicate differential expression in different tissues. Hence, our findings suggest that there are corresponding regions between human and mouse, which contain...

  10. "Beijing Region" (3pter-D3S3397) of the Human Genome: Complete sequence and analysis

    Institute of Scientific and Technical Information of China (English)

    The; Chinese; Human; Genome; Sequencing; Consortium

    2005-01-01

    The goal of the Human Genome Project (HGP) is to determine a complete and high-quality sequence of the human genome. China, as one of the six member states, takes a region between 3pter and D3S3397 of the human chromosome 3 as its share of this historic project, referred as "Beijing Region". The complete sequence of this region comprises of 17.4 megabasepairs (Mb) with an average GC content of 42% and an average recombination rate of 2.14 cM/Mb. Within Beijing Region, 122 known and 20 novel genes are identified, as well as 42607 single nucleotide polymorphisms (SNPs). Comprehensive analyses also reveal: (i) gene density and GC-content of Beijing Region are in agreement with human cytogenetic maps, i.e. G-minus bands are GC-rich and of a high gene density, whereas G-plus bands are GC-poor and of a relatively low gene density; (ii) the average recombination rate within Beijing Region is relatively high compared with other regions of chromosome 3, with the highest recombination rate of 6.06 cM/Mb in the subtelomeric area; (iii) it is most likely that a large gene, associated with the mammary gland, may reside in the 1.1 Mb gene-poor area near the telomere; (iv) many disease-related genes are genetically mapped to Beijing Region, including those associated with cancers and metabolic syndromes. All make Beijing Region an important target for in-depth molecular investigations with a purpose of medical applications.

  11. Identifying selected regions from heterozygosity and divergence using a light-coverage genomic dataset from two human populations.

    Directory of Open Access Journals (Sweden)

    Taras K Oleksyk

    Full Text Available When a selective sweep occurs in the chromosomal region around a target gene in two populations that have recently separated, it produces three dramatic genomic consequences: 1 decreased multi-locus heterozygosity in the region; 2 elevated or diminished genetic divergence (F(ST of multiple polymorphic variants adjacent to the selected locus between the divergent populations, due to the alternative fixation of alleles; and 3 a consequent regional increase in the variance of F(ST (S(2F(ST for the same clustered variants, due to the increased alternative fixation of alleles in the loci surrounding the selection target. In the first part of our study, to search for potential targets of directional selection, we developed and validated a resampling-based computational approach; we then scanned an array of 31 different-sized moving windows of SNP variants (5-65 SNPs across the human genome in a set of European and African American population samples with 183,997 SNP loci after correcting for the recombination rate variation. The analysis revealed 180 regions of recent selection with very strong evidence in either population or both. In the second part of our study, we compared the newly discovered putative regions to those sites previously postulated in the literature, using methods based on inspecting patterns of linkage disequilibrium, population divergence and other methodologies. The newly found regions were cross-validated with those found in nine other studies that have searched for selection signals. Our study was replicated especially well in those regions confirmed by three or more studies. These validated regions were independently verified, using a combination of different methods and different databases in other studies, and should include fewer false positives. The main strength of our analysis method compared to others is that it does not require dense genotyping and therefore can be used with data from population-based genome SNP scans

  12. Characterization of promoter region and genomic structure of the murine and human genes encoding Src like adapter protein.

    Science.gov (United States)

    Kratchmarova, I; Sosinowski, T; Weiss, A; Witter, K; Vincenz, C; Pandey, A

    2001-01-10

    Src-like adapter protein (SLAP) was identified as a signaling molecule in a yeast two-hybrid system using the cytoplasmic domain of EphA2, a receptor protein tyrosine kinase (Pandey et al., 1995. Characterization of a novel Src-like adapter protein that associates with the Eck receptor tyrosine kinase. J. Biol. Chem. 270, 19201-19204). It is very similar to members of the Src family of cytoplasmic tyrosine kinases in that it contains very homologous SH3 and SH2 domains (Abram and Courtneidge, 2000. Src family tyrosine kinases and growth factor signaling. Exp. Cell. Res. 254, 1-13.). However, instead of a kinase domain at the C-terminus, it contains a unique C-terminal region. In order to exclude the possibility that an alternative form exists, we have isolated genomic clones containing the murine Slap gene as well as the human SLA gene. The coding regions of murine Slap and human SLA genes contain seven exons and six introns. Absence of any kinase domain in the genomic region confirm its designation as an adapter protein. Additionally, we have cloned and sequenced approximately 2.6 kb of the region 5' to the initiator methionine of the murine Slap gene. When subcloned upstream of a luciferase gene, this fragment increased the transcriptional activity about 6-fold in a human Jurkat T cell line and approximately 52-fold in a murine T cell line indicating that this region contains promoter elements that dictate SLAP expression. We have also cloned the promoter region of the human SLA gene. Since SLAP is transcriptionally regulated by retinoic acid and by activation of B cells, the cloning of its promoter region will permit a detailed analysis of the elements required for its transcriptional regulation.

  13. Chromosome region-specific libraries for human genome analysis. Final progress report, 1 March 1991--28 February 1994

    Energy Technology Data Exchange (ETDEWEB)

    Kao, F.T.

    1994-04-01

    The objectives of this grant proposal include (1) development of a chromosome microdissection and PCR-mediated microcloning technology, (2) application of this microtechnology to the construction of region-specific libraries for human genome analysis. During this grant period, the authors have successfully developed this microtechnology and have applied it to the construction of microdissection libraries for the following chromosome regions: a whole chromosome 21 (21E), 2 region-specific libraries for the long arm of chromosome 2, 2q35-q37 (2Q1) and 2q33-q35 (2Q2), and 4 region-specific libraries for the entire short arm of chromosome 2, 2p23-p25 (2P1), 2p21-p23 (2P2), 2p14-p16 (wP3) and 2p11-p13 (2P4). In addition, 20--40 unique sequence microclones have been isolated and characterized for genomic studies. These region-specific libraries and the single-copy microclones from the library have been used as valuable resources for (1) isolating microsatellite probes in linkage analysis to further refine the disease locus; (2) isolating corresponding clones with large inserts, e.g. YAC, BAC, P1, cosmid and phage, to facilitate construction of contigs for high resolution physical mapping; and (3) isolating region-specific cDNA clones for use as candidate genes. These libraries are being deposited in the American Type Culture Collection (ATCC) for general distribution.

  14. National Human Genome Research Institute

    Science.gov (United States)

    ... the Director Organization Reports & Publications Español The National Human Genome Research Institute conducts genetic and genomic research, funds ... Landscape Social Media Videos Image Gallery Fact Sheets Human Genome Project Clinical Studies Genomic Careers DNA Day Calendar ...

  15. Whole-Genome Bisulfite Sequencing of Human Pancreatic Islets Reveals Novel Differentially Methylated Regions in Type 2 Diabetes Pathogenesis.

    Science.gov (United States)

    Volkov, Petr; Bacos, Karl; Ofori, Jones K; Esguerra, Jonathan Lou S; Eliasson, Lena; Rönn, Tina; Ling, Charlotte

    2017-04-01

    Current knowledge about the role of epigenetics in type 2 diabetes (T2D) remains limited. Only a few studies have investigated DNA methylation of selected candidate genes or a very small fraction of genomic CpG sites in human pancreatic islets, the tissue of primary pathogenic importance for diabetes. Our aim was to characterize the whole-genome DNA methylation landscape in human pancreatic islets, to identify differentially methylated regions (DMRs) in diabetic islets, and to investigate the function of DMRs in islet biology. Here, we performed whole-genome bisulfite sequencing, which is a comprehensive and unbiased method to study DNA methylation throughout the genome at a single nucleotide resolution, in pancreatic islets from donors with T2D and control subjects without diabetes. We identified 25,820 DMRs in islets from individuals with T2D. These DMRs cover loci with known islet function, e.g., PDX1, TCF7L2, and ADCY5 Importantly, binding sites previously identified by ChIP-seq for islet-specific transcription factors, enhancer regions, and different histone marks were enriched in the T2D-associated DMRs. We also identified 457 genes, including NR4A3, PARK2, PID1, SLC2A2, and SOCS2, that had both DMRs and significant expression changes in T2D islets. To mimic the situation in T2D islets, candidate genes were overexpressed or silenced in cultured β-cells. This resulted in impaired insulin secretion, thereby connecting differential methylation to islet dysfunction. We further explored the islet methylome and found a strong link between methylation levels and histone marks. Additionally, DNA methylation in different genomic regions and of different transcript types (i.e., protein coding, noncoding, and pseudogenes) was associated with islet expression levels. Our study provides a comprehensive picture of the islet DNA methylome in individuals with and without diabetes and highlights the importance of epigenetic dysregulation in pancreatic islets and T2D

  16. Relative effects of mutability and selection on single nucleotide polymorphisms in transcribed regions of the human genome

    Directory of Open Access Journals (Sweden)

    Amos Christopher I

    2008-06-01

    Full Text Available Abstract Motivation Single nucleotide polymorphisms (SNPs are the most common type of genetic variation in humans. However, the factors that affect SNP density are poorly understood. The goal of this study was to estimate the relative effects of mutability and selection on SNP density in transcribed regions of human genes. It is important for prediction of the regions that harbor functional polymorphisms. Results We used frequency-validated SNPs resulting from single-nucleotide substitutions. SNPs were subdivided into five functional categories: (i 5' untranslated region (UTR SNPs, (ii 3' UTR SNPs, (iii synonymous SNPs, (iv SNPs producing conservative missense mutations, and (v SNPs producing radical missense mutations. Each of these categories was further subdivided into nine mutational categories on the basis of the single-nucleotide substitution type. Thus, 45 functional/mutational categories were analyzed. The relative mutation rate in each mutational category was estimated on the basis of published data. The proportion of segregating sites (PSSs for each functional/mutational category was estimated by dividing the observed number of SNPs by the number of potential sites in the genome for a given functional/mutational category. By analyzing each functional group separately, we found significant positive correlations between PSSs and relative mutation rates (Spearman's correlation coefficient, at least r = 0.96, df = 9, P P = 0.001, suggesting that selection affects SNP density in transcribed regions of the genome. We used analyses of variance and covariance to estimate the relative effects of selection (functional category and mutability (relative mutation rate on the PSSs and found that approximately 87% of variation in PSS was due to variation in the mutation rate and approximately 13% was due to selection, suggesting that the probability that a site located in a transcribed region of a gene is polymorphic mostly depends on the mutability

  17. Human Genome Project

    Energy Technology Data Exchange (ETDEWEB)

    Block, S. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Cornwall, J. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Dally, W. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Dyson, F. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Fortson, N. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Joyce, G. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Kimble, H. J. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Lewis, N. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Max, C. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Prince, T. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Schwitters, R. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Weinberger, P. [The MITRE Corporation, McLean, VA (US). JASON Program Office; Woodin, W. H. [The MITRE Corporation, McLean, VA (US). JASON Program Office

    1998-01-04

    The study reviews Department of Energy supported aspects of the United States Human Genome Project, the joint National Institutes of Health/Department of Energy program to characterize all human genetic material, to discover the set of human genes, and to render them accessible for further biological study. The study concentrates on issues of technology, quality assurance/control, and informatics relevant to current effort on the genome project and needs beyond it. Recommendations are presented on areas of the genome program that are of particular interest to and supported by the Department of Energy.

  18. Positive selection in the chromosome 16 VKORC1 genomic region has contributed to the variability of anticoagulant response in humans.

    Directory of Open Access Journals (Sweden)

    Blandine Patillon

    Full Text Available VKORC1 (vitamin K epoxide reductase complex subunit 1, 16p11.2 is the main genetic determinant of human response to oral anticoagulants of antivitamin K type (AVK. This gene was recently suggested to be a putative target of positive selection in East Asian populations. In this study, we genotyped the HGDP-CEPH Panel for six VKORC1 SNPs and downloaded chromosome 16 genotypes from the HGDP-CEPH database in order to characterize the geographic distribution of footprints of positive selection within and around this locus. A unique VKORC1 haplotype carrying the promoter mutation associated with AVK sensitivity showed especially high frequencies in all the 17 HGDP-CEPH East Asian population samples. VKORC1 and 24 neighboring genes were found to lie in a 505 kb region of strong linkage disequilibrium in these populations. Patterns of allele frequency differentiation and haplotype structure suggest that this genomic region has been submitted to a near complete selective sweep in all East Asian populations and only in this geographic area. The most extreme scores of the different selection tests are found within a smaller 45 kb region that contains VKORC1 and three other genes (BCKDK, MYST1 (KAT8, and PRSS8 with different functions. Because of the strong linkage disequilibrium, it is not possible to determine if VKORC1 or one of the three other genes is the target of this strong positive selection that could explain present-day differences among human populations in AVK dose requirement. Our results show that the extended region surrounding a presumable single target of positive selection should be analyzed for genetic variation in a wide range of genetically diverse populations in order to account for other neighboring and confounding selective events and the hitchhiking effect.

  19. Positive selection in the chromosome 16 VKORC1 genomic region has contributed to the variability of anticoagulant response in humans.

    Science.gov (United States)

    Patillon, Blandine; Luisi, Pierre; Blanché, Hélène; Patin, Etienne; Cann, Howard M; Génin, Emmanuelle; Sabbagh, Audrey

    2012-01-01

    VKORC1 (vitamin K epoxide reductase complex subunit 1, 16p11.2) is the main genetic determinant of human response to oral anticoagulants of antivitamin K type (AVK). This gene was recently suggested to be a putative target of positive selection in East Asian populations. In this study, we genotyped the HGDP-CEPH Panel for six VKORC1 SNPs and downloaded chromosome 16 genotypes from the HGDP-CEPH database in order to characterize the geographic distribution of footprints of positive selection within and around this locus. A unique VKORC1 haplotype carrying the promoter mutation associated with AVK sensitivity showed especially high frequencies in all the 17 HGDP-CEPH East Asian population samples. VKORC1 and 24 neighboring genes were found to lie in a 505 kb region of strong linkage disequilibrium in these populations. Patterns of allele frequency differentiation and haplotype structure suggest that this genomic region has been submitted to a near complete selective sweep in all East Asian populations and only in this geographic area. The most extreme scores of the different selection tests are found within a smaller 45 kb region that contains VKORC1 and three other genes (BCKDK, MYST1 (KAT8), and PRSS8) with different functions. Because of the strong linkage disequilibrium, it is not possible to determine if VKORC1 or one of the three other genes is the target of this strong positive selection that could explain present-day differences among human populations in AVK dose requirement. Our results show that the extended region surrounding a presumable single target of positive selection should be analyzed for genetic variation in a wide range of genetically diverse populations in order to account for other neighboring and confounding selective events and the hitchhiking effect.

  20. Human social genomics.

    Directory of Open Access Journals (Sweden)

    Steven W Cole

    2014-08-01

    Full Text Available A growing literature in human social genomics has begun to analyze how everyday life circumstances influence human gene expression. Social-environmental conditions such as urbanity, low socioeconomic status, social isolation, social threat, and low or unstable social status have been found to associate with differential expression of hundreds of gene transcripts in leukocytes and diseased tissues such as metastatic cancers. In leukocytes, diverse types of social adversity evoke a common conserved transcriptional response to adversity (CTRA characterized by increased expression of proinflammatory genes and decreased expression of genes involved in innate antiviral responses and antibody synthesis. Mechanistic analyses have mapped the neural "social signal transduction" pathways that stimulate CTRA gene expression in response to social threat and may contribute to social gradients in health. Research has also begun to analyze the functional genomics of optimal health and thriving. Two emerging opportunities now stand to revolutionize our understanding of the everyday life of the human genome: network genomics analyses examining how systems-level capabilities emerge from groups of individual socially sensitive genomes and near-real-time transcriptional biofeedback to empirically optimize individual well-being in the context of the unique genetic, geographic, historical, developmental, and social contexts that jointly shape the transcriptional realization of our innate human genomic potential for thriving.

  1. Human Genome Program

    Energy Technology Data Exchange (ETDEWEB)

    1993-01-01

    The DOE Human Genome program has grown tremendously, as shown by the marked increase in the number of genome-funded projects since the last workshop held in 1991. The abstracts in this book describe the genome research of DOE-funded grantees and contractors and invited guests, and all projects are represented at the workshop by posters. The 3-day meeting includes plenary sessions on ethical, legal, and social issues pertaining to the availability of genetic data; sequencing techniques, informatics support; and chromosome and cDNA mapping and sequencing.

  2. Human Genome Program

    Energy Technology Data Exchange (ETDEWEB)

    1993-01-01

    The DOE Human Genome program has grown tremendously, as shown by the marked increase in the number of genome-funded projects since the last workshop held in 1991. The abstracts in this book describe the genome research of DOE-funded grantees and contractors and invited guests, and all projects are represented at the workshop by posters. The 3-day meeting includes plenary sessions on ethical, legal, and social issues pertaining to the availability of genetic data; sequencing techniques, informatics support; and chromosome and cDNA mapping and sequencing.

  3. hSmad5 gene, a human hSmad family member: its full length cDNA, genomic structure, promoter region and mutation analysis in human tumors.

    Science.gov (United States)

    Gemma, A; Hagiwara, K; Vincent, F; Ke, Y; Hancock, A R; Nagashima, M; Bennett, W P; Harris, C C

    1998-02-19

    hSmad (mothers against decapentaplegic)-related proteins are important messengers within the Transforming Growth Factor-beta1 (TGF-beta1) superfamily signal transduction pathways. To further characterize a member of this family, we obtained a full length cDNA of the human hSmad5 (hSmad5) gene by rapid amplification of cDNA ends (RACE) and then determined the genomic structure of the gene. There are eight exons and two alternative transcripts; the shorter transcript lacks exon 2. We identified the hSmad5 promoter region from a human genomic YAC clone by obtaining the nucleotide sequence extending 1235 base pairs upstream of the 5' end of the cDNA. We found a CpG island consistent with a promoter region, and we demonstrated promoter activity in a 1232 bp fragment located upstream of the transcription initiation site. To investigate the frequency of somatic hSmad5 mutations in human cancers, we designed intron-based primers to examine coding regions by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. Neither homozygous deletions or point mutations were found in 40 primary gastric tumors and 51 cell lines derived from diverse types of human cancer including 20 cell lines resistant to the growth inhibitory effects of TGF-beta1. These results suggest that the hSmad5 gene is not commonly mutated and that other genetic alterations mediate the loss of TGF-beta1 responsiveness in human cancers.

  4. Genomic structure and paralogous regions of the inversion breakpoint occurring between human chromosome 3p12.3 and orangutan chromosome 2.

    Science.gov (United States)

    Yue, Y; Grossmann, B; Tsend-Ayush, E; Grützner, F; Ferguson-Smith, M A; Yang, F; Haaf, T

    2005-01-01

    Intrachromosomal duplications play a significant role in human genome pathology and evolution. To better understand the molecular basis of evolutionary chromosome rearrangements, we performed molecular cytogenetic and sequence analyses of the breakpoint region that distinguishes human chromosome 3p12.3 and orangutan chromosome 2. FISH with region-specific BAC clones demonstrated that the breakpoint-flanking sequences are duplicated intrachromosomally on orangutan 2 and human 3q21 as well as at many pericentromeric and subtelomeric sites throughout the genomes. Breakage and rearrangement of the human 3p12.3-homologous region in the orangutan lineage were associated with a partial loss of duplicated sequences in the breakpoint region. Consistent with our FISH mapping results, computational analysis of the human chromosome 3 genomic sequence revealed three 3p12.3-paralogous sequence blocks on human chromosome 3q21 and smaller blocks on the short arm end 3p26-->p25. This is consistent with the view that sequences from an ancestral site at 3q21 were duplicated at 3p12.3 in a common ancestor of orangutan and humans. Our results show that evolutionary chromosome rearrangements are associated with microduplications and microdeletions, contributing to the DNA differences between closely related species. Copyright (c) 2005 S. Karger AG, Basel.

  5. Genome-wide DNA methylation analyses in the brain reveal four differentially methylated regions between humans and non-human primates

    Directory of Open Access Journals (Sweden)

    Wang Jinkai

    2012-08-01

    Full Text Available Abstract Background The highly improved cognitive function is the most significant change in human evolutionary history. Recently, several large-scale studies reported the evolutionary roles of DNA methylation; however, the role of DNA methylation on brain evolution is largely unknown. Results To test if DNA methylation has contributed to the evolution of human brain, with the use of MeDIP-Chip and SEQUENOM MassARRAY, we conducted a genome-wide analysis to identify differentially methylated regions (DMRs in the brain between humans and rhesus macaques. We first identified a total of 150 candidate DMRs by the MeDIP-Chip method, among which 4 DMRs were confirmed by the MassARRAY analysis. All 4 DMRs are within or close to the CpG islands, and a MIR3 repeat element was identified in one DMR, but no repeat sequence was observed in the other 3 DMRs. For the 4 DMR genes, their proteins tend to be conserved and two genes have neural related functions. Bisulfite sequencing and phylogenetic comparison among human, chimpanzee, rhesus macaque and rat suggested several regions of lineage specific DNA methylation, including a human specific hypomethylated region in the promoter of K6IRS2 gene. Conclusions Our study provides a new angle of studying human brain evolution and understanding the evolutionary role of DNA methylation in the central nervous system. The results suggest that the patterns of DNA methylation in the brain are in general similar between humans and non-human primates, and only a few DMRs were identified.

  6. Pan-Genome Analysis of Human Gastric Pathogen H. pylori: Comparative Genomics and Pathogenomics Approaches to Identify Regions Associated with Pathogenicity and Prediction of Potential Core Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Amjad Ali

    2015-01-01

    Full Text Available Helicobacter pylori is a human gastric pathogen implicated as the major cause of peptic ulcer and second leading cause of gastric cancer (~70% around the world. Conversely, an increased resistance to antibiotics and hindrances in the development of vaccines against H. pylori are observed. Pan-genome analyses of the global representative H. pylori isolates consisting of 39 complete genomes are presented in this paper. Phylogenetic analyses have revealed close relationships among geographically diverse strains of H. pylori. The conservation among these genomes was further analyzed by pan-genome approach; the predicted conserved gene families (1,193 constitute ~77% of the average H. pylori genome and 45% of the global gene repertoire of the species. Reverse vaccinology strategies have been adopted to identify and narrow down the potential core-immunogenic candidates. Total of 28 nonhost homolog proteins were characterized as universal therapeutic targets against H. pylori based on their functional annotation and protein-protein interaction. Finally, pathogenomics and genome plasticity analysis revealed 3 highly conserved and 2 highly variable putative pathogenicity islands in all of the H. pylori genomes been analyzed.

  7. The bonobo genome compared with the chimpanzee and human genomes

    Science.gov (United States)

    Prüfer, Kay; Munch, Kasper; Hellmann, Ines; Akagi, Keiko; Miller, Jason R.; Walenz, Brian; Koren, Sergey; Sutton, Granger; Kodira, Chinnappa; Winer, Roger; Knight, James R.; Mullikin, James C.; Meader, Stephen J.; Ponting, Chris P.; Lunter, Gerton; Higashino, Saneyuki; Hobolth, Asger; Dutheil, Julien; Karakoç, Emre; Alkan, Can; Sajjadian, Saba; Catacchio, Claudia Rita; Ventura, Mario; Marques-Bonet, Tomas; Eichler, Evan E.; André, Claudine; Atencia, Rebeca; Mugisha, Lawrence; Junhold, Jörg; Patterson, Nick; Siebauer, Michael; Good, Jeffrey M.; Fischer, Anne; Ptak, Susan E.; Lachmann, Michael; Symer, David E.; Mailund, Thomas; Schierup, Mikkel H.; Andrés, Aida M.; Kelso, Janet; Pääbo, Svante

    2012-01-01

    Two African apes are the closest living relatives of humans: the chimpanzee (Pan troglodytes) and the bonobo (Pan paniscus). Although they are similar in many respects, bonobos and chimpanzees differ strikingly in key social and sexual behaviours1–4, and for some of these traits they show more similarity with humans than with each other. Here we report the sequencing and assembly of the bonobo genome to study its evolutionary relationship with the chimpanzee and human genomes. We find that more than three per cent of the human genome is more closely related to either the bonobo or the chimpanzee genome than these are to each other. These regions allow various aspects of the ancestry of the two ape species to be reconstructed. In addition, many of the regions that overlap genes may eventually help us understand the genetic basis of phenotypes that humans share with one of the two apes to the exclusion of the other. PMID:22722832

  8. The bonobo genome compared with the chimpanzee and human genomes.

    Science.gov (United States)

    Prüfer, Kay; Munch, Kasper; Hellmann, Ines; Akagi, Keiko; Miller, Jason R; Walenz, Brian; Koren, Sergey; Sutton, Granger; Kodira, Chinnappa; Winer, Roger; Knight, James R; Mullikin, James C; Meader, Stephen J; Ponting, Chris P; Lunter, Gerton; Higashino, Saneyuki; Hobolth, Asger; Dutheil, Julien; Karakoç, Emre; Alkan, Can; Sajjadian, Saba; Catacchio, Claudia Rita; Ventura, Mario; Marques-Bonet, Tomas; Eichler, Evan E; André, Claudine; Atencia, Rebeca; Mugisha, Lawrence; Junhold, Jörg; Patterson, Nick; Siebauer, Michael; Good, Jeffrey M; Fischer, Anne; Ptak, Susan E; Lachmann, Michael; Symer, David E; Mailund, Thomas; Schierup, Mikkel H; Andrés, Aida M; Kelso, Janet; Pääbo, Svante

    2012-06-28

    Two African apes are the closest living relatives of humans: the chimpanzee (Pan troglodytes) and the bonobo (Pan paniscus). Although they are similar in many respects, bonobos and chimpanzees differ strikingly in key social and sexual behaviours, and for some of these traits they show more similarity with humans than with each other. Here we report the sequencing and assembly of the bonobo genome to study its evolutionary relationship with the chimpanzee and human genomes. We find that more than three per cent of the human genome is more closely related to either the bonobo or the chimpanzee genome than these are to each other. These regions allow various aspects of the ancestry of the two ape species to be reconstructed. In addition, many of the regions that overlap genes may eventually help us understand the genetic basis of phenotypes that humans share with one of the two apes to the exclusion of the other.

  9. Genomics of human longevity.

    Science.gov (United States)

    Slagboom, P E; Beekman, M; Passtoors, W M; Deelen, J; Vaarhorst, A A M; Boer, J M; van den Akker, E B; van Heemst, D; de Craen, A J M; Maier, A B; Rozing, M; Mooijaart, S P; Heijmans, B T; Westendorp, R G J

    2011-01-12

    In animal models, single-gene mutations in genes involved in insulin/IGF and target of rapamycin signalling pathways extend lifespan to a considerable extent. The genetic, genomic and epigenetic influences on human longevity are expected to be much more complex. Strikingly however, beneficial metabolic and cellular features of long-lived families resemble those in animals for whom the lifespan is extended by applying genetic manipulation and, especially, dietary restriction. Candidate gene studies in humans support the notion that human orthologues from longevity genes identified in lower species do contribute to longevity but that the influence of the genetic variants involved is small. Here we discuss how an integration of novel study designs, labour-intensive biobanking, deep phenotyping and genomic research may provide insights into the mechanisms that drive human longevity and healthy ageing, beyond the associations usually provided by molecular and genetic epidemiology. Although prospective studies of humans from the cradle to the grave have never been performed, it is feasible to extract life histories from different cohorts jointly covering the molecular changes that occur with age from early development all the way up to the age at death. By the integration of research in different study cohorts, and with research in animal models, biological research into human longevity is thus making considerable progress.

  10. Mapping the human genome

    Energy Technology Data Exchange (ETDEWEB)

    Cantor, Charles R.

    1989-06-01

    The following pages aim to lay a foundation for understanding the excitement surrounding the ''human genome project,'' as well as to convey a flavor of the ongoing efforts and plans at the Human Genome Center at the Lawrence Berkeley Laboratory. Our own work, of course, is only part of a broad international effort that will dramatically enhance our understanding of human molecular genetics before the end of this century. In this country, the bulk of the effort will be carried out under the auspices of the Department of Energy and the National Institutes of Health, but significant contributions have already been made both by nonprofit private foundations and by private corporation. The respective roles of the DOE and the NIH are being coordinated by an inter-agency committee, the aims of which are to emphasize the strengths of each agency, to facilitate cooperation, and to avoid unnecessary duplication of effort. The NIH, for example, will continue its crucial work in medical genetics and in mapping the genomes of nonhuman species. The DOE, on the other hand, has unique experience in managing large projects, and its national laboratories are repositories of expertise in physics, engineering, and computer science, as well as the life sciences. The tools and techniques the project will ultimately rely on are thus likely to be developed in multidisciplinary efforts at laboratories like LBL. Accordingly, we at LBL take great pride in this enterprise -- an enterprise that will eventually transform our understanding of ourselves.

  11. PCR analysis of the upstream regulatory region of human papillomavirus genomes in cervical intraepithelial neoplasia and cervical carcinoma.

    OpenAIRE

    Donaldson, Y K; Arends, M. J.; Duvall, E.; Bird, C C

    1993-01-01

    AIMS--To test whether human papillomavirus (HPV) variants with large scale sequence alterations to the upstream regulatory region are present in cervical intraepithelial neoplasias (CIN) and cervical carcinomas. METHODS--New PCR based assays were designed specifically to detect large scale insertion/deletion alterations in the upstream regulatory region of HPV 16 and 18. The assays were applied to 24 cases of CIN and 34 cases of cervical carcinoma previously shown to contain these two high ri...

  12. [Isolation and characteristics of DNA fragments for the region of the tissue plasminogen activator genes and areas adjacent to it in the human genome].

    Science.gov (United States)

    Sarafanov, A G; Timofeeva, M Ia; Aleshkov, S B; Kupriianova, N S; Bannikov, V M; Zakhar'ev, V M; Baev, A A

    1994-01-01

    Fragments overlapping the tPA gene and its 5'- and 3'-flanking regions were isolated from human liver DNA library cloned in lambda Charon4A vector. A BglII fragment comprising the 3' end and the adjacent genomic region (total length 3.7 kb) was subcloned in plasmid pUC19 and its restriction map was determined. The nucleotide sequence of the 5' region of this fragment was compared with the 3' end region of the tPA gene and the corresponding regions of five published variants of tPA mRNA cDNA from different tissues; discrepancies in seven positions were revealed, which might be caused by intragenomic polymorphism.

  13. Human myoblast genome therapy

    Institute of Scientific and Technical Information of China (English)

    Peter K Law; Leo A Bockeria; Choong-Chin Liew; Danlin M Law; Ping Lu; Eugene KW Sim; Khawja H Haider; Lei Ye; Xun Li; Margarita N Vakhromeeva; Ilia I Berishvili

    2006-01-01

    Human Myoblast Genome Therapy (HMGT) is a platform technology of cell transplantation, nuclear transfer, and tissue engineering. Unlike stem cells, myoblasts are differentiated, immature cells destined to become muscles. Myoblasts cultured from satellite cells of adult muscle biopsies survive, develop, and function to revitalize degenerative muscles upon transplantation. Injection injury activates regeneration of host myofibers that fuse with the engrafted myoblasts, sharing their nuclei in a common gene pool of the syncytium. Thus, through nuclear transfer and complementation, the normal human genome can be transferred into muscles of patients with genetic disorders to achieve phenotype repair or disease prevention. Myoblasts are safe and efficient gene transfer vehicles endogenous to muscles that constitute 50% of body weight. Results of over 280 HMGT procedures on Duchenne Muscular Dystrophy (DMD) subjects in the past 15 years demonstrated absolute safety. Myoblast-injected DMD muscles showed improved histology.Strength increase at 18 months post-operatively averaged 123%. In another application of HMGT on ischemic cardiomyopathy, the first human myoblast transfer into porcine myocardium revealed that it was safe and effective. Clinical trials on approximately 220 severe cardiomyopathy patients in 15 countries showed a <10% mortality. Most subjects received autologous cells implanted on the epicardial surface during coronory artery bypass graft, or injected on the endomyocardial surface percutaneously through guiding catheters. Significant increases in left ventricular ejection fraction, wall thickness, and wall motion have been reported, with reduction in perfusion defective areas, angina, and shortness of breath. As a new modality of treatment for disease in the skeletal muscle or myocardium, HMGT emerged as safe and effective. Large randomized multi-center trials are under way to confirm these preliminary results. The future of HMGT is bright and exciting

  14. Pan-Genome Analysis of Human Gastric Pathogen H. pylori: Comparative Genomics and Pathogenomics Approaches to Identify Regions Associated with Pathogenicity and Prediction of Potential Core Therapeutic Targets

    DEFF Research Database (Denmark)

    Ali, Amjad; Naz, Anam; Soares, Siomar C.

    2015-01-01

    . Pan-genome analyses of the global representative H. pylori isolates consisting of 39 complete genomes are presented in this paper. Phylogenetic analyses have revealed close relationships among geographically diverse strains of H. pylori. The conservation among these genomes was further analyzed by pan-genome...

  15. Sequence analysis of the E3 region and fiber gene of human adenovirus genome type 7h.

    Science.gov (United States)

    Kajon, A E; Wadell, G

    1996-01-15

    Adenovirus type 7h is currently the predominant virulent genome type of serotype 7 isolated in Argentina, Chile, and Uruguay in association with severe infantile pneumonia. In order to characterize possible molecular determinants of pathogenicity, the nucleotide sequence of a 5904-bp fragment (76 to 93 mu) containing the entire E3 region and the fiber gene of Ad7h was established. The organization of the ORFs within the E3 region was similar to that reported for the prototype strains of Ad7 and Ad3. A comparison of the nucleotide and amino acid sequences of all ORFs revealed a higher homology between Ad7h and Ad7p than between Ad7h and Ad3 for 12.0K and 16.1K, whereas the 15.3K ORF and the adjacent fiber gene were strikingly more homologous to those of Ad3 (99.5 vs 81.1% and 98.2 vs 66.6%, respectively). The equivalent to ORF 7.7K in Ad7p was missing in Ad7h due to a deletion and a mutation affecting the start codon (ATG-->ATT). Although the hemagglutinin of the Ad7h fiber could not be characterized due to its lack of activity on monkey erythrocytes, our results indicate that Ad7h is an intermediate strain 7-3.

  16. Genome engineering in human cells.

    Science.gov (United States)

    Song, Minjung; Kim, Young-Hoon; Kim, Jin-Soo; Kim, Hyongbum

    2014-01-01

    Genome editing in human cells is of great value in research, medicine, and biotechnology. Programmable nucleases including zinc-finger nucleases, transcription activator-like effector nucleases, and RNA-guided engineered nucleases recognize a specific target sequence and make a double-strand break at that site, which can result in gene disruption, gene insertion, gene correction, or chromosomal rearrangements. The target sequence complexities of these programmable nucleases are higher than 3.2 mega base pairs, the size of the haploid human genome. Here, we briefly introduce the structure of the human genome and the characteristics of each programmable nuclease, and review their applications in human cells including pluripotent stem cells. In addition, we discuss various delivery methods for nucleases, programmable nickases, and enrichment of gene-edited human cells, all of which facilitate efficient and precise genome editing in human cells.

  17. All about the Human Genome Project (HGP)

    Science.gov (United States)

    ... Genome Resources Access to the full human sequence All About The Human Genome Project (HGP) The Human ... an international research effort to sequence and map all of the genes - together known as the genome - ...

  18. Z-DNA-forming sites identified by ChIP-Seq are associated with actively transcribed regions in the human genome

    Science.gov (United States)

    Shin, So-I.; Ham, Seokjin; Park, Jihwan; Seo, Seong Hye; Lim, Chae Hyun; Jeon, Hyeongrin; Huh, Jounghyun; Roh, Tae-Young

    2016-01-01

    Z-DNA, a left-handed double helical DNA is structurally different from the most abundant B-DNA. Z-DNA has been known to play a significant role in transcription and genome stability but the biological meaning and positions of Z-DNA-forming sites (ZFSs) in the human genome has not been fully explored. To obtain genome-wide map of ZFSs, Zaa with two Z-DNA-binding domains was used for ChIP-Seq analysis. A total of 391 ZFSs were found and their functions were examined in vivo. A large portion of ZFSs was enriched in the promoter regions and contain sequences with high potential to form Z-DNA. Genes containing ZFSs were occupied by RNA polymerase II at the promoters and showed high levels of expression. Moreover, ZFSs were significantly related to active histone marks such as H3K4me3 and H3K9ac. The association of Z-DNA with active transcription was confirmed by the reporter assay system. Overall, our results suggest that Z-DNA formation depends on chromatin structure as well as sequence composition, and is associated with active transcription in human cells. The global information about ZFSs positioning will provide a useful resource for further understanding of DNA structure-dependent transcriptional regulation. PMID:27374614

  19. Human genome. 1993 Program report

    Energy Technology Data Exchange (ETDEWEB)

    1994-03-01

    The purpose of this report is to update the Human Genome 1991-92 Program Report and provide new information on the DOE genome program to researchers, program managers, other government agencies, and the interested public. This FY 1993 supplement includes abstracts of 60 new or renewed projects and listings of 112 continuing and 28 completed projects. These two reports, taken together, present the most complete published view of the DOE Human Genome Program through FY 1993. Research is progressing rapidly toward 15-year goals of mapping and sequencing the DNA of each of the 24 different human chromosomes.

  20. Genomic disorders: A window into human gene and genome evolution

    Science.gov (United States)

    Carvalho, Claudia M. B.; Zhang, Feng; Lupski, James R.

    2010-01-01

    Gene duplications alter the genetic constitution of organisms and can be a driving force of molecular evolution in humans and the great apes. In this context, the study of genomic disorders has uncovered the essential role played by the genomic architecture, especially low copy repeats (LCRs) or segmental duplications (SDs). In fact, regardless of the mechanism, LCRs can mediate or stimulate rearrangements, inciting genomic instability and generating dynamic and unstable regions prone to rapid molecular evolution. In humans, copy-number variation (CNV) has been implicated in common traits such as neuropathy, hypertension, color blindness, infertility, and behavioral traits including autism and schizophrenia, as well as disease susceptibility to HIV, lupus nephritis, and psoriasis among many other clinical phenotypes. The same mechanisms implicated in the origin of genomic disorders may also play a role in the emergence of segmental duplications and the evolution of new genes by means of genomic and gene duplication and triplication, exon shuffling, exon accretion, and fusion/fission events. PMID:20080665

  1. Gender And The Human Genome

    Directory of Open Access Journals (Sweden)

    Chadwick Ruth

    2009-01-01

    Full Text Available Gender issues arise in relation to the human genome across a number of dimensions: the level of attention given to the nuclear genome as opposed to the mitochondrial; the level of basic scientific research; decision-making in the clinic related to both reproductive decision-making on the one hand, and diagnostic and predictive testing on the other; and wider societal implications. Feminist bioethics offers a useful perspective for addressing these issues.

  2. [Novel bidirectional promoter from human genome].

    Science.gov (United States)

    Orekhova, A S; Sverdlova, P S; Spirin, P V; Leonova, O G; Popenko, V I; Prasolov, V S; Rubtsov, P M

    2011-01-01

    In human and other mammalian genomes a number of closely linked gene pairs transcribed in opposite directions are found. According to bioinformatic analysis up to 10% of human genes are arranged in this way. In present work the fragment of human genome was cloned that separates genes localized at 2p13.1 and oriented "head-to-head", coding for hypothetical proteins with unknown functions--CCDC (Coiled Coil Domain Containing) 142 and TTC (TetraTricopeptide repeat Containing) 31. Intergenic CCDC142-TTC31 region overlaps with CpG-island and contains a number of potential binding sites for transcription factors. This fragment functions as bidirectional promoter in the system ofluciferase reporter gene expression upon transfection of human embryonic kidney (HEK293) cells. The vectors containing genes of two fluorescent proteins--green (EGFP) and red (DsRed2) in opposite orientations separated by the fragment of CCDC142-TTC31 intergenic region were constructed. In HEK293 cells transfected with these vectors simultaneous expression of two fluorescent proteins is observed. Truncated versions of intergenic region were obtained and their promoter activity measured. Minimal promoter fragment contains elements Inr, BRE, DPE characteristic for TATA-less promoters. Thus, from the human genome the novel bidirectional promoter was cloned that can be used for simultaneous constitutive expression of two genes in human cells.

  3. Genomic Structure and Evolution of the Ancestral Chromosome Fusion Site in 2q13–2q14.1 and Paralogous Regions on Other Human Chromosomes

    Science.gov (United States)

    Fan, Yuxin; Linardopoulou, Elena; Friedman, Cynthia; Williams, Eleanor; Trask, Barbara J.

    2002-01-01

    Human chromosome 2 was formed by the head-to-head fusion of two ancestral chromosomes that remained separate in other primates. Sequences that once resided near the ends of the ancestral chromosomes are now interstitially located in 2q13–2q14.1. Portions of these sequences had duplicated to other locations prior to the fusion. Here we present analyses of the genomic structure and evolutionary history of >600 kb surrounding the fusion site and closely related sequences on other human chromosomes. Sequence blocks that closely flank the inverted arrays of degenerate telomere repeats marking the fusion site are duplicated at many, primarily subtelomeric, locations. In addition, large portions of a 168-kb centromere-proximal block are duplicated at 9pter, 9p11.2, and 9q13, with 98%–99% average sequence identity. A 67-kb block on the distal side of the fusion site is highly homologous to sequences at 22qter. A third ∼100-kb segment is 96% identical to a region in 2q11.2. By integrating data on the extent and similarity of these paralogous blocks, including the presence of phylogenetically informative repetitive elements, with observations of their chromosomal distribution in nonhuman primates, we infer the order of the duplications that led to their current arrangement. Several of these duplicated blocks may be associated with breakpoints of inversions that occurred during primate evolution and of recurrent chromosome rearrangements in humans. [Supplemental material is available online at http://www.genome.org. The following individuals kindly provided reagents, samples, or unpublished information as indicated in the paper: T. Newman, C. Harris, and J. Young.] PMID:12421751

  4. Genomic structure and evolution of the ancestral chromosome fusion site in 2q13-2q14.1 and paralogous regions on other human chromosomes.

    Science.gov (United States)

    Fan, Yuxin; Linardopoulou, Elena; Friedman, Cynthia; Williams, Eleanor; Trask, Barbara J

    2002-11-01

    Human chromosome 2 was formed by the head-to-head fusion of two ancestral chromosomes that remained separate in other primates. Sequences that once resided near the ends of the ancestral chromosomes are now interstitially located in 2q13-2q14.1. Portions of these sequences had duplicated to other locations prior to the fusion. Here we present analyses of the genomic structure and evolutionary history of >600 kb surrounding the fusion site and closely related sequences on other human chromosomes. Sequence blocks that closely flank the inverted arrays of degenerate telomere repeats marking the fusion site are duplicated at many, primarily subtelomeric, locations. In addition, large portions of a 168-kb centromere-proximal block are duplicated at 9pter, 9p11.2, and 9q13, with 98%-99% average sequence identity. A 67-kb block on the distal side of the fusion site is highly homologous to sequences at 22qter. A third ~100-kb segment is 96% identical to a region in 2q11.2. By integrating data on the extent and similarity of these paralogous blocks, including the presence of phylogenetically informative repetitive elements, with observations of their chromosomal distribution in nonhuman primates, we infer the order of the duplications that led to their current arrangement. Several of these duplicated blocks may be associated with breakpoints of inversions that occurred during primate evolution and of recurrent chromosome rearrangements in humans.

  5. Building the sequence map of the human pan-genome

    DEFF Research Database (Denmark)

    Li, Ruiqiang; Li, Yingrui; Zheng, Hancheng

    2010-01-01

    Here we integrate the de novo assembly of an Asian and an African genome with the NCBI reference human genome, as a step toward constructing the human pan-genome. We identified approximately 5 Mb of novel sequences not present in the reference genome in each of these assemblies. Most novel...... analysis of predicted genes indicated that the novel sequences contain potentially functional coding regions. We estimate that a complete human pan-genome would contain approximately 19-40 Mb of novel sequence not present in the extant reference genome. The extensive amount of novel sequence contributing...... to the genetic variation of the pan-genome indicates the importance of using complete genome sequencing and de novo assembly....

  6. Predicting distinct organization of transcription factor binding sites on the promoter regions: a new genome-based approach to expand human embryonic stem cell regulatory network.

    Science.gov (United States)

    Hosseinpour, Batool; Bakhtiarizadeh, Mohammad Reza; Khosravi, Pegah; Ebrahimie, Esmaeil

    2013-12-01

    Self-proliferation and differentiation into distinct cell types have been made stem cell as a promising target for regenerative medicine. Several key genes can regulate self-renewal and pluripotency of embryonic stem cells (hESCs). They work together and build a transcriptional hierarchy. Coexpression and coregulation of genes control by common regulatory elements on the promoter regions. Consequently, distinct organization and combination of transcription factor binding sites (TFBSs modules) on promoter regions, in view of order and distance, lead to a common specific expression pattern within a set of genes. To gain insights into transcriptional regulation of hESCs, we selected promoter regions of eleven common expressed hESC genes including SOX2, LIN28, STAT3, NANOG, LEFTB, TDGF1, POU5F1, FOXD3, TERF1, REX1 and GDF3 to predict activating regulatory modules on promoters and discover key corresponding transcription factors. Then, promoter regions in human genome were explored for modules and 328 genes containing the same modules were detected. Using microarray data, we verified that 102 of 328 genes commonly upregulate in hESCs. Also, using output data of DNA-protein interaction assays, we found that 42 of all predicted genes are targets of SOX2, NANOG and POU5F1. Additionally, a protein interaction network of hESC genes was constructed based on biological processes, and interestingly, 126 downregulated genes along with upregulated ones identified by promoter analysis were predicted in the network. Based on the results, we suggest that the identified genes, coregulating with common hESC genes, represent a novel approach for gene discovery based on whole genome promoter analysis irrespective of gene expression. Altogether, promoter profiling can be used to expand hESC transcriptional regulatory circuitry by analysis of shared functional sequences between genes. This approach provides a clear image on underlying regulatory mechanism of gene expression profile and

  7. An overview of the human genome project

    Energy Technology Data Exchange (ETDEWEB)

    Batzer, M.A.

    1994-01-01

    The human genome project is one of the most ambitious scientific projects to date, with the ultimate goal being a nucleotide sequence for all four billion bases of human DNA. In the process of determining the nucleotide sequence for each base, the location, function, and regulatory regions from the estimated 100,000 human genes will be identified. The genome project itself relies upon maps of the human genetic code derived from several different levels of resolution. Genetic linkage analysis provides a low resolution genome map. The information for genetic linkage maps is derived from the analysis of chromosome specific markers such as Sequence Tagged Sites (STSs), Variable Number of Tandem Repeats (VNTRs) or other polymorphic (highly informative) loci in a number of different-families. Using this information the location of an unknown disease gene can be limited to a region comprised of one million base pairs of DNA or less. After this point, one must construct or have access to a physical map of the region of interest. Physical mapping involves the construction of an ordered overlapping (contiguous) set of recombinant DNA clones. These clones may be derived from a number of different vectors including cosmids, Bacterial Artificial Chromosomes (BACs), P1 derived Artificial Chromosomes (PACs), somatic cell hybrids, or Yeast Artificial Chromosomes (YACs). The ultimate goal for physical mapping is to establish a completely overlapping (contiguous) set of clones for the entire genome. After a gene or region of interest has been localized using physical mapping the nucleotide sequence is determined. The overlap between genetic mapping, physical mapping and DNA sequencing has proven to be a powerful tool for the isolation of disease genes through positional cloning.

  8. Genomic regions associated with kyphosis in swine

    Directory of Open Access Journals (Sweden)

    Shackelford Steven D

    2010-12-01

    Full Text Available Abstract Background A back curvature defect similar to kyphosis in humans has been observed in swine herds. The defect ranges from mild to severe curvature of the thoracic vertebrate in split carcasses and has an estimated heritability of 0.3. The objective of this study was to identify genomic regions that affect this trait. Results Single nucleotide polymorphism (SNP associations performed with 198 SNPs and microsatellite markers in a Duroc-Landrace-Yorkshire resource population (U.S. Meat Animal Research Center, USMARC resource population of swine provided regions of association with this trait on 15 chromosomes. Positional candidate genes, especially those involved in human skeletal development pathways, were selected for SNP identification. SNPs in 16 candidate genes were genotyped in an F2 population (n = 371 and the USMARC resource herd (n = 1,257 with kyphosis scores. SNPs in KCNN2 on SSC2, RYR1 and PLOD1 on SSC6 and MYST4 on SSC14 were significantly associated with kyphosis in the resource population of swine (P ≤ 0.05. SNPs in CER1 and CDH7 on SSC1, PSMA5 on SSC4, HOXC6 and HOXC8 on SSC5, ADAMTS18 on SSC6 and SOX9 on SSC12 were significantly associated with the kyphosis trait in the F2 population of swine (P ≤ 0.05. Conclusions These data suggest that this kyphosis trait may be affected by several loci and that these may differ by population. Carcass value could be improved by effectively removing this undesirable trait from pig populations.

  9. Targeted genome-wide enrichment of functional regions.

    Directory of Open Access Journals (Sweden)

    Periannan Senapathy

    Full Text Available Only a small fraction of large genomes such as that of the human contains the functional regions such as the exons, promoters, and polyA sites. A platform technique for selective enrichment of functional genomic regions will enable several next-generation sequencing applications that include the discovery of causal mutations for disease and drug response. Here, we describe a powerful platform technique, termed "functional genomic fingerprinting" (FGF, for the multiplexed genomewide isolation and analysis of targeted regions such as the exome, promoterome, or exon splice enhancers. The technique employs a fixed part of a uniquely designed Fixed-Randomized primer, while the randomized part contains all the possible sequence permutations. The Fixed-Randomized primers bind with full sequence complementarity at multiple sites where the fixed sequence (such as the splice signals occurs within the genome, and multiplex amplify many regions bounded by the fixed sequences (e.g., exons. Notably, validation of this technique using cardiac myosin binding protein-C (MYBPC3 gene as an example strongly supports the application and efficacy of this method. Further, assisted by genomewide computational analyses of such sequences, the FGF technique may provide a unique platform for high-throughput sample production and analysis of targeted genomic regions by the next-generation sequencing techniques, with powerful applications in discovering disease and drug response genes.

  10. The Human Genome Diversity Project

    Energy Technology Data Exchange (ETDEWEB)

    Cavalli-Sforza, L. [Stanford Univ., CA (United States)

    1994-12-31

    The Human Genome Diversity Project (HGD Project) is an international anthropology project that seeks to study the genetic richness of the entire human species. This kind of genetic information can add a unique thread to the tapestry knowledge of humanity. Culture, environment, history, and other factors are often more important, but humanity`s genetic heritage, when analyzed with recent technology, brings another type of evidence for understanding species` past and present. The Project will deepen the understanding of this genetic richness and show both humanity`s diversity and its deep and underlying unity. The HGD Project is still largely in its planning stages, seeking the best ways to reach its goals. The continuing discussions of the Project, throughout the world, should improve the plans for the Project and their implementation. The Project is as global as humanity itself; its implementation will require the kinds of partnerships among different nations and cultures that make the involvement of UNESCO and other international organizations particularly appropriate. The author will briefly discuss the Project`s history, describe the Project, set out the core principles of the Project, and demonstrate how the Project will help combat the scourge of racism.

  11. GRAbB : Selective Assembly of Genomic Regions, a New Niche for Genomic Research

    NARCIS (Netherlands)

    Brankovics, Balázs; Zhang, Hao; van Diepeningen, Anne D; van der Lee, Theo A J; Waalwijk, Cees; de Hoog, G Sybren

    2016-01-01

    GRAbB (Genomic Region Assembly by Baiting) is a new program that is dedicated to assemble specific genomic regions from NGS data. This approach is especially useful when dealing with multi copy regions, such as mitochondrial genome and the rDNA repeat region, parts of the genome that are often negle

  12. The complete mitochondrial genome of human parasitic roundworm, Ascaris lumbricoides.

    Science.gov (United States)

    Park, Yung Chul; Kim, Won; Park, Joong-Ki

    2011-08-01

    The genome length of the Ascaris lumbricoides, human parasitic roundworm, is 14,281 bp with a nucleotide composition of 22.1% A, 49.8% T, 7.8% C, and 20.3% G. The genome consists of 12 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and 1 control region.

  13. Does selection against transcriptional interference shape retroelement-free regions in mammalian genomes?

    DEFF Research Database (Denmark)

    Mourier, Tobias; Willerslev, Eske

    2008-01-01

    BACKGROUND: Eukaryotic genomes are scattered with retroelements that proliferate through retrotransposition. Although retroelements make up around 40 percent of the human genome, large regions are found to be completely devoid of retroelements. This has been hypothesised to be a result of genomic...

  14. Recent and ongoing selection in the human genome

    DEFF Research Database (Denmark)

    Nielsen, Rasmus; Hellmann, Ines; Hubisz, Melissa

    2007-01-01

    The recent availability of genome-scale genotyping data has led to the identification of regions of the human genome that seem to have been targeted by selection. These findings have increased our understanding of the evolutionary forces that affect the human genome, have augmented our knowledge...... of gene function and promise to increase our understanding of the genetic basis of disease. However, inferences of selection are challenged by several confounding factors, especially the complex demographic history of human populations, and concordance between studies is variable. Although such studies...

  15. The evolution of the human genome.

    Science.gov (United States)

    Simonti, Corinne N; Capra, John A

    2015-12-01

    Human genomes hold a record of the evolutionary forces that have shaped our species. Advances in DNA sequencing, functional genomics, and population genetic modeling have deepened our understanding of human demographic history, natural selection, and many other long-studied topics. These advances have also revealed many previously underappreciated factors that influence the evolution of the human genome, including functional modifications to DNA and histones, conserved 3D topological chromatin domains, structural variation, and heterogeneous mutation patterns along the genome. Using evolutionary theory as a lens to study these phenomena will lead to significant breakthroughs in understanding what makes us human and why we get sick.

  16. Life in our hands? Some ethical perspectives on the human genome and human genome diversity projects

    Directory of Open Access Journals (Sweden)

    Cornelius W. du Toit

    2014-01-01

    Full Text Available The article dealt with implications of the human genome and the human genome diversity project. It examined some theological implications, such as: humans as the image of God, God as the creator of life, the changed role of miracles and healings in religion, the sacredness of nature, life and the genome. Ethical issues that were addressed include eugenics, germline intervention, determinism and the human genome diversity project. Economic and legal factors that play a role were also discussed. Whilst positive aspects of genome research were considered, a critical stance was adopted towards patenting the human genome and some concluding guidelines were proposed.

  17. Human genome: proto-oncogenes and proretroviruses.

    Science.gov (United States)

    Kisselev, L L; Chumakov, I M; Zabarovsky, E R; Prassolov, V S; Mett, V L; Berditchevsky, F B; Tret'yakov, L D

    1985-01-01

    A brief review of the studies undertaken at the Laboratory for Molecular Bases of Oncogenesis (Institute of Molecular Biology, Moscow) till middle of 1984 is presented. The human genome contains multiple dispersed nucleotide sequences related to the proto-oncogene mos and to proretroviral sequences in tight juxtaposition to each other. From sequencing appropriate cloned fragments of human DNA in phage and plasmid vectors it follows that one of these regions, NV-1, is a pseudogene of proto-mos with partial duplications and two Alu elements intervening its coding sequence, and the other, CL-1, seems to be also a mos-related gene with a deletion of the internal part of the structural gene. CL-1 is flanked by a proretroviral-like sequence including tRNAiMet binding site and U5 (part of the long terminal repeat). The proretroviral-like sequences are transcribed in 21-35S poly(A)+RNA abundant in normal and malignant human cells. Two hypotheses are proposed: endogenous retroviruses take part in amplification of at least some proto-oncogenes; proto-oncogenes are inactivated via insertion of movable genetic elements and conversion into pseudogenes. Potential oncogenicity of a normal human genome undergoes two controversial influences: it increases due to proto-oncogene amplification and decreases due to inactivation of some of them.

  18. Nucleolar organizer regions: genomic 'dark matter' requiring illumination.

    Science.gov (United States)

    McStay, Brian

    2016-07-15

    Nucleoli form around tandem arrays of a ribosomal gene repeat, termed nucleolar organizer regions (NORs). During metaphase, active NORs adopt a characteristic undercondensed morphology. Recent evidence indicates that the HMG-box-containing DNA-binding protein UBF (upstream binding factor) is directly responsible for this morphology and provides a mitotic bookmark to ensure rapid nucleolar formation beginning in telophase in human cells. This is likely to be a widely employed strategy, as UBF is present throughout metazoans. In higher eukaryotes, NORs are typically located within regions of chromosomes that form perinucleolar heterochromatin during interphase. Typically, the genomic architecture of NORs and the chromosomal regions within which they lie is very poorly described, yet recent evidence points to a role for context in their function. In Arabidopsis, NOR silencing appears to be controlled by sequences outside the rDNA (ribosomal DNA) array. Translocations reveal a role for context in the expression of the NOR on the X chromosome in Drosophila Recent work has begun on characterizing the genomic architecture of human NORs. A role for distal sequences located in perinucleolar heterochromatin has been inferred, as they exhibit a complex transcriptionally active chromatin structure. Links between rDNA genomic stability and aging in Saccharomyces cerevisiae are now well established, and indications are emerging that this is important in aging and replicative senescence in higher eukaryotes. This, combined with the fact that rDNA arrays are recombinational hot spots in cancer cells, has focused attention on DNA damage responses in NORs. The introduction of DNA double-strand breaks into rDNA arrays leads to a dramatic reorganization of nucleolar structure. Damaged rDNA repeats move from the nucleolar interior to form caps at the nucleolar periphery, presumably to facilitate repair, suggesting that the chromosomal context of human NORs contributes to their genomic

  19. Evolutionary history of the ABCB2 genomic region in teleosts

    Science.gov (United States)

    Palti, Y.; Rodriguez, M.F.; Gahr, S.A.; Hansen, J.D.

    2007-01-01

    Gene duplication, silencing and translocation have all been implicated in shaping the unique genomic architecture of the teleost MH regions. Previously, we demonstrated that trout possess five unlinked regions encoding MH genes. One of these regions harbors ABCB2 which in all other vertebrate classes is found in the MHC class II region. In this study, we sequenced a BAC contig for the trout ABCB2 region. Analysis of this region revealed the presence of genes homologous to those located in the human class II (ABCB2, BRD2, ??DAA), extended class II (RGL2, PHF1, SYGP1) and class III (PBX2, Notch-L) regions. The organization and syntenic relationships of this region were then compared to similar regions in humans, Tetraodon and zebrafish to learn more about the evolutionary history of this region. Our analysis indicates that this region was generated during the teleost-specific duplication event while also providing insight about potential MH paralogous regions in teleosts. ?? 2006 Elsevier Ltd. All rights reserved.

  20. Human Genome Sequencing in Health and Disease

    Science.gov (United States)

    Gonzaga-Jauregui, Claudia; Lupski, James R.; Gibbs, Richard A.

    2013-01-01

    Following the “finished,” euchromatic, haploid human reference genome sequence, the rapid development of novel, faster, and cheaper sequencing technologies is making possible the era of personalized human genomics. Personal diploid human genome sequences have been generated, and each has contributed to our better understanding of variation in the human genome. We have consequently begun to appreciate the vastness of individual genetic variation from single nucleotide to structural variants. Translation of genome-scale variation into medically useful information is, however, in its infancy. This review summarizes the initial steps undertaken in clinical implementation of personal genome information, and describes the application of whole-genome and exome sequencing to identify the cause of genetic diseases and to suggest adjuvant therapies. Better analysis tools and a deeper understanding of the biology of our genome are necessary in order to decipher, interpret, and optimize clinical utility of what the variation in the human genome can teach us. Personal genome sequencing may eventually become an instrument of common medical practice, providing information that assists in the formulation of a differential diagnosis. We outline herein some of the remaining challenges. PMID:22248320

  1. Localizing recent adaptive evolution in the human genome

    DEFF Research Database (Denmark)

    Williamson, Scott H; Hubisz, Melissa J; Clark, Andrew G;

    2007-01-01

    Identifying genomic locations that have experienced selective sweeps is an important first step toward understanding the molecular basis of adaptive evolution. Using statistical methods that account for the confounding effects of population demography, recombination rate variation, and single......-nucleotide polymorphism ascertainment, while also providing fine-scale estimates of the position of the selected site, we analyzed a genomic dataset of 1.2 million human single-nucleotide polymorphisms genotyped in African-American, European-American, and Chinese samples. We identify 101 regions of the human genome......, clusters of olfactory receptors, genes involved in nervous system development and function, immune system genes, and heat shock genes. We also observe consistent evidence of selective sweeps in centromeric regions. In general, we find that recent adaptation is strikingly pervasive in the human genome...

  2. Defining functional DNA elements in the human genome.

    Science.gov (United States)

    Kellis, Manolis; Wold, Barbara; Snyder, Michael P; Bernstein, Bradley E; Kundaje, Anshul; Marinov, Georgi K; Ward, Lucas D; Birney, Ewan; Crawford, Gregory E; Dekker, Job; Dunham, Ian; Elnitski, Laura L; Farnham, Peggy J; Feingold, Elise A; Gerstein, Mark; Giddings, Morgan C; Gilbert, David M; Gingeras, Thomas R; Green, Eric D; Guigo, Roderic; Hubbard, Tim; Kent, Jim; Lieb, Jason D; Myers, Richard M; Pazin, Michael J; Ren, Bing; Stamatoyannopoulos, John A; Weng, Zhiping; White, Kevin P; Hardison, Ross C

    2014-04-29

    With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease.

  3. Characterization of copy number variation in genomic regions containing STR loci using array comparative genomic hybridization.

    Science.gov (United States)

    Repnikova, Elena A; Rosenfeld, Jill A; Bailes, Andrea; Weber, Cecilia; Erdman, Linda; McKinney, Aimee; Ramsey, Sarah; Hashimoto, Sayaka; Lamb Thrush, Devon; Astbury, Caroline; Reshmi, Shalini C; Shaffer, Lisa G; Gastier-Foster, Julie M; Pyatt, Robert E

    2013-09-01

    Short tandem repeat (STR) loci are commonly used in forensic casework, familial analysis for human identification, and for monitoring hematopoietic cell engraftment after bone marrow transplant. Unexpected genetic variation leading to sequence and length differences in STR loci can complicate STR typing, and presents challenges in casework interpretation. Copy number variation (CNV) is a relatively recently identified form of genetic variation consisting of genomic regions present at variable copy numbers within an individual compared to a reference genome. Large scale population studies have demonstrated that likely all individuals carry multiple regions with CNV of 1kb in size or greater in their genome. To date, no study correlating genomic regions containing STR loci with CNV has been conducted. In this study, we analyzed results from 32,850 samples sent for clinical array comparative genomic hybridization (CGH) analysis for the presence of CNV at regions containing the 13 CODIS (Combined DNA Index System) STR, and the Amelogenin X (AMELX) and Amelogenin Y (AMELY) loci. Thirty-two individuals with CNV involving STR loci on chromosomes 2, 4, 7, 11, 12, 13, 16, and 21, and twelve with CNV involving the AMELX/AMELY loci were identified. These results were correlated with data from publicly available databases housing information on CNV identified in normal populations and additional clinical cases. These collective results demonstrate the presence of CNV in regions containing 9 of the 13 CODIS STR and AMELX/Y loci. Further characterization of STR profiles within regions of CNV, additional cataloging of these variants in multiple populations, and contributing such examples to the public domain will provide valuable information for reliable use of these loci.

  4. A decade of human genome project conclusion: Scientific diffusion about our genome knowledge.

    Science.gov (United States)

    Moraes, Fernanda; Góes, Andréa

    2016-05-06

    The Human Genome Project (HGP) was initiated in 1990 and completed in 2003. It aimed to sequence the whole human genome. Although it represented an advance in understanding the human genome and its complexity, many questions remained unanswered. Other projects were launched in order to unravel the mysteries of our genome, including the ENCyclopedia of DNA Elements (ENCODE). This review aims to analyze the evolution of scientific knowledge related to both the HGP and ENCODE projects. Data were retrieved from scientific articles published in 1990-2014, a period comprising the development and the 10 years following the HGP completion. The fact that only 20,000 genes are protein and RNA-coding is one of the most striking HGP results. A new concept about the organization of genome arose. The ENCODE project was initiated in 2003 and targeted to map the functional elements of the human genome. This project revealed that the human genome is pervasively transcribed. Therefore, it was determined that a large part of the non-protein coding regions are functional. Finally, a more sophisticated view of chromatin structure emerged. The mechanistic functioning of the genome has been redrafted, revealing a much more complex picture. Besides, a gene-centric conception of the organism has to be reviewed. A number of criticisms have emerged against the ENCODE project approaches, raising the question of whether non-conserved but biochemically active regions are truly functional. Thus, HGP and ENCODE projects accomplished a great map of the human genome, but the data generated still requires further in depth analysis. © 2016 by The International Union of Biochemistry and Molecular Biology, 44:215-223, 2016.

  5. The genomic landscapes of histone H3-Lys9 modifications of gene promoter regions and expression profiles in human bone marrow mesenchymal stem cells

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Mesenchymal stem cells (MSCs) of nonembryortic origins possess the proliferation and multi-lineage differentiation potentials. It has been established that epigenetic mechanisms could be critical for determining the fate of stem ceils, and MSCs derived from different origins exhibited different expression profiles individually to a certain extent. In this study, ChiP-on-chip was used to generate genome-wide historic H3-Lys9 acetylation and dimethylation profiles at gene promoters in human bone marrow MSCs. We showed that modifications of histone H3-Lys9 at gene promoters correlated well with mRNA expression in human bone marrow MSCs. Functional analysis revealed that many key cellular pathways in human bone marrow MSC self-renewal, such as the canonical signaling pathways,cell cycle pathways and cytokine related pathways may be regulated by H3-Lys9 modifications. These data suggest that gene activation and silencing affected by H3-Lys9 acetylation and dimethylation, respectively, may be essential to the maintenance of human bone marrow MSC self-renewal and multi-potency.

  6. Big Data Analysis of Human Genome Variations

    KAUST Repository

    Gojobori, Takashi

    2016-01-25

    Since the human genome draft sequence was in public for the first time in 2000, genomic analyses have been intensively extended to the population level. The following three international projects are good examples for large-scale studies of human genome variations: 1) HapMap Data (1,417 individuals) (http://hapmap.ncbi.nlm.nih.gov/downloads/genotypes/2010-08_phaseII+III/forward/), 2) HGDP (Human Genome Diversity Project) Data (940 individuals) (http://www.hagsc.org/hgdp/files.html), 3) 1000 genomes Data (2,504 individuals) http://ftp.1000genomes.ebi.ac.uk/vol1/ftp/release/20130502/ If we can integrate all three data into a single volume of data, we should be able to conduct a more detailed analysis of human genome variations for a total number of 4,861 individuals (= 1,417+940+2,504 individuals). In fact, we successfully integrated these three data sets by use of information on the reference human genome sequence, and we conducted the big data analysis. In particular, we constructed a phylogenetic tree of about 5,000 human individuals at the genome level. As a result, we were able to identify clusters of ethnic groups, with detectable admixture, that were not possible by an analysis of each of the three data sets. Here, we report the outcome of this kind of big data analyses and discuss evolutionary significance of human genomic variations. Note that the present study was conducted in collaboration with Katsuhiko Mineta and Kosuke Goto at KAUST.

  7. Insights from Human/Mouse genome comparisons

    Energy Technology Data Exchange (ETDEWEB)

    Pennacchio, Len A.

    2003-03-30

    Large-scale public genomic sequencing efforts have provided a wealth of vertebrate sequence data poised to provide insights into mammalian biology. These include deep genomic sequence coverage of human, mouse, rat, zebrafish, and two pufferfish (Fugu rubripes and Tetraodon nigroviridis) (Aparicio et al. 2002; Lander et al. 2001; Venter et al. 2001; Waterston et al. 2002). In addition, a high-priority has been placed on determining the genomic sequence of chimpanzee, dog, cow, frog, and chicken (Boguski 2002). While only recently available, whole genome sequence data have provided the unique opportunity to globally compare complete genome contents. Furthermore, the shared evolutionary ancestry of vertebrate species has allowed the development of comparative genomic approaches to identify ancient conserved sequences with functionality. Accordingly, this review focuses on the initial comparison of available mammalian genomes and describes various insights derived from such analysis.

  8. Triplex-forming oligonucleotide target sequences in the human genome

    OpenAIRE

    Goñi, J Ramon; de la Cruz, Xavier; Orozco, Modesto

    2004-01-01

    The existence of sequences in the human genome which can be a target for triplex formation, and accordingly are candidates for anti-gene therapies, has been studied by using bioinformatics tools. It was found that the population of triplex-forming oligonucleotide target sequences (TTS) is much more abundant than that expected from simple random models. The population of TTS is large in all the genome, without major differences between chromosomes. A wide analysis along annotated regions of th...

  9. Implementing genomics and pharmacogenomics in the clinic: The National Human Genome Research Institute's genomic medicine portfolio.

    Science.gov (United States)

    Manolio, Teri A

    2016-10-01

    Increasing knowledge about the influence of genetic variation on human health and growing availability of reliable, cost-effective genetic testing have spurred the implementation of genomic medicine in the clinic. As defined by the National Human Genome Research Institute (NHGRI), genomic medicine uses an individual's genetic information in his or her clinical care, and has begun to be applied effectively in areas such as cancer genomics, pharmacogenomics, and rare and undiagnosed diseases. In 2011 NHGRI published its strategic vision for the future of genomic research, including an ambitious research agenda to facilitate and promote the implementation of genomic medicine. To realize this agenda, NHGRI is consulting and facilitating collaborations with the external research community through a series of "Genomic Medicine Meetings," under the guidance and leadership of the National Advisory Council on Human Genome Research. These meetings have identified and begun to address significant obstacles to implementation, such as lack of evidence of efficacy, limited availability of genomics expertise and testing, lack of standards, and difficulties in integrating genomic results into electronic medical records. The six research and dissemination initiatives comprising NHGRI's genomic research portfolio are designed to speed the evaluation and incorporation, where appropriate, of genomic technologies and findings into routine clinical care. Actual adoption of successful approaches in clinical care will depend upon the willingness, interest, and energy of professional societies, practitioners, patients, and payers to promote their responsible use and share their experiences in doing so.

  10. Genomic divergences among cattle, dog and human estimated from large-scale alignments of genomic sequences

    Directory of Open Access Journals (Sweden)

    Shade Larry L

    2006-06-01

    Full Text Available Abstract Background Approximately 11 Mb of finished high quality genomic sequences were sampled from cattle, dog and human to estimate genomic divergences and their regional variation among these lineages. Results Optimal three-way multi-species global sequence alignments for 84 cattle clones or loci (each >50 kb of genomic sequence were constructed using the human and dog genome assemblies as references. Genomic divergences and substitution rates were examined for each clone and for various sequence classes under different functional constraints. Analysis of these alignments revealed that the overall genomic divergences are relatively constant (0.32–0.37 change/site for pairwise comparisons among cattle, dog and human; however substitution rates vary across genomic regions and among different sequence classes. A neutral mutation rate (2.0–2.2 × 10(-9 change/site/year was derived from ancestral repetitive sequences, whereas the substitution rate in coding sequences (1.1 × 10(-9 change/site/year was approximately half of the overall rate (1.9–2.0 × 10(-9 change/site/year. Relative rate tests also indicated that cattle have a significantly faster rate of substitution as compared to dog and that this difference is about 6%. Conclusion This analysis provides a large-scale and unbiased assessment of genomic divergences and regional variation of substitution rates among cattle, dog and human. It is expected that these data will serve as a baseline for future mammalian molecular evolution studies.

  11. Human and mouse genome analysis using array comparative genomic hybridization

    NARCIS (Netherlands)

    Snijders, Antoine Maria

    2004-01-01

    Almost all human cancers as well as developmental abnormalities are characterized by the presence of genetic alterations, most of which target a gene or a particular genomic locus resulting in altered gene expression and ultimately an altered phenotype. Different types of genetic alterations include

  12. The characterization of twenty sequenced human genomes.

    Directory of Open Access Journals (Sweden)

    Kimberly Pelak

    2010-09-01

    Full Text Available We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten "case" genomes from individuals with severe hemophilia A and ten "control" genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways.

  13. Recurrent DNA inversion rearrangements in the human genome

    DEFF Research Database (Denmark)

    Flores, Margarita; Morales, Lucía; Gonzaga-Jauregui, Claudia

    2007-01-01

    Several lines of evidence suggest that reiterated sequences in the human genome are targets for nonallelic homologous recombination (NAHR), which facilitates genomic rearrangements. We have used a PCR-based approach to identify breakpoint regions of rearranged structures in the human genome...... on chromosomes 3, 15, and 19, were analyzed. The relative proportion of wild-type to rearranged structures was determined in DNA samples from blood obtained from different, unrelated individuals. The results obtained indicate that recurrent genomic rearrangements occur at relatively high frequency in somatic...... cells. Interestingly, the rearrangements studied were significantly more abundant in adults than in newborn individuals, suggesting that such DNA rearrangements might start to appear during embryogenesis or fetal life and continue to accumulate after birth. The relevance of our results in regard...

  14. The diploid genome sequence of an individual human.

    Directory of Open Access Journals (Sweden)

    Samuel Levy

    2007-09-01

    Full Text Available Presented here is a genome sequence of an individual human. It was produced from approximately 32 million random DNA fragments, sequenced by Sanger dideoxy technology and assembled into 4,528 scaffolds, comprising 2,810 million bases (Mb of contiguous sequence with approximately 7.5-fold coverage for any given region. We developed a modified version of the Celera assembler to facilitate the identification and comparison of alternate alleles within this individual diploid genome. Comparison of this genome and the National Center for Biotechnology Information human reference assembly revealed more than 4.1 million DNA variants, encompassing 12.3 Mb. These variants (of which 1,288,319 were novel included 3,213,401 single nucleotide polymorphisms (SNPs, 53,823 block substitutions (2-206 bp, 292,102 heterozygous insertion/deletion events (indels(1-571 bp, 559,473 homozygous indels (1-82,711 bp, 90 inversions, as well as numerous segmental duplications and copy number variation regions. Non-SNP DNA variation accounts for 22% of all events identified in the donor, however they involve 74% of all variant bases. This suggests an important role for non-SNP genetic alterations in defining the diploid genome structure. Moreover, 44% of genes were heterozygous for one or more variants. Using a novel haplotype assembly strategy, we were able to span 1.5 Gb of genome sequence in segments >200 kb, providing further precision to the diploid nature of the genome. These data depict a definitive molecular portrait of a diploid human genome that provides a starting point for future genome comparisons and enables an era of individualized genomic information.

  15. Rapid detection of structural variation in a human genome using nanochannel-based genome mapping technology

    DEFF Research Database (Denmark)

    Cao, Hongzhi; Hastie, Alex R.; Cao, Dandan

    2014-01-01

    mutations; however, none of the current detection methods are comprehensive, and currently available methodologies are incapable of providing sufficient resolution and unambiguous information across complex regions in the human genome. To address these challenges, we applied a high-throughput, cost......BACKGROUND: Structural variants (SVs) are less common than single nucleotide polymorphisms and indels in the population, but collectively account for a significant fraction of genetic polymorphism and diseases. Base pair differences arising from SVs are on a much higher order (>100 fold) than point...... mapping technology as a comprehensive and cost-effective method for detecting structural variation and studying complex regions in the human genome, as well as deciphering viral integration into the host genome....

  16. High resolution physical map of porcine chromosome 7 QTL region and comparative mapping of this region among vertebrate genomes

    Directory of Open Access Journals (Sweden)

    Demeure Olivier

    2006-01-01

    Full Text Available Abstract Background On porcine chromosome 7, the region surrounding the Major Histocompatibility Complex (MHC contains several Quantitative Trait Loci (QTL influencing many traits including growth, back fat thickness and carcass composition. Previous studies highlighted that a fragment of ~3.7 Mb is located within the Swine Leucocyte Antigen (SLA complex. Internal rearrangements of this fragment were suggested, and partial contigs had been built, but further characterization of this region and identification of all human chromosomal fragments orthologous to this porcine fragment had to be carried out. Results A whole physical map of the region was constructed by integrating Radiation Hybrid (RH mapping, BAC fingerprinting data of the INRA BAC library and anchoring BAC end sequences on the human genome. 17 genes and 2 reference microsatellites were ordered on the high resolution IMNpRH212000rad Radiation Hybrid panel. A 1000:1 framework map covering 550 cR12000 was established and a complete contig of the region was developed. New micro rearrangements were highlighted between the porcine and human genomes. A bovine RH map was also developed in this region by mapping 16 genes. Comparison of the organization of this region in pig, cattle, human, mouse, dog and chicken genomes revealed that 1 the translocation of the fragment described previously is observed only on the bovine and porcine genomes and 2 the new internal micro rearrangements are specific of the porcine genome. Conclusion We estimate that the region contains several rearrangements and covers 5.2 Mb of the porcine genome. The study of this complete BAC contig showed that human chromosomal fragments homologs of this heavily rearranged QTL region are all located in the region of HSA6 that surrounds the centromere. This work allows us to define a list of all candidate genes that could explain these QTL effects.

  17. A periodic pattern of SNPs in the human genome

    DEFF Research Database (Denmark)

    Madsen, Bo Eskerod; Villesen, Palle; Wiuf, Carsten

    2007-01-01

    or alignment errors, for example, transposable elements (SINE, LINE, and LTR), tandem repeats, and large duplicated regions. However, we found that the pattern is almost entirely confined to what we define as "periodic DNA." Periodic DNA is a genomic region with a high degree of periodicity in nucleotide usage...... periodic DNA. Our results suggest that not all SNPs in the human genome are created by independent single nucleotide mutations, and that care should be taken in analysis of SNPs from periodic DNA. The latter may have important consequences for SNP and association studies....

  18. An integrated encyclopedia of DNA elements in the human genome.

    Science.gov (United States)

    2012-09-01

    The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

  19. Human evolution: a tale from ancient genomes.

    Science.gov (United States)

    Llamas, Bastien; Willerslev, Eske; Orlando, Ludovic

    2017-02-05

    The field of human ancient DNA (aDNA) has moved from mitochondrial sequencing that suffered from contamination and provided limited biological insights, to become a fully genomic discipline that is changing our conception of human history. Recent successes include the sequencing of extinct hominins, and true population genomic studies of Bronze Age populations. Among the emerging areas of aDNA research, the analysis of past epigenomes is set to provide more new insights into human adaptation and disease susceptibility through time. Starting as a mere curiosity, ancient human genetics has become a major player in the understanding of our evolutionary history.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'.

  20. Segmenting the Human Genome into Isochores.

    Science.gov (United States)

    Cozzi, Paolo; Milanesi, Luciano; Bernardi, Giorgio

    2015-01-01

    The human genome is a mosaic of isochores, which are long (>200 kb) DNA sequences that are fairly homogeneous in base composition and can be assigned to five families comprising 33%-59% of GC composition. Although the compartmentalized organization of the mammalian genome has been investigated for more than 40 years, no satisfactory automatic procedure for segmenting the genome into isochores is available so far. We present a critical discussion of the currently available methods and a new approach called isoSegmenter which allows segmenting the genome into isochores in a fast and completely automatic manner. This approach relies on two types of experimentally defined parameters, the compositional boundaries of isochore families and an optimal window size of 100 kb. The approach represents an improvement over the existing methods, is ideally suited for investigating long-range features of sequenced and assembled genomes, and is publicly available at https://github.com/bunop/isoSegmenter.

  1. High Species C Human Adenovirus Genome Copy Numbers in the Treated Water Supply of a Neotropical Area of the Central-West Region of Brazil.

    Science.gov (United States)

    Silva, Hugo D; Fongaro, Gislaine; Garcíazapata, Marco T A; Melo, Arthur T O; Silveira-Lacerda, Elisângela P; de Faria, Karla M S; Anunciação, Carlos E

    2015-09-01

    There is little information about the presence of human adenovirus (HAdV) in drinking water in Neotropical regions. Thus, the present study sought to conduct quantification and molecular characterization of HAdVs detected in treated water samples from an area of the Cerrado ecoregion of Brazil. Between August and November 2012, samples were collected from four treated water reservoirs and their respective sites along the water distribution network of the city of Goiânia, for a total of 80 samples. All samples were concentrated and analyzed by qPCR, and selected samples were sequenced. Overall, 76.6 (10(0)-10(9) GC mL(-1)) and 37.5% (10(1)-10(8) GC mL(-1)) of samples drawn from reservoirs and their distribution sites, respectively, were positive for virus by qPCR. All samples selected for sequencing were characterized as species C human adenovirus. Such high HAdV counts have in treated water samples. This finding merits special attention, particularly from the sanitation authorities, because the high number of GC mL(-1) may be an indicative of risk to human health.

  2. Evolutionary forces shaping genomic islands of population differentiation in humans

    Directory of Open Access Journals (Sweden)

    Hofer Tamara

    2012-03-01

    Full Text Available Abstract Background Levels of differentiation among populations depend both on demographic and selective factors: genetic drift and local adaptation increase population differentiation, which is eroded by gene flow and balancing selection. We describe here the genomic distribution and the properties of genomic regions with unusually high and low levels of population differentiation in humans to assess the influence of selective and neutral processes on human genetic structure. Methods Individual SNPs of the Human Genome Diversity Panel (HGDP showing significantly high or low levels of population differentiation were detected under a hierarchical-island model (HIM. A Hidden Markov Model allowed us to detect genomic regions or islands of high or low population differentiation. Results Under the HIM, only 1.5% of all SNPs are significant at the 1% level, but their genomic spatial distribution is significantly non-random. We find evidence that local adaptation shaped high-differentiation islands, as they are enriched for non-synonymous SNPs and overlap with previously identified candidate regions for positive selection. Moreover there is a negative relationship between the size of islands and recombination rate, which is stronger for islands overlapping with genes. Gene ontology analysis supports the role of diet as a major selective pressure in those highly differentiated islands. Low-differentiation islands are also enriched for non-synonymous SNPs, and contain an overly high proportion of genes belonging to the 'Oncogenesis' biological process. Conclusions Even though selection seems to be acting in shaping islands of high population differentiation, neutral demographic processes might have promoted the appearance of some genomic islands since i as much as 20% of islands are in non-genic regions ii these non-genic islands are on average two times shorter than genic islands, suggesting a more rapid erosion by recombination, and iii most loci are

  3. Justice and the Human Genome Project

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, T.F.; Lappe, M. [eds.

    1992-12-31

    Most of the essays gathered in this volume were first presented at a conference, Justice and the Human Genome, in Chicago in early November, 1991. The goal of the, conference was to consider questions of justice as they are and will be raised by the Human Genome Project. To achieve its goal of identifying and elucidating the challenges of justice inherent in genomic research and its social applications the conference drew together in one forum members from academia, medicine, and industry with interests divergent as rate-setting for insurance, the care of newborns, and the history of ethics. The essays in this volume address a number of theoretical and practical concerns relative to the meaning of genomic research.

  4. Justice and the Human Genome Project

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, T.F.; Lappe, M. (eds.)

    1992-01-01

    Most of the essays gathered in this volume were first presented at a conference, Justice and the Human Genome, in Chicago in early November, 1991. The goal of the, conference was to consider questions of justice as they are and will be raised by the Human Genome Project. To achieve its goal of identifying and elucidating the challenges of justice inherent in genomic research and its social applications the conference drew together in one forum members from academia, medicine, and industry with interests divergent as rate-setting for insurance, the care of newborns, and the history of ethics. The essays in this volume address a number of theoretical and practical concerns relative to the meaning of genomic research.

  5. Initial genomics of the human nucleolus.

    Directory of Open Access Journals (Sweden)

    Attila Németh

    2010-03-01

    Full Text Available We report for the first time the genomics of a nuclear compartment of the eukaryotic cell. 454 sequencing and microarray analysis revealed the pattern of nucleolus-associated chromatin domains (NADs in the linear human genome and identified different gene families and certain satellite repeats as the major building blocks of NADs, which constitute about 4% of the genome. Bioinformatic evaluation showed that NAD-localized genes take part in specific biological processes, like the response to other organisms, odor perception, and tissue development. 3D FISH and immunofluorescence experiments illustrated the spatial distribution of NAD-specific chromatin within interphase nuclei and its alteration upon transcriptional changes. Altogether, our findings describe the nature of DNA sequences associated with the human nucleolus and provide insights into the function of the nucleolus in genome organization and establishment of nuclear architecture.

  6. New complete genome sequences of human rhinoviruses shed light on their phylogeny and genomic features

    Directory of Open Access Journals (Sweden)

    Zdobnov Evgeny M

    2007-07-01

    Full Text Available Abstract Background Human rhinoviruses (HRV, the most frequent cause of respiratory infections, include 99 different serotypes segregating into two species, A and B. Rhinoviruses share extensive genomic sequence similarity with enteroviruses and both are part of the picornavirus family. Nevertheless they differ significantly at the phenotypic level. The lack of HRV full-length genome sequences and the absence of analysis comparing picornaviruses at the whole genome level limit our knowledge of the genomic features supporting these differences. Results Here we report complete genome sequences of 12 HRV-A and HRV-B serotypes, more than doubling the current number of available HRV sequences. The whole-genome maximum-likelihood phylogenetic analysis suggests that HRV-B and human enteroviruses (HEV diverged from the last common ancestor after their separation from HRV-A. On the other hand, compared to HEV, HRV-B are more related to HRV-A in the capsid and 3B-C regions. We also identified the presence of a 2C cis-acting replication element (cre in HRV-B that is not present in HRV-A, and that had been previously characterized only in HEV. In contrast to HEV viruses, HRV-A and HRV-B share also markedly lower GC content along the whole genome length. Conclusion Our findings provide basis to speculate about both the biological similarities and the differences (e.g. tissue tropism, temperature adaptation or acid lability of these three groups of viruses.

  7. Mapping and Sequencing the Human Genome

    Science.gov (United States)

    1988-01-01

    Numerous meetings have been held and a debate has developed in the biological community over the merits of mapping and sequencing the human genome. In response a committee to examine the desirability and feasibility of mapping and sequencing the human genome was formed to suggest options for implementing the project. The committee asked many questions. Should the analysis of the human genome be left entirely to the traditionally uncoordinated, but highly successful, support systems that fund the vast majority of biomedical research. Or should a more focused and coordinated additional support system be developed that is limited to encouraging and facilitating the mapping and eventual sequencing of the human genome. If so, how can this be done without distorting the broader goals of biological research that are crucial for any understanding of the data generated in such a human genome project. As the committee became better informed on the many relevant issues, the opinions of its members coalesced, producing a shared consensus of what should be done. This report reflects that consensus.

  8. Templated sequence insertion polymorphisms in the human genome

    Science.gov (United States)

    Onozawa, Masahiro; Aplan, Peter

    2016-11-01

    Templated Sequence Insertion Polymorphism (TSIP) is a recently described form of polymorphism recognized in the human genome, in which a sequence that is templated from a distant genomic region is inserted into the genome, seemingly at random. TSIPs can be grouped into two classes based on nucleotide sequence features at the insertion junctions; Class 1 TSIPs show features of insertions that are mediated via the LINE-1 ORF2 protein, including 1) target-site duplication (TSD), 2) polyadenylation 10-30 nucleotides downstream of a “cryptic” polyadenylation signal, and 3) preference for insertion at a 5’-TTTT/A-3’ sequence. In contrast, class 2 TSIPs show features consistent with repair of a DNA double-strand break via insertion of a DNA “patch” that is derived from a distant genomic region. Survey of a large number of normal human volunteers demonstrates that most individuals have 25-30 TSIPs, and that these TSIPs track with specific geographic regions. Similar to other forms of human polymorphism, we suspect that these TSIPs may be important for the generation of human diversity and genetic diseases.

  9. Clusters of adaptive evolution in the human genome

    Directory of Open Access Journals (Sweden)

    Laura B. Scheinfeldt

    2011-09-01

    Full Text Available Considerable work has been devoted to identifying regions of the human genome that have been subjected to recent positive selection. Although detailed follow-up studies of putatively selected regions are critical for a deeper understanding of human evolutionary history, such studies have received comparably less attention. Recently, we have shown that ALMS1 has been the target of recent positive selection acting on standing variation in Eurasian populations. Here, we describe a careful follow-up analysis of genetic variation across the ALMS1 region, which unexpectedly revealed a cluster of substrates of positive selection. Specifically, through the analysis of SNP data from the HapMap and HGDP-CEPH samples as well sequence data from the region, we find compelling evidence for three independent and distinct signals of recent positive selection across this 3 Mb region surrounding ALMS1. Moreover, we analyzed the HapMap data to identify other putative clusters of independent selective events and conservatively discovered 19 additional clusters of adaptive evolution. This work has important implications for the interpretation of genome-scans for positive selection in humans and more broadly contributes to a better understanding of how recent positive selection has shaped genetic variation across the human genome.

  10. Genome editing for human gene therapy.

    Science.gov (United States)

    Meissner, Torsten B; Mandal, Pankaj K; Ferreira, Leonardo M R; Rossi, Derrick J; Cowan, Chad A

    2014-01-01

    The rapid advancement of genome-editing techniques holds much promise for the field of human gene therapy. From bacteria to model organisms and human cells, genome editing tools such as zinc-finger nucleases (ZNFs), TALENs, and CRISPR/Cas9 have been successfully used to manipulate the respective genomes with unprecedented precision. With regard to human gene therapy, it is of great interest to test the feasibility of genome editing in primary human hematopoietic cells that could potentially be used to treat a variety of human genetic disorders such as hemoglobinopathies, primary immunodeficiencies, and cancer. In this chapter, we explore the use of the CRISPR/Cas9 system for the efficient ablation of genes in two clinically relevant primary human cell types, CD4+ T cells and CD34+ hematopoietic stem and progenitor cells. By using two guide RNAs directed at a single locus, we achieve highly efficient and predictable deletions that ablate gene function. The use of a Cas9-2A-GFP fusion protein allows FACS-based enrichment of the transfected cells. The ease of designing, constructing, and testing guide RNAs makes this dual guide strategy an attractive approach for the efficient deletion of clinically relevant genes in primary human hematopoietic stem and effector cells and enables the use of CRISPR/Cas9 for gene therapy.

  11. Natural selection affects multiple aspects of genetic variation at putatively peutral sites across the human genome

    DEFF Research Database (Denmark)

    Lohmueller, Kirk E; Albrechtsen, Anders; Li, Yingrui

    2011-01-01

    A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries...... affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations....... these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination...

  12. Human Genome Editing and Ethical Considerations.

    Science.gov (United States)

    Krishan, Kewal; Kanchan, Tanuj; Singh, Bahadur

    2016-04-01

    Editing human germline genes may act as boon in some genetic and other disorders. Recent editing of the genome of the human embryo with the CRISPR/Cas9 editing tool generated a debate amongst top scientists of the world for the ethical considerations regarding its effect on the future generations. It needs to be seen as to what transformation human gene editing brings to humankind in the times to come.

  13. Genomic characterization of large heterochromatic gaps in the human genome assembly.

    Directory of Open Access Journals (Sweden)

    Nicolas Altemose

    2014-05-01

    Full Text Available The largest gaps in the human genome assembly correspond to multi-megabase heterochromatic regions composed primarily of two related families of tandem repeats, Human Satellites 2 and 3 (HSat2,3. The abundance of repetitive DNA in these regions challenges standard mapping and assembly algorithms, and as a result, the sequence composition and potential biological functions of these regions remain largely unexplored. Furthermore, existing genomic tools designed to predict consensus-based descriptions of repeat families cannot be readily applied to complex satellite repeats such as HSat2,3, which lack a consistent repeat unit reference sequence. Here we present an alignment-free method to characterize complex satellites using whole-genome shotgun read datasets. Utilizing this approach, we classify HSat2,3 sequences into fourteen subfamilies and predict their chromosomal distributions, resulting in a comprehensive satellite reference database to further enable genomic studies of heterochromatic regions. We also identify 1.3 Mb of non-repetitive sequence interspersed with HSat2,3 across 17 unmapped assembly scaffolds, including eight annotated gene predictions. Finally, we apply our satellite reference database to high-throughput sequence data from 396 males to estimate array size variation of the predominant HSat3 array on the Y chromosome, confirming that satellite array sizes can vary between individuals over an order of magnitude (7 to 98 Mb and further demonstrating that array sizes are distributed differently within distinct Y haplogroups. In summary, we present a novel framework for generating initial reference databases for unassembled genomic regions enriched with complex satellite DNA, and we further demonstrate the utility of these reference databases for studying patterns of sequence variation within human populations.

  14. Complex Loci in human and mouse genomes.

    Science.gov (United States)

    Engström, Pär G; Suzuki, Harukazu; Ninomiya, Noriko; Akalin, Altuna; Sessa, Luca; Lavorgna, Giovanni; Brozzi, Alessandro; Luzi, Lucilla; Tan, Sin Lam; Yang, Liang; Kunarso, Galih; Ng, Edwin Lian-Chong; Batalov, Serge; Wahlestedt, Claes; Kai, Chikatoshi; Kawai, Jun; Carninci, Piero; Hayashizaki, Yoshihide; Wells, Christine; Bajic, Vladimir B; Orlando, Valerio; Reid, James F; Lenhard, Boris; Lipovich, Leonard

    2006-04-01

    Mammalian genomes harbor a larger than expected number of complex loci, in which multiple genes are coupled by shared transcribed regions in antisense orientation and/or by bidirectional core promoters. To determine the incidence, functional significance, and evolutionary context of mammalian complex loci, we identified and characterized 5,248 cis-antisense pairs, 1,638 bidirectional promoters, and 1,153 chains of multiple cis-antisense and/or bidirectionally promoted pairs from 36,606 mouse transcriptional units (TUs), along with 6,141 cis-antisense pairs, 2,113 bidirectional promoters, and 1,480 chains from 42,887 human TUs. In both human and mouse, 25% of TUs resided in cis-antisense pairs, only 17% of which were conserved between the two organisms, indicating frequent species specificity of antisense gene arrangements. A sampling approach indicated that over 40% of all TUs might actually be in cis-antisense pairs, and that only a minority of these arrangements are likely to be conserved between human and mouse. Bidirectional promoters were characterized by variable transcriptional start sites and an identifiable midpoint at which overall sequence composition changed strand and the direction of transcriptional initiation switched. In microarray data covering a wide range of mouse tissues, genes in cis-antisense and bidirectionally promoted arrangement showed a higher probability of being coordinately expressed than random pairs of genes. In a case study on homeotic loci, we observed extensive transcription of nonconserved sequences on the noncoding strand, implying that the presence rather than the sequence of these transcripts is of functional importance. Complex loci are ubiquitous, host numerous nonconserved gene structures and lineage-specific exonification events, and may have a cis-regulatory impact on the member genes.

  15. Complex Loci in human and mouse genomes.

    Directory of Open Access Journals (Sweden)

    Pär G Engström

    2006-04-01

    Full Text Available Mammalian genomes harbor a larger than expected number of complex loci, in which multiple genes are coupled by shared transcribed regions in antisense orientation and/or by bidirectional core promoters. To determine the incidence, functional significance, and evolutionary context of mammalian complex loci, we identified and characterized 5,248 cis-antisense pairs, 1,638 bidirectional promoters, and 1,153 chains of multiple cis-antisense and/or bidirectionally promoted pairs from 36,606 mouse transcriptional units (TUs, along with 6,141 cis-antisense pairs, 2,113 bidirectional promoters, and 1,480 chains from 42,887 human TUs. In both human and mouse, 25% of TUs resided in cis-antisense pairs, only 17% of which were conserved between the two organisms, indicating frequent species specificity of antisense gene arrangements. A sampling approach indicated that over 40% of all TUs might actually be in cis-antisense pairs, and that only a minority of these arrangements are likely to be conserved between human and mouse. Bidirectional promoters were characterized by variable transcriptional start sites and an identifiable midpoint at which overall sequence composition changed strand and the direction of transcriptional initiation switched. In microarray data covering a wide range of mouse tissues, genes in cis-antisense and bidirectionally promoted arrangement showed a higher probability of being coordinately expressed than random pairs of genes. In a case study on homeotic loci, we observed extensive transcription of nonconserved sequences on the noncoding strand, implying that the presence rather than the sequence of these transcripts is of functional importance. Complex loci are ubiquitous, host numerous nonconserved gene structures and lineage-specific exonification events, and may have a cis-regulatory impact on the member genes.

  16. A new approach for using genome scans to detect recent positive selection in the human genome.

    Directory of Open Access Journals (Sweden)

    Kun Tang

    2007-07-01

    Full Text Available Genome-wide scanning for signals of recent positive selection is essential for a comprehensive and systematic understanding of human adaptation. Here, we present a genomic survey of recent local selective sweeps, especially aimed at those nearly or recently completed. A novel approach was developed for such signals, based on contrasting the extended haplotype homozygosity (EHH profiles between populations. We applied this method to the genome single nucleotide polymorphism (SNP data of both the International HapMap Project and Perlegen Sciences, and detected widespread signals of recent local selection across the genome, consisting of both complete and partial sweeps. A challenging problem of genomic scans of recent positive selection is to clearly distinguish selection from neutral effects, given the high sensitivity of the test statistics to departures from neutral demographic assumptions and the lack of a single, accurate neutral model of human history. We therefore developed a new procedure that is robust across a wide range of demographic and ascertainment models, one that indicates that certain portions of the genome clearly depart from neutrality. Simulations of positive selection showed that our tests have high power towards strong selection sweeps that have undergone fixation. Gene ontology analysis of the candidate regions revealed several new functional groups that might help explain some important interpopulation differences in phenotypic traits.

  17. Many human accelerated regions are developmental enhancers.

    Science.gov (United States)

    Capra, John A; Erwin, Genevieve D; McKinsey, Gabriel; Rubenstein, John L R; Pollard, Katherine S

    2013-12-19

    The genetic changes underlying the dramatic differences in form and function between humans and other primates are largely unknown, although it is clear that gene regulatory changes play an important role. To identify regulatory sequences with potentially human-specific functions, we and others used comparative genomics to find non-coding regions conserved across mammals that have acquired many sequence changes in humans since divergence from chimpanzees. These regions are good candidates for performing human-specific regulatory functions. Here, we analysed the DNA sequence, evolutionary history, histone modifications, chromatin state and transcription factor (TF) binding sites of a combined set of 2649 non-coding human accelerated regions (ncHARs) and predicted that at least 30% of them function as developmental enhancers. We prioritized the predicted ncHAR enhancers using analysis of TF binding site gain and loss, along with the functional annotations and expression patterns of nearby genes. We then tested both the human and chimpanzee sequence for 29 ncHARs in transgenic mice, and found 24 novel developmental enhancers active in both species, 17 of which had very consistent patterns of activity in specific embryonic tissues. Of these ncHAR enhancers, five drove expression patterns suggestive of different activity for the human and chimpanzee sequence at embryonic day 11.5. The changes to human non-coding DNA in these ncHAR enhancers may modify the complex patterns of gene expression necessary for proper development in a human-specific manner and are thus promising candidates for understanding the genetic basis of human-specific biology.

  18. Identification of Low-Confidence Regions in the Pig Reference Genome (Sscrofa10.2)

    Science.gov (United States)

    Warr, Amanda; Robert, Christelle; Hume, David; Archibald, Alan L.; Deeb, Nader; Watson, Mick

    2015-01-01

    Many applications of high throughput sequencing rely on the availability of an accurate reference genome. Variant calling often produces large data sets that cannot be realistically validated and which may contain large numbers of false-positives. Errors in the reference assembly increase the number of false-positives. While resources are available to aid in the filtering of variants from human data, for other species these do not yet exist and strict filtering techniques must be employed which are more likely to exclude true-positives. This work assesses the accuracy of the pig reference genome (Sscrofa10.2) using whole genome sequencing reads from the Duroc sow whose genome the assembly was based on. Indicators of structural variation including high regional coverage, unexpected insert sizes, improper pairing and homozygous variants were used to identify low quality (LQ) regions of the assembly. Low coverage (LC) regions were also identified and analyzed separately. The LQ regions covered 13.85% of the genome, the LC regions covered 26.6% of the genome and combined (LQLC) they covered 33.07% of the genome. Over half of dbSNP variants were located in the LQLC regions. Of copy number variable regions identified in a previous study, 86.3% were located in the LQLC regions. The regions were also enriched for gene predictions from RNA-seq data with 42.98% falling in the LQLC regions. Excluding variants in the LQ, LC, or LQLC from future analyses will help reduce the number of false-positive variant calls. Researchers using WGS data should be aware that the current pig reference genome does not give an accurate representation of the copy number of alleles in the original Duroc sow’s genome. PMID:26640477

  19. Identification of Low-Confidence Regions in the Pig Reference Genome (Sscrofa10.2).

    Science.gov (United States)

    Warr, Amanda; Robert, Christelle; Hume, David; Archibald, Alan L; Deeb, Nader; Watson, Mick

    2015-01-01

    Many applications of high throughput sequencing rely on the availability of an accurate reference genome. Variant calling often produces large data sets that cannot be realistically validated and which may contain large numbers of false-positives. Errors in the reference assembly increase the number of false-positives. While resources are available to aid in the filtering of variants from human data, for other species these do not yet exist and strict filtering techniques must be employed which are more likely to exclude true-positives. This work assesses the accuracy of the pig reference genome (Sscrofa10.2) using whole genome sequencing reads from the Duroc sow whose genome the assembly was based on. Indicators of structural variation including high regional coverage, unexpected insert sizes, improper pairing and homozygous variants were used to identify low quality (LQ) regions of the assembly. Low coverage (LC) regions were also identified and analyzed separately. The LQ regions covered 13.85% of the genome, the LC regions covered 26.6% of the genome and combined (LQLC) they covered 33.07% of the genome. Over half of dbSNP variants were located in the LQLC regions. Of copy number variable regions identified in a previous study, 86.3% were located in the LQLC regions. The regions were also enriched for gene predictions from RNA-seq data with 42.98% falling in the LQLC regions. Excluding variants in the LQ, LC, or LQLC from future analyses will help reduce the number of false-positive variant calls. Researchers using WGS data should be aware that the current pig reference genome does not give an accurate representation of the copy number of alleles in the original Duroc sow's genome.

  20. Implications of the Human Genome Project

    Energy Technology Data Exchange (ETDEWEB)

    Kitcher, P.

    1998-11-01

    The Human Genome Project (HGP), launched in 1991, aims to map and sequence the human genome by 2006. During the fifteen-year life of the project, it is projected that $3 billion in federal funds will be allocated to it. The ultimate aims of spending this money are to analyze the structure of human DNA, to identify all human genes, to recognize the functions of those genes, and to prepare for the biology and medicine of the twenty-first century. The following summary examines some of the implications of the program, concentrating on its scientific import and on the ethical and social problems that it raises. Its aim is to expose principles that might be used in applying the information which the HGP will generate. There is no attempt here to translate the principles into detailed proposals for legislation. Arguments and discussion can be found in the full report, but, like this summary, that report does not contain any legislative proposals.

  1. The zebrafish reference genome sequence and its relationship to the human genome.

    Science.gov (United States)

    Howe, Kerstin; Clark, Matthew D; Torroja, Carlos F; Torrance, James; Berthelot, Camille; Muffato, Matthieu; Collins, John E; Humphray, Sean; McLaren, Karen; Matthews, Lucy; McLaren, Stuart; Sealy, Ian; Caccamo, Mario; Churcher, Carol; Scott, Carol; Barrett, Jeffrey C; Koch, Romke; Rauch, Gerd-Jörg; White, Simon; Chow, William; Kilian, Britt; Quintais, Leonor T; Guerra-Assunção, José A; Zhou, Yi; Gu, Yong; Yen, Jennifer; Vogel, Jan-Hinnerk; Eyre, Tina; Redmond, Seth; Banerjee, Ruby; Chi, Jianxiang; Fu, Beiyuan; Langley, Elizabeth; Maguire, Sean F; Laird, Gavin K; Lloyd, David; Kenyon, Emma; Donaldson, Sarah; Sehra, Harminder; Almeida-King, Jeff; Loveland, Jane; Trevanion, Stephen; Jones, Matt; Quail, Mike; Willey, Dave; Hunt, Adrienne; Burton, John; Sims, Sarah; McLay, Kirsten; Plumb, Bob; Davis, Joy; Clee, Chris; Oliver, Karen; Clark, Richard; Riddle, Clare; Elliot, David; Eliott, David; Threadgold, Glen; Harden, Glenn; Ware, Darren; Begum, Sharmin; Mortimore, Beverley; Mortimer, Beverly; Kerry, Giselle; Heath, Paul; Phillimore, Benjamin; Tracey, Alan; Corby, Nicole; Dunn, Matthew; Johnson, Christopher; Wood, Jonathan; Clark, Susan; Pelan, Sarah; Griffiths, Guy; Smith, Michelle; Glithero, Rebecca; Howden, Philip; Barker, Nicholas; Lloyd, Christine; Stevens, Christopher; Harley, Joanna; Holt, Karen; Panagiotidis, Georgios; Lovell, Jamieson; Beasley, Helen; Henderson, Carl; Gordon, Daria; Auger, Katherine; Wright, Deborah; Collins, Joanna; Raisen, Claire; Dyer, Lauren; Leung, Kenric; Robertson, Lauren; Ambridge, Kirsty; Leongamornlert, Daniel; McGuire, Sarah; Gilderthorp, Ruth; Griffiths, Coline; Manthravadi, Deepa; Nichol, Sarah; Barker, Gary; Whitehead, Siobhan; Kay, Michael; Brown, Jacqueline; Murnane, Clare; Gray, Emma; Humphries, Matthew; Sycamore, Neil; Barker, Darren; Saunders, David; Wallis, Justene; Babbage, Anne; Hammond, Sian; Mashreghi-Mohammadi, Maryam; Barr, Lucy; Martin, Sancha; Wray, Paul; Ellington, Andrew; Matthews, Nicholas; Ellwood, Matthew; Woodmansey, Rebecca; Clark, Graham; Cooper, James D; Cooper, James; Tromans, Anthony; Grafham, Darren; Skuce, Carl; Pandian, Richard; Andrews, Robert; Harrison, Elliot; Kimberley, Andrew; Garnett, Jane; Fosker, Nigel; Hall, Rebekah; Garner, Patrick; Kelly, Daniel; Bird, Christine; Palmer, Sophie; Gehring, Ines; Berger, Andrea; Dooley, Christopher M; Ersan-Ürün, Zübeyde; Eser, Cigdem; Geiger, Horst; Geisler, Maria; Karotki, Lena; Kirn, Anette; Konantz, Judith; Konantz, Martina; Oberländer, Martina; Rudolph-Geiger, Silke; Teucke, Mathias; Lanz, Christa; Raddatz, Günter; Osoegawa, Kazutoyo; Zhu, Baoli; Rapp, Amanda; Widaa, Sara; Langford, Cordelia; Yang, Fengtang; Schuster, Stephan C; Carter, Nigel P; Harrow, Jennifer; Ning, Zemin; Herrero, Javier; Searle, Steve M J; Enright, Anton; Geisler, Robert; Plasterk, Ronald H A; Lee, Charles; Westerfield, Monte; de Jong, Pieter J; Zon, Leonard I; Postlethwait, John H; Nüsslein-Volhard, Christiane; Hubbard, Tim J P; Roest Crollius, Hugues; Rogers, Jane; Stemple, Derek L

    2013-04-25

    Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.

  2. The zebrafish reference genome sequence and its relationship to the human genome

    Science.gov (United States)

    Howe, Kerstin; Clark, Matthew D.; Torroja, Carlos F.; Torrance, James; Berthelot, Camille; Muffato, Matthieu; Collins, John E.; Humphray, Sean; McLaren, Karen; Matthews, Lucy; McLaren, Stuart; Sealy, Ian; Caccamo, Mario; Churcher, Carol; Scott, Carol; Barrett, Jeffrey C.; Koch, Romke; Rauch, Gerd-Jörg; White, Simon; Chow, William; Kilian, Britt; Quintais, Leonor T.; Guerra-Assunção, José A.; Zhou, Yi; Gu, Yong; Yen, Jennifer; Vogel, Jan-Hinnerk; Eyre, Tina; Redmond, Seth; Banerjee, Ruby; Chi, Jianxiang; Fu, Beiyuan; Langley, Elizabeth; Maguire, Sean F.; Laird, Gavin K.; Lloyd, David; Kenyon, Emma; Donaldson, Sarah; Sehra, Harminder; Almeida-King, Jeff; Loveland, Jane; Trevanion, Stephen; Jones, Matt; Quail, Mike; Willey, Dave; Hunt, Adrienne; Burton, John; Sims, Sarah; McLay, Kirsten; Plumb, Bob; Davis, Joy; Clee, Chris; Oliver, Karen; Clark, Richard; Riddle, Clare; Eliott, David; Threadgold, Glen; Harden, Glenn; Ware, Darren; Mortimer, Beverly; Kerry, Giselle; Heath, Paul; Phillimore, Benjamin; Tracey, Alan; Corby, Nicole; Dunn, Matthew; Johnson, Christopher; Wood, Jonathan; Clark, Susan; Pelan, Sarah; Griffiths, Guy; Smith, Michelle; Glithero, Rebecca; Howden, Philip; Barker, Nicholas; Stevens, Christopher; Harley, Joanna; Holt, Karen; Panagiotidis, Georgios; Lovell, Jamieson; Beasley, Helen; Henderson, Carl; Gordon, Daria; Auger, Katherine; Wright, Deborah; Collins, Joanna; Raisen, Claire; Dyer, Lauren; Leung, Kenric; Robertson, Lauren; Ambridge, Kirsty; Leongamornlert, Daniel; McGuire, Sarah; Gilderthorp, Ruth; Griffiths, Coline; Manthravadi, Deepa; Nichol, Sarah; Barker, Gary; Whitehead, Siobhan; Kay, Michael; Brown, Jacqueline; Murnane, Clare; Gray, Emma; Humphries, Matthew; Sycamore, Neil; Barker, Darren; Saunders, David; Wallis, Justene; Babbage, Anne; Hammond, Sian; Mashreghi-Mohammadi, Maryam; Barr, Lucy; Martin, Sancha; Wray, Paul; Ellington, Andrew; Matthews, Nicholas; Ellwood, Matthew; Woodmansey, Rebecca; Clark, Graham; Cooper, James; Tromans, Anthony; Grafham, Darren; Skuce, Carl; Pandian, Richard; Andrews, Robert; Harrison, Elliot; Kimberley, Andrew; Garnett, Jane; Fosker, Nigel; Hall, Rebekah; Garner, Patrick; Kelly, Daniel; Bird, Christine; Palmer, Sophie; Gehring, Ines; Berger, Andrea; Dooley, Christopher M.; Ersan-Ürün, Zübeyde; Eser, Cigdem; Geiger, Horst; Geisler, Maria; Karotki, Lena; Kirn, Anette; Konantz, Judith; Konantz, Martina; Oberländer, Martina; Rudolph-Geiger, Silke; Teucke, Mathias; Osoegawa, Kazutoyo; Zhu, Baoli; Rapp, Amanda; Widaa, Sara; Langford, Cordelia; Yang, Fengtang; Carter, Nigel P.; Harrow, Jennifer; Ning, Zemin; Herrero, Javier; Searle, Steve M. J.; Enright, Anton; Geisler, Robert; Plasterk, Ronald H. A.; Lee, Charles; Westerfield, Monte; de Jong, Pieter J.; Zon, Leonard I.; Postlethwait, John H.; Nüsslein-Volhard, Christiane; Hubbard, Tim J. P.; Crollius, Hugues Roest; Rogers, Jane; Stemple, Derek L.

    2013-01-01

    Zebrafish have become a popular organism for the study of vertebrate gene function1,2. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease3–5. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes6, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination. PMID:23594743

  3. The Human Genome Project and Biology Education.

    Science.gov (United States)

    McInerney, Joseph D.

    1996-01-01

    Highlights the importance of the Human Genome Project in educating the public about genetics. Discusses four challenges that science educators must address: teaching for conceptual understanding, the nature of science, the personal and social impact of science and technology, and the principles of technology. Contains 45 references. (JRH)

  4. Genomics of the human carnitine acyltransferase genes

    NARCIS (Netherlands)

    van der Leij, FR; Huijkman, NCA; Boomsma, C; Kuipers, JRG; Bartelds, B

    2000-01-01

    Five genes in the human genome are known to encode different active forms of related carnitine acyltransferases: CPT1A for liver-type carnitine palmitoyltransferase I, CPT1B for muscle-type carnitine palmitoyltransferase I, CPT2 for carnitine palmitoyltransferase II, CROT for carnitine octanoyltrans

  5. Patentering af det humane genom

    DEFF Research Database (Denmark)

    Sommer, Tine

    2004-01-01

    Direktiv 98/44/EF om retlig beskyttelse af bioteknologiske opfindelser blev gennemført i dansk ret med ikrafttrædelse den 30. juli 2000. Direktivet indeholder i artikel 5 en central bestemmelse som giver adgang til patent på humane gener. I artikel 5, stk. 3, er indføjet et skærpet krav til...

  6. Chromatin structure and evolution in the human genome

    Directory of Open Access Journals (Sweden)

    Dunlop Malcolm G

    2007-05-01

    Full Text Available Abstract Background Evolutionary rates are not constant across the human genome but genes in close proximity have been shown to experience similar levels of divergence and selection. The higher-order organisation of chromosomes has often been invoked to explain such phenomena but previously there has been insufficient data on chromosome structure to investigate this rigorously. Using the results of a recent genome-wide analysis of open and closed human chromatin structures we have investigated the global association between divergence, selection and chromatin structure for the first time. Results In this study we have shown that, paradoxically, synonymous site divergence (dS at non-CpG sites is highest in regions of open chromatin, primarily as a result of an increased number of transitions, while the rates of other traditional measures of mutation (intergenic, intronic and ancient repeat divergence as well as SNP density are highest in closed regions of the genome. Analysis of human-chimpanzee divergence across intron-exon boundaries indicates that although genes in relatively open chromatin generally display little selection at their synonymous sites, those in closed regions show markedly lower divergence at their fourfold degenerate sites than in neighbouring introns and intergenic regions. Exclusion of known Exonic Splice Enhancer hexamers has little affect on the divergence observed at fourfold degenerate sites across chromatin categories; however, we show that closed chromatin is enriched with certain classes of ncRNA genes whose RNA secondary structure may be particularly important. Conclusion We conclude that, overall, non-CpG mutation rates are lowest in open regions of the genome and that regions of the genome with a closed chromatin structure have the highest background mutation rate. This might reflect lower rates of DNA damage or enhanced DNA repair processes in regions of open chromatin. Our results also indicate that dS is a poor

  7. The transcriptionally active regions in the genome of Bacillus subtilis

    DEFF Research Database (Denmark)

    Rasmussen, Simon; Nielsen, Henrik Bjørn; Jarmer, Hanne Østergaard

    2009-01-01

    The majority of all genes have so far been identified and annotated systematically through in silico gene finding. Here we report the finding of 3662 strand-specific transcriptionally active regions (TARs) in the genome of Bacillus subtilis by the use of tiling arrays. We have measured the genome...

  8. Combining two technologies for full genome sequencing of human.

    Science.gov (United States)

    Skryabin, K G; Prokhortchouk, E B; Mazur, A M; Boulygina, E S; Tsygankova, S V; Nedoluzhko, A V; Rastorguev, S M; Matveev, V B; Chekanov, N N; D A, Goranskaya; Teslyuk, A B; Gruzdeva, N M; Velikhov, V E; Zaridze, D G; Kovalchuk, M V

    2009-10-01

    At present, the new technologies of DNA sequencing are rapidly developing allowing quick and efficient characterisation of organisms at the level of the genome structure. In this study, the whole genome sequencing of a human (Russian man) was performed using two technologies currently present on the market - Sequencing by Oligonucleotide Ligation and Detection (SOLiD™) (Applied Biosystems) and sequencing technologies of molecular clusters using fluorescently labeled precursors (Illumina). The total number of generated data resulted in 108.3 billion base pairs (60.2 billion from Illumina technology and 48.1 billion from SOLiD technology). Statistics performed on reads generated by GAII and SOLiD showed that they covered 75% and 96% of the genome respectively. Short polymorphic regions were detected with comparable accuracy however, the absolute amount of them revealed by SOLiD was several times less than by GAII. Optimal algorithm for using the latest methods of sequencing was established for the analysis of individual human genomes. The study is the first Russian effort towards whole human genome sequencing.

  9. Viral symbiosis and the holobiontic nature of the human genome.

    Science.gov (United States)

    Ryan, Francis Patrick

    2016-01-01

    The human genome is a holobiontic union of the mammalian nuclear genome, the mitochondrial genome and large numbers of endogenized retroviral genomes. This article defines and explores this symbiogenetic pattern of evolution, looking at the implications for human genetics, epigenetics, embryogenesis, physiology and the pathogenesis of inborn errors of metabolism and many other diseases.

  10. Genome-Wide Associations of Gene Expression Variation in Humans.

    Directory of Open Access Journals (Sweden)

    2005-12-01

    Full Text Available The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis- to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.

  11. Genome-wide associations of gene expression variation in humans.

    Directory of Open Access Journals (Sweden)

    Barbara E Stranger

    2005-12-01

    Full Text Available The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis- to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.

  12. Identification of low-confidence regions in the pig reference genome (Sscrofa10.2

    Directory of Open Access Journals (Sweden)

    Amanda eWarr

    2015-11-01

    Full Text Available Many applications of high throughput sequencing rely on the availability of an accurate reference genome. Variant calling often produces large data sets that cannot be realistically validated and which may contain large numbers of false-positives. Errors in the reference assembly increase the number of false-positives. While resources are available to aid in the filtering of variants from human data, for other species these do not yet exist and strict filtering techniques must be employed which are more likely to exclude true-positives. This work assesses the accuracy of the pig reference genome (Sscrofa10.2 using whole genome sequencing reads from the Duroc sow whose genome the assembly was based on. Indicators of structural variation including high regional coverage, unexpected insert sizes, improper pairing and homozygous variants were used to identify low quality (LQ regions of the assembly. Low coverage (LC regions were also identified and analyzed separately. The LQ regions covered 13.85% of the genome, the LC regions covered 26.6% of the genome and combined (LQLC they covered 33.07% of the genome. Over half of dbSNP variants were located in the LQLC regions. Of CNVRs identified in a previous study, 86.3% were located in the LQLC regions. The regions were also enriched for gene predictions from RNA-seq data with 42.98% falling in the LQLC regions. Excluding variants in the LQ, LC or LQLC from future analyses will help reduce the number of false-positive variant calls. Researchers using WGS data should be aware that the current pig reference genome does not give an accurate representation of the copy number of alleles in the original Duroc sow’s genome.

  13. Helminth genomics: The implications for human health.

    Directory of Open Access Journals (Sweden)

    Paul J Brindley

    Full Text Available More than two billion people (one-third of humanity are infected with parasitic roundworms or flatworms, collectively known as helminth parasites. These infections cause diseases that are responsible for enormous levels of morbidity and mortality, delays in the physical development of children, loss of productivity among the workforce, and maintenance of poverty. Genomes of the major helminth species that affect humans, and many others of agricultural and veterinary significance, are now the subject of intensive genome sequencing and annotation. Draft genome sequences of the filarial worm Brugia malayi and two of the human schistosomes, Schistosoma japonicum and S. mansoni, are now available, among others. These genome data will provide the basis for a comprehensive understanding of the molecular mechanisms involved in helminth nutrition and metabolism, host-dependent development and maturation, immune evasion, and evolution. They are likely also to predict new potential vaccine candidates and drug targets. In this review, we present an overview of these efforts and emphasize the potential impact and importance of these new findings.

  14. Genomic correlates of atherosclerosis in ancient humans.

    Science.gov (United States)

    Zink, Albert; Wann, L Samuel; Thompson, Randall C; Keller, Andreas; Maixner, Frank; Allam, Adel H; Finch, Caleb E; Frohlich, Bruno; Kaplan, Hillard; Lombardi, Guido P; Sutherland, M Linda; Sutherland, James D; Watson, Lucia; Cox, Samantha L; Miyamoto, Michael I; Narula, Jagat; Stewart, Alexandre F R; Thomas, Gregory S; Krause, Johannes

    2014-06-01

    Paleogenetics offers a unique opportunity to study human evolution, population dynamics, and disease evolution in situ. Although histologic and computed x-ray tomographic investigations of ancient mummies have clearly shown that atherosclerosis has been present in humans for more than 5,000 years, limited data are available on the presence of genetic predisposition for cardiovascular disease in ancient human populations. In a previous whole-genome study of the Tyrolean Iceman, a 5,300-year-old glacier mummy from the Alps, an increased risk for coronary heart disease was detected. The Iceman's genome revealed several single nucleotide polymorphisms that are linked with cardiovascular disease in genome-wide association studies. Future genetic studies of ancient humans from various geographic origins and time periods have the potential to provide more insights into the presence and possible changes of genetic risk factors in our ancestors. The study of ancient humans and a better understanding of the interaction between environmental and genetic influences on the development of heart diseases may lead to a more effective prevention and treatment of the most common cause of death in the modern world.

  15. RNA-guided human genome engineering via Cas9

    National Research Council Canada - National Science Library

    Mali, Prashant; Yang, Luhan; Esvelt, Kevin M; Aach, John; Guell, Marc; DiCarlo, James E; Norville, Julie E; Church, George M

    2013-01-01

    .... We also compute a genome-wide resource of ~190 K unique gRNAs targeting ~40.5% of human exons. Our results establish an RNA-guided editing tool for facile, robust, and multiplexable human genome engineering.

  16. The human genome project and the future of medical practice ...

    African Journals Online (AJOL)

    The human genome project and the future of medical practice. ... the planning stages of the human genome project, the technology and sequence data ... the quality of healthcare available in the resource-rich and the resource-poor countries.

  17. Does selection against transcriptional interference shape retroelement-free regions in mammalian genomes?

    Directory of Open Access Journals (Sweden)

    Tobias Mourier

    Full Text Available BACKGROUND: Eukaryotic genomes are scattered with retroelements that proliferate through retrotransposition. Although retroelements make up around 40 percent of the human genome, large regions are found to be completely devoid of retroelements. This has been hypothesised to be a result of genomic regions being intolerant to insertions of retroelements. The inadvertent transcriptional activity of retroelements may affect neighbouring genes, which in turn could be detrimental to an organism. We speculate that such retroelement transcription, or transcriptional interference, is a contributing factor in generating and maintaining retroelement-free regions in the human genome. METHODOLOGY/PRINCIPAL FINDINGS: Based on the known transcriptional properties of retroelements, we expect long interspersed elements (LINEs to be able to display a high degree of transcriptional interference. In contrast, we expect short interspersed elements (SINEs to display very low levels of transcriptional interference. We find that genomic regions devoid of long interspersed elements (LINEs are enriched for protein-coding genes, but that this is not the case for regions devoid of short interspersed elements (SINEs. This is expected if genes are subject to selection against transcriptional interference. We do not find microRNAs to be associated with genomic regions devoid of either SINEs or LINEs. We further observe an increased relative activity of genes overlapping LINE-free regions during early embryogenesis, where activity of LINEs has been identified previously. CONCLUSIONS/SIGNIFICANCE: Our observations are consistent with the notion that selection against transcriptional interference has contributed to the maintenance and/or generation of retroelement-free regions in the human genome.

  18. ENGINES: exploring single nucleotide variation in entire human genomes

    Directory of Open Access Journals (Sweden)

    Salas Antonio

    2011-04-01

    Full Text Available Abstract Background Next generation ultra-sequencing technologies are starting to produce extensive quantities of data from entire human genome or exome sequences, and therefore new software is needed to present and analyse this vast amount of information. The 1000 Genomes project has recently released raw data for 629 complete genomes representing several human populations through their Phase I interim analysis and, although there are certain public tools available that allow exploration of these genomes, to date there is no tool that permits comprehensive population analysis of the variation catalogued by such data. Description We have developed a genetic variant site explorer able to retrieve data for Single Nucleotide Variation (SNVs, population by population, from entire genomes without compromising future scalability and agility. ENGINES (ENtire Genome INterface for Exploring SNVs uses data from the 1000 Genomes Phase I to demonstrate its capacity to handle large amounts of genetic variation (>7.3 billion genotypes and 28 million SNVs, as well as deriving summary statistics of interest for medical and population genetics applications. The whole dataset is pre-processed and summarized into a data mart accessible through a web interface. The query system allows the combination and comparison of each available population sample, while searching by rs-number list, chromosome region, or genes of interest. Frequency and FST filters are available to further refine queries, while results can be visually compared with other large-scale Single Nucleotide Polymorphism (SNP repositories such as HapMap or Perlegen. Conclusions ENGINES is capable of accessing large-scale variation data repositories in a fast and comprehensive manner. It allows quick browsing of whole genome variation, while providing statistical information for each variant site such as allele frequency, heterozygosity or FST values for genetic differentiation. Access to the data mart

  19. About human genome Acerca del genoma humano

    Directory of Open Access Journals (Sweden)

    Mojica Tobias

    2000-12-01

    Full Text Available The sequence ofthe human genome, an undertaking ofadvanced countries, is nearly complete. In fact The Human Genome Project has around 85% ofthe genome sequenced 4 times on the average, with an accuracy of roughly 1 in 1000 nucleotides. Celera Genomics, on the other hand, has 99% of the sequence of one person, with an accuracy of slightly less than 1 in 100. The Human Genome project trives to produce a physical map for public consumption following a step by step strategy, in which the researcher sequences short DNA fragments belonging to Iarger fragments of known relative
    position. Celera Genomics wants to have very rapidly a physical map which can be quickly used to develop genetic tests and drugs, which can be later sold. We feel that the sequence ofthe human genome is something, which will widen the gap between advanced and backward countries.En este artículo se revisan los eventos, alrededor del secuenciamiento del genoma humano, que han llevado a tanta excitación en los medios noticiosos y académicos en meses recientes. Se explican las estrategias que han llevado a que tengamos dos borradores diferentes pero complementarios, la estrategia llevada a cabo con el dinero
    de los contribuyentes que consiste en establecer el orden de fragmentos grandes de DNA antes de ser secuenciados y la estrategia llevada a cabo con dineros aportados por la industria privada, con la intención de explotar gananciosamente el conocimiento derivado del genoma humano. El genoma humano a mediados del año 2000 es
    un borrador incompleto que cubre aliededor del 85% de la secuencia con una precisión de un error en 1000 y el 99% de la secuencia con una precisión menor de 1 en 100 nucleótidos, También se discuten algunas de las posibles avenidas

  20. Contrast features of CpG islands in the promoter and other regions in the dog genome.

    Science.gov (United States)

    Han, Leng; Zhao, Zhongming

    2009-08-01

    The recent release of the domestic dog genome provides us with an ideal opportunity to investigate dog-specific genomic features. In this study, we performed a systematic analysis of CpG islands (CGIs), which are often considered gene markers, in the dog genome. Relative to the human and mouse genomes, the dog genome has a remarkably large number of CGIs and high CGI density, which is contributed by its noncoding sequences. Surprisingly, the dog genome has fewer CGIs associated with the promoter regions of genes than the human or the mouse. Further examination of functional features of dog-human-mouse homologous genes suggests that the dog might have undergone a faster erosion rate of promoter-associated CGIs than the human or mouse. Some genetic or genomic factors such as local recombination rate and karyotype may be related to the unique dog CGI features.

  1. [Mapping and human genome sequence program].

    Science.gov (United States)

    Weissenbach, J

    1997-03-01

    Until recently, human genome programs focused primarily on establishing maps that would provide signposts to researchers seeking to identify genes responsible for inherited diseases, as well as a basis for genome sequencing studies. Preestablished gene mapping goals have been reached. The over 7,000 microsatellite markers identified to date provide a map of sufficient density to allow localization of the gene of a monogenic disease with a precision of 1 to 2 million base pairs. The physical map, based on systematically arranged overlapping sets of artificial yeast chromosomes (YACs), has also made considerable headway during the last few years. The most recently published map covers more than 90% of the genome. However, currently available physical maps cannot be used for sequencing studies because multiple rearrangements occur in YACs. The recently developed sets of radioinduced hybrids are extremely useful for incorporating genes into existing maps. A network of American and European laboratories has successfully used these radioinduced hybrids to map 15,000 gene tags from large-scale cDNA library sequencing programs. There are increasingly pressing reasons for initiating large scale human genome sequencing studies.

  2. High-density rhesus macaque oligonucleotide microarray design using early-stage rhesus genome sequence information and human genome annotations

    Directory of Open Access Journals (Sweden)

    Magness Charles L

    2007-01-01

    Full Text Available Abstract Background Until recently, few genomic reagents specific for non-human primate research have been available. To address this need, we have constructed a macaque-specific high-density oligonucleotide microarray by using highly fragmented low-pass sequence contigs from the rhesus genome project together with the detailed sequence and exon structure of the human genome. Using this method, we designed oligonucleotide probes to over 17,000 distinct rhesus/human gene orthologs and increased by four-fold the number of available genes relative to our first-generation expressed sequence tag (EST-derived array. Results We constructed a database containing 248,000 exon sequences from 23,000 human RefSeq genes and compared each human exon with its best matching sequence in the January 2005 version of the rhesus genome project list of 486,000 DNA contigs. Best matching rhesus exon sequences for each of the 23,000 human genes were then concatenated in the proper order and orientation to produce a rhesus "virtual transcriptome." Microarray probes were designed, one per gene, to the region closest to the 3' untranslated region (UTR of each rhesus virtual transcript. Each probe was compared to a composite rhesus/human transcript database to test for cross-hybridization potential yielding a final probe set representing 18,296 rhesus/human gene orthologs, including transcript variants, and over 17,000 distinct genes. We hybridized mRNA from rhesus brain and spleen to both the EST- and genome-derived microarrays. Besides four-fold greater gene coverage, the genome-derived array also showed greater mean signal intensities for genes present on both arrays. Genome-derived probes showed 99.4% identity when compared to 4,767 rhesus GenBank sequence tag site (STS sequences indicating that early stage low-pass versions of complex genomes are of sufficient quality to yield valuable functional genomic information when combined with finished genome information from

  3. Sequence space coverage, entropy of genomes and the potential to detect non-human DNA in human samples

    Directory of Open Access Journals (Sweden)

    Maley Carlo C

    2008-10-01

    Full Text Available Abstract Background Genomes store information for building and maintaining organisms. Complete sequencing of many genomes provides the opportunity to study and compare global information properties of those genomes. Results We have analyzed aspects of the information content of Homo sapiens, Mus musculus, Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana, Saccharomyces cerevisiae, and Escherichia coli (K-12 genomes. Virtually all possible (> 98% 12 bp oligomers appear in vertebrate genomes while 98% to D. melanogaster (12–17 bp, C. elegans (11–17 bp, A. thaliana (11–17 bp, S. cerevisiae (10–16 bp and E. coli (9–15 bp. Frequencies of unique oligomers in the genomes follow similar patterns. We identified a set of 2.6 M 15-mers that are more than 1 nucleotide different from all 15-mers in the human genome and so could be used as probes to detect microbes in human samples. In a human sample, these probes would detect 100% of the 433 currently fully sequenced prokaryotes and 75% of the 3065 fully sequenced viruses. The human genome is significantly more compact in sequence space than a random genome. We identified the most frequent 5- to 20-mers in the human genome, which may prove useful as PCR primers. We also identified a bacterium, Anaeromyxobacter dehalogenans, which has an exceptionally low diversity of oligomers given the size of its genome and its GC content. The entropy of coding regions in the human genome is significantly higher than non-coding regions and chromosomes. However chromosomes 1, 2, 9, 12 and 14 have a relatively high proportion of coding DNA without high entropy, and chromosome 20 is the opposite with a low frequency of coding regions but relatively high entropy. Conclusion Measures of the frequency of oligomers are useful for designing PCR assays and for identifying chromosomes and organisms with hidden structure that had not been previously recognized. This information may be used to detect

  4. Population-specific recombination sites within the human MHC region

    OpenAIRE

    2013-01-01

    Genetic rearrangement by recombination is one of the major driving forces for genome evolution, and recombination is known to occur in non-random, discreet recombination sites within the genome. Mapping of recombination sites has proved to be difficult, particularly, in the human MHC region that is complicated by both population variation and highly polymorphic HLA genes. To overcome these problems, HLA-typed individuals from three representative populations: Asian, European an...

  5. A novel statistical method to estimate the effective SNP size in vertebrate genomes and categorized genomic regions

    Directory of Open Access Journals (Sweden)

    Zhao Zhongming

    2006-12-01

    Full Text Available Abstract Background The local environment of single nucleotide polymorphisms (SNPs contains abundant genetic information for the study of mechanisms of mutation, genome evolution, and causes of diseases. Recent studies revealed that neighboring-nucleotide biases on SNPs were strong and the genome-wide bias patterns could be represented by a small subset of the total SNPs. It remains unsolved for the estimation of the effective SNP size, the number of SNPs that are sufficient to represent the bias patterns observed from the whole SNP data. Results To estimate the effective SNP size, we developed a novel statistical method, SNPKS, which considers both the statistical and biological significances. SNPKS consists of two major steps: to obtain an initial effective size by the Kolmogorov-Smirnov test (KS test and to find an intermediate effective size by interval evaluation. The SNPKS algorithm was implemented in computer programs and applied to the real SNP data. The effective SNP size was estimated to be 38,200, 39,300, 38,000, and 38,700 in the human, chimpanzee, dog, and mouse genomes, respectively, and 39,100, 39,600, 39,200, and 42,200 in human intergenic, genic, intronic, and CpG island regions, respectively. Conclusion SNPKS is the first statistical method to estimate the effective SNP size. It runs efficiently and greatly outperforms the algorithm implemented in SNPNB. The application of SNPKS to the real SNP data revealed the similar small effective SNP size (38,000 – 42,200 in the human, chimpanzee, dog, and mouse genomes as well as in human genomic regions. The findings suggest strong influence of genetic factors across vertebrate genomes.

  6. Genomic shotgun array: a procedure linking large-scale DNA sequencing with regional transcript mapping.

    Science.gov (United States)

    Li, Ling-Hui; Li, Jian-Chiuan; Lin, Yung-Feng; Lin, Chung-Yen; Chen, Chung-Yung; Tsai, Shih-Feng

    2004-02-11

    To facilitate transcript mapping and to investigate alterations in genomic structure and gene expression in a defined genomic target, we developed a novel microarray-based method to detect transcriptional activity of the human chromosome 4q22-24 region. Loss of heterozygosity of human 4q22-24 is frequently observed in hepatocellular carcinoma (HCC). One hundred and eighteen well-characterized genes have been identified from this region. We took previously sequenced shotgun subclones as templates to amplify overlapping sequences for the genomic segment and constructed a chromosome-region-specific microarray. Using genomic DNA fragments as probes, we detected transcriptional activity from within this region among five different tissues. The hybridization results indicate that there are new transcripts that have not yet been identified by other methods. The existence of new transcripts encoded by genes in this region was confirmed by PCR cloning or cDNA library screening. The procedure reported here allows coupling of shotgun sequencing with transcript mapping and, potentially, detailed analysis of gene expression and chromosomal copy of the genomic sequence for the putative HCC tumor suppressor gene(s) in the 4q candidate region.

  7. 76 FR 58023 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2011-09-19

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Initial Review Group; Genome Research Review... Review, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892,...

  8. 76 FR 28056 - National Human Genome Research Institute; Notice of Closed Meetings

    Science.gov (United States)

    2011-05-13

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Initial Review Group, Genome Research Review... Scientific Review, National Human Genome Research Institute, National Institutes of Health, Bethesda,...

  9. 77 FR 61770 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2012-10-11

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel; Genomic Medicine RFAs..., Human Genome Research, National Institutes of Health, HHS) ] Dated: October 4, 2012. David...

  10. 77 FR 28888 - National Human Genome Research Institute Notice of Closed Meeting

    Science.gov (United States)

    2012-05-16

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute Notice of Closed... of Committee: National Human Genome Research Institute Initial Review Group; Genome Research Review... applications. Place: National Human Genome Research Institute, 3635 Fishers Lane, Suite 4076, ] Rockville,...

  11. De novo assembly of a haplotype-resolved human genome.

    Science.gov (United States)

    Cao, Hongzhi; Wu, Honglong; Luo, Ruibang; Huang, Shujia; Sun, Yuhui; Tong, Xin; Xie, Yinlong; Liu, Binghang; Yang, Hailong; Zheng, Hancheng; Li, Jian; Li, Bo; Wang, Yu; Yang, Fang; Sun, Peng; Liu, Siyang; Gao, Peng; Huang, Haodong; Sun, Jing; Chen, Dan; He, Guangzhu; Huang, Weihua; Huang, Zheng; Li, Yue; Tellier, Laurent C A M; Liu, Xiao; Feng, Qiang; Xu, Xun; Zhang, Xiuqing; Bolund, Lars; Krogh, Anders; Kristiansen, Karsten; Drmanac, Radoje; Drmanac, Snezana; Nielsen, Rasmus; Li, Songgang; Wang, Jian; Yang, Huanming; Li, Yingrui; Wong, Gane Ka-Shu; Wang, Jun

    2015-06-01

    The human genome is diploid, and knowledge of the variants on each chromosome is important for the interpretation of genomic information. Here we report the assembly of a haplotype-resolved diploid genome without using a reference genome. Our pipeline relies on fosmid pooling together with whole-genome shotgun strategies, based solely on next-generation sequencing and hierarchical assembly methods. We applied our sequencing method to the genome of an Asian individual and generated a 5.15-Gb assembled genome with a haplotype N50 of 484 kb. Our analysis identified previously undetected indels and 7.49 Mb of novel coding sequences that could not be aligned to the human reference genome, which include at least six predicted genes. This haplotype-resolved genome represents the most complete de novo human genome assembly to date. Application of our approach to identify individual haplotype differences should aid in translating genotypes to phenotypes for the development of personalized medicine.

  12. De novo assembly of a haplotype-resolved human genome

    DEFF Research Database (Denmark)

    Cao, Hongzhi; Wu, Honglong; Luo, Ruibang

    2015-01-01

    The human genome is diploid, and knowledge of the variants on each chromosome is important for the interpretation of genomic information. Here we report the assembly of a haplotype-resolved diploid genome without using a reference genome. Our pipeline relies on fosmid pooling together with whole-genome...... of novel coding sequences that could not be aligned to the human reference genome, which include at least six predicted genes. This haplotype-resolved genome represents the most complete de novo human genome assembly to date. Application of our approach to identify individual haplotype differences should...... shotgun strategies, based solely on next-generation sequencing and hierarchical assembly methods. We applied our sequencing method to the genome of an Asian individual and generated a 5.15-Gb assembled genome with a haplotype N50 of 484 kb. Our analysis identified previously undetected indels and 7.49 Mb...

  13. Genome-wide analysis of regions similar to promoters of histone genes

    KAUST Repository

    Chowdhary, Rajesh

    2010-05-28

    Background: The purpose of this study is to: i) develop a computational model of promoters of human histone-encoding genes (shortly histone genes), an important class of genes that participate in various critical cellular processes, ii) use the model so developed to identify regions across the human genome that have similar structure as promoters of histone genes; such regions could represent potential genomic regulatory regions, e.g. promoters, of genes that may be coregulated with histone genes, and iii/ identify in this way genes that have high likelihood of being coregulated with the histone genes.Results: We successfully developed a histone promoter model using a comprehensive collection of histone genes. Based on leave-one-out cross-validation test, the model produced good prediction accuracy (94.1% sensitivity, 92.6% specificity, and 92.8% positive predictive value). We used this model to predict across the genome a number of genes that shared similar promoter structures with the histone gene promoters. We thus hypothesize that these predicted genes could be coregulated with histone genes. This hypothesis matches well with the available gene expression, gene ontology, and pathways data. Jointly with promoters of the above-mentioned genes, we found a large number of intergenic regions with similar structure as histone promoters.Conclusions: This study represents one of the most comprehensive computational analyses conducted thus far on a genome-wide scale of promoters of human histone genes. Our analysis suggests a number of other human genes that share a high similarity of promoter structure with the histone genes and thus are highly likely to be coregulated, and consequently coexpressed, with the histone genes. We also found that there are a large number of intergenic regions across the genome with their structures similar to promoters of histone genes. These regions may be promoters of yet unidentified genes, or may represent remote control regions that

  14. Positive selection on the human genome.

    Science.gov (United States)

    Vallender, Eric J; Lahn, Bruce T

    2004-10-01

    Positive selection has undoubtedly played a critical role in the evolution of Homo sapiens. Of the many phenotypic traits that define our species--notably the enormous brain, advanced cognitive abilities, complex vocal organs, bipedalism and opposable thumbs--most (if not all) are likely the product of strong positive selection. Many other aspects of human biology not necessarily related to the 'branding' of our species, such as host-pathogen interactions, reproduction, dietary adaptation and physical appearance, have also been the substrate of varying levels of positive selection. Comparative genetics/genomics studies in recent years have uncovered a growing list of genes that might have experienced positive selection during the evolution of human and/or primates. These genes offer valuable inroads into understanding the biological processes specific to humans, and the evolutionary forces that gave rise to them. Here, we present a comprehensive review of these genes, and their implications for human evolution.

  15. Structured RNAs and synteny regions in the pig genome

    DEFF Research Database (Denmark)

    Anthon, Christian; Tafer, Hakim; Havgaard, Jakob Hull;

    2014-01-01

    for Laurasiatheria (pig, cow, dolphin, horse, cat, dog, hedgehog). CONCLUSIONS: We have obtained one of the most comprehensive annotations for structured ncRNAs of a mammalian genome, which is likely to play central roles in both health modelling and production. The core annotation is available in Ensembl 70......BACKGROUND: Annotating mammalian genomes for noncoding RNAs (ncRNAs) is nontrivial since far from all ncRNAs are known and the computational models are resource demanding. Currently, the human genome holds the best mammalian ncRNA annotation, a result of numerous efforts by several groups. However...

  16. Report on the Human Genome Initiative

    Energy Technology Data Exchange (ETDEWEB)

    Tinoco, I.; Cahill, G.; Cantor, C.; Caskey, T.; Dulbecco, R.; Engelhardt, D. L.; Hood, L.; Lerman, L. S.; Mendelsohn, M. L.; Sinsheimer, R. L.; Smith, T.; Soll, D.; Stormo, G.; White, R. L.

    1987-04-01

    The report urges DOE and the Nation to commit to a large. multi-year. multidisciplinary. technological undertaking to order and sequence the human genome. This effort will first require significant innovation in general capability to manipulate DNA. major new analytical methods for ordering and sequencing. theoretical developments in computer science and mathematical biology, and great expansions in our ability to store and manipulate the information and to interface it with other large and diverse genetic databases. The actual ordering and sequencing involves the coordinated processing of some 3 billion bases from a reference human genome. Science is poised on the rudimentary edge of being able to read and understand human genes. A concerted. broadly based. scientific effort to provide new methods of sufficient power and scale should transform this activity from an inefficient one-gene-at-a-time. single laboratory effort into a coordinated. worldwide. comprehensive reading of "the book of man". The effort will be extraordinary in scope and magnitude. but so will be the benefit to biological understanding. new technology and the diagnosis and treatment of human disease.

  17. ECRbase: Database of Evolutionary Conserved Regions, Promoters, and Transcription Factor Binding Sites in Vertebrate Genomes

    Energy Technology Data Exchange (ETDEWEB)

    Loots, G; Ovcharenko, I

    2006-08-08

    Evolutionary conservation of DNA sequences provides a tool for the identification of functional elements in genomes. We have created a database of evolutionary conserved regions (ECRs) in vertebrate genomes entitled ECRbase that is constructed from a collection of pairwise vertebrate genome alignments produced by the ECR Browser database. ECRbase features a database of syntenic blocks that recapitulate the evolution of rearrangements in vertebrates and a collection of promoters in all vertebrate genomes presented in the database. The database also contains a collection of annotated transcription factor binding sites (TFBS) in all ECRs and promoter elements. ECRbase currently includes human, rhesus macaque, dog, opossum, rat, mouse, chicken, frog, zebrafish, and two pufferfish genomes. It is freely accessible at http://ECRbase.dcode.org.

  18. Bioinformatics Assisted Gene Discovery and Annotation of Human Genome

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    As the sequencing stage of human genome project is near the end, the work has begun for discovering novel genes from genome sequences and annotating their biological functions. Here are reviewed current major bioinformatics tools and technologies available for large scale gene discovery and annotation from human genome sequences. Some ideas about possible future development are also provided.

  19. LD-Spline: Mapping SNPs on genotyping platforms to genomic regions using patterns of linkage disequilibrium

    Directory of Open Access Journals (Sweden)

    Bush William S

    2009-12-01

    Full Text Available Abstract Background Gene-centric analysis tools for genome-wide association study data are being developed both to annotate single locus statistics and to prioritize or group single nucleotide polymorphisms (SNPs prior to analysis. These approaches require knowledge about the relationships between SNPs on a genotyping platform and genes in the human genome. SNPs in the genome can represent broader genomic regions via linkage disequilibrium (LD, and population-specific patterns of LD can be exploited to generate a data-driven map of SNPs to genes. Methods In this study, we implemented LD-Spline, a database routine that defines the genomic boundaries a particular SNP represents using linkage disequilibrium statistics from the International HapMap Project. We compared the LD-Spline haplotype block partitioning approach to that of the four gamete rule and the Gabriel et al. approach using simulated data; in addition, we processed two commonly used genome-wide association study platforms. Results We illustrate that LD-Spline performs comparably to the four-gamete rule and the Gabriel et al. approach; however as a SNP-centric approach LD-Spline has the added benefit of systematically identifying a genomic boundary for each SNP, where the global block partitioning approaches may falter due to sampling variation in LD statistics. Conclusion LD-Spline is an integrated database routine that quickly and effectively defines the genomic region marked by a SNP using linkage disequilibrium, with a SNP-centric block definition algorithm.

  20. Complete genome sequence of human astrovirus genotype 6

    Directory of Open Access Journals (Sweden)

    Vernet Guy

    2010-02-01

    Full Text Available Abstract Background Human astroviruses (HAstVs are one of the important causes of acute gastroenteritis in children. Currently, eight HAstV genotypes have been identified and all but two (HAstV-6 and HAstV-7 have been fully sequenced. We here sequenced and analyzed the complete genome of a HAstV-6 strain (192-BJ07, which was identified in Beijing, China. Results The genome of 192-BJ07 consists of 6745 nucleotides. The 192-BJ07 strain displays a 77.2-78.0% nucleotide sequence identity with other HAstV genotypes and exhibits amino acid sequence identities of 86.5-87.4%, 94.2-95.1%, and 65.5-74.8% in the ORF1a, ORF1b, and ORF2 regions, respectively. Homological analysis of ORF2 shows that 192-BJ07 is 96.3% identical to the documented HAstV-6 strain. Further, phylogenetic analysis indicates that different genomic regions are likely undergoing different evolutionary and selective pressures. No recombination event was observed in HAstV-6 in this study. Conclusion The completely sequenced and characterized genome of HAstV-6 (192-BJ07 provides further insight into the genetics of astroviruses and aids in the surveillance and control of HAstV gastroenteritis.

  1. Human genome libraries. Final progress report, February 1, 1994--August 31, 1997

    Energy Technology Data Exchange (ETDEWEB)

    Kao, Fa-Ten

    1998-01-01

    The goal of this program is to use a novel technology of chromosome microdissection and microcloning to construct chromosome region-specific libraries as resources for various human genome program studies. Region specific libraries have been constructed for the entire human chromosomes 2 and 18.

  2. [Human genomic project and human genomic haplotype map project: opportunitiy, challenge and strategy in stomatology].

    Science.gov (United States)

    Wu, Rui-qing; Zeng, Xin; Wang, Zhi

    2010-08-01

    The human genomic project and the international HapMap project were designed to create a genome-wide database of patterns of human genetic variation, with the expectation that these patterns would be useful for genetic association studies of common diseases, thus lead to molecular diagnosis and personnel therapy. The article briefly reviewed the creation, target and achievement of those two projects. Furthermore, the authors have given four suggestions in facing to the opportunities and challenges brought by the two projects, including cultivation improvement of elites, cross binding of multi-subjects, strengthening construction of research base and initiation of natural key scientific project.

  3. Natural selection and the distribution of identity-by-descent in the human genome

    DEFF Research Database (Denmark)

    Albrechtsen, Anders; Moltke, Ida; Nielsen, Rasmus

    2010-01-01

    There has recently been considerable interest in detecting natural selection in the human genome. Selection will usually tend to increase identity-by-descent (IBD) among individuals in a population, and many methods for detecting recent and ongoing positive selection indirectly take advantage......, we use a recently developed method for identifying IBD sharing among individuals from genome-wide data to scan populations from the new HapMap phase 3 project for regions with excess IBD sharing in order to identify regions in the human genome that have been under strong, very recent selection....... The HLA region is by far the region showing the most extreme signal, suggesting that much of the strong recent selection acting on the human genome has been immune related and acting on HLA loci. As equilibrium overdominance does not tend to increase IBD, we argue that this type of selection cannot...

  4. Sequencing and annotated analysis of an Estonian human genome.

    Science.gov (United States)

    Lilleoja, Rutt; Sarapik, Aili; Reimann, Ene; Reemann, Paula; Jaakma, Ülle; Vasar, Eero; Kõks, Sulev

    2012-02-01

    In present study we describe the sequencing and annotated analysis of the individual genome of Estonian. Using SOLID technology we generated 2,449,441,916 of 50-bp reads. The Bioscope version 1.3 was used for mapping and pairing of reads to the NCBI human genome reference (build 36, hg18). Bioscope enables also the annotation of the results of variant (tertiary) analysis. The average mapping of reads was 75.5% with total coverage of 107.72 Gb. resulting in mean fold coverage of 34.6. We found 3,482,975 SNPs out of which 352,492 were novel. 21,222 SNPs were in coding region: 10,649 were synonymous SNPs, 10,360 were nonsynonymous missense SNPs, 155 were nonsynonymous nonsense SNPs and 58 were nonsynonymous frameshifts. We identified 219 CNVs with total base pair coverage of 37,326,300 bp and 87,451 large insertion/deletion polymorphisms covering 10,152,256 bp of the genome. In addition, we found 285,864 small size insertion/deletion polymorphisms out of which 133,969 were novel. Finally, we identified 53 inversions, 19 overlapped genes and 2 overlapped exons. Interestingly, we found the region in chromosome 6 to be enriched with the coding SNPs and CNVs. This study confirms previous findings, that our genomes are more complex and variable as thought before. Therefore, sequencing of the personal genomes followed by annotation would improve the analysis of heritability of phenotypes and our understandings on the functions of genome.

  5. Understanding the Human Genome Project -- A Fact Sheet

    Science.gov (United States)

    ... that contribute to human disease. In 1953, James Watson and Francis Crick described the double helix structure ... of sequencing whole exomes or genomes, groundbreaking comparative genomic studies are now identifiying the causes of rare ...

  6. Genic regions of a large salamander genome contain long introns and novel genes

    Directory of Open Access Journals (Sweden)

    Bryant Susan V

    2009-01-01

    Full Text Available Abstract Background The basis of genome size variation remains an outstanding question because DNA sequence data are lacking for organisms with large genomes. Sixteen BAC clones from the Mexican axolotl (Ambystoma mexicanum: c-value = 32 × 109 bp were isolated and sequenced to characterize the structure of genic regions. Results Annotation of genes within BACs showed that axolotl introns are on average 10× longer than orthologous vertebrate introns and they are predicted to contain more functional elements, including miRNAs and snoRNAs. Loci were discovered within BACs for two novel EST transcripts that are differentially expressed during spinal cord regeneration and skin metamorphosis. Unexpectedly, a third novel gene was also discovered while manually annotating BACs. Analysis of human-axolotl protein-coding sequences suggests there are 2% more lineage specific genes in the axolotl genome than the human genome, but the great majority (86% of genes between axolotl and human are predicted to be 1:1 orthologs. Considering that axolotl genes are on average 5× larger than human genes, the genic component of the salamander genome is estimated to be incredibly large, approximately 2.8 gigabases! Conclusion This study shows that a large salamander genome has a correspondingly large genic component, primarily because genes have incredibly long introns. These intronic sequences may harbor novel coding and non-coding sequences that regulate biological processes that are unique to salamanders.

  7. Genomic characterization of echovirus 6 causing aseptic meningitis in Hokkaido, Japan: a novel cluster in the nonstructural protein coding region of human enterovirus B.

    Science.gov (United States)

    Miyoshi, Masahiro; Komagome, Rika; Ishida, Setsuko; Nagano, Hideki; Takahashi, Kenichi; Okano, Motohiko

    2013-04-01

    We determined four complete nucleotide sequences of echovirus 6 (E6) isolated from an epidemic of aseptic meningitis (AM) in Hokkaido, Japan, in 2011. Phylogenetic analysis of the genes encoding viral capsid protein 1 revealed that the strains were closely related to E6 strains isolated in China in recent years, but they were distantly related to E6 strains isolated from patients with AM in Osaka Prefecture, Japan, in 2011. The genes encoding the viral protease and RNA-dependent RNA polymerase (3CD) were closely related to those of several non-E6 strains of the species Human enterovirus B isolated in China, South Korea, and Australia from 1999 to 2010, resulting in a novel cluster in the phylogenetic tree. These results suggest that the incidence of AM in Japan in 2011 was caused by at least two lineages of E6 strains, and a lineage of the 3CD gene was interspersed among different serotypic strains isolated in Western Pacific countries.

  8. Personal and population genomics of human regulatory variation.

    Science.gov (United States)

    Vernot, Benjamin; Stergachis, Andrew B; Maurano, Matthew T; Vierstra, Jeff; Neph, Shane; Thurman, Robert E; Stamatoyannopoulos, John A; Akey, Joshua M

    2012-09-01

    The characteristics and evolutionary forces acting on regulatory variation in humans remains elusive because of the difficulty in defining functionally important noncoding DNA. Here, we combine genome-scale maps of regulatory DNA marked by DNase I hypersensitive sites (DHSs) from 138 cell and tissue types with whole-genome sequences of 53 geographically diverse individuals in order to better delimit the patterns of regulatory variation in humans. We estimate that individuals likely harbor many more functionally important variants in regulatory DNA compared with protein-coding regions, although they are likely to have, on average, smaller effect sizes. Moreover, we demonstrate that there is significant heterogeneity in the level of functional constraint in regulatory DNA among different cell types. We also find marked variability in functional constraint among transcription factor motifs in regulatory DNA, with sequence motifs for major developmental regulators, such as HOX proteins, exhibiting levels of constraint comparable to protein-coding regions. Finally, we perform a genome-wide scan of recent positive selection and identify hundreds of novel substrates of adaptive regulatory evolution that are enriched for biologically interesting pathways such as melanogenesis and adipocytokine signaling. These data and results provide new insights into patterns of regulatory variation in individuals and populations and demonstrate that a large proportion of functionally important variation lies beyond the exome.

  9. Microsatellite interruptions stabilize primate genomes and exist as population-specific single nucleotide polymorphisms within individual human genomes.

    Science.gov (United States)

    Ananda, Guruprasad; Hile, Suzanne E; Breski, Amanda; Wang, Yanli; Kelkar, Yogeshwar; Makova, Kateryna D; Eckert, Kristin A

    2014-07-01

    Interruptions of microsatellite sequences impact genome evolution and can alter disease manifestation. However, human polymorphism levels at interrupted microsatellites (iMSs) are not known at a genome-wide scale, and the pathways for gaining interruptions are poorly understood. Using the 1000 Genomes Phase-1 variant call set, we interrogated mono-, di-, tri-, and tetranucleotide repeats up to 10 units in length. We detected ∼26,000-40,000 iMSs within each of four human population groups (African, European, East Asian, and American). We identified population-specific iMSs within exonic regions, and discovered that known disease-associated iMSs contain alleles present at differing frequencies among the populations. By analyzing longer microsatellites in primate genomes, we demonstrate that single interruptions result in a genome-wide average two- to six-fold reduction in microsatellite mutability, as compared with perfect microsatellites. Centrally located interruptions lowered mutability dramatically, by two to three orders of magnitude. Using a biochemical approach, we tested directly whether the mutability of a specific iMS is lower because of decreased DNA polymerase strand slippage errors. Modeling the adenomatous polyposis coli tumor suppressor gene sequence, we observed that a single base substitution interruption reduced strand slippage error rates five- to 50-fold, relative to a perfect repeat, during synthesis by DNA polymerases α, β, or η. Computationally, we demonstrate that iMSs arise primarily by base substitution mutations within individual human genomes. Our biochemical survey of human DNA polymerase α, β, δ, κ, and η error rates within certain microsatellites suggests that interruptions are created most frequently by low fidelity polymerases. Our combined computational and biochemical results demonstrate that iMSs are abundant in human genomes and are sources of population-specific genetic variation that may affect genome stability. The

  10. Origins of the Human Genome Project

    Energy Technology Data Exchange (ETDEWEB)

    Cook-Deegan, Robert

    1993-07-01

    The human genome project was borne of technology, grew into a science bureaucracy in the US and throughout the world, and is now being transformed into a hybrid academic and commercial enterprise. The next phase of the project promises to veer more sharply toward commercial application, harnessing both the technical prowess of molecular biology and the rapidly growing body of knowledge about DNA structure to the pursuit of practical benefits. Faith that the systematic analysis of DNA structure will prove to be a powerful research tool underlies the rationale behind the genome project. The notion that most genetic information is embedded in the sequence of CNA base pairs comprising chromosomes is a central tenet. A rough analogy is to liken an organism's genetic code to computer code. The coal of the genome project, in this parlance, is to identify and catalog 75,000 or more files (genes) in the software that directs construction of a self-modifying and self-replicating system -- a living organism.

  11. Origins of the Human Genome Project

    Science.gov (United States)

    Cook-Deegan, Robert (Affiliation: Institute of Medicine, National Academy of Sciences)

    1993-07-01

    The human genome project was borne of technology, grew into a science bureaucracy in the United States and throughout the world, and is now being transformed into a hybrid academic and commercial enterprise. The next phase of the project promises to veer more sharply toward commercial application, harnessing both the technical prowess of molecular biology and the rapidly growing body of knowledge about DNA structure to the pursuit of practical benefits. Faith that the systematic analysis of DNA structure will prove to be a powerful research tool underlies the rationale behind the genome project. The notion that most genetic information is embedded in the sequence of CNA base pairs comprising chromosomes is a central tenet. A rough analogy is to liken an organism's genetic code to computer code. The coal of the genome project, in this parlance, is to identify and catalog 75,000 or more files (genes) in the software that directs construction of a self-modifying and self-replicating system -- a living organism.

  12. Report of the second Human Genome Diversity workshop

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1992-12-31

    The Second Human Genome Diversity Workshop was successfully held at Penn State University from October 29--31, 1992. The Workshop was essentially organized around 7 groups, each comprising approximately 10 participants, representing the sampling issues in different regions of the world. These groups worked independently, using a common format provided by the organizers; this was adjusted as needed by the individual groups. The Workshop began with a presentation of the mandate to the participants, and of the procedures to be followed during the workshop. Dr. Feldman presented a summary of the results from the First Workshop. He and the other organizers also presented brief comments giving their perspective on the objectives of the Second Workshop. Dr. Julia Bodmer discussed the study of European genetic diversity, especially in the context of the HLA experience there, and of plans to extend such studies in the coming years. She also discussed surveys of world HLA laboratories in regard to resources related to Human Genome Diversity. Dr. Mark Weiss discussed the relevance of nonhuman primate studies for understanding how demographic processes, such as mate exchange between local groups, affected the local dispersion of genetic variation. Primate population geneticists have some relevant experience in interpreting variation at this local level, in particular, with various DNA fingerprinting methods. This experience may be relevant to the Human Genome Diversity Project, in terms of practical and statistical issues.

  13. Harnessing genomics to improve health in the Eastern Mediterranean Region - an executive course in genomics policy.

    Science.gov (United States)

    Acharya, Tara; Rab, Mohammed Abdur; Singer, Peter A; Daar, Abdallah S

    2005-01-21

    BACKGROUND: While innovations in medicine, science and technology have resulted in improved health and quality of life for many people, the benefits of modern medicine continue to elude millions of people in many parts of the world. To assess the potential of genomics to address health needs in EMR, the World Health Organization's Eastern Mediterranean Regional Office and the University of Toronto Joint Centre for Bioethics jointly organized a Genomics and Public Health Policy Executive Course, held September 20th-23rd, 2003, in Muscat, Oman. The 4-day course was sponsored by WHO-EMRO with additional support from the Canadian Program in Genomics and Global Health. The overall objective of the course was to collectively explore how to best harness genomics to improve health in the region. This article presents the course findings and recommendations for genomics policy in EMR. METHODS: The course brought together senior representatives from academia, biotechnology companies, regulatory bodies, media, voluntary, and legal organizations to engage in discussion. Topics covered included scientific advances in genomics, followed by innovations in business models, public sector perspectives, ethics, legal issues and national innovation systems. RESULTS: A set of recommendations, summarized below, was formulated for the Regional Office, the Member States and for individuals.* Advocacy for genomics and biotechnology for political leadership;* Networking between member states to share information, expertise, training, and regional cooperation in biotechnology; coordination of national surveys for assessment of health biotechnology innovation systems, science capacity, government policies, legislation and regulations, intellectual property policies, private sector activity;* Creation in each member country of an effective National Body on genomics, biotechnology and health to:- formulate national biotechnology strategies- raise biotechnology awareness- encourage teaching and

  14. Exuberant innovation: The Human Genome Project

    CERN Document Server

    Gisler, Monika; Woodard, Ryan

    2010-01-01

    We present a detailed synthesis of the development of the Human Genome Project (HGP) from 1986 to 2003 in order to test the "social bubble" hypothesis that strong social interactions between enthusiastic supporters of the HGP weaved a network of reinforcing feedbacks that led to a widespread endorsement and extraordinary commitment by those involved in the project, beyond what would be rationalized by a standard cost-benefit analysis in the presence of extraordinary uncertainties and risks. The vigorous competition and race between the initially public project and several private initiatives is argued to support the social bubble hypothesis. We also present quantitative analyses of the concomitant financial bubble concentrated on the biotech sector. Confirmation of this hypothesis is offered by the present consensus that it will take decades to exploit the fruits of the HGP, via a slow and arduous process aiming at disentangling the extraordinary complexity of the human complex body. The HGP has ushered other...

  15. The PCNA pseudogenes in the human genome

    Directory of Open Access Journals (Sweden)

    Stoimenov Ivaylo

    2012-02-01

    Full Text Available Abstract Background The proliferating cell nuclear antigen (PCNA is a key protein in the eukaryotic DNA replication and cell proliferation. Following the cloning and characterisation of the human PCNA gene, the question of the existence of pseudogenes in the human genome was raised. Findings In this short communication we summarise the existing information about the PCNA pseudogenes and critically assess their status. Conclusions We propose the existence of at least four valid PCNA pseudogenes, PCNAP1, PCNAP2, LOC392454 and LOC390102. We would like to recommend assignment of a name for LOC392454 as "proliferating cell nuclear antigen pseudogene 3" (alias PCNAP3 and a name for LOC390102 as "proliferating cell nuclear antigen pseudogene 4" (alias PCNAP4. We prompt for more critical evaluation of the existence of a PCNA pseudogene, designated as PCNAP.

  16. Comparative genomics of emerging human ehrlichiosis agents.

    Directory of Open Access Journals (Sweden)

    Julie C Dunning Hotopp

    2006-02-01

    Full Text Available Anaplasma (formerly Ehrlichia phagocytophilum, Ehrlichia chaffeensis, and Neorickettsia (formerly Ehrlichia sennetsu are intracellular vector-borne pathogens that cause human ehrlichiosis, an emerging infectious disease. We present the complete genome sequences of these organisms along with comparisons to other organisms in the Rickettsiales order. Ehrlichia spp. and Anaplasma spp. display a unique large expansion of immunodominant outer membrane proteins facilitating antigenic variation. All Rickettsiales have a diminished ability to synthesize amino acids compared to their closest free-living relatives. Unlike members of the Rickettsiaceae family, these pathogenic Anaplasmataceae are capable of making all major vitamins, cofactors, and nucleotides, which could confer a beneficial role in the invertebrate vector or the vertebrate host. Further analysis identified proteins potentially involved in vacuole confinement of the Anaplasmataceae, a life cycle involving a hematophagous vector, vertebrate pathogenesis, human pathogenesis, and lack of transovarial transmission. These discoveries provide significant insights into the biology of these obligate intracellular pathogens.

  17. Genomic Regions Affecting Cheese Making Properties Identified in Danish Holsteins

    DEFF Research Database (Denmark)

    Gregersen, Vivi Raundahl; Bertelsen, Henriette Pasgaard; Poulsen, Nina Aagaard

    The cheese renneting process is affected by a number of factors associated to milk composition and a number of Danish Holsteins has previously been identified to have poor milk coagulation ability. Therefore, the aim of this study was to identify genomic regions affecting the technological...

  18. Genomic Regions Affecting Cheese Making Properties Identified in Danish Holsteins

    DEFF Research Database (Denmark)

    Gregersen, Vivi Raundahl; Bertelsen, Henriette Pasgaard; Poulsen, Nina Aagaard

    The cheese renneting process is affected by a number of factors associated to milk composition and a number of Danish Holsteins has previously been identified to have poor milk coagulation ability. Therefore, the aim of this study was to identify genomic regions affecting the technological...

  19. The Human Genome Initiative of the Department of Energy

    Science.gov (United States)

    1988-01-01

    The structural characterization of genes and elucidation of their encoded functions have become a cornerstone of modern health research, biology and biotechnology. A genome program is an organized effort to locate and identify the functions of all the genes of an organism. Beginning with the DOE-sponsored, 1986 human genome workshop at Santa Fe, the value of broadly organized efforts supporting total genome characterization became a subject of intensive study. There is now national recognition that benefits will rapidly accrue from an effective scientific infrastructure for total genome research. In the US genome research is now receiving dedicated funds. Several other nations are implementing genome programs. Supportive infrastructure is being improved through both national and international cooperation. The Human Genome Initiative of the Department of Energy (DOE) is a focused program of Resource and Technology Development, with objectives of speeding and bringing economies to the national human genome effort. This report relates the origins and progress of the Initiative.

  20. The Human Genome Initiative of the Department of Energy

    Energy Technology Data Exchange (ETDEWEB)

    None

    1988-01-01

    The structural characterization of genes and elucidation of their encoded functions have become a cornerstone of modern health research, biology and biotechnology. A genome program is an organized effort to locate and identify the functions of all the genes of an organism. Beginning with the DOE-sponsored, 1986 human genome workshop at Santa Fe, the value of broadly organized efforts supporting total genome characterization became a subject of intensive study. There is now national recognition that benefits will rapidly accrue from an effective scientific infrastructure for total genome research. In the US genome research is now receiving dedicated funds. Several other nations are implementing genome programs. Supportive infrastructure is being improved through both national and international cooperation. The Human Genome Initiative of the Department of Energy (DOE) is a focused program of Resource and Technology Development, with objectives of speeding and bringing economies to the national human genome effort. This report relates the origins and progress of the Initiative. 34 refs.

  1. Global genomic diversity of human papillomavirus 6 based on 724 isolates and 190 complete genome sequences.

    Science.gov (United States)

    Jelen, Mateja M; Chen, Zigui; Kocjan, Boštjan J; Burt, Felicity J; Chan, Paul K S; Chouhy, Diego; Combrinck, Catharina E; Coutlée, François; Estrade, Christine; Ferenczy, Alex; Fiander, Alison; Franco, Eduardo L; Garland, Suzanne M; Giri, Adriana A; González, Joaquín Víctor; Gröning, Arndt; Heidrich, Kerstin; Hibbitts, Sam; Hošnjak, Lea; Luk, Tommy N M; Marinic, Karina; Matsukura, Toshihiko; Neumann, Anna; Oštrbenk, Anja; Picconi, Maria Alejandra; Richardson, Harriet; Sagadin, Martin; Sahli, Roland; Seedat, Riaz Y; Seme, Katja; Severini, Alberto; Sinchi, Jessica L; Smahelova, Jana; Tabrizi, Sepehr N; Tachezy, Ruth; Tohme, Sarah; Uloza, Virgilijus; Vitkauskiene, Astra; Wong, Yong Wee; Zidovec Lepej, Snježana; Burk, Robert D; Poljak, Mario

    2014-07-01

    Human papillomavirus type 6 (HPV6) is the major etiological agent of anogenital warts and laryngeal papillomas and has been included in both the quadrivalent and nonavalent prophylactic HPV vaccines. This study investigated the global genomic diversity of HPV6, using 724 isolates and 190 complete genomes from six continents, and the association of HPV6 genomic variants with geographical location, anatomical site of infection/disease, and gender. Initially, a 2,800-bp E5a-E5b-L1-LCR fragment was sequenced from 492/530 (92.8%) HPV6-positive samples collected for this study. Among them, 130 exhibited at least one single nucleotide polymorphism (SNP), indel, or amino acid change in the E5a-E5b-L1-LCR fragment and were sequenced in full. A global alignment and maximum likelihood tree of 190 complete HPV6 genomes (130 fully sequenced in this study and 60 obtained from sequence repositories) revealed two variant lineages, A and B, and five B sublineages: B1, B2, B3, B4, and B5. HPV6 (sub)lineage-specific SNPs and a 960-bp representative region for whole-genome-based phylogenetic clustering within the L2 open reading frame were identified. Multivariate logistic regression analysis revealed that lineage B predominated globally. Sublineage B3 was more common in Africa and North and South America, and lineage A was more common in Asia. Sublineages B1 and B3 were associated with anogenital infections, indicating a potential lesion-specific predilection of some HPV6 sublineages. Females had higher odds for infection with sublineage B3 than males. In conclusion, a global HPV6 phylogenetic analysis revealed the existence of two variant lineages and five sublineages, showing some degree of ethnogeographic, gender, and/or disease predilection in their distribution. This study established the largest database of globally circulating HPV6 genomic variants and contributed a total of 130 new, complete HPV6 genome sequences to available sequence repositories. Two HPV6 variant lineages

  2. Segmenting the human genome based on states of neutral genetic divergence.

    Science.gov (United States)

    Kuruppumullage Don, Prabhani; Ananda, Guruprasad; Chiaromonte, Francesca; Makova, Kateryna D

    2013-09-03

    Many studies have demonstrated that divergence levels generated by different mutation types vary and covary across the human genome. To improve our still-incomplete understanding of the mechanistic basis of this phenomenon, we analyze several mutation types simultaneously, anchoring their variation to specific regions of the genome. Using hidden Markov models on insertion, deletion, nucleotide substitution, and microsatellite divergence estimates inferred from human-orangutan alignments of neutrally evolving genomic sequences, we segment the human genome into regions corresponding to different divergence states--each uniquely characterized by specific combinations of divergence levels. We then parsed the mutagenic contributions of various biochemical processes associating divergence states with a broad range of genomic landscape features. We find that high divergence states inhabit guanine- and cytosine (GC)-rich, highly recombining subtelomeric regions; low divergence states cover inner parts of autosomes; chromosome X forms its own state with lowest divergence; and a state of elevated microsatellite mutability is interspersed across the genome. These general trends are mirrored in human diversity data from the 1000 Genomes Project, and departures from them highlight the evolutionary history of primate chromosomes. We also find that genes and noncoding functional marks [annotations from the Encyclopedia of DNA Elements (ENCODE)] are concentrated in high divergence states. Our results provide a powerful tool for biomedical data analysis: segmentations can be used to screen personal genome variants--including those associated with cancer and other diseases--and to improve computational predictions of noncoding functional elements.

  3. Initial sequencing and analysis of the human genome.

    Science.gov (United States)

    Lander, E S; Linton, L M; Birren, B; Nusbaum, C; Zody, M C; Baldwin, J; Devon, K; Dewar, K; Doyle, M; FitzHugh, W; Funke, R; Gage, D; Harris, K; Heaford, A; Howland, J; Kann, L; Lehoczky, J; LeVine, R; McEwan, P; McKernan, K; Meldrim, J; Mesirov, J P; Miranda, C; Morris, W; Naylor, J; Raymond, C; Rosetti, M; Santos, R; Sheridan, A; Sougnez, C; Stange-Thomann, Y; Stojanovic, N; Subramanian, A; Wyman, D; Rogers, J; Sulston, J; Ainscough, R; Beck, S; Bentley, D; Burton, J; Clee, C; Carter, N; Coulson, A; Deadman, R; Deloukas, P; Dunham, A; Dunham, I; Durbin, R; French, L; Grafham, D; Gregory, S; Hubbard, T; Humphray, S; Hunt, A; Jones, M; Lloyd, C; McMurray, A; Matthews, L; Mercer, S; Milne, S; Mullikin, J C; Mungall, A; Plumb, R; Ross, M; Shownkeen, R; Sims, S; Waterston, R H; Wilson, R K; Hillier, L W; McPherson, J D; Marra, M A; Mardis, E R; Fulton, L A; Chinwalla, A T; Pepin, K H; Gish, W R; Chissoe, S L; Wendl, M C; Delehaunty, K D; Miner, T L; Delehaunty, A; Kramer, J B; Cook, L L; Fulton, R S; Johnson, D L; Minx, P J; Clifton, S W; Hawkins, T; Branscomb, E; Predki, P; Richardson, P; Wenning, S; Slezak, T; Doggett, N; Cheng, J F; Olsen, A; Lucas, S; Elkin, C; Uberbacher, E; Frazier, M; Gibbs, R A; Muzny, D M; Scherer, S E; Bouck, J B; Sodergren, E J; Worley, K C; Rives, C M; Gorrell, J H; Metzker, M L; Naylor, S L; Kucherlapati, R S; Nelson, D L; Weinstock, G M; Sakaki, Y; Fujiyama, A; Hattori, M; Yada, T; Toyoda, A; Itoh, T; Kawagoe, C; Watanabe, H; Totoki, Y; Taylor, T; Weissenbach, J; Heilig, R; Saurin, W; Artiguenave, F; Brottier, P; Bruls, T; Pelletier, E; Robert, C; Wincker, P; Smith, D R; Doucette-Stamm, L; Rubenfield, M; Weinstock, K; Lee, H M; Dubois, J; Rosenthal, A; Platzer, M; Nyakatura, G; Taudien, S; Rump, A; Yang, H; Yu, J; Wang, J; Huang, G; Gu, J; Hood, L; Rowen, L; Madan, A; Qin, S; Davis, R W; Federspiel, N A; Abola, A P; Proctor, M J; Myers, R M; Schmutz, J; Dickson, M; Grimwood, J; Cox, D R; Olson, M V; Kaul, R; Raymond, C; Shimizu, N; Kawasaki, K; Minoshima, S; Evans, G A; Athanasiou, M; Schultz, R; Roe, B A; Chen, F; Pan, H; Ramser, J; Lehrach, H; Reinhardt, R; McCombie, W R; de la Bastide, M; Dedhia, N; Blöcker, H; Hornischer, K; Nordsiek, G; Agarwala, R; Aravind, L; Bailey, J A; Bateman, A; Batzoglou, S; Birney, E; Bork, P; Brown, D G; Burge, C B; Cerutti, L; Chen, H C; Church, D; Clamp, M; Copley, R R; Doerks, T; Eddy, S R; Eichler, E E; Furey, T S; Galagan, J; Gilbert, J G; Harmon, C; Hayashizaki, Y; Haussler, D; Hermjakob, H; Hokamp, K; Jang, W; Johnson, L S; Jones, T A; Kasif, S; Kaspryzk, A; Kennedy, S; Kent, W J; Kitts, P; Koonin, E V; Korf, I; Kulp, D; Lancet, D; Lowe, T M; McLysaght, A; Mikkelsen, T; Moran, J V; Mulder, N; Pollara, V J; Ponting, C P; Schuler, G; Schultz, J; Slater, G; Smit, A F; Stupka, E; Szustakowki, J; Thierry-Mieg, D; Thierry-Mieg, J; Wagner, L; Wallis, J; Wheeler, R; Williams, A; Wolf, Y I; Wolfe, K H; Yang, S P; Yeh, R F; Collins, F; Guyer, M S; Peterson, J; Felsenfeld, A; Wetterstrand, K A; Patrinos, A; Morgan, M J; de Jong, P; Catanese, J J; Osoegawa, K; Shizuya, H; Choi, S; Chen, Y J; Szustakowki, J

    2001-02-15

    The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

  4. Unusual assortment of segments in 2 rare human rotavirus genomes.

    Science.gov (United States)

    De Grazia, Simona; Giammanco, Giovanni M; Potgieter, Christiaan A; Matthijnssens, Jelle; Banyai, Krisztian; Platia, Maria A; Colomba, Claudia; Martella, Vito

    2010-05-01

    Using full-length genome sequence analysis, we investigated 2 rare G3P[9] human rotavirus strains isolated from children with diarrhea. The genomes were recognized as assortments of genes closely related to rotaviruses originating from cats, ruminants, and humans. Results suggest multiple transmissions of genes from animal to human strains of rotaviruses.

  5. Differentiation of regions with atypical oligonucleotide composition in bacterial genomes

    Directory of Open Access Journals (Sweden)

    Reva Oleg N

    2005-10-01

    Full Text Available Abstract Background Complete sequencing of bacterial genomes has become a common technique of present day microbiology. Thereafter, data mining in the complete sequence is an essential step. New in silico methods are needed that rapidly identify the major features of genome organization and facilitate the prediction of the functional class of ORFs. We tested the usefulness of local oligonucleotide usage (OU patterns to recognize and differentiate types of atypical oligonucleotide composition in DNA sequences of bacterial genomes. Results A total of 163 bacterial genomes of eubacteria and archaea published in the NCBI database were analyzed. Local OU patterns exhibit substantial intrachromosomal variation in bacteria. Loci with alternative OU patterns were parts of horizontally acquired gene islands or ancient regions such as genes for ribosomal proteins and RNAs. OU statistical parameters, such as local pattern deviation (D, pattern skew (PS and OU variance (OUV enabled the detection and visualization of gene islands of different functional classes. Conclusion A set of approaches has been designed for the statistical analysis of nucleotide sequences of bacterial genomes. These methods are useful for the visualization and differentiation of regions with atypical oligonucleotide composition prior to or accompanying gene annotation.

  6. Genome-wide analysis of DNA methylation dynamics during early human development.

    Science.gov (United States)

    Okae, Hiroaki; Chiba, Hatsune; Hiura, Hitoshi; Hamada, Hirotaka; Sato, Akiko; Utsunomiya, Takafumi; Kikuchi, Hiroyuki; Yoshida, Hiroaki; Tanaka, Atsushi; Suyama, Mikita; Arima, Takahiro

    2014-12-01

    DNA methylation is globally reprogrammed during mammalian preimplantation development, which is critical for normal development. Recent reduced representation bisulfite sequencing (RRBS) studies suggest that the methylome dynamics are essentially conserved between human and mouse early embryos. RRBS is known to cover 5-10% of all genomic CpGs, favoring those contained within CpG-rich regions. To obtain an unbiased and more complete representation of the methylome during early human development, we performed whole genome bisulfite sequencing of human gametes and blastocysts that covered>70% of all genomic CpGs. We found that the maternal genome was demethylated to a much lesser extent in human blastocysts than in mouse blastocysts, which could contribute to an increased number of imprinted differentially methylated regions in the human genome. Global demethylation of the paternal genome was confirmed, but SINE-VNTR-Alu elements and some other tandem repeat-containing regions were found to be specifically protected from this global demethylation. Furthermore, centromeric satellite repeats were hypermethylated in human oocytes but not in mouse oocytes, which might be explained by differential expression of de novo DNA methyltransferases. These data highlight both conserved and species-specific regulation of DNA methylation during early mammalian development. Our work provides further information critical for understanding the epigenetic processes underlying differentiation and pluripotency during early human development.

  7. Final report. Human artificial episomal chromosome (HAEC) for building large genomic libraries

    Energy Technology Data Exchange (ETDEWEB)

    Jean-Michael H. Vos

    1999-12-09

    Collections of human DNA fragments are maintained for research purposes as clones in bacterial host cells. However for unknown reasons, some regions of the human genome appear to be unclonable or unstable in bacteria. Their team has developed a system using episomes (extrachromosomal, autonomously replication DNA) that maintains large DNA fragments in human cells. This human artificial episomal chromosomal (HAEC) system may prove useful for coverage of these especially difficult regions. In the broader biomedical community, the HAEC system also shows promise for use in functional genomics and gene therapy. Recent improvements to the HAEC system and its application to mapping, sequencing, and functionally studying human and mouse DNA are summarized. Mapping and sequencing the human genome and model organisms are only the first steps in determining the function of various genetic units critical for gene regulation, DNA replication, chromatin packaging, chromosomal stability, and chromatid segregation. Such studies will require the ability to transfer and manipulate entire functional units into mammalian cells.

  8. Detection of genomic variation by selection of a 9 mb DNA region and high throughput sequencing.

    Directory of Open Access Journals (Sweden)

    Sergey I Nikolaev

    Full Text Available Detection of the rare polymorphisms and causative mutations of genetic diseases in a targeted genomic area has become a major goal in order to understand genomic and phenotypic variability. We have interrogated repeat-masked regions of 8.9 Mb on human chromosomes 21 (7.8 Mb and 7 (1.1 Mb from an individual from the International HapMap Project (NA12872. We have optimized a method of genomic selection for high throughput sequencing. Microarray-based selection and sequencing resulted in 260-fold enrichment, with 41% of reads mapping to the target region. 83% of SNPs in the targeted region had at least 4-fold sequence coverage and 54% at least 15-fold. When assaying HapMap SNPs in NA12872, our sequence genotypes are 91.3% concordant in regions with coverage > or = 4-fold, and 97.9% concordant in regions with coverage > or = 15-fold. About 81% of the SNPs recovered with both thresholds are listed in dbSNP. We observed that regions with low sequence coverage occur in close proximity to low-complexity DNA. Validation experiments using Sanger sequencing were performed for 46 SNPs with 15-20 fold coverage, with a confirmation rate of 96%, suggesting that DNA selection provides an accurate and cost-effective method for identifying rare genomic variants.

  9. Genome dynamics of the human embryonic kidney 293 lineage in response to cell biology manipulations.

    Science.gov (United States)

    Lin, Yao-Cheng; Boone, Morgane; Meuris, Leander; Lemmens, Irma; Van Roy, Nadine; Soete, Arne; Reumers, Joke; Moisse, Matthieu; Plaisance, Stéphane; Drmanac, Radoje; Chen, Jason; Speleman, Frank; Lambrechts, Diether; Van de Peer, Yves; Tavernier, Jan; Callewaert, Nico

    2014-09-03

    The HEK293 human cell lineage is widely used in cell biology and biotechnology. Here we use whole-genome resequencing of six 293 cell lines to study the dynamics of this aneuploid genome in response to the manipulations used to generate common 293 cell derivatives, such as transformation and stable clone generation (293T); suspension growth adaptation (293S); and cytotoxic lectin selection (293SG). Remarkably, we observe that copy number alteration detection could identify the genomic region that enabled cell survival under selective conditions (i.c. ricin selection). Furthermore, we present methods to detect human/vector genome breakpoints and a user-friendly visualization tool for the 293 genome data. We also establish that the genome structure composition is in steady state for most of these cell lines when standard cell culturing conditions are used. This resource enables novel and more informed studies with 293 cells, and we will distribute the sequenced cell lines to this effect.

  10. 75 FR 10488 - National Human Genome Research Institute; Notice of Closed Meetings

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    2010-03-08

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel; NHGRI MAP Review... Human Genome Research Institute Special Emphasis Panel; LRP 2010 Teleconference. Date: April 7,...

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    2013-04-08

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel Loan Repayment Program... applications. Place: National Human Genome Research Institute, Room 3055, 5635 Fishers Lane, Rockville,...

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    2011-06-16

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  18. 78 FR 14806 - National Human Genome Research Institute; Notice of Closed Meeting

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    2013-03-07

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel: Clinically Relevant... grant applications. Place: National Human Genome Research Institute, 4th Floor Conference Room,...

  19. Controls of nucleosome positioning in the human genome.

    Directory of Open Access Journals (Sweden)

    Daniel J Gaffney

    Full Text Available Nucleosomes are important for gene regulation because their arrangement on the genome can control which proteins bind to DNA. Currently, few human nucleosomes are thought to be consistently positioned across cells; however, this has been difficult to assess due to the limited resolution of existing data. We performed paired-end sequencing of micrococcal nuclease-digested chromatin (MNase-seq from seven lymphoblastoid cell lines and mapped over 3.6 billion MNase-seq fragments to the human genome to create the highest-resolution map of nucleosome occupancy to date in a human cell type. In contrast to previous results, we find that most nucleosomes have more consistent positioning than expected by chance and a substantial fraction (8.7% of nucleosomes have moderate to strong positioning. In aggregate, nucleosome sequences have 10 bp periodic patterns in dinucleotide frequency and DNase I sensitivity; and, across cells, nucleosomes frequently have translational offsets that are multiples of 10 bp. We estimate that almost half of the genome contains regularly spaced arrays of nucleosomes, which are enriched in active chromatin domains. Single nucleotide polymorphisms that reduce DNase I sensitivity can disrupt the phasing of nucleosome arrays, which indicates that they often result from positioning against a barrier formed by other proteins. However, nucleosome arrays can also be created by DNA sequence alone. The most striking example is an array of over 400 nucleosomes on chromosome 12 that is created by tandem repetition of sequences with strong positioning properties. In summary, a large fraction of nucleosomes are consistently positioned--in some regions because they adopt favored sequence positions, and in other regions because they are forced into specific arrangements by chromatin remodeling or DNA binding proteins.

  20. Identification of candidate genome regions controlling disease resistance in Arachis

    Directory of Open Access Journals (Sweden)

    Pike Jodie

    2009-08-01

    Full Text Available Abstract Background Worldwide, diseases are important reducers of peanut (Arachis hypogaea yield. Sources of resistance against many diseases are available in cultivated peanut genotypes, although often not in farmer preferred varieties. Wild species generally harbor greater levels of resistance and even apparent immunity, although the linkage of agronomically un-adapted wild alleles with wild disease resistance genes is inevitable. Marker-assisted selection has the potential to facilitate the combination of both cultivated and wild resistance loci with agronomically adapted alleles. However, in peanut there is an almost complete lack of knowledge of the regions of the Arachis genome that control disease resistance. Results In this work we identified candidate genome regions that control disease resistance. For this we placed candidate disease resistance genes and QTLs against late leaf spot disease on the genetic map of the A-genome of Arachis, which is based on microsatellite markers and legume anchor markers. These marker types are transferable within the genus Arachis and to other legumes respectively, enabling this map to be aligned to other Arachis maps and to maps of other legume crops including those with sequenced genomes. In total, 34 sequence-confirmed candidate disease resistance genes and five QTLs were mapped. Conclusion Candidate genes and QTLs were distributed on all linkage groups except for the smallest, but the distribution was not even. Groupings of candidate genes and QTLs for late leaf spot resistance were apparent on the upper region of linkage group 4 and the lower region of linkage group 2, indicating that these regions are likely to control disease resistance.

  1. Structured RNAs and synteny regions in the pig genome

    DEFF Research Database (Denmark)

    Anthon, Christian; Tafer, Hakim; Havgaard, Jakob Hull

    2014-01-01

    BACKGROUND: Annotating mammalian genomes for noncoding RNAs (ncRNAs) is nontrivial since far from all ncRNAs are known and the computational models are resource demanding. Currently, the human genome holds the best mammalian ncRNA annotation, a result of numerous efforts by several groups. However......, a more direct strategy is desired for the increasing number of sequenced mammalian genomes of which some, such as the pig, are relevant as disease models and production animals. RESULTS: We present a comprehensive annotation of structured RNAs in the pig genome. Combining sequence and structure...... lncRNA loci, 11 conflicts of annotation, and 3,183 ncRNA genes. The ncRNA genes comprise 359 miRNAs, 8 ribozymes, 185 rRNAs, 638 snoRNAs, 1,030 snRNAs, 810 tRNAs and 153 ncRNA genes not belonging to the here fore mentioned classes. When running the pipeline on a local shuffled version of the genome...

  2. Online genetic databases informing human genome epidemiology

    Directory of Open Access Journals (Sweden)

    Higgins Julian PT

    2007-07-01

    Full Text Available Abstract Background With the advent of high throughput genotyping technology and the information available via projects such as the human genome sequencing and the HapMap project, more and more data relevant to the study of genetics and disease risk will be produced. Systematic reviews and meta-analyses of human genome epidemiology studies rely on the ability to identify relevant studies and to obtain suitable data from these studies. A first port of call for most such reviews is a search of MEDLINE. We examined whether this could be usefully supplemented by identifying databases on the World Wide Web that contain genetic epidemiological information. Methods We conducted a systematic search for online databases containing genetic epidemiological information on gene prevalence or gene-disease association. In those containing information on genetic association studies, we examined what additional information could be obtained to supplement a MEDLINE literature search. Results We identified 111 databases containing prevalence data, 67 databases specific to a single gene and only 13 that contained information on gene-disease associations. Most of the latter 13 databases were linked to MEDLINE, although five contained information that may not be available from other sources. Conclusion There is no single resource of structured data from genetic association studies covering multiple diseases, and in relation to the number of studies being conducted there is very little information specific to gene-disease association studies currently available on the World Wide Web. Until comprehensive data repositories are created and utilized regularly, new data will remain largely inaccessible to many systematic review authors and meta-analysts.

  3. GRAbB: Selective Assembly of Genomic Regions, a New Niche for Genomic Research.

    Science.gov (United States)

    Brankovics, Balázs; Zhang, Hao; van Diepeningen, Anne D; van der Lee, Theo A J; Waalwijk, Cees; de Hoog, G Sybren

    2016-06-01

    GRAbB (Genomic Region Assembly by Baiting) is a new program that is dedicated to assemble specific genomic regions from NGS data. This approach is especially useful when dealing with multi copy regions, such as mitochondrial genome and the rDNA repeat region, parts of the genome that are often neglected or poorly assembled, although they contain interesting information from phylogenetic or epidemiologic perspectives, but also single copy regions can be assembled. The program is capable of targeting multiple regions within a single run. Furthermore, GRAbB can be used to extract specific loci from NGS data, based on homology, like sequences that are used for barcoding. To make the assembly specific, a known part of the region, such as the sequence of a PCR amplicon or a homologous sequence from a related species must be specified. By assembling only the region of interest, the assembly process is computationally much less demanding and may lead to assemblies of better quality. In this study the different applications and functionalities of the program are demonstrated such as: exhaustive assembly (rDNA region and mitochondrial genome), extracting homologous regions or genes (IGS, RPB1, RPB2 and TEF1a), as well as extracting multiple regions within a single run. The program is also compared with MITObim, which is meant for the exhaustive assembly of a single target based on a similar query sequence. GRAbB is shown to be more efficient than MITObim in terms of speed, memory and disk usage. The other functionalities (handling multiple targets simultaneously and extracting homologous regions) of the new program are not matched by other programs. The program is available with explanatory documentation at https://github.com/b-brankovics/grabb. GRAbB has been tested on Ubuntu (12.04 and 14.04), Fedora (23), CentOS (7.1.1503) and Mac OS X (10.7). Furthermore, GRAbB is available as a docker repository: brankovics/grabb (https://hub.docker.com/r/brankovics/grabb/).

  4. GRAbB: Selective Assembly of Genomic Regions, a New Niche for Genomic Research.

    Directory of Open Access Journals (Sweden)

    Balázs Brankovics

    2016-06-01

    Full Text Available GRAbB (Genomic Region Assembly by Baiting is a new program that is dedicated to assemble specific genomic regions from NGS data. This approach is especially useful when dealing with multi copy regions, such as mitochondrial genome and the rDNA repeat region, parts of the genome that are often neglected or poorly assembled, although they contain interesting information from phylogenetic or epidemiologic perspectives, but also single copy regions can be assembled. The program is capable of targeting multiple regions within a single run. Furthermore, GRAbB can be used to extract specific loci from NGS data, based on homology, like sequences that are used for barcoding. To make the assembly specific, a known part of the region, such as the sequence of a PCR amplicon or a homologous sequence from a related species must be specified. By assembling only the region of interest, the assembly process is computationally much less demanding and may lead to assemblies of better quality. In this study the different applications and functionalities of the program are demonstrated such as: exhaustive assembly (rDNA region and mitochondrial genome, extracting homologous regions or genes (IGS, RPB1, RPB2 and TEF1a, as well as extracting multiple regions within a single run. The program is also compared with MITObim, which is meant for the exhaustive assembly of a single target based on a similar query sequence. GRAbB is shown to be more efficient than MITObim in terms of speed, memory and disk usage. The other functionalities (handling multiple targets simultaneously and extracting homologous regions of the new program are not matched by other programs. The program is available with explanatory documentation at https://github.com/b-brankovics/grabb. GRAbB has been tested on Ubuntu (12.04 and 14.04, Fedora (23, CentOS (7.1.1503 and Mac OS X (10.7. Furthermore, GRAbB is available as a docker repository: brankovics/grabb (https://hub.docker.com/r/brankovics/grabb/.

  5. Genome Architecture and Its Roles in Human Copy Number Variation

    Directory of Open Access Journals (Sweden)

    Lu Chen

    2014-12-01

    Full Text Available Besides single-nucleotide variants in the human genome, large-scale genomic variants, such as copy number variations (CNVs, are being increasingly discovered as a genetic source of human diversity and the pathogenic factors of diseases. Recent experimental findings have shed light on the links between different genome architectures and CNV mutagenesis. In this review, we summarize various genomic features and discuss their contributions to CNV formation. Genomic repeats, including both low-copy and high-copy repeats, play important roles in CNV instability, which was initially known as DNA recombination events. Furthermore, it has been found that human genomic repeats can also induce DNA replication errors and consequently result in CNV mutations. Some recent studies showed that DNA replication timing, which reflects the high-order information of genomic organization, is involved in human CNV mutations. Our review highlights that genome architecture, from DNA sequence to high-order genomic organization, is an important molecular factor in CNV mutagenesis and human genomic instability.

  6. Detecting genomic regions associated with a disease using variability functions and Adjusted Rand Index

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    Makarenkov Vladimir

    2011-10-01

    Full Text Available Abstract Background The identification of functional regions contained in a given multiple sequence alignment constitutes one of the major challenges of comparative genomics. Several studies have focused on the identification of conserved regions and motifs. However, most of existing methods ignore the relationship between the functional genomic regions and the external evidence associated with the considered group of species (e.g., carcinogenicity of Human Papilloma Virus. In the past, we have proposed a method that takes into account the prior knowledge on an external evidence (e.g., carcinogenicity or invasivity of the considered organisms and identifies genomic regions related to a specific disease. Results and conclusion We present a new algorithm for detecting genomic regions that may be associated with a disease. Two new variability functions and a bipartition optimization procedure are described. We validate and weigh our results using the Adjusted Rand Index (ARI, and thus assess to what extent the selected regions are related to carcinogenicity, invasivity, or any other species classification, given as input. The predictive power of different hit region detection functions was assessed on synthetic and real data. Our simulation results suggest that there is no a single function that provides the best results in all practical situations (e.g., monophyletic or polyphyletic evolution, and positive or negative selection, and that at least three different functions might be useful. The proposed hit region identification functions that do not benefit from the prior knowledge (i.e., carcinogenicity or invasivity of the involved organisms can provide equivalent results than the existing functions that take advantage of such a prior knowledge. Using the new algorithm, we examined the Neisseria meningitidis FrpB gene product for invasivity and immunologic activity, and human papilloma virus (HPV E6 oncoprotein for carcinogenicity, and confirmed

  7. Complete Genome Sequence of the Human Gut Symbiont Roseburia hominis

    DEFF Research Database (Denmark)

    Travis, Anthony J.; Kelly, Denise; Flint, Harry J;

    2015-01-01

    We report here the complete genome sequence of the human gut symbiont Roseburia hominis A2-183(T) (= DSM 16839(T) = NCIMB 14029(T)), isolated from human feces. The genome is represented by a 3,592,125-bp chromosome with 3,405 coding sequences. A number of potential functions contributing to host-...

  8. Child Development and Structural Variation in the Human Genome

    Science.gov (United States)

    Zhang, Ying; Haraksingh, Rajini; Grubert, Fabian; Abyzov, Alexej; Gerstein, Mark; Weissman, Sherman; Urban, Alexander E.

    2013-01-01

    Structural variation of the human genome sequence is the insertion, deletion, or rearrangement of stretches of DNA sequence sized from around 1,000 to millions of base pairs. Over the past few years, structural variation has been shown to be far more common in human genomes than previously thought. Very little is currently known about the effects…

  9. Child Development and Structural Variation in the Human Genome

    Science.gov (United States)

    Zhang, Ying; Haraksingh, Rajini; Grubert, Fabian; Abyzov, Alexej; Gerstein, Mark; Weissman, Sherman; Urban, Alexander E.

    2013-01-01

    Structural variation of the human genome sequence is the insertion, deletion, or rearrangement of stretches of DNA sequence sized from around 1,000 to millions of base pairs. Over the past few years, structural variation has been shown to be far more common in human genomes than previously thought. Very little is currently known about the effects…

  10. Small tumor virus genomes are integrated near nuclear matrix attachment regions in transformed cells.

    Science.gov (United States)

    Shera, K A; Shera, C A; McDougall, J K

    2001-12-01

    More than 15% of human cancers have a viral etiology. In benign lesions induced by the small DNA tumor viruses, viral genomes are typically maintained extrachromosomally. Malignant progression is often associated with viral integration into host cell chromatin. To study the role of viral integration in tumorigenesis, we analyzed the positions of integrated viral genomes in tumors and tumor cell lines induced by the small oncogenic viruses, including the high-risk human papillomaviruses, hepatitis B virus, simian virus 40, and human T-cell leukemia virus type 1. We show that viral integrations in tumor cells lie near cellular sequences identified as nuclear matrix attachment regions (MARs), while integrations in nonneoplastic cells show no significant correlation with these regions. In mammalian cells, the nuclear matrix functions in gene expression and DNA replication. MARs play varied but poorly understood roles in eukaryotic gene expression. Our results suggest that integrated tumor virus genomes are subject to MAR-mediated transcriptional regulation, providing insight into mechanisms of viral carcinogenesis. Furthermore, the viral oncoproteins serve as invaluable tools for the study of mechanisms controlling cellular growth. Similarly, our demonstration that integrated viral genomes may be subject to MAR-mediated transcriptional effects should facilitate elucidation of fundamental mechanisms regulating eukaryotic gene expression.

  11. The latent origin of replication of Epstein-Barr virus directs viral genomes to active regions of the nucleus.

    Science.gov (United States)

    Deutsch, Manuel J; Ott, Elisabeth; Papior, Peer; Schepers, Aloys

    2010-03-01

    The Epstein-Barr virus efficiently infects human B cells. The EBV genome is maintained extrachromosomally and replicates synchronously with the host's chromosomes. The latent origin of replication (oriP) guarantees plasmid stability by mediating two basic functions: replication and segregation of the viral genome. While the segregation process of EBV genomes is well understood, little is known about its chromatin association and nuclear distribution during interphase. Here, we analyzed the nuclear localization of EBV genomes and the role of functional oriP domains FR and DS for basic functions such as the transformation of primary cells, their role in targeting EBV genomes to distinct nuclear regions, and their association with epigenetic domains. Fluorescence in situ hybridization visualized the localization of extrachromosomal EBV genomes in the regions adjacent to chromatin-dense territories called the perichromatin. Further, immunofluorescence experiments demonstrated a preference of the viral genome for histone 3 lysine 4-trimethylated (H3K4me3) and histone 3 lysine 9-acetylated (H3K9ac) nuclear regions. To determine the role of FR and DS for establishment and subnuclear localization of EBV genomes, we transformed primary human B lymphocytes with recombinant mini-EBV genomes containing different oriP mutants. The loss of DS results in a slightly increased association in H3K27me3 domains. This study demonstrates that EBV genomes or oriP-based extrachromosomal vector systems are integrated into the higher order nuclear organization. We found that viral genomes are not randomly distributed in the nucleus. FR but not DS is crucial for the localization of EBV in perichromatic regions that are enriched for H3K4me3 and H3K9ac, which are hallmarks of transcriptionally active regions.

  12. Identification of the most informative regions of the mitochondrial genome for phylogenetic and coalescent analyses.

    Science.gov (United States)

    Non, A L; Kitchen, A; Mulligan, C J

    2007-09-01

    Analysis of complete mitochondrial genome sequences is becoming increasingly common in genetic studies. The availability of full genome datasets enables an analysis of the information content distributed throughout the mitochondrial genome in order to optimize the research design of future evolutionary studies. The goal of our study was to identify informative regions of the human mitochondrial genome using two criteria: (1) accurate reconstruction of a phylogeny and (2) consistent estimates of time to most recent common ancestor (TMRCA). We created two series of datasets by deleting individual genes of varied length and by deleting 10 equal-size fragments throughout the coding region. Phylogenies were statistically compared to the full-coding-region tree, while coalescent methods were used to estimate the TMRCA and associated credible intervals. Individual fragments important for maintaining a phylogeny similar to the full-coding-region tree encompassed bp 577-2122 and 11,399-16,023, including all or part of 12S rRNA, 16S rRNA, ND4, ND5, ND6, and cytb. The control region only tree was the most poorly resolved with the majority of the tree manifest as an unresolved polytomy. Coalescent estimates of TMRCA were less sensitive to removal of any particular fragment(s) than reconstruction of a consistent phylogeny. Overall, we discovered that half the genome, i.e., bp 3669-11,398, could be removed with no significant change in the phylogeny (p(AU)=0.077) while still maintaining overlap of TMRCA 95% credible intervals. Thus, sequencing a contiguous fragment from bp 11,399 through the control region to bp 3668 would create a dataset that optimizes the information necessary for phylogenetic and coalescent analyses and also takes advantage of the wealth of data already available on the control region.

  13. Heteroplasmy in the mitochondrial genomes of human lice and ticks revealed by high throughput sequencing.

    Directory of Open Access Journals (Sweden)

    Haoyu Xiong

    Full Text Available The typical mitochondrial (mt genomes of bilateral animals consist of 37 genes on a single circular chromosome. The mt genomes of the human body louse, Pediculus humanus, and the human head louse, Pediculus capitis, however, are extensively fragmented and contain 20 minichromosomes, with one to three genes on each minichromosome. Heteroplasmy, i.e. nucleotide polymorphisms in the mt genome within individuals, has been shown to be significantly higher in the mt cox1 gene of human lice than in humans and other animals that have the typical mt genomes. To understand whether the extent of heteroplasmy in human lice is associated with mt genome fragmentation, we sequenced the entire coding regions of all of the mt minichromosomes of six human body lice and six human head lice from Ethiopia, China and France with an Illumina HiSeq platform. For comparison, we also sequenced the entire coding regions of the mt genomes of seven species of ticks, which have the typical mitochondrial genome organization of bilateral animals. We found that the level of heteroplasmy varies significantly both among the human lice and among the ticks. The human lice from Ethiopia have significantly higher level of heteroplasmy than those from China and France (Pt<0.05. The tick, Amblyomma cajennense, has significantly higher level of heteroplasmy than other ticks (Pt<0.05. Our results indicate that heteroplasmy level can be substantially variable within a species and among closely related species, and does not appear to be determined by single factors such as genome fragmentation.

  14. Analysis of segmental duplications, mouse genome synteny and recurrent cancer-associated amplicons in human chromosome 6p21-p12.

    Science.gov (United States)

    Martin, J W; Yoshimoto, M; Ludkovski, O; Thorner, P S; Zielenska, M; Squire, J A; Nuin, P A S

    2010-06-01

    It has been proposed that regions of microhomology in the human genome could facilitate genomic rearrangements, copy number transitions, and rapid genomic change during tumor progression. To investigate this idea, this study examines the role of repetitive sequence elements, and corresponding syntenic mouse genomic features, in targeting cancer-associated genomic instability of specific regions of the human genome. Automated database-mining algorithms designed to search for frequent copy number transitions and genomic breakpoints were applied to 2 publicly-available online databases and revealed that 6p21-p12 is one of the regions of the human genome most frequently involved in tumor-specific alterations. In these analyses, 6p21-p12 exhibited the highest frequency of genomic amplification in osteosarcomas. Analysis of repetitive elements in regions of homology between human chromosome 6p and the syntenic regions of the mouse genome revealed a strong association between the location of segmental duplications greater than 5 kilobase-pairs and the position of discontinuities at the end of the syntenic region. The presence of clusters of segmental duplications flanking these syntenic regions also correlated with a high frequency of amplification and genomic alteration. Collectively, the experimental findings, in silico analyses, and comparative genomic studies presented here suggest that segmental duplications may facilitate cancer-associated copy number transitions and rearrangements at chromosome 6p21-p12. This process may involve homology-dependent DNA recombination and/or repair, which may also contribute towards the overall plasticity of the human genome.

  15. Genome-wide analysis of the human Alu Yb-lineage

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    Carter Anthony B

    2004-03-01

    Full Text Available Abstract The Alu Yb-lineage is a 'young' primarily human-specific group of short interspersed element (SINE subfamilies that have integrated throughout the human genome. In this study, we have computationally screened the draft sequence of the human genome for Alu Yb-lineage subfamily members present on autosomal chromosomes. A total of 1,733 Yb Alu subfamily members have integrated into human autosomes. The average ages of Yb-lineage subfamilies, Yb7, Yb8 and Yb9, are estimated as 4.81, 2.39 and 2.32 million years, respectively. In order to determine the contribution of the Alu Yb-lineage to human genomic diversity, 1,202 loci were analysed using polymerase chain reaction (PCR-based assays, which amplify the genomic regions containing individual Yb-lineage subfamily members. Approximately 20 per cent of the Yb-lineage Alu elements are polymorphic for insertion presence/absence in the human genome. Fewer than 0.5 per cent of the Yb loci also demonstrate insertions at orthologous positions in non-human primate genomes. Genomic sequencing of these unusual loci demonstrates that each of the orthologous loci from non-human primate genomes contains older Y, Sg and Sx Alu family members that have been altered, through various mechanisms, into Yb8 sequences. These data suggest that Alu Yb-lineage subfamily members are largely restricted to the human genome. The high copy number, level of insertion polymorphism and estimated age indicate that members of the Alu Yb elements will be useful in a wide range of genetic analyses.

  16. Evolution and genomics of the human brain.

    Science.gov (United States)

    Rosales-Reynoso, M A; Juárez-Vázquez, C I; Barros-Núñez, P

    2015-08-21

    Most living beings are able to perform actions that can be considered intelligent or, at the very least, the result of an appropriate reaction to changing circumstances in their environment. However, the intelligence or intellectual processes of humans are vastly superior to those achieved by all other species. The adult human brain is a highly complex organ weighing approximately 1500g, which accounts for only 2% of the total body weight but consumes an amount of energy equal to that required by all skeletal muscle at rest. Although the human brain displays a typical primate structure, it can be identified by its specific distinguishing features. The process of evolution and humanisation of the Homo sapiens brain resulted in a unique and distinct organ with the largest relative volume of any animal species. It also permitted structural reorganization of tissues and circuits in specific segments and regions. These steps explain the remarkable cognitive abilities of modern humans compared not only with other species in our genus, but also with older members of our own species. Brain evolution required the coexistence of two adaptation mechanisms. The first involves genetic changes that occur at the species level, and the second occurs at the individual level and involves changes in chromatin organisation or epigenetic changes. The genetic mechanisms include: a) genetic changes in coding regions that lead to changes in the sequence and activity of existing proteins; b) duplication and deletion of previously existing genes; c) changes in gene expression through changes in the regulatory sequences of different genes; and d) synthesis of non-coding RNAs. Lastly, this review describes some of the main documented chromosomal differences between humans and great apes. These differences have also contributed to the evolution and humanisation process of the H. sapiens brain. Copyright © 2014 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights

  17. De novo assembly and phasing of a Korean human genome.

    Science.gov (United States)

    Seo, Jeong-Sun; Rhie, Arang; Kim, Junsoo; Lee, Sangjin; Sohn, Min-Hwan; Kim, Chang-Uk; Hastie, Alex; Cao, Han; Yun, Ji-Young; Kim, Jihye; Kuk, Junho; Park, Gun Hwa; Kim, Juhyeok; Ryu, Hanna; Kim, Jongbum; Roh, Mira; Baek, Jeonghun; Hunkapiller, Michael W; Korlach, Jonas; Shin, Jong-Yeon; Kim, Changhoon

    2016-10-13

    Advances in genome assembly and phasing provide an opportunity to investigate the diploid architecture of the human genome and reveal the full range of structural variation across population groups. Here we report the de novo assembly and haplotype phasing of the Korean individual AK1 (ref. 1) using single-molecule real-time sequencing, next-generation mapping, microfluidics-based linked reads, and bacterial artificial chromosome (BAC) sequencing approaches. Single-molecule sequencing coupled with next-generation mapping generated a highly contiguous assembly, with a contig N50 size of 17.9 Mb and a scaffold N50 size of 44.8 Mb, resolving 8 chromosomal arms into single scaffolds. The de novo assembly, along with local assemblies and spanning long reads, closes 105 and extends into 72 out of 190 euchromatic gaps in the reference genome, adding 1.03 Mb of previously intractable sequence. High concordance between the assembly and paired-end sequences from 62,758 BAC clones provides strong support for the robustness of the assembly. We identify 18,210 structural variants by direct comparison of the assembly with the human reference, identifying thousands of breakpoints that, to our knowledge, have not been reported before. Many of the insertions are reflected in the transcriptome and are shared across the Asian population. We performed haplotype phasing of the assembly with short reads, long reads and linked reads from whole-genome sequencing and with short reads from 31,719 BAC clones, thereby achieving phased blocks with an N50 size of 11.6 Mb. Haplotigs assembled from single-molecule real-time reads assigned to haplotypes on phased blocks covered 89% of genes. The haplotigs accurately characterized the hypervariable major histocompatability complex region as well as demonstrating allele configuration in clinically relevant genes such as CYP2D6. This work presents the most contiguous diploid human genome assembly so far, with extensive investigation of

  18. Genomics and identity: the bioinformatisation of human life.

    Science.gov (United States)

    Zwart, Hub

    2009-06-01

    The genomics "revolution" is spreading. Originating in the molecular life sciences, it initially affected a number of biomedical research fields such as cancer genomics and clinical genetics. Now, however, a new "wave" of genomic bioinformation is transforming a widening array of disciplines, including those that address the social, historical and cultural dimensions of human life. Increasingly, bioinformation is affecting "human sciences" such as psychiatry, psychology, brain research, behavioural research ("behavioural genomics"), but also anthropology and archaeology ("bioarchaeology"). Thus, bioinformatics is having an impact on how we define and understand ourselves, how identities are formed and constituted, and, finally, on how we (on the basis of these redefined identities) assess and address some of the more concrete societal issues involved in genomics governance in various settings. This article explores how genomics and bioinformation, by influencing research agendas in the human sciences and the humanities, are affecting our self-image, our identity, the way we see ourselves. The impact of bioinformation on self-understanding will be assessed on three levels: (1) the collective level (the impact of comparative genomics on our understanding of human beings as a species), (2) the individual level (the impact of behavioural genomics on our understanding of ourselves as individuals), and (3) the genealogical level (the impact of population genomics on our understanding of human history, notably early human history). This threefold impact will be assessed from two seemingly incompatible philosophical perspectives, namely a "humanistic" perspective (represented in this article by Francis Fukuyama) and a "post-humanistic" one (represented by Peter Sloterdijk). On the basis of this analysis it will be concluded that, rather than focussing on human "enhancement" by adding or deleting genes, genome-oriented practices of the Self will focus on using genomics

  19. Genome-wide comparisons of phylogenetic similarities between partial genomic regions and the full-length genome in Hepatitis E virus genotyping.

    Directory of Open Access Journals (Sweden)

    Shuai Wang

    Full Text Available Besides the complete genome, different partial genomic sequences of Hepatitis E virus (HEV have been used in genotyping studies, making it difficult to compare the results based on them. No commonly agreed partial region for HEV genotyping has been determined. In this study, we used a statistical method to evaluate the phylogenetic performance of each partial genomic sequence from a genome wide, by comparisons of evolutionary distances between genomic regions and the full-length genomes of 101 HEV isolates to identify short genomic regions that can reproduce HEV genotype assignments based on full-length genomes. Several genomic regions, especially one genomic region at the 3'-terminal of the papain-like cysteine protease domain, were detected to have relatively high phylogenetic correlations with the full-length genome. Phylogenetic analyses confirmed the identical performances between these regions and the full-length genome in genotyping, in which the HEV isolates involved could be divided into reasonable genotypes. This analysis may be of value in developing a partial sequence-based consensus classification of HEV species.

  20. The genomic landscape of Neanderthal ancestry in present-day humans.

    Science.gov (United States)

    Sankararaman, Sriram; Mallick, Swapan; Dannemann, Michael; Prüfer, Kay; Kelso, Janet; Pääbo, Svante; Patterson, Nick; Reich, David

    2014-03-20

    Genomic studies have shown that Neanderthals interbred with modern humans, and that non-Africans today are the products of this mixture. The antiquity of Neanderthal gene flow into modern humans means that genomic regions that derive from Neanderthals in any one human today are usually less than a hundred kilobases in size. However, Neanderthal haplotypes are also distinctive enough that several studies have been able to detect Neanderthal ancestry at specific loci. We systematically infer Neanderthal haplotypes in the genomes of 1,004 present-day humans. Regions that harbour a high frequency of Neanderthal alleles are enriched for genes affecting keratin filaments, suggesting that Neanderthal alleles may have helped modern humans to adapt to non-African environments. We identify multiple Neanderthal-derived alleles that confer risk for disease, suggesting that Neanderthal alleles continue to shape human biology. An unexpected finding is that regions with reduced Neanderthal ancestry are enriched in genes, implying selection to remove genetic material derived from Neanderthals. Genes that are more highly expressed in testes than in any other tissue are especially reduced in Neanderthal ancestry, and there is an approximately fivefold reduction of Neanderthal ancestry on the X chromosome, which is known from studies of diverse species to be especially dense in male hybrid sterility genes. These results suggest that part of the explanation for genomic regions of reduced Neanderthal ancestry is Neanderthal alleles that caused decreased fertility in males when moved to a modern human genetic background.

  1. The Past, Present, and Future of Human Centromere Genomics

    Directory of Open Access Journals (Sweden)

    Megan E. Aldrup-MacDonald

    2014-01-01

    Full Text Available The centromere is the chromosomal locus essential for chromosome inheritance and genome stability. Human centromeres are located at repetitive alpha satellite DNA arrays that compose approximately 5% of the genome. Contiguous alpha satellite DNA sequence is absent from the assembled reference genome, limiting current understanding of centromere organization and function. Here, we review the progress in centromere genomics spanning the discovery of the sequence to its molecular characterization and the work done during the Human Genome Project era to elucidate alpha satellite structure and sequence variation. We discuss exciting recent advances in alpha satellite sequence assembly that have provided important insight into the abundance and complex organization of this sequence on human chromosomes. In light of these new findings, we offer perspectives for future studies of human centromere assembly and function.

  2. The Human Genome Project, and recent advances in personalized genomics

    Directory of Open Access Journals (Sweden)

    Wilson BJ

    2015-02-01

    Full Text Available Brenda J Wilson, Stuart G Nicholls Department of Epidemiology and Community Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada Abstract: The language of “personalized medicine” and “personal genomics” has now entered the common lexicon. The idea of personalized medicine is the integration of genomic risk assessment alongside other clinical investigations. Consistent with this approach, testing is delivered by health care professionals who are not medical geneticists, and where results represent risks, as opposed to clinical diagnosis of disease, to be interpreted alongside the entirety of a patient's health and medical data. In this review we consider the evidence concerning the application of such personalized genomics within the context of population screening, and potential implications that arise from this. We highlight two general approaches which illustrate potential uses of genomic information in screening. The first is a narrowly targeted approach in which genetic profiling is linked with standard population-based screening for diseases; the second is a broader targeting of variants associated with multiple single gene disorders, performed opportunistically on patients being investigated for unrelated conditions. In doing so we consider the organization and evaluation of tests and services, the challenge of interpretation with less targeted testing, professional confidence, barriers in practice, and education needs. We conclude by discussing several issues pertinent to health policy, namely: avoiding the conflation of genetics with biological determinism, resisting the “technological imperative”, due consideration of the organization of screening services, the need for professional education, as well as informed decision making and public understanding. Keywords: genomics, personalized medicine, ethics, population health, evidence, education

  3. Efficient assembly of de novo human artificial chromosomes from large genomic loci

    Directory of Open Access Journals (Sweden)

    Stromberg Gregory

    2005-07-01

    Full Text Available Abstract Background Human Artificial Chromosomes (HACs are potentially useful vectors for gene transfer studies and for functional annotation of the genome because of their suitability for cloning, manipulating and transferring large segments of the genome. However, development of HACs for the transfer of large genomic loci into mammalian cells has been limited by difficulties in manipulating high-molecular weight DNA, as well as by the low overall frequencies of de novo HAC formation. Indeed, to date, only a small number of large (>100 kb genomic loci have been reported to be successfully packaged into de novo HACs. Results We have developed novel methodologies to enable efficient assembly of HAC vectors containing any genomic locus of interest. We report here the creation of a novel, bimolecular system based on bacterial artificial chromosomes (BACs for the construction of HACs incorporating any defined genomic region. We have utilized this vector system to rapidly design, construct and validate multiple de novo HACs containing large (100–200 kb genomic loci including therapeutically significant genes for human growth hormone (HGH, polycystic kidney disease (PKD1 and ß-globin. We report significant differences in the ability of different genomic loci to support de novo HAC formation, suggesting possible effects of cis-acting genomic elements. Finally, as a proof of principle, we have observed sustained ß-globin gene expression from HACs incorporating the entire 200 kb ß-globin genomic locus for over 90 days in the absence of selection. Conclusion Taken together, these results are significant for the development of HAC vector technology, as they enable high-throughput assembly and functional validation of HACs containing any large genomic locus. We have evaluated the impact of different genomic loci on the frequency of HAC formation and identified segments of genomic DNA that appear to facilitate de novo HAC formation. These genomic loci

  4. Genome-wide map of regulatory interactions in the human genome.

    Science.gov (United States)

    Heidari, Nastaran; Phanstiel, Douglas H; He, Chao; Grubert, Fabian; Jahanbani, Fereshteh; Kasowski, Maya; Zhang, Michael Q; Snyder, Michael P

    2014-12-01

    Increasing evidence suggests that interactions between regulatory genomic elements play an important role in regulating gene expression. We generated a genome-wide interaction map of regulatory elements in human cells (ENCODE tier 1 cells, K562, GM12878) using Chromatin Interaction Analysis by Paired-End Tag sequencing (ChIA-PET) experiments targeting six broadly distributed factors. Bound regions covered 80% of DNase I hypersensitive sites including 99.7% of TSS and 98% of enhancers. Correlating this map with ChIP-seq and RNA-seq data sets revealed cohesin, CTCF, and ZNF143 as key components of three-dimensional chromatin structure and revealed how the distal chromatin state affects gene transcription. Comparison of interactions between cell types revealed that enhancer-promoter interactions were highly cell-type-specific. Construction and comparison of distal and proximal regulatory networks revealed stark differences in structure and biological function. Proximal binding events are enriched at genes with housekeeping functions, while distal binding events interact with genes involved in dynamic biological processes including response to stimulus. This study reveals new mechanistic and functional insights into regulatory region organization in the nucleus. © 2014 Heidari et al.; Published by Cold Spring Harbor Laboratory Press.

  5. Searching for additional disease loci in a genomic region.

    Science.gov (United States)

    Thomson, Glenys; Barcellos, Lisa F; Valdes, Ana M

    2008-01-01

    Our aim is to review methods to optimize detection of all disease genes in a genetic region. As a starting point, we assume there is sufficient evidence from linkage and/or association studies, based on significance levels or replication studies, for the involvement in disease risk of the genetic region under study. For closely linked markers, there will often be multiple associations with disease, and linkage analyses identify a region rather than the specific disease-predisposing gene. Hence, the first task is to identify the primary (major) disease-predisposing gene or genes in a genetic region, and single nucleotide polymorphisms thereof, that is, how to distinguish true associations from those that are just due to linkage disequilibrium with the actual disease-predisposing variants. Then, how do we detect additional disease genes in this genetic region? These two issues are of course very closely interrelated. No existing programs, either individually or in aggregate, can handle the magnitude and complexity of the analyses needed using currently available methods. Further, even with modern computers, one cannot study every possible combination of genetic markers and their haplotypes across the genome, or even within a genetic region. Although we must rely heavily on computers, in the final analysis of multiple effects in a genetic region and/or interaction or independent effects between unlinked genes, manipulation of the data by the individual investigator will play a crucial role. We recommend a multistrategy approach using a variety of complementary methods described below.

  6. Minimal absent words in four human genome assemblies.

    Directory of Open Access Journals (Sweden)

    Sara P Garcia

    Full Text Available Minimal absent words have been computed in genomes of organisms from all domains of life. Here, we aim to contribute to the catalogue of human genomic variation by investigating the variation in number and content of minimal absent words within a species, using four human genome assemblies. We compare the reference human genome GRCh37 assembly, the HuRef assembly of the genome of Craig Venter, the NA12878 assembly from cell line GM12878, and the YH assembly of the genome of a Han Chinese individual. We find the variation in number and content of minimal absent words between assemblies more significant for large and very large minimal absent words, where the biases of sequencing and assembly methodologies become more pronounced. Moreover, we find generally greater similarity between the human genome assemblies sequenced with capillary-based technologies (GRCh37 and HuRef than between the human genome assemblies sequenced with massively parallel technologies (NA12878 and YH. Finally, as expected, we find the overall variation in number and content of minimal absent words within a species to be generally smaller than the variation between species.

  7. Minimal absent words in four human genome assemblies.

    Science.gov (United States)

    Garcia, Sara P; Pinho, Armando J

    2011-01-01

    Minimal absent words have been computed in genomes of organisms from all domains of life. Here, we aim to contribute to the catalogue of human genomic variation by investigating the variation in number and content of minimal absent words within a species, using four human genome assemblies. We compare the reference human genome GRCh37 assembly, the HuRef assembly of the genome of Craig Venter, the NA12878 assembly from cell line GM12878, and the YH assembly of the genome of a Han Chinese individual. We find the variation in number and content of minimal absent words between assemblies more significant for large and very large minimal absent words, where the biases of sequencing and assembly methodologies become more pronounced. Moreover, we find generally greater similarity between the human genome assemblies sequenced with capillary-based technologies (GRCh37 and HuRef) than between the human genome assemblies sequenced with massively parallel technologies (NA12878 and YH). Finally, as expected, we find the overall variation in number and content of minimal absent words within a species to be generally smaller than the variation between species.

  8. Genetic variation and the de novo assembly of human genomes.

    Science.gov (United States)

    Chaisson, Mark J P; Wilson, Richard K; Eichler, Evan E

    2015-11-01

    The discovery of genetic variation and the assembly of genome sequences are both inextricably linked to advances in DNA-sequencing technology. Short-read massively parallel sequencing has revolutionized our ability to discover genetic variation but is insufficient to generate high-quality genome assemblies or resolve most structural variation. Full resolution of variation is only guaranteed by complete de novo assembly of a genome. Here, we review approaches to genome assembly, the nature of gaps or missing sequences, and biases in the assembly process. We describe the challenges of generating a complete de novo genome assembly using current technologies and the impact that being able to perfectly sequence the genome would have on understanding human disease and evolution. Finally, we summarize recent technological advances that improve both contiguity and accuracy and emphasize the importance of complete de novo assembly as opposed to read mapping as the primary means to understanding the full range of human genetic variation.

  9. Ancient Human Genome Sequence of an Extinct Palaeo-Eskimo

    DEFF Research Database (Denmark)

    Rasmussen, Morten; Li, Yingrui; Lindgreen, Stinus;

    2010-01-01

    We report here the genome sequence of an ancient human. Obtained from approximately 4,000-year-old permafrost-preserved hair, the genome represents a male individual from the first known culture to settle in Greenland. Sequenced to an average depth of 20x, we recover 79% of the diploid genome, an...... for a migration from Siberia into the New World some 5,500 years ago, independent of that giving rise to the modern Native Americans and Inuit....

  10. The accessible chromatin landscape of the human genome.

    Science.gov (United States)

    Thurman, Robert E; Rynes, Eric; Humbert, Richard; Vierstra, Jeff; Maurano, Matthew T; Haugen, Eric; Sheffield, Nathan C; Stergachis, Andrew B; Wang, Hao; Vernot, Benjamin; Garg, Kavita; John, Sam; Sandstrom, Richard; Bates, Daniel; Boatman, Lisa; Canfield, Theresa K; Diegel, Morgan; Dunn, Douglas; Ebersol, Abigail K; Frum, Tristan; Giste, Erika; Johnson, Audra K; Johnson, Ericka M; Kutyavin, Tanya; Lajoie, Bryan; Lee, Bum-Kyu; Lee, Kristen; London, Darin; Lotakis, Dimitra; Neph, Shane; Neri, Fidencio; Nguyen, Eric D; Qu, Hongzhu; Reynolds, Alex P; Roach, Vaughn; Safi, Alexias; Sanchez, Minerva E; Sanyal, Amartya; Shafer, Anthony; Simon, Jeremy M; Song, Lingyun; Vong, Shinny; Weaver, Molly; Yan, Yongqi; Zhang, Zhancheng; Zhang, Zhuzhu; Lenhard, Boris; Tewari, Muneesh; Dorschner, Michael O; Hansen, R Scott; Navas, Patrick A; Stamatoyannopoulos, George; Iyer, Vishwanath R; Lieb, Jason D; Sunyaev, Shamil R; Akey, Joshua M; Sabo, Peter J; Kaul, Rajinder; Furey, Terrence S; Dekker, Job; Crawford, Gregory E; Stamatoyannopoulos, John A

    2012-09-06

    DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ∼2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect ∼580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation.

  11. Population genetic inference from personal genome data: impact of ancestry and admixture on human genomic variation.

    Science.gov (United States)

    Kidd, Jeffrey M; Gravel, Simon; Byrnes, Jake; Moreno-Estrada, Andres; Musharoff, Shaila; Bryc, Katarzyna; Degenhardt, Jeremiah D; Brisbin, Abra; Sheth, Vrunda; Chen, Rong; McLaughlin, Stephen F; Peckham, Heather E; Omberg, Larsson; Bormann Chung, Christina A; Stanley, Sarah; Pearlstein, Kevin; Levandowsky, Elizabeth; Acevedo-Acevedo, Suehelay; Auton, Adam; Keinan, Alon; Acuña-Alonzo, Victor; Barquera-Lozano, Rodrigo; Canizales-Quinteros, Samuel; Eng, Celeste; Burchard, Esteban G; Russell, Archie; Reynolds, Andy; Clark, Andrew G; Reese, Martin G; Lincoln, Stephen E; Butte, Atul J; De La Vega, Francisco M; Bustamante, Carlos D

    2012-10-05

    Full sequencing of individual human genomes has greatly expanded our understanding of human genetic variation and population history. Here, we present a systematic analysis of 50 human genomes from 11 diverse global populations sequenced at high coverage. Our sample includes 12 individuals who have admixed ancestry and who have varying degrees of recent (within the last 500 years) African, Native American, and European ancestry. We found over 21 million single-nucleotide variants that contribute to a 1.75-fold range in nucleotide heterozygosity across diverse human genomes. This heterozygosity ranged from a high of one heterozygous site per kilobase in west African genomes to a low of 0.57 heterozygous sites per kilobase in segments inferred to have diploid Native American ancestry from the genomes of Mexican and Puerto Rican individuals. We show evidence of all three continental ancestries in the genomes of Mexican, Puerto Rican, and African American populations, and the genome-wide statistics are highly consistent across individuals from a population once ancestry proportions have been accounted for. Using a generalized linear model, we identified subtle variations across populations in the proportion of neutral versus deleterious variation and found that genome-wide statistics vary in admixed populations even once ancestry proportions have been factored in. We further infer that multiple periods of gene flow shaped the diversity of admixed populations in the Americas-70% of the European ancestry in today's African Americans dates back to European gene flow happening only 7-8 generations ago.

  12. Analysis of segmental duplications reveals a distinct pattern of continuation-of-synteny between human and mouse genomes.

    Science.gov (United States)

    Mehan, Michael R; Almonte, Maricel; Slaten, Erin; Freimer, Nelson B; Rao, P Nagesh; Ophoff, Roel A

    2007-03-01

    About 5% of the human genome consists of large-scale duplicated segments of almost identical sequences. Segmental duplications (SDs) have been proposed to be involved in non-allelic homologous recombination leading to recurrent genomic variation and disease. It has also been suggested that these SDs are associated with syntenic rearrangements that have shaped the human genome. We have analyzed 14 members of a single family of closely related SDs in the human genome, some of which are associated with common inversion polymorphisms at chromosomes 8p23 and 4p16. Comparative analysis with the mouse genome revealed syntenic inversions for these two human polymorphic loci. In addition, 12 of the 14 SDs, while absent in the mouse genome, occur at the breaks of synteny; suggesting a non-random involvement of these sequences in genome evolution. Furthermore, we observed a syntenic familial relationship between 8 and 12 breakpoint-loci, where broken synteny that ends at one family member resumes at another, even across different chromosomes. Subsequent genome-wide assessment revealed that this relationship, which we named continuation-of-synteny, is not limited to the 8p23 family and occurs 46 times in the human genome with high frequency at specific chromosomes. Our analysis supports a non-random breakage model of genomic evolution with an active involvement of segmental duplications for specific regions of the human genome.

  13. Retrocopy contributions to the evolution of the human genome

    Directory of Open Access Journals (Sweden)

    Haussler David

    2008-10-01

    Full Text Available Abstract Background Evolution via point mutations is a relatively slow process and is unlikely to completely explain the differences between primates and other mammals. By contrast, 45% of the human genome is composed of retroposed elements, many of which were inserted in the primate lineage. A subset of retroposed mRNAs (retrocopies shows strong evidence of expression in primates, often yielding functional retrogenes. Results To identify and analyze the relatively recently evolved retrogenes, we carried out BLASTZ alignments of all human mRNAs against the human genome and scored a set of features indicative of retroposition. Of over 12,000 putative retrocopy-derived genes that arose mainly in the primate lineage, 726 with strong evidence of transcript expression were examined in detail. These mRNA retroposition events fall into three categories: I 34 retrocopies and antisense retrocopies that added potential protein coding space and UTRs to existing genes; II 682 complete retrocopy duplications inserted into new loci; and III an unexpected set of 13 retrocopies that contributed out-of-frame, or antisense sequences in combination with other types of transposed elements (SINEs, LINEs, LTRs, even unannotated sequence to form potentially novel genes with no homologs outside primates. In addition to their presence in human, several of the gene candidates also had potentially viable ORFs in chimpanzee, orangutan, and rhesus macaque, underscoring their potential of function. Conclusion mRNA-derived retrocopies provide raw material for the evolution of genes in a wide variety of ways, duplicating and amending the protein coding region of existing genes as well as generating the potential for new protein coding space, or non-protein coding RNAs, by unexpected contributions out of frame, in reverse orientation, or from previously non-protein coding sequence.

  14. Dissecting the human microbiome with single-cell genomics.

    Science.gov (United States)

    Tolonen, Andrew C; Xavier, Ramnik J

    2017-06-14

    Recent advances in genome sequencing of single microbial cells enable the assignment of functional roles to members of the human microbiome that cannot currently be cultured. This approach can reveal the genomic basis of phenotypic variation between closely related strains and can be applied to the targeted study of immunogenic bacteria in disease.

  15. Genome Editing: A New Approach to Human Therapeutics.

    Science.gov (United States)

    Porteus, Matthew

    2016-01-01

    The ability to manipulate the genome with precise spatial and nucleotide resolution (genome editing) has been a powerful research tool. In the past decade, the tools and expertise for using genome editing in human somatic cells and pluripotent cells have increased to such an extent that the approach is now being developed widely as a strategy to treat human disease. The fundamental process depends on creating a site-specific DNA double-strand break (DSB) in the genome and then allowing the cell's endogenous DSB repair machinery to fix the break such that precise nucleotide changes are made to the DNA sequence. With the development and discovery of several different nuclease platforms and increasing knowledge of the parameters affecting different genome editing outcomes, genome editing frequencies now reach therapeutic relevance for a wide variety of diseases. Moreover, there is a series of complementary approaches to assessing the safety and toxicity of any genome editing process, irrespective of the underlying nuclease used. Finally, the development of genome editing has raised the issue of whether it should be used to engineer the human germline. Although such an approach could clearly prevent the birth of people with devastating and destructive genetic diseases, questions remain about whether human society is morally responsible enough to use this tool.

  16. CAG-encoded polyglutamine length polymorphism in the human genome

    Directory of Open Access Journals (Sweden)

    Hayden Michael R

    2007-05-01

    Full Text Available Abstract Background Expansion of polyglutamine-encoding CAG trinucleotide repeats has been identified as the pathogenic mutation in nine different genes associated with neurodegenerative disorders. The majority of individuals clinically diagnosed with spinocerebellar ataxia do not have mutations within known disease genes, and it is likely that additional ataxias or Huntington disease-like disorders will be found to be caused by this common mutational mechanism. We set out to determine the length distributions of CAG-polyglutamine tracts for the entire human genome in a set of healthy individuals in order to characterize the nature of polyglutamine repeat length variation across the human genome, to establish the background against which pathogenic repeat expansions can be detected, and to prioritize candidate genes for repeat expansion disorders. Results We found that repeats, including those in known disease genes, have unique distributions of glutamine tract lengths, as measured by fragment analysis of PCR-amplified repeat regions. This emphasizes the need to characterize each distribution and avoid making generalizations between loci. The best predictors of known disease genes were occurrence of a long CAG-tract uninterrupted by CAA codons in their reference genome sequence, and high glutamine tract length variance in the normal population. We used these parameters to identify eight priority candidate genes for polyglutamine expansion disorders. Twelve CAG-polyglutamine repeats were invariant and these can likely be excluded as candidates. We outline some confusion in the literature about this type of data, difficulties in comparing such data between publications, and its application to studies of disease prevalence in different populations. Analysis of Gene Ontology-based functions of CAG-polyglutamine-containing genes provided a visual framework for interpretation of these genes' functions. All nine known disease genes were involved in DNA

  17. Predicting Tissue-Specific Enhancers in the Human Genome

    Energy Technology Data Exchange (ETDEWEB)

    Pennacchio, Len A.; Loots, Gabriela G.; Nobrega, Marcelo A.; Ovcharenko, Ivan

    2006-07-01

    Determining how transcriptional regulatory signals areencoded in vertebrate genomes is essential for understanding the originsof multi-cellular complexity; yet the genetic code of vertebrate generegulation remains poorly understood. In an attempt to elucidate thiscode, we synergistically combined genome-wide gene expression profiling,vertebrate genome comparisons, and transcription factor binding siteanalysis to define sequence signatures characteristic of candidatetissue-specific enhancers in the human genome. We applied this strategyto microarray-based gene expression profiles from 79 human tissues andidentified 7,187 candidate enhancers that defined their flanking geneexpression, the majority of which were located outside of knownpromoters. We cross-validated this method for its ability to de novopredict tissue-specific gene expression and confirmed its reliability in57 of the 79 available human tissues, with an average precision inenhancer recognition ranging from 32 percent to 63 percent, and asensitivity of 47 percent. We used the sequence signatures identified bythis approach to assign tissue-specific predictions to ~;328,000human-mouse conserved noncoding elements in the human genome. Byoverlapping these genome-wide predictions with a large in vivo dataset ofenhancers validated in transgenic mice, we confirmed our results with a28 percent sensitivity and 50 percent precision. These results indicatethe power of combining complementary genomic datasets as an initialcomputational foray into the global view of tissue-specific generegulation in vertebrates.

  18. Genomic instability of human embryonic stem cell lines using different passaging culture methods.

    Science.gov (United States)

    Tosca, Lucie; Feraud, Olivier; Magniez, Aurélie; Bas, Cécile; Griscelli, Frank; Bennaceur-Griscelli, Annelise; Tachdjian, Gérard

    2015-01-01

    Human embryonic stem cells exhibit genomic instability that can be related to culture duration or to the passaging methods used for cell dissociation. In order to study the impact of cell dissociation techniques on human embryonic stem cells genomic instability, we cultured H1 and H9 human embryonic stem cells lines using mechanical/manual or enzymatic/collagenase-IV dissociation methods. Genomic instability was evaluated at early (p60) passages by using oligonucleotide based array-comparative genomic hybridization 105 K with a mean resolution of 50 Kb. DNA variations were mainly located on subtelomeric and pericentromeric regions with sizes <100 Kb. In this study, 9 recurrent genomic variations were acquired during culture including the well known duplication 20q11.21. When comparing cell dissociation methods, we found no significant differences between DNA variations number and size, DNA gain or DNA loss frequencies, homozygous loss frequencies and no significant difference on the content of genes involved in development, cell cycle tumorigenesis and syndrome disease. In addition, we have never found any malignant tissue in 4 different teratoma representative of the two independent stem cell lines. These results show that the occurrence of genomic instability in human embryonic stem cells is similar using mechanical or collagenase IV-based enzymatic cell culture dissociation methods. All the observed genomic variations have no impact on the development of malignancy.

  19. Comprehensive genomic characterization defines human glioblastoma genes and core pathways

    NARCIS (Netherlands)

    Chin, L.; Meyerson, M.; Aldape, K.; Bigner, D.; Mikkelsen, T.; VandenBerg, S.; Kahn, A.; Penny, R.; Gerhard, D. S.; Getz, G.; Brennan, C.; Taylor, B. S.; Winckler, W.; Park, P.; Ladanyi, M.; Hoadley, K. A.; Verhaak, R. G. W.; Hayes, D. N.; Spellman, Paul T.; Absher, D.; Weir, B. A.; Ding, L.; Wheeler, D.; Lawrence, M. S.; Cibulskis, K.; Mardis, E.; Zhang, Jinghui; Wilson, R. K.; Donehower, L.; Wheeler, D. A.; Purdom, E.; Wallis, J.; Laird, P. W.; Herman, J. G.; Schuebel, K. E.; Weisenberger, D. J.; Baylin, S. B.; Schultz, N.; Yao, Jun; Wiedemeyer, R.; Weinstein, J.; Sander, C.; Gibbs, R. A.; Gray, J.; Kucherlapati, R.; Lander, E. S.; Myers, R. M.; Perou, C. M.; McLendon, Roger; Friedman, Allan; Van Meir, Erwin G; Brat, Daniel J; Mastrogianakis, Gena Marie; Olson, Jeffrey J; Lehman, Norman; Yung, W. K. Alfred; Bogler, Oliver; Berger, Mitchel; Prados, Michael; Muzny, Donna; Morgan, Margaret; Scherer, Steve; Sabo, Aniko; Nazareth, Lynn; Lewis, Lora; Hall, Otis; Zhu, Yiming; Ren, Yanru; Alvi, Omar; Yao, Jiqiang; Hawes, Alicia; Jhangiani, Shalini; Fowler, Gerald; San Lucas, Anthony; Kovar, Christie; Cree, Andrew; Dinh, Huyen; Santibanez, Jireh; Joshi, Vandita; Gonzalez-Garay, Manuel L.; Miller, Christopher A.; Milosavljevic, Aleksandar; Sougnez, Carrie; Fennell, Tim; Mahan, Scott; Wilkinson, Jane; Ziaugra, Liuda; Onofrio, Robert; Bloom, Toby; Nicol, Rob; Ardlie, Kristin; Baldwin, Jennifer; Gabriel, Stacey; Fulton, Robert S.; McLellan, Michael D.; Larson, David E.; Shi, Xiaoqi; Abbott, Rachel; Fulton, Lucinda; Chen, Ken; Koboldt, Daniel C.; Wendl, Michael C.; Meyer, Rick; Tang, Yuzhu; Lin, Ling; Osborne, John R.; Dunford-Shore, Brian H.; Miner, Tracie L.; Delehaunty, Kim; Markovic, Chris; Swift, Gary; Courtney, William; Pohl, Craig; Abbott, Scott; Hawkins, Amy; Leong, Shin; Haipek, Carrie; Schmidt, Heather; Wiechert, Maddy; Vickery, Tammi; Scott, Sacha; Dooling, David J.; Chinwalla, Asif; Weinstock, George M.; O'Kelly, Michael; Robinson, Jim; Alexe, Gabriele; Beroukhim, Rameen; Carter, Scott; Chiang, Derek; Gould, Josh; Gupta, Supriya; Korn, Josh; Mermel, Craig; Mesirov, Jill; Monti, Stefano; Nguyen, Huy; Parkin, Melissa; Reich, Michael; Stransky, Nicolas; Garraway, Levi; Golub, Todd; Protopopov, Alexei; Perna, Ilana; Aronson, Sandy; Sathiamoorthy, Narayan; Ren, Georgia; Kim, Hyunsoo; Kong, Sek Won; Xiao, Yonghong; Kohane, Isaac S.; Seidman, Jon; Cope, Leslie; Pan, Fei; Van Den Berg, David; Van Neste, Leander; Yi, Joo Mi; Li, Jun Z.; Southwick, Audrey; Brady, Shannon; Aggarwal, Amita; Chung, Tisha; Sherlock, Gavin; Brooks, James D.; Jakkula, Lakshmi R.; Lapuk, Anna V.; Marr, Henry; Dorton, Shannon; Choi, Yoon Gi; Han, Ju; Ray, Amrita; Wang, Victoria; Durinck, Steffen; Robinson, Mark; Wang, Nicholas J.; Vranizan, Karen; Peng, Vivian; Van Name, Eric; Fontenay, Gerald V.; Ngai, John; Conboy, John G.; Parvin, Bahram; Feiler, Heidi S.; Speed, Terence P.; Socci, Nicholas D.; Olshen, Adam; Lash, Alex; Reva, Boris; Antipin, Yevgeniy; Stukalov, Alexey; Gross, Benjamin; Cerami, Ethan; Wang, Wei Qing; Qin, Li-Xuan; Seshan, Venkatraman E.; Villafania, Liliana; Cavatore, Magali; Borsu, Laetitia; Viale, Agnes; Gerald, William; Topal, Michael D.; Qi, Yuan; Balu, Sai; Shi, Yan; Wu, George; Bittner, Michael; Shelton, Troy; Lenkiewicz, Elizabeth; Morris, Scott; Beasley, Debbie; Sanders, Sheri; Sfeir, Robert; Chen, Jessica; Nassau, David; Feng, Larry; Hickey, Erin; Schaefer, Carl; Madhavan, Subha; Buetow, Ken; Barker, Anna; Vockley, Joseph; Compton, Carolyn; Vaught, Jim; Fielding, Peter; Collins, Francis; Good, Peter; Guyer, Mark; Ozenberger, Brad; Peterson, Jane; Thomson, Elizabeth

    2008-01-01

    Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular

  20. Comprehensive genomic characterization defines human glioblastoma genes and core pathways

    NARCIS (Netherlands)

    Chin, L.; Meyerson, M.; Aldape, K.; Bigner, D.; Mikkelsen, T.; VandenBerg, S.; Kahn, A.; Penny, R.; Gerhard, D. S.; Getz, G.; Brennan, C.; Taylor, B. S.; Winckler, W.; Park, P.; Ladanyi, M.; Hoadley, K. A.; Verhaak, R. G. W.; Hayes, D. N.; Spellman, Paul T.; Absher, D.; Weir, B. A.; Ding, L.; Wheeler, D.; Lawrence, M. S.; Cibulskis, K.; Mardis, E.; Zhang, Jinghui; Wilson, R. K.; Donehower, L.; Wheeler, D. A.; Purdom, E.; Wallis, J.; Laird, P. W.; Herman, J. G.; Schuebel, K. E.; Weisenberger, D. J.; Baylin, S. B.; Schultz, N.; Yao, Jun; Wiedemeyer, R.; Weinstein, J.; Sander, C.; Gibbs, R. A.; Gray, J.; Kucherlapati, R.; Lander, E. S.; Myers, R. M.; Perou, C. M.; McLendon, Roger; Friedman, Allan; Van Meir, Erwin G; Brat, Daniel J; Mastrogianakis, Gena Marie; Olson, Jeffrey J; Lehman, Norman; Yung, W. K. Alfred; Bogler, Oliver; Berger, Mitchel; Prados, Michael; Muzny, Donna; Morgan, Margaret; Scherer, Steve; Sabo, Aniko; Nazareth, Lynn; Lewis, Lora; Hall, Otis; Zhu, Yiming; Ren, Yanru; Alvi, Omar; Yao, Jiqiang; Hawes, Alicia; Jhangiani, Shalini; Fowler, Gerald; San Lucas, Anthony; Kovar, Christie; Cree, Andrew; Dinh, Huyen; Santibanez, Jireh; Joshi, Vandita; Gonzalez-Garay, Manuel L.; Miller, Christopher A.; Milosavljevic, Aleksandar; Sougnez, Carrie; Fennell, Tim; Mahan, Scott; Wilkinson, Jane; Ziaugra, Liuda; Onofrio, Robert; Bloom, Toby; Nicol, Rob; Ardlie, Kristin; Baldwin, Jennifer; Gabriel, Stacey; Fulton, Robert S.; McLellan, Michael D.; Larson, David E.; Shi, Xiaoqi; Abbott, Rachel; Fulton, Lucinda; Chen, Ken; Koboldt, Daniel C.; Wendl, Michael C.; Meyer, Rick; Tang, Yuzhu; Lin, Ling; Osborne, John R.; Dunford-Shore, Brian H.; Miner, Tracie L.; Delehaunty, Kim; Markovic, Chris; Swift, Gary; Courtney, William; Pohl, Craig; Abbott, Scott; Hawkins, Amy; Leong, Shin; Haipek, Carrie; Schmidt, Heather; Wiechert, Maddy; Vickery, Tammi; Scott, Sacha; Dooling, David J.; Chinwalla, Asif; Weinstock, George M.; O'Kelly, Michael; Robinson, Jim; Alexe, Gabriele; Beroukhim, Rameen; Carter, Scott; Chiang, Derek; Gould, Josh; Gupta, Supriya; Korn, Josh; Mermel, Craig; Mesirov, Jill; Monti, Stefano; Nguyen, Huy; Parkin, Melissa; Reich, Michael; Stransky, Nicolas; Garraway, Levi; Golub, Todd; Protopopov, Alexei; Perna, Ilana; Aronson, Sandy; Sathiamoorthy, Narayan; Ren, Georgia; Kim, Hyunsoo; Kong, Sek Won; Xiao, Yonghong; Kohane, Isaac S.; Seidman, Jon; Cope, Leslie; Pan, Fei; Van Den Berg, David; Van Neste, Leander; Yi, Joo Mi; Li, Jun Z.; Southwick, Audrey; Brady, Shannon; Aggarwal, Amita; Chung, Tisha; Sherlock, Gavin; Brooks, James D.; Jakkula, Lakshmi R.; Lapuk, Anna V.; Marr, Henry; Dorton, Shannon; Choi, Yoon Gi; Han, Ju; Ray, Amrita; Wang, Victoria; Durinck, Steffen; Robinson, Mark; Wang, Nicholas J.; Vranizan, Karen; Peng, Vivian; Van Name, Eric; Fontenay, Gerald V.; Ngai, John; Conboy, John G.; Parvin, Bahram; Feiler, Heidi S.; Speed, Terence P.; Socci, Nicholas D.; Olshen, Adam; Lash, Alex; Reva, Boris; Antipin, Yevgeniy; Stukalov, Alexey; Gross, Benjamin; Cerami, Ethan; Wang, Wei Qing; Qin, Li-Xuan; Seshan, Venkatraman E.; Villafania, Liliana; Cavatore, Magali; Borsu, Laetitia; Viale, Agnes; Gerald, William; Topal, Michael D.; Qi, Yuan; Balu, Sai; Shi, Yan; Wu, George; Bittner, Michael; Shelton, Troy; Lenkiewicz, Elizabeth; Morris, Scott; Beasley, Debbie; Sanders, Sheri; Sfeir, Robert; Chen, Jessica; Nassau, David; Feng, Larry; Hickey, Erin; Schaefer, Carl; Madhavan, Subha; Buetow, Ken; Barker, Anna; Vockley, Joseph; Compton, Carolyn; Vaught, Jim; Fielding, Peter; Collins, Francis; Good, Peter; Guyer, Mark; Ozenberger, Brad; Peterson, Jane; Thomson, Elizabeth

    2008-01-01

    Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular char

  1. In situ genomic DNA extraction for PCR analysis of regions of interest in four plant species and one filamentous fungi

    Directory of Open Access Journals (Sweden)

    Luis E. Rojas

    2014-07-01

    Full Text Available The extraction methods of genomic DNA are usually laborious and hazardous to human health and the environment by the use of organic solvents (chloroform and phenol. In this work a protocol for in situ extraction of genomic DNA by alkaline lysis is validated. It was used in order to amplify regions of DNA in four species of plants and fungi by polymerase chain reaction (PCR. From plant material of Saccharum officinarum L., Carica papaya L. and Digitalis purpurea L. it was possible to extend different regions of the genome through PCR. Furthermore, it was possible to amplify a fragment of avr-4 gene DNA purified from lyophilized mycelium of Mycosphaerella fijiensis. Additionally, it was possible to amplify the region ap24 transgene inserted into the genome of banana cv. `Grande naine' (Musa AAA. Key words: alkaline lysis, Carica papaya L., Digitalis purpurea L., Musa, Saccharum officinarum L.

  2. Thinking regionally: narrative, the medical humanities and region.

    Science.gov (United States)

    Waddington, Keir

    2015-06-01

    Drawing on multiple literatures from history, geography, anthropology, sociology and literature, this essay asks questions about what we mean by region and why narratives of region should matter to the medical humanities. The essay surveys how region can be used as a lens of analysis, exploring the various academic approaches to region and their limitations. It argues that regions are dynamic but also unstable as a category of analysis and are often used uncritically by scholars. In encouraging scholars working in the medical humanities to be aware that regions are not simple objective or analytical boxes, the essay shows how an awareness of region helps challenge metropolitan whiggism and ideas of core and periphery to give a more prominent place to hinterlands, market towns and rural environments. Furthermore, the essay considers how incorporating region into our understanding of illness can offer new insights. It demonstrates the need for scholars to be attuned to the narratives constructed around regions, suggesting that regions can be viewed as discursive formations that provide a frame for understanding both collective and personal ideas of, and responses to, health and illness, disease and healing, to create what Megan Davies calls a more nuanced 'intellectual cartography'.

  3. The Human Genome Project: big science transforms biology and medicine.

    Science.gov (United States)

    Hood, Leroy; Rowen, Lee

    2013-01-01

    The Human Genome Project has transformed biology through its integrated big science approach to deciphering a reference human genome sequence along with the complete sequences of key model organisms. The project exemplifies the power, necessity and success of large, integrated, cross-disciplinary efforts - so-called 'big science' - directed towards complex major objectives. In this article, we discuss the ways in which this ambitious endeavor led to the development of novel technologies and analytical tools, and how it brought the expertise of engineers, computer scientists and mathematicians together with biologists. It established an open approach to data sharing and open-source software, thereby making the data resulting from the project accessible to all. The genome sequences of microbes, plants and animals have revolutionized many fields of science, including microbiology, virology, infectious disease and plant biology. Moreover, deeper knowledge of human sequence variation has begun to alter the practice of medicine. The Human Genome Project has inspired subsequent large-scale data acquisition initiatives such as the International HapMap Project, 1000 Genomes, and The Cancer Genome Atlas, as well as the recently announced Human Brain Project and the emerging Human Proteome Project.

  4. Chimeric antibody with human constant regions and mouse variable regions directed against carcinoma-associated antigen 17-1A

    Energy Technology Data Exchange (ETDEWEB)

    Sun, L.K.; Curtis, P.; Rakowicz-Szulczynska, E.; Ghrayeb, J.; Chang, N.; Morrison, S.L.; Koprowski, H.

    1987-01-01

    The authors have cloned the genomic DNA fragments encoding the heavy and light chain variable regions of monoclonal antibody 17-1A, and they have inserted them into mammalian expression vectors containing genomic DNA segments encoding human ..gamma..3 and kappa constant regions. The transfer of these expression vectors containing mouse-human chimeric immunoglobulin genes into Sp2/0 mouse myeloma cells resulted in the production of functional IgG that retained the specific binding to the surface antigen 17-1A expressed on colorectal carcinoma cells.

  5. Rat Genome Database: a unique resource for rat, human, and mouse quantitative trait locus data.

    Science.gov (United States)

    Nigam, Rajni; Laulederkind, Stanley J F; Hayman, G Thomas; Smith, Jennifer R; Wang, Shur-Jen; Lowry, Timothy F; Petri, Victoria; De Pons, Jeff; Tutaj, Marek; Liu, Weisong; Jayaraman, Pushkala; Munzenmaier, Diane H; Worthey, Elizabeth A; Dwinell, Melinda R; Shimoyama, Mary; Jacob, Howard J

    2013-09-16

    The rat has been widely used as a disease model in a laboratory setting, resulting in an abundance of genetic and phenotype data from a wide variety of studies. These data can be found at the Rat Genome Database (RGD, http://rgd.mcw.edu/), which provides a platform for researchers interested in linking genomic variations to phenotypes. Quantitative trait loci (QTLs) form one of the earliest and core datasets, allowing researchers to identify loci harboring genes associated with disease. These QTLs are not only important for those using the rat to identify genes and regions associated with disease, but also for cross-organism analyses of syntenic regions on the mouse and the human genomes to identify potential regions for study in these organisms. Currently, RGD has data on >1,900 rat QTLs that include details about the methods and animals used to determine the respective QTL along with the genomic positions and markers that define the region. RGD also curates human QTLs (>1,900) and houses>4,000 mouse QTLs (imported from Mouse Genome Informatics). Multiple ontologies are used to standardize traits, phenotypes, diseases, and experimental methods to facilitate queries, analyses, and cross-organism comparisons. QTLs are visualized in tools such as GBrowse and GViewer, with additional tools for analysis of gene sets within QTL regions. The QTL data at RGD provide valuable information for the study of mapped phenotypes and identification of candidate genes for disease associations.

  6. Resolving the complexity of the human genome using single-molecule sequencing.

    Science.gov (United States)

    Chaisson, Mark J P; Huddleston, John; Dennis, Megan Y; Sudmant, Peter H; Malig, Maika; Hormozdiari, Fereydoun; Antonacci, Francesca; Surti, Urvashi; Sandstrom, Richard; Boitano, Matthew; Landolin, Jane M; Stamatoyannopoulos, John A; Hunkapiller, Michael W; Korlach, Jonas; Eichler, Evan E

    2015-01-29

    The human genome is arguably the most complete mammalian reference assembly, yet more than 160 euchromatic gaps remain and aspects of its structural variation remain poorly understood ten years after its completion. To identify missing sequence and genetic variation, here we sequence and analyse a haploid human genome (CHM1) using single-molecule, real-time DNA sequencing. We close or extend 55% of the remaining interstitial gaps in the human GRCh37 reference genome--78% of which carried long runs of degenerate short tandem repeats, often several kilobases in length, embedded within (G+C)-rich genomic regions. We resolve the complete sequence of 26,079 euchromatic structural variants at the base-pair level, including inversions, complex insertions and long tracts of tandem repeats. Most have not been previously reported, with the greatest increases in sensitivity occurring for events less than 5 kilobases in size. Compared to the human reference, we find a significant insertional bias (3:1) in regions corresponding to complex insertions and long short tandem repeats. Our results suggest a greater complexity of the human genome in the form of variation of longer and more complex repetitive DNA that can now be largely resolved with the application of this longer-read sequencing technology.

  7. Deciphering heterogeneity in pig genome assembly Sscrofa9 by isochore and isochore-like region analyses.

    Directory of Open Access Journals (Sweden)

    Wenqian Zhang

    Full Text Available BACKGROUND: The isochore, a large DNA sequence with relatively small GC variance, is one of the most important structures in eukaryotic genomes. Although the isochore has been widely studied in humans and other species, little is known about its distribution in pigs. PRINCIPAL FINDINGS: In this paper, we construct a map of long homogeneous genome regions (LHGRs, i.e., isochores and isochore-like regions, in pigs to provide an intuitive version of GC heterogeneity in each chromosome. The LHGR pattern study not only quantifies heterogeneities, but also reveals some primary characteristics of the chromatin organization, including the followings: (1 the majority of LHGRs belong to GC-poor families and are in long length; (2 a high gene density tends to occur with the appearance of GC-rich LHGRs; and (3 the density of LINE repeats decreases with an increase in the GC content of LHGRs. Furthermore, a portion of LHGRs with particular GC ranges (50%-51% and 54%-55% tend to have abnormally high gene densities, suggesting that biased gene conversion (BGC, as well as time- and energy-saving principles, could be of importance to the formation of genome organization. CONCLUSION: This study significantly improves our knowledge of chromatin organization in the pig genome. Correlations between the different biological features (e.g., gene density and repeat density and GC content of LHGRs provide a unique glimpse of in silico gene and repeats prediction.

  8. Variants in Several Genomic Regions Associated with Asperger Disorder

    Science.gov (United States)

    Salyakina, D.; Ma, D.Q.; Jaworski, J.M.; Konidari, I.; Whitehead, P.L.; Henson, R.; Martinez, D.; Robinson, J.L.; Sacharow, S.; Wright, H.H.; Abramson, R.K.; Gilbert, J.R.; Cuccaro, M.L.; Pericak-Vance, M.A.

    2010-01-01

    Asperger disorder (ASP) is one of the autism spectrum disorders (ASD) and is differentiated from autism largely on the absence of clinically significant cognitive and language delays. Analysis of a homogenous subset of families with ASP may help to address the corresponding effect of genetic heterogeneity on identifying ASD genetic risk factors. To examine the hypothesis that common variation is important in ASD, we performed a genome-wide association study (GWAS) in 124 ASP families in a discovery data set and 110 ASP families in a validation data set. We prioritized the top 100 association results from both cohorts by employing a ranking strategy. Novel regions on 5q21.1 (P = 9.7 × 10−7) and 15q22.1–q22.2 (P = 7.3 × 10−6) were our most significant findings in the combined data set. Three chromosomal regions showing association, 3p14.2 (P = 3.6 × 10−6), 3q25–26 (P = 6.0 × 10−5) and 3p23 (P = 3.3 × 10−4) overlapped linkage regions reported in Finnish ASP families, and eight association regions overlapped ASD linkage areas. Our findings suggest that ASP shares both ASD-related genetic risk factors, as well as has genetic risk factors unique to the ASP phenotype. PMID:21182207

  9. Genetical genomic determinants of alcohol consumption in rats and humans

    Directory of Open Access Journals (Sweden)

    Mangion Jonathan

    2009-10-01

    Full Text Available Abstract Background We have used a genetical genomic approach, in conjunction with phenotypic analysis of alcohol consumption, to identify candidate genes that predispose to varying levels of alcohol intake by HXB/BXH recombinant inbred rat strains. In addition, in two populations of humans, we assessed genetic polymorphisms associated with alcohol consumption using a custom genotyping array for 1,350 single nucleotide polymorphisms (SNPs. Our goal was to ascertain whether our approach, which relies on statistical and informatics techniques, and non-human animal models of alcohol drinking behavior, could inform interpretation of genetic association studies with human populations. Results In the HXB/BXH recombinant inbred (RI rats, correlation analysis of brain gene expression levels with alcohol consumption in a two-bottle choice paradigm, and filtering based on behavioral and gene expression quantitative trait locus (QTL analyses, generated a list of candidate genes. A literature-based, functional analysis of the interactions of the products of these candidate genes defined pathways linked to presynaptic GABA release, activation of dopamine neurons, and postsynaptic GABA receptor trafficking, in brain regions including the hypothalamus, ventral tegmentum and amygdala. The analysis also implicated energy metabolism and caloric intake control as potential influences on alcohol consumption by the recombinant inbred rats. In the human populations, polymorphisms in genes associated with GABA synthesis and GABA receptors, as well as genes related to dopaminergic transmission, were associated with alcohol consumption. Conclusion Our results emphasize the importance of the signaling pathways identified using the non-human animal models, rather than single gene products, in identifying factors responsible for complex traits such as alcohol consumption. The results suggest cross-species similarities in pathways that influence predisposition to consume

  10. Relevance of the Human Genome Project to inherited metabolic disease.

    Science.gov (United States)

    Burn, J

    1994-01-01

    The Human Genome Project is an international effort to identify the complete structure of the human genome. HUGO, the Human Genome Organization, facilitates international cooperation and exchange of information while the Genome Data Base will act as the on-line information retrieval and storage system for the huge amount of information being accumulated. The clinical register MIM (Mendelian Inheritance in Man) established by Victor McKusick is now an on-line resource that will allow biochemists working with inborn errors of metabolism to access the rapidly expanding body of knowledge. Biochemical and molecular genetics are complementary and should draw together to find solutions to the academic and clinical problems posed by inborn errors of metabolism.

  11. Genome editing: a robust technology for human stem cells.

    Science.gov (United States)

    Chandrasekaran, Arun Pandian; Song, Minjung; Ramakrishna, Suresh

    2017-09-01

    Human pluripotent stem cells comprise induced pluripotent and embryonic stem cells, which have tremendous potential for biological and therapeutic applications. The development of efficient technologies for the targeted genome alteration of stem cells in disease models is a prerequisite for utilizing stem cells to their full potential. Genome editing of stem cells is possible with the help of synthetic nucleases that facilitate site-specific modification of a gene of interest. Recent advances in genome editing techniques have improved the efficiency and speed of the development of stem cells for human disease models. Zinc finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system are powerful tools for editing DNA at specific loci. Here, we discuss recent technological advances in genome editing with site-specific nucleases in human stem cells.

  12. The genomic structure of the human UFO receptor.

    Science.gov (United States)

    Schulz, A S; Schleithoff, L; Faust, M; Bartram, C R; Janssen, J W

    1993-02-01

    Using a DNA transfection-tumorigenicity assay we have recently identified the UFO oncogene. It encodes a tyrosine kinase receptor characterized by the juxtaposition of two immunoglobulin-like and two fibronectin type III repeats in its extracellular domain. Here we describe the genomic organization of the human UFO locus. The UFO receptor is encoded by 20 exons that are distributed over a region of 44 kb. Different isoforms of UFO mRNA are generated by alternative splicing of exon 10 and differential usage of two imperfect polyadenylation sites resulting in the presence or absence of 1.5-kb 3' untranslated sequences. Primer extension and S1 nuclease analyses revealed multiple transcriptional initiation sites including a major site 169 bp upstream of the translation start site. The promoter region is GC rich, lacks TATA and CAAT boxes, but contains potential recognition sites for a variety of trans-acting factors, including Sp1, AP-2 and the cyclic AMP response element-binding protein. Proto-UFO and its oncogenic counterpart exhibit identical cDNA and promoter regions sequences. Possible modes of UFO activation are discussed.

  13. [The Human Genome Project and the right to intellectual property].

    Science.gov (United States)

    Cambrón, A

    2000-01-01

    The Human Genome Project was designed to achieve two objectives. The scientific goal was the mapping and sequencing of the human genome and the social objective was to benefit the health and well-being of humanity. Although the first objective is nearing successful conclusion, the same cannot be said for the second, mainly because the benefits will take some time to be applicable and effective, but also due to the very nature of the project. The HGP also had a clear economic dimension, which has had a major bearing on its social side. Operating in the midst of these three dimensions is the right to intellectual property (although not just this right), which has facilitated the granting of patents on human genes. Put another way, the carrying out of the HGP has required the privatisation of knowledge of the human genome, and this can be considered an attack on the genetic heritage of mankind.

  14. Identification of a novel gene by whole human genome tiling array.

    Science.gov (United States)

    Ishida, Hirokazu; Yagi, Tomohito; Tanaka, Masami; Tokuda, Yuichi; Kamoi, Kazumi; Hongo, Fumiya; Kawauchi, Akihiro; Nakano, Masakazu; Miki, Tsuneharu; Tashiro, Kei

    2013-03-01

    When the whole human genome sequence was determined by the Human Genome Project, the number of identified genes was fewer than expected. However, recent studies suggest that undiscovered transcripts still exist in the human genome. Furthermore, a new technology, the DNA microarray, which can simultaneously characterize huge amounts of genome sequence data, has become a useful tool for analyzing genetic changes in various diseases. A version of this tool, the tiling DNA microarray, was designed to search all the transcripts of the entire human genome, and provides huge amounts of data, including both exon and intron sequences, by a simple process. Although some previous studies using tiling DNA microarray analysis have indicated that numerous novel transcripts can be found in the human genome, none of them has reported any novel full-length human genes. Here, to find novel genes, we analyzed all the transcripts expressed in normal human prostate cells using this microarray. Because the optimal analytical parameters for using tiling DNA microarray data for this purpose had not been established, we established parameters for extracting the most likely regions for novel transcripts. The three parameters we optimized were the threshold for positive signal intensity, the Max gap, and the Min run, which we set to detect all transcriptional regions that were above the average length of known exons and had a signal intensity in the top 5%. We succeeded in obtaining the full-length sequence of one novel gene, located on chromosome 12q24.13. We named the novel gene "POTAGE". Its 5841-bp mRNA consists of 26 exons. We detected part of exon 2 in the tiling data analysis. The full-length sequence was then obtained by RT-PCR and RACE. Although the function of POTAGE is unclear, its sequence showed high homology with genes in other species, suggesting it might have an important or essential function. This study demonstrates that the tiling DNA microarray can be useful for

  15. 75 FR 52537 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2010-08-26

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Initial Review Group; Genome Research Review... Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes of Health, HHS)...

  16. 75 FR 2148 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2010-01-14

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Initial Review Group, Genome Research Review... Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes of Health, HHS)...

  17. 78 FR 24223 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2013-04-24

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Initial Review Group; Genome Research Review... applications. Place: National Human Genome Research Institute, 3rd floor Conf. Room 3146, 5635 Fishers...

  18. 76 FR 3643 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2011-01-20

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Initial Review Group; Genome Research Review... Assistance Program Nos. 93.172, Human Genome Research, National Institutes of Health, HHS) Dated: January...

  19. Tandem repeat regions within the Burkholderia pseudomallei genome and their application for high resolution genotyping

    Directory of Open Access Journals (Sweden)

    Harvey Steven P

    2007-03-01

    Full Text Available Abstract Background The facultative, intracellular bacterium Burkholderia pseudomallei is the causative agent of melioidosis, a serious infectious disease of humans and animals. We identified and categorized tandem repeat arrays and their distribution throughout the genome of B. pseudomallei strain K96243 in order to develop a genetic typing method for B. pseudomallei. We then screened 104 of the potentially polymorphic loci across a diverse panel of 31 isolates including B. pseudomallei, B. mallei and B. thailandensis in order to identify loci with varying degrees of polymorphism. A subset of these tandem repeat arrays were subsequently developed into a multiple-locus VNTR analysis to examine 66 B. pseudomallei and 21 B. mallei isolates from around the world, as well as 95 lineages from a serial transfer experiment encompassing ~18,000 generations. Results B. pseudomallei contains a preponderance of tandem repeat loci throughout its genome, many of which are duplicated elsewhere in the genome. The majority of these loci are composed of repeat motif lengths of 6 to 9 bp with 4 to 10 repeat units and are predominately located in intergenic regions of the genome. Across geographically diverse B. pseudomallei and B.mallei isolates, the 32 VNTR loci displayed between 7 and 28 alleles, with Nei's diversity values ranging from 0.47 and 0.94. Mutation rates for these loci are comparable (>10-5 per locus per generation to that of the most diverse tandemly repeated regions found in other less diverse bacteria. Conclusion The frequency, location and duplicate nature of tandemly repeated regions within the B. pseudomallei genome indicate that these tandem repeat regions may play a role in generating and maintaining adaptive genomic variation. Multiple-locus VNTR analysis revealed extensive diversity within the global isolate set containing B. pseudomallei and B. mallei, and it detected genotypic differences within clonal lineages of both species that were

  20. Genome-Wide Association Study Reveals Genetic Architecture of Eating Behaviors in Pigs and its Implications for Humans Obesity by Comparative Genome Mapping

    DEFF Research Database (Denmark)

    Do, Duy Ngoc; Strathe, Anders Bjerring; Ostersen, Tage;

    2013-01-01

    This study was aimed at identifying genomic regions controlling feeding behaviors inDanish Duroc boars and its potential implications for eating behaviors in humans.Individual daily feed intake (DFI), total daily time spent in feeder (TPD), number of dailyvisits to feeder (NVD), time spent to eat...... chromosome (SSC) 14 was very strongly associated with NVD (p =9.6E-07). Thirty six SNPs were located in genome regions where QTLs havepreviously been reported...... for geneticimprovement of pig feed efficiency. The results of pig-human comparative genemapping revealed some important genomic regions and/or genes on the humangenome that may influence eating behavior in human and consequently affect thedevelopment of obesity and metabolic syndromes. This is the first...

  1. Genetic recombination pathways and their application for genome modification of human embryonic stem cells.

    Science.gov (United States)

    Nieminen, Mikko; Tuuri, Timo; Savilahti, Harri

    2010-10-01

    Human embryonic stem cells are pluripotent cells derived from early human embryo and retain a potential to differentiate into all adult cell types. They provide vast opportunities in cell replacement therapies and are expected to become significant tools in drug discovery as well as in the studies of cellular and developmental functions of human genes. The progress in applying different types of DNA recombination reactions for genome modification in a variety of eukaryotic cell types has provided means to utilize recombination-based strategies also in human embryonic stem cells. Homologous recombination-based methods, particularly those utilizing extended homologous regions and those employing zinc finger nucleases to boost genomic integration, have shown their usefulness in efficient genome modification. Site-specific recombination systems are potent genome modifiers, and they can be used to integrate DNA into loci that contain an appropriate recombination signal sequence, either naturally occurring or suitably pre-engineered. Non-homologous recombination can be used to generate random integrations in genomes relatively effortlessly, albeit with a moderate efficiency and precision. DNA transposition-based strategies offer substantially more efficient random strategies and provide means to generate single-copy insertions, thus potentiating the generation of genome-wide insertion libraries applicable in genetic screens.

  2. Genome-wide studies highlight indirect links between human replication origins and gene regulation.

    Science.gov (United States)

    Cadoret, Jean-Charles; Meisch, Françoise; Hassan-Zadeh, Vahideh; Luyten, Isabelle; Guillet, Claire; Duret, Laurent; Quesneville, Hadi; Prioleau, Marie-Noëlle

    2008-10-14

    To get insights into the regulation of replication initiation, we systematically mapped replication origins along 1% of the human genome in HeLa cells. We identified 283 origins, 10 times more than previously known. Origin density is strongly correlated with genomic landscapes, with clusters of closely spaced origins in GC-rich regions and no origins in large GC-poor regions. Origin sequences are evolutionarily conserved, and half of them map within or near CpG islands. Most of the origins overlap transcriptional regulatory elements, providing further evidence of a connection with gene regulation. Moreover, we identify c-JUN and c-FOS as important regulators of origin selection. Half of the identified replication initiation sites do not have an open chromatin configuration, showing the absence of a direct link with gene regulation. Replication timing analyses coupled with our origin mapping suggest that a relatively strict origin-timing program regulates the replication of the human genome.

  3. Human genome and open source: balancing ethics and business.

    Science.gov (United States)

    Marturano, Antonio

    2011-01-01

    The Human Genome Project has been completed thanks to a massive use of computer techniques, as well as the adoption of the open-source business and research model by the scientists involved. This model won over the proprietary model and allowed a quick propagation and feedback of research results among peers. In this paper, the author will analyse some ethical and legal issues emerging by the use of such computer model in the Human Genome property rights. The author will argue that the Open Source is the best business model, as it is able to balance business and human rights perspectives.

  4. Sequencing and analysis of an Irish human genome.

    LENUS (Irish Health Repository)

    Tong, Pin

    2010-01-01

    Recent studies generating complete human sequences from Asian, African and European subgroups have revealed population-specific variation and disease susceptibility loci. Here, choosing a DNA sample from a population of interest due to its relative geographical isolation and genetic impact on further populations, we extend the above studies through the generation of 11-fold coverage of the first Irish human genome sequence.

  5. From hacking the human genome to editing organs.

    Science.gov (United States)

    Tobita, Takamasa; Guzman-Lepe, Jorge; Collin de l'Hortet, Alexandra

    2015-01-01

    In the recent decades, human genome engineering has been one of the major interesting research subjects, essentially because it raises new possibilities for personalized medicine and biotechnologies. With the development of engineered nucleases such as the Zinc Finger Nucleases (ZFNs), the Transcription activator-like effector nucleases (TALENs) and more recently the Clustered Regularly Interspaced short Palindromic Repeats (CRISPR), the field of human genome edition has evolved very rapidly. Every new genetic tool is broadening the scope of applications on human tissues, even before we can completely master each of these tools. In this review, we will present the recent advances regarding human genome edition tools, we will discuss the numerous implications they have in research and medicine, and we will mention the limits and concerns about such technologies.

  6. Progress in the detection of human genome structural variations

    Institute of Scientific and Technical Information of China (English)

    WU XueMei; XIAO HuaSheng

    2009-01-01

    The emerging of high.throughput and high-resolution genomic technologies led to the detection of submicroscopic variants ranging from 1 kb to 3 Mb in the human genome. These variants include copy number variations (CNVs), inversions, insertions, deletions and other complex rearrangements of DNA sequences. This paper briefly reviews the commonly used technologies to discover both genomic structural variants and their potential influences. Particularly, we highlight the array-based, PCR-based and sequencing-based assays, including array-based comparative genomic hybridization (aCGH),representational oligonucleotide microarray analysis (ROMA), multiplex amplifiable probe hybridization (MAPH), multiplex ligation-dependent probe amplification (MLPA), paired-end mapping (PEM), and next-generation DNA sequencing technologies. Furthermore, we discuss the limitations and challenges of current assays and give advices on how to make the database of genomic variations more reliable.

  7. Progress in the detection of human genome structural variations

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    The emerging of high-throughput and high-resolution genomic technologies led to the detection of submicroscopic variants ranging from 1 kb to 3 Mb in the human genome.These variants include copy number variations(CNVs),inversions,insertions,deletions and other complex rearrangements of DNA sequences.This paper briefly reviews the commonly used technologies to discover both genomic structural variants and their potential influences.Particularly,we highlight the array-based,PCR-based and sequencing-based assays,including array-based comparative genomic hybridization(aCGH),representational oligonucleotide microarray analysis(ROMA),multiplex amplifiable probe hybridization(MAPH),multiplex ligation-dependent probe amplification(MLPA),paired-end mapping(PEM),and next-generation DNA sequencing technologies.Furthermore,we discuss the limitations and challenges of current assays and give advices on how to make the database of genomic variations more reliable.

  8. Organization and evolution of a gene-rich region of the mouse genome: a 12.7-Mb region deleted in the Del(13)Svea36H mouse.

    Science.gov (United States)

    Mallon, Ann-Marie; Wilming, Laurens; Weekes, Joseph; Gilbert, James G R; Ashurst, Jennifer; Peyrefitte, Sandrine; Matthews, Lucy; Cadman, Matthew; McKeone, Richard; Sellick, Chris A; Arkell, Ruth; Botcherby, Marc R M; Strivens, Mark A; Campbell, R Duncan; Gregory, Simon; Denny, Paul; Hancock, John M; Rogers, Jane; Brown, Steve D M

    2004-10-01

    Del(13)Svea36H (Del36H) is a deletion of approximately 20% of mouse chromosome 13 showing conserved synteny with human chromosome 6p22.1-6p22.3/6p25. The human region is lost in some deletion syndromes and is the site of several disease loci. Heterozygous Del36H mice show numerous phenotypes and may model aspects of human genetic disease. We describe 12.7 Mb of finished, annotated sequence from Del36H. Del36H has a higher gene density than the draft mouse genome, reflecting high local densities of three gene families (vomeronasal receptors, serpins, and prolactins) which are greatly expanded relative to human. Transposable elements are concentrated near these gene families. We therefore suggest that their neighborhoods are gene factories, regions of frequent recombination in which gene duplication is more frequent. The gene families show different proportions of pseudogenes, likely reflecting different strengths of purifying selection and/or gene conversion. They are also associated with relatively low simple sequence concentrations, which vary across the region with a periodicity of approximately 5 Mb. Del36H contains numerous evolutionarily conserved regions (ECRs). Many lie in noncoding regions, are detectable in species as distant as Ciona intestinalis, and therefore are candidate regulatory sequences. This analysis will facilitate functional genomic analysis of Del36H and provides insights into mouse genome evolution.

  9. Learning about human population history from ancient and modern genomes.

    Science.gov (United States)

    Stoneking, Mark; Krause, Johannes

    2011-08-18

    Genome-wide data, both from SNP arrays and from complete genome sequencing, are becoming increasingly abundant and are now even available from extinct hominins. These data are providing new insights into population history; in particular, when combined with model-based analytical approaches, genome-wide data allow direct testing of hypotheses about population history. For example, genome-wide data from both contemporary populations and extinct hominins strongly support a single dispersal of modern humans from Africa, followed by two archaic admixture events: one with Neanderthals somewhere outside Africa and a second with Denisovans that (so far) has only been detected in New Guinea. These new developments promise to reveal new stories about human population history, without having to resort to storytelling.

  10. Natural selection affects multiple aspects of genetic variation at putatively peutral sites across the human genome

    DEFF Research Database (Denmark)

    Lohmueller, Kirk E; Albrechtsen, Anders; Li, Yingrui;

    2011-01-01

    throughout the genome. Further, we show that the widespread presence of weakly deleterious alleles, rather than a small number of strongly positively selected mutations, is responsible for the correlation between neutral genetic diversity and recombination rate. This work suggests that natural selection has......A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries...... and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations...

  11. Evolutionary genomic remodelling of the human 4q subtelomere (4q35.2

    Directory of Open Access Journals (Sweden)

    Riva Paola

    2007-03-01

    Full Text Available Abstract Background In order to obtain insights into the functionality of the human 4q35.2 domain harbouring the facioscapulohumeral muscular dystrophy (FSHD locus, we investigated in African apes genomic and chromatin organisations, and the nuclear topology of orthologous regions. Results A basic block consisting of short D4Z4 arrays (10–15 repeats, 4q35.2 specific sequences, and approximately 35 kb of interspersed repeats from different LINE subfamilies was repeated at least twice in the gorilla 4qter. This genomic organisation has undergone evolutionary remodelling, leading to the single representation of both the D4Z4 array and LINE block in chimpanzee, and the loss of the LINE block in humans. The genomic remodelling has had an impact on 4qter chromatin organisation, but not its interphase nuclear topology. In comparison with humans, African apes show very low or undetectable levels of FRG1 and FRG2 histone 4 acetylation and gene transcription, although histone deacetylase inhibition restores gene transcription to levels comparable with those of human cells, thus indicating that the 4qter region is capable of acquiring a more open chromatin structure. Conversely, as in humans, the 4qter region in African apes has a very peripheral nuclear localisation. Conclusion The 4q subtelomere has undergone substantial genomic changes during evolution that have had an impact on chromatin condensation and the region's transcriptional regulation. Consequently, the 4qter genes in African apes and humans seem to be subjected to a different strategy of regulation in which LINE and D4Z4 sequences may play a pivotal role. However, the effect of peripheral nuclear anchoring of 4qter on these regulation mechanisms is still unclear. The observed differences in the regulation of 4qter gene expression between African apes and humans suggest that the human 4q35.2 locus has acquired a novel functional relevance.

  12. Primer on Molecular Genetics; DOE Human Genome Program

    Science.gov (United States)

    1992-04-01

    This report is taken from the April 1992 draft of the DOE Human Genome 1991--1992 Program Report, which is expected to be published in May 1992. The primer is intended to be an introduction to basic principles of molecular genetics pertaining to the genome project. The material contained herein is not final and may be incomplete. Techniques of genetic mapping and DNA sequencing are described.

  13. Genomics of Streptococcus salivarius, a major human commensal.

    Science.gov (United States)

    Delorme, Christine; Abraham, Anne-Laure; Renault, Pierre; Guédon, Eric

    2015-07-01

    The salivarius group of streptococci is of particular importance for humans. This group consists of three genetically similar species, Streptococcus salivarius, Streptococcus vestibularis and Streptococcus thermophilus. S. salivarius and S. vestibularis are commensal organisms that may occasionally cause opportunistic infections in humans, whereas S. thermophilus is a food bacterium widely used in dairy production. We developed Multilocus sequence typing (MLST) and comparative genomic analysis to confirm the clear separation of these three species. These analyses also identified a subgroup of four strains, with a core genome diverging by about 10%, in terms of its nucleotide sequence, from that of S. salivarius sensu stricto. S. thermophilus species displays a low level of nucleotide variability, due to its recent emergence with the development of agriculture. By contrast, nucleotide variability is high in the other two species of the salivarius group, reflecting their long-standing association with humans. The species of the salivarius group have genome sizes ranging from the smallest (∼ 1.7 Mb for S. thermophilus) to the largest (∼ 2.3 Mb for S. salivarius) among streptococci, reflecting genome reduction linked to a narrow, nutritionally rich environment for S. thermophilus, and natural, more competitive niches for the other two species. Analyses of genomic content have indicated that the core genes of S. salivarius account for about two thirds of the genome, indicating considerable variability of gene content and differences in potential adaptive features. Furthermore, we showed that the genome of this species is exceptionally rich in genes encoding surface factors, glycosyltransferases and response regulators. Evidence of widespread genetic exchanges was obtained, probably involving a natural competence system and the presence of diverse mobile elements. However, although the S. salivarius strains studied were isolated from several human body-related sites

  14. Primer on molecular genetics. DOE Human Genome Program

    Energy Technology Data Exchange (ETDEWEB)

    1992-04-01

    This report is taken from the April 1992 draft of the DOE Human Genome 1991--1992 Program Report, which is expected to be published in May 1992. The primer is intended to be an introduction to basic principles of molecular genetics pertaining to the genome project. The material contained herein is not final and may be incomplete. Techniques of genetic mapping and DNA sequencing are described.

  15. The human genome project: Prospects and implications for clinical medicine

    Energy Technology Data Exchange (ETDEWEB)

    Green, E.D.; Waterston, R.H. (Washington Univ., St. Louis, MO (United States))

    1991-10-09

    The recently initiated human genome project is a large international effort to elucidate the genetic architecture of the genomes of man and several model organisms. The initial phases of this endeavor involve the establishment of rough blueprints (maps) of the genetic landscape of these genomes, with the long-term goal of determining their precise nucleotide sequences and identifying the genes. The knowledge gained by these studies will provide a vital tool for the study of many biologic processes and will have a profound impact on clinical medicine.

  16. How rapidly does the human mitochondrial genome evolve?

    Energy Technology Data Exchange (ETDEWEB)

    Howell, N.; Kubacka, I. [Univ. of Texas Medical Branch, Galveston, TX (United States); Mackey, D.A. [Univ. of Melbourne (Australia)]|[Univ. of Tasmania, Launceston (Australia)

    1996-09-01

    The results of an empirical nucleotide-sequencing approach indicate that the evolution of the human mitochondrial noncoding D-loop is both more rapid and more complex than is revealed by standard phylogenetic approaches. The nucleotide sequence of the D-loop region of the mitochondrial genome was determined for 45 members of a large matrilineal Leber hereditary optic neuropathy pedigree. Two germ-line mutations have arisen in members of one branch of the family, thereby leading to triplasmic descendants with three mitochondrial genotypes. Segregation toward the homoplasmic state can occur within a single generation in some of these descendants, a result that suggests rapid fixation of mitochondrial mutations as a result of developmental bottlenecking. However, slow segregation was observed in other offspring, and therefore no single or simple pattern of segregation can be generalized from the available data. Evidence for rare mtDNA recombination within the D-loop was obtained for one family member. In addition to these germ-line mutations, a somatic mutation was found in the D-loop of one family member. When this genealogical approach was applied to the nucleotide sequences of mitochondrial coding regions, the results again indicated a very rapid rate of evolution. 44 refs., 2 figs., 2 tabs.

  17. Genome-Wide Analysis of DNA Methylation in Human Amnion

    Directory of Open Access Journals (Sweden)

    Jinsil Kim

    2013-01-01

    Full Text Available The amnion is a specialized tissue in contact with the amniotic fluid, which is in a constantly changing state. To investigate the importance of epigenetic events in this tissue in the physiology and pathophysiology of pregnancy, we performed genome-wide DNA methylation profiling of human amnion from term (with and without labor and preterm deliveries. Using the Illumina Infinium HumanMethylation27 BeadChip, we identified genes exhibiting differential methylation associated with normal labor and preterm birth. Functional analysis of the differentially methylated genes revealed biologically relevant enriched gene sets. Bisulfite sequencing analysis of the promoter region of the oxytocin receptor (OXTR gene detected two CpG dinucleotides showing significant methylation differences among the three groups of samples. Hypermethylation of the CpG island of the solute carrier family 30 member 3 (SLC30A3 gene in preterm amnion was confirmed by methylation-specific PCR. This work provides preliminary evidence that DNA methylation changes in the amnion may be at least partially involved in the physiological process of labor and the etiology of preterm birth and suggests that DNA methylation profiles, in combination with other biological data, may provide valuable insight into the mechanisms underlying normal and pathological pregnancies.

  18. Genome-Wide Analysis of DNA Methylation in Human Amnion

    Science.gov (United States)

    Kim, Jinsil; Pitlick, Mitchell M.; Christine, Paul J.; Schaefer, Amanda R.; Saleme, Cesar; Comas, Belén; Cosentino, Viviana; Gadow, Enrique; Murray, Jeffrey C.

    2013-01-01

    The amnion is a specialized tissue in contact with the amniotic fluid, which is in a constantly changing state. To investigate the importance of epigenetic events in this tissue in the physiology and pathophysiology of pregnancy, we performed genome-wide DNA methylation profiling of human amnion from term (with and without labor) and preterm deliveries. Using the Illumina Infinium HumanMethylation27 BeadChip, we identified genes exhibiting differential methylation associated with normal labor and preterm birth. Functional analysis of the differentially methylated genes revealed biologically relevant enriched gene sets. Bisulfite sequencing analysis of the promoter region of the oxytocin receptor (OXTR) gene detected two CpG dinucleotides showing significant methylation differences among the three groups of samples. Hypermethylation of the CpG island of the solute carrier family 30 member 3 (SLC30A3) gene in preterm amnion was confirmed by methylation-specific PCR. This work provides preliminary evidence that DNA methylation changes in the amnion may be at least partially involved in the physiological process of labor and the etiology of preterm birth and suggests that DNA methylation profiles, in combination with other biological data, may provide valuable insight into the mechanisms underlying normal and pathological pregnancies. PMID:23533356

  19. Human genome and the african personality: implications for social work.

    Science.gov (United States)

    Mickel, Elijah; Miller, Sheila D

    2011-01-01

    The integration of the human genome with the African personality should be viewed as an interdependent whole. The African personality, for purposes of this article, comprises Black experiences, Negritude, and an Africa-centered axiology and epistemology. The outcome results in a spiritual focused collective consciousness. Anthropologically, historically (and with the Human Genome Project), genetically Africa has proven to be the source of all human life. Human kind wherever they exist on the planet using the African personality must be viewed as interconnected. Although racism and its progeny discrimination preexist the human genome project (HGP), the human genome provides an evidence-based rationale for the end to all policy and subsequent practice based on race and racism. Policy must be based on evidence to be competent practice. It would be remiss if not irresponsible of social work and the other behavioral scientist concerned with intervention and prevention behaviors to not infuse the findings of the HCPs. The African personality is a concept that provides a wholistic way to evaluate human behavior from an African worldview.

  20. A complex genome-microRNA interplay in human mitochondria.

    Science.gov (United States)

    Shinde, Santosh; Bhadra, Utpal

    2015-01-01

    Small noncoding regulatory RNA exist in wide spectrum of organisms ranging from prokaryote bacteria to humans. In human, a systematic search for noncoding RNA is mainly limited to the nuclear and cytosolic compartments. To investigate whether endogenous small regulatory RNA are present in cell organelles, human mitochondrial genome was also explored for prediction of precursor microRNA (pre-miRNA) and mature miRNA (miRNA) sequences. Six novel miRNA were predicted from the organelle genome by bioinformatics analysis. The structures are conserved in other five mammals including chimp, orangutan, mouse, rat, and rhesus genome. Experimentally, six human miRNA are well accumulated or deposited in human mitochondria. Three of them are expressed less prominently in Northern analysis. To ascertain their presence in human skeletal muscles, total RNA was extracted from enriched mitochondria by an immunomagnetic method. The expression of six novel pre-miRNA and miRNA was confirmed by Northern blot analysis; however, low level of remaining miRNA was found by sensitive Northern analysis. Their presence is further confirmed by real time RT-PCR. The six miRNA find their multiple targets throughout the human genome in three different types of software. The luciferase assay was used to confirm that MT-RNR2 gene was the potential target of hsa-miR-mit3 and hsa-miR-mit4.

  1. Dynamic evolution of Rht-1 homologous regions in grass genomes

    Science.gov (United States)

    Bread wheat contains A, B, and D subgenomes with its well characterized ancestral genomes that exist at the diploid and tetraploid levels. Therefore, the wheat genome system acts as a model specie for studying genome evolutionary dynamics. Here, we performed intra- and inter-species comparative ana...

  2. Phylogenetic analysis of the genomes of two strains of human adenovirus type 3

    Institute of Scientific and Technical Information of China (English)

    RONG ZHOU; XIAO Bo SU; QI WEI ZIIANG; QI YI ZENG; BING ZHU; CHU Yu ZHANG; Hou Bo WU; ZAO HE WU; SI TANG GONG

    2007-01-01

    Human adenovirus type 3 (HAdV-3) is widely prevalent all over the world, especially in Asia. The objective of this study is to carry out complete genomic DNA sequencing and the phylogenetic analysis for two strains (Guangzhou01 and Guangzhou02) of HAdV-3 wild virus isolated from South China. Nasopharyngeal secretion aspirate specimens of sick children were inoculated into HEp-2 and HeLa culture tubes, and the cultures were identified by neutralization assay with type-specific reference rabbit antisermn. Type-specific primers were also utilized to confirm the serotype. The restriction fragments of HAdV genome DNA were cloned into pBlueScript SK ( + ) vectors and sequenced, and the 5' and 3'ends of the linear HAdV-3 genome were directly sequenced with double purified genomic DNA as templates. General features of the HAdV-3 genome sequences were explored by using several bio-software.Phylogenetic analysis was done with MEGA 3.0 software. The genomic sequences of Guangzhou01 and Guangzhou02 possess the same 4 early regions and 5 late regions and have 39 ceding sequences and two RNA coding sequences. Other non-ceding regions are conservative. Inverted repeats and palindromes were identified in the genome sequences. The genomes of group B human adenovirus as well as HAdV-3have close phylogenetic relationship with that of chimpanzee adenovirus type 21. The genomie lengths of these two isolated strains are 35 273 bp and 35 269 bp, respectively. The phylogenetie analysis showed that HAdV-B species has some relationship with eertain types of chimpanzee adenovirus.

  3. Genomic signatures of diet-related shifts during human origins.

    Science.gov (United States)

    Babbitt, Courtney C; Warner, Lisa R; Fedrigo, Olivier; Wall, Christine E; Wray, Gregory A

    2011-04-07

    There are numerous anthropological analyses concerning the importance of diet during human evolution. Diet is thought to have had a profound influence on the human phenotype, and dietary differences have been hypothesized to contribute to the dramatic morphological changes seen in modern humans as compared with non-human primates. Here, we attempt to integrate the results of new genomic studies within this well-developed anthropological context. We then review the current evidence for adaptation related to diet, both at the level of sequence changes and gene expression. Finally, we propose some ways in which new technologies can help identify specific genomic adaptations that have resulted in metabolic and morphological differences between humans and non-human primates.

  4. Genome-wide association identifies multiple genomic regions associated with susceptibility to and control of ovine lentivirus.

    Directory of Open Access Journals (Sweden)

    Stephen N White

    Full Text Available BACKGROUND: Like human immunodeficiency virus (HIV, ovine lentivirus (OvLV is macrophage-tropic and causes lifelong infection. OvLV infects one quarter of U.S. sheep and induces pneumonia and body condition wasting. There is no vaccine to prevent OvLV infection and no cost-effective treatment for infected animals. However, breed differences in prevalence and proviral concentration have indicated a genetic basis for susceptibility to OvLV. A recent study identified TMEM154 variants in OvLV susceptibility. The objective here was to identify additional loci associated with odds and/or control of OvLV infection. METHODOLOGY/PRINCIPAL FINDINGS: This genome-wide association study (GWAS included 964 sheep from Rambouillet, Polypay, and Columbia breeds with serological status and proviral concentration phenotypes. Analytic models accounted for breed and age, as well as genotype. This approach identified TMEM154 (nominal P=9.2×10(-7; empirical P=0.13, provided 12 additional genomic regions associated with odds of infection, and provided 13 regions associated with control of infection (all nominal P<1 × 10(-5. Rapid decline of linkage disequilibrium with distance suggested many regions included few genes each. Genes in regions associated with odds of infection included DPPA2/DPPA4 (empirical P=0.006, and SYTL3 (P=0.051. Genes in regions associated with control of infection included a zinc finger cluster (ZNF192, ZSCAN16, ZNF389, and ZNF165; P=0.001, C19orf42/TMEM38A (P=0.047, and DLGAP1 (P=0.092. CONCLUSIONS/SIGNIFICANCE: These associations provide targets for mutation discovery in sheep susceptibility to OvLV. Aside from TMEM154, these genes have not been associated previously with lentiviral infection in any species, to our knowledge. Further, data from other species suggest functional hypotheses for future testing of these genes in OvLV and other lentiviral infections. Specifically, SYTL3 binds and may regulate RAB27A, which is required for enveloped

  5. Genome-wide expression profiling of complex regional pain syndrome.

    Directory of Open Access Journals (Sweden)

    Eun-Heui Jin

    Full Text Available Complex regional pain syndrome (CRPS is a chronic, progressive, and devastating pain syndrome characterized by spontaneous pain, hyperalgesia, allodynia, altered skin temperature, and motor dysfunction. Although previous gene expression profiling studies have been conducted in animal pain models, there genome-wide expression profiling in the whole blood of CRPS patients has not been reported yet. Here, we successfully identified certain pain-related genes through genome-wide expression profiling in the blood from CRPS patients. We found that 80 genes were differentially expressed between 4 CRPS patients (2 CRPS I and 2 CRPS II and 5 controls (cut-off value: 1.5-fold change and p<0.05. Most of those genes were associated with signal transduction, developmental processes, cell structure and motility, and immunity and defense. The expression levels of major histocompatibility complex class I A subtype (HLA-A29.1, matrix metalloproteinase 9 (MMP9, alanine aminopeptidase N (ANPEP, l-histidine decarboxylase (HDC, granulocyte colony-stimulating factor 3 receptor (G-CSF3R, and signal transducer and activator of transcription 3 (STAT3 genes selected from the microarray were confirmed in 24 CRPS patients and 18 controls by quantitative reverse transcription-polymerase chain reaction (qRT-PCR. We focused on the MMP9 gene that, by qRT-PCR, showed a statistically significant difference in expression in CRPS patients compared to controls with the highest relative fold change (4.0±1.23 times and p = 1.4×10(-4. The up-regulation of MMP9 gene in the blood may be related to the pain progression in CRPS patients. Our findings, which offer a valuable contribution to the understanding of the differential gene expression in CRPS may help in the understanding of the pathophysiology of CRPS pain progression.

  6. High-Throughput resequencing of maize landraces at genomic regions associated with flowering time

    Science.gov (United States)

    Despite the reduction in the price of sequencing, it remains expensive to sequence and assemble whole, complex genomes of multiple samples for population studies, particularly for large genomes like those of many crop species. Enrichment of target genome regions coupled with next generation sequenci...

  7. Prospects for the Chinese Human Genome Project (HGP)at the beginning of next century

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Chinese Human Genome Project (CHGP) as part of the international human genome research has achieved significant progress and created a solid foundation for further development. While participating in the human genome sequencing and gene discovery, the emphasis of CHGP in the next century will be laid on functional genomics. The strategy, resources and some policy issues will be addressed.

  8. AluScan: a method for genome-wide scanning of sequence and structure variations in the human genome

    Directory of Open Access Journals (Sweden)

    Mei Lingling

    2011-11-01

    Full Text Available Abstract Background To complement next-generation sequencing technologies, there is a pressing need for efficient pre-sequencing capture methods with reduced costs and DNA requirement. The Alu family of short interspersed nucleotide elements is the most abundant type of transposable elements in the human genome and a recognized source of genome instability. With over one million Alu elements distributed throughout the genome, they are well positioned to facilitate genome-wide sequence amplification and capture of regions likely to harbor genetic variation hotspots of biological relevance. Results Here we report on the use of inter-Alu PCR with an enhanced range of amplicons in conjunction with next-generation sequencing to generate an Alu-anchored scan, or 'AluScan', of DNA sequences between Alu transposons, where Alu consensus sequence-based 'H-type' PCR primers that elongate outward from the head of an Alu element are combined with 'T-type' primers elongating from the poly-A containing tail to achieve huge amplicon range. To illustrate the method, glioma DNA was compared with white blood cell control DNA of the same patient by means of AluScan. The over 10 Mb sequences obtained, derived from more than 8,000 genes spread over all the chromosomes, revealed a highly reproducible capture of genomic sequences enriched in genic sequences and cancer candidate gene regions. Requiring only sub-micrograms of sample DNA, the power of AluScan as a discovery tool for genetic variations was demonstrated by the identification of 357 instances of loss of heterozygosity, 341 somatic indels, 274 somatic SNVs, and seven potential somatic SNV hotspots between control and glioma DNA. Conclusions AluScan, implemented with just a small number of H-type and T-type inter-Alu PCR primers, provides an effective capture of a diversity of genome-wide sequences for analysis. The method, by enabling an examination of gene-enriched regions containing exons, introns, and

  9. Pan-genome sequence analysis using Panseq: an online tool for the rapid analysis of core and accessory genomic regions

    Directory of Open Access Journals (Sweden)

    Villegas Andre

    2010-09-01

    Full Text Available Abstract Background The pan-genome of a bacterial species consists of a core and an accessory gene pool. The accessory genome is thought to be an important source of genetic variability in bacterial populations and is gained through lateral gene transfer, allowing subpopulations of bacteria to better adapt to specific niches. Low-cost and high-throughput sequencing platforms have created an exponential increase in genome sequence data and an opportunity to study the pan-genomes of many bacterial species. In this study, we describe a new online pan-genome sequence analysis program, Panseq. Results Panseq was used to identify Escherichia coli O157:H7 and E. coli K-12 genomic islands. Within a population of 60 E. coli O157:H7 strains, the existence of 65 accessory genomic regions identified by Panseq analysis was confirmed by PCR. The accessory genome and binary presence/absence data, and core genome and single nucleotide polymorphisms (SNPs of six L. monocytogenes strains were extracted with Panseq and hierarchically clustered and visualized. The nucleotide core and binary accessory data were also used to construct maximum parsimony (MP trees, which were compared to the MP tree generated by multi-locus sequence typing (MLST. The topology of the accessory and core trees was identical but differed from the tree produced using seven MLST loci. The Loci Selector module found the most variable and discriminatory combinations of four loci within a 100 loci set among 10 strains in 1 s, compared to the 449 s required to exhaustively search for all possible combinations; it also found the most discriminatory 20 loci from a 96 loci E. coli O157:H7 SNP dataset. Conclusion Panseq determines the core and accessory regions among a collection of genomic sequences based on user-defined parameters. It readily extracts regions unique to a genome or group of genomes, identifies SNPs within shared core genomic regions, constructs files for use in phylogeny programs

  10. [From human genome to individualized medicine].

    Science.gov (United States)

    Del Barrio, Jaime

    2008-01-01

    Advances in the knowledge of our genome, and a deeper understanding of the molecular basis of disease are laying the foundations of Individualised Medicine. This new approach to Medicine seeks to establish a consistent relation between the genetic profile of each individual and the clinical profile of every disease, thereby helping healthcare professionals to individualise treatment for each patient, in order to administrate the right drug at the right dose, while optimising its efficacy and safety. Translational research, Pharmacogenetics, Pharmacogenomics, biomarkers and diagnostic tests are bringing profound change already under way to our healthcare systems, and pose new ethical and social challenges that our legal framework will have to address.

  11. Genome-wide approaches to understanding human ageing

    Directory of Open Access Journals (Sweden)

    Kaeberlein Matt

    2006-06-01

    Full Text Available Abstract The use of genomic technologies in biogerontology has the potential to greatly enhance our understanding of human ageing. High-throughput screens for alleles correlated with survival in long-lived people have uncovered novel genes involved in age-associated disease. Genome-wide longevity studies in simple eukaryotes are identifying evolutionarily conserved pathways that determine longevity. It is hoped that validation of these 'public' aspects of ageing in mice, along with analyses of variation in candidate human ageing genes, will provide targets for future interventions to slow the ageing process and retard the onset of age-associated pathologies.

  12. On Expression Patterns and Developmental Origin of Human Brain Regions.

    Science.gov (United States)

    Kirsch, Lior; Chechik, Gal

    2016-08-01

    Anatomical substructures of the human brain have characteristic cell-types, connectivity and local circuitry, which are reflected in area-specific transcriptome signatures, but the principles governing area-specific transcription and their relation to brain development are still being studied. In adult rodents, areal transcriptome patterns agree with the embryonic origin of brain regions, but the processes and genes that preserve an embryonic signature in regional expression profiles were not quantified. Furthermore, it is not clear how embryonic-origin signatures of adult-brain expression interplay with changes in expression patterns during development. Here we first quantify which genes have regional expression-patterns related to the developmental origin of brain regions, using genome-wide mRNA expression from post-mortem adult human brains. We find that almost all human genes (92%) exhibit an expression pattern that agrees with developmental brain-region ontology, but that this agreement changes at multiple phases during development. Agreement is particularly strong in neuron-specific genes, but also in genes that are not spatially correlated with neuron-specific or glia-specific markers. Surprisingly, agreement is also stronger in early-evolved genes. We further find that pairs of similar genes having high agreement to developmental region ontology tend to be more strongly correlated or anti-correlated, and that the strength of spatial correlation changes more strongly in gene pairs with stronger embryonic signatures. These results suggest that transcription regulation of most genes in the adult human brain is spatially tuned in a way that changes through life, but in agreement with development-determined brain regions.

  13. Three-dimensional genome architecture influences partner selection for chromosomal translocations in human disease.

    Directory of Open Access Journals (Sweden)

    Jesse M Engreitz

    Full Text Available Chromosomal translocations are frequent features of cancer genomes that contribute to disease progression. These rearrangements result from formation and illegitimate repair of DNA double-strand breaks (DSBs, a process that requires spatial colocalization of chromosomal breakpoints. The "contact first" hypothesis suggests that translocation partners colocalize in the nuclei of normal cells, prior to rearrangement. It is unclear, however, the extent to which spatial interactions based on three-dimensional genome architecture contribute to chromosomal rearrangements in human disease. Here we intersect Hi-C maps of three-dimensional chromosome conformation with collections of 1,533 chromosomal translocations from cancer and germline genomes. We show that many translocation-prone pairs of regions genome-wide, including the cancer translocation partners BCR-ABL and MYC-IGH, display elevated Hi-C contact frequencies in normal human cells. Considering tissue specificity, we find that translocation breakpoints reported in human hematologic malignancies have higher Hi-C contact frequencies in lymphoid cells than those reported in sarcomas and epithelial tumors. However, translocations from multiple tissue types show significant correlation with Hi-C contact frequencies, suggesting that both tissue-specific and universal features of chromatin structure contribute to chromosomal alterations. Our results demonstrate that three-dimensional genome architecture shapes the landscape of rearrangements directly observed in human disease and establish Hi-C as a key method for dissecting these effects.

  14. Genomics and the Ark: an ecocentric perspective on human history.

    Science.gov (United States)

    Zwart, Hub; Penders, Bart

    2011-01-01

    Views of ourselves in relationship to the rest of the biosphere are changing. Theocentric and anthropocentric perspectives are giving way to more ecocentric views on the history, present, and future of humankind. Novel sciences, such as genomics, have deepened and broadened our understanding of the process of anthropogenesis, the coming into being of humans. Genomics suggests that early human history must be regarded as a complex narrative of evolving ecosystems, in which human evolution both influenced and was influenced by the evolution of companion species. During the agricultural revolution, human beings designed small-scale artificial ecosystems or evolutionary "Arks," in which networks of plants, animals, and microorganisms coevolved. Currently, our attitude towards this process seems subject to a paradoxical reversal. The boundaries of the Ark have dramatically broadened, and genomics is not only being used to increase our understanding of our ecological past, but may also help us to conserve, reconstruct, or even revivify species and ecosystems to whose degradation or (near) extinction we have contributed. This article explores the role of genomics in the elaboration of a more ecocentric view of ourselves with the help of two examples, namely the renaissance of Paleolithic diets and of Pleistocene parks. It argues that an understanding of the world in ecocentric terms requires new partnerships and mutually beneficial forms of collaboration and convergence between life sciences, social sciences, and the humanities.

  15. Phylogeny Inference of Closely Related Bacterial Genomes: Combining the Features of Both Overlapping Genes and Collinear Genomic Regions

    Science.gov (United States)

    Zhang, Yan-Cong; Lin, Kui

    2015-01-01

    Overlapping genes (OGs) represent one type of widespread genomic feature in bacterial genomes and have been used as rare genomic markers in phylogeny inference of closely related bacterial species. However, the inference may experience a decrease in performance for phylogenomic analysis of too closely or too distantly related genomes. Another drawback of OGs as phylogenetic markers is that they usually take little account of the effects of genomic rearrangement on the similarity estimation, such as intra-chromosome/genome translocations, horizontal gene transfer, and gene losses. To explore such effects on the accuracy of phylogeny reconstruction, we combine phylogenetic signals of OGs with collinear genomic regions, here called locally collinear blocks (LCBs). By putting these together, we refine our previous metric of pairwise similarity between two closely related bacterial genomes. As a case study, we used this new method to reconstruct the phylogenies of 88 Enterobacteriale genomes of the class Gammaproteobacteria. Our results demonstrated that the topological accuracy of the inferred phylogeny was improved when both OGs and LCBs were simultaneously considered, suggesting that combining these two phylogenetic markers may reduce, to some extent, the influence of gene loss on phylogeny inference. Such phylogenomic studies, we believe, will help us to explore a more effective approach to increasing the robustness of phylogeny reconstruction of closely related bacterial organisms. PMID:26715828

  16. Transcription factor binding sites are genetic determinants of retroviral integration in the human genome.

    Directory of Open Access Journals (Sweden)

    Barbara Felice

    Full Text Available Gamma-retroviruses and lentiviruses integrate non-randomly in mammalian genomes, with specific preferences for active chromatin, promoters and regulatory regions. Gene transfer vectors derived from gamma-retroviruses target at high frequency genes involved in the control of growth, development and differentiation of the target cell, and may induce insertional tumors or pre-neoplastic clonal expansions in patients treated by gene therapy. The gene expression program of the target cell is apparently instrumental in directing gamma-retroviral integration, although the molecular basis of this phenomenon is poorly understood. We report a bioinformatic analysis of the distribution of transcription factor binding sites (TFBSs flanking >4,000 integrated proviruses in human hematopoietic and non-hematopoietic cells. We show that gamma-retroviral, but not lentiviral vectors, integrate in genomic regions enriched in cell-type specific subsets of TFBSs, independently from their relative position with respect to genes and transcription start sites. Analysis of sequences flanking the integration sites of Moloney leukemia virus (MLV- and human immunodeficiency virus (HIV-derived vectors carrying mutations in their long terminal repeats (LTRs, and of HIV vectors packaged with an MLV integrase, indicates that the MLV integrase and LTR enhancer are the viral determinants of the selection of TFBS-rich regions in the genome. This study identifies TFBSs as differential genomic determinants of retroviral target site selection in the human genome, and suggests that transcription factors binding the LTR enhancer may synergize with the integrase in tethering retroviral pre-integration complexes to transcriptionally active regulatory regions. Our data indicate that gamma-retroviruses and lentiviruses have evolved dramatically different strategies to interact with the host cell chromatin, and predict a higher risk in using gamma-retroviral vs. lentiviral vectors for human

  17. Comprehensive repertoire of foldable regions within whole genomes.

    Directory of Open Access Journals (Sweden)

    Guilhem Faure

    2013-10-01

    Full Text Available In order to get a comprehensive repertoire of foldable domains within whole proteomes, including orphan domains, we developed a novel procedure, called SEG-HCA. From only the information of a single amino acid sequence, SEG-HCA automatically delineates segments possessing high densities in hydrophobic clusters, as defined by Hydrophobic Cluster Analysis (HCA. These hydrophobic clusters mainly correspond to regular secondary structures, which together form structured or foldable regions. Genome-wide analyses revealed that SEG-HCA is opposite of disorder predictors, both addressing distinct structural states. Interestingly, there is however an overlap between the two predictions, including small segments of disordered sequences, which undergo coupled folding and binding. SEG-HCA thus gives access to these specific domains, which are generally poorly represented in domain databases. Comparison of the whole set of SEG-HCA predictions with the Conserved Domain Database (CDD also highlighted a wide proportion of predicted large (length >50 amino acids segments, which are CDD orphan. These orphan sequences may either correspond to highly divergent members of already known families or belong to new families of domains. Their comprehensive description thus opens new avenues to investigate new functional and/or structural features, which remained so far uncovered. Altogether, the data described here provide new insights into the protein architecture and organization throughout the three kingdoms of life.

  18. Regional genomic instability predisposes to complex dystrophin gene rearrangements.

    Science.gov (United States)

    Oshima, Junko; Magner, Daniel B; Lee, Jennifer A; Breman, Amy M; Schmitt, Eric S; White, Lisa D; Crowe, Carol A; Merrill, Michelle; Jayakar, Parul; Rajadhyaksha, Aparna; Eng, Christine M; del Gaudio, Daniela

    2009-09-01

    Mutations in the dystrophin gene (DMD) cause Duchenne and Becker muscular dystrophies and the majority of cases are due to DMD gene rearrangements. Despite the high incidence of these aberrations, little is known about their causative molecular mechanism(s). We examined 792 DMD/BMD clinical samples by oligonucleotide array-CGH and report on the junction sequence analysis of 15 unique deletion cases and three complex intragenic rearrangements to elucidate potential underlying mechanism(s). Furthermore, we present three cases with intergenic rearrangements involving DMD and neighboring loci. The cases with intragenic rearrangements include an inversion with flanking deleted sequences; a duplicated segment inserted in direct orientation into a deleted region; and a splicing mutation adjacent to a deletion. Bioinformatic analysis demonstrated that 7 of 12 breakpoints combined among 3 complex cases aligned with repetitive sequences, as compared to 4 of 30 breakpoints for the 15 deletion cases. Moreover, the inversion/deletion case may involve a stem-loop structure that has contributed to the initiation of this rearrangement. For the duplication/deletion and splicing mutation/deletion cases, the presence of the first mutation, either a duplication or point mutation, may have elicited the deletion events in an attempt to correct preexisting mutations. While NHEJ is one potential mechanism for these complex rearrangements, the highly complex junction sequence of the inversion/deletion case suggests the involvement of a replication-based mechanism. Our results support the notion that regional genomic instability, aided by the presence of repetitive elements, a stem-loop structure, and possibly preexisting mutations, may elicit complex rearrangements of the DMD gene.

  19. Data mining and the human genome

    Energy Technology Data Exchange (ETDEWEB)

    Abarbanel, Henry [The MITRE Corporation, McLean, VA (US). JASON Program Office; Callan, Curtis [The MITRE Corporation, McLean, VA (US). JASON Program Office; Dally, William [The MITRE Corporation, McLean, VA (US). JASON Program Office; Dyson, Freeman [The MITRE Corporation, McLean, VA (US). JASON Program Office; Hwa, Terence [The MITRE Corporation, McLean, VA (US). JASON Program Office; Koonin, Steven [The MITRE Corporation, McLean, VA (US). JASON Program Office; Levine, Herbert [The MITRE Corporation, McLean, VA (US). JASON Program Office; Rothaus, Oscar [The MITRE Corporation, McLean, VA (US). JASON Program Office; Schwitters, Roy [The MITRE Corporation, McLean, VA (US). JASON Program Office; Stubbs, Christopher [The MITRE Corporation, McLean, VA (US). JASON Program Office; Weinberger, Peter [The MITRE Corporation, McLean, VA (US). JASON Program Office

    2000-01-07

    As genomics research moves from an era of data acquisition to one of both acquisition and interpretation, new methods are required for organizing and prioritizing the data. These methods would allow an initial level of data analysis to be carried out before committing resources to a particular genetic locus. This JASON study sought to delineate the main problems that must be faced in bioinformatics and to identify information technologies that can help to overcome those problems. While the current influx of data greatly exceeds what biologists have experienced in the past, other scientific disciplines and the commercial sector have been handling much larger datasets for many years. Powerful datamining techniques have been developed in other fields that, with appropriate modification, could be applied to the biological sciences.

  20. Augmenting Chinese hamster genome assembly by identifying regions of high confidence.

    Science.gov (United States)

    Vishwanathan, Nandita; Bandyopadhyay, Arpan A; Fu, Hsu-Yuan; Sharma, Mohit; Johnson, Kathryn C; Mudge, Joann; Ramaraj, Thiruvarangan; Onsongo, Getiria; Silverstein, Kevin A T; Jacob, Nitya M; Le, Huong; Karypis, George; Hu, Wei-Shou

    2016-09-01

    Chinese hamster Ovary (CHO) cell lines are the dominant industrial workhorses for therapeutic recombinant protein production. The availability of genome sequence of Chinese hamster and CHO cells will spur further genome and RNA sequencing of producing cell lines. However, the mammalian genomes assembled using shot-gun sequencing data still contain regions of uncertain quality due to assembly errors. Identifying high confidence regions in the assembled genome will facilitate its use for cell engineering and genome engineering. We assembled two independent drafts of Chinese hamster genome by de novo assembly from shotgun sequencing reads and by re-scaffolding and gap-filling the draft genome from NCBI for improved scaffold lengths and gap fractions. We then used the two independent assemblies to identify high confidence regions using two different approaches. First, the two independent assemblies were compared at the sequence level to identify their consensus regions as "high confidence regions" which accounts for at least 78 % of the assembled genome. Further, a genome wide comparison of the Chinese hamster scaffolds with mouse chromosomes revealed scaffolds with large blocks of collinearity, which were also compiled as high-quality scaffolds. Genome scale collinearity was complemented with EST based synteny which also revealed conserved gene order compared to mouse. As cell line sequencing becomes more commonly practiced, the approaches reported here are useful for assessing the quality of assembly and potentially facilitate the engineering of cell lines.

  1. New genomic resources for switchgrass: a BAC library and comparative analysis of homoeologous genomic regions harboring bioenergy traits

    Directory of Open Access Journals (Sweden)

    Feltus Frank A

    2011-07-01

    Full Text Available Abstract Background Switchgrass, a C4 species and a warm-season grass native to the prairies of North America, has been targeted for development into an herbaceous biomass fuel crop. Genetic improvement of switchgrass feedstock traits through marker-assisted breeding and biotechnology approaches calls for genomic tools development. Establishment of integrated physical and genetic maps for switchgrass will accelerate mapping of value added traits useful to breeding programs and to isolate important target genes using map based cloning. The reported polyploidy series in switchgrass ranges from diploid (2X = 18 to duodecaploid (12X = 108. Like in other large, repeat-rich plant genomes, this genomic complexity will hinder whole genome sequencing efforts. An extensive physical map providing enough information to resolve the homoeologous genomes would provide the necessary framework for accurate assembly of the switchgrass genome. Results A switchgrass BAC library constructed by partial digestion of nuclear DNA with EcoRI contains 147,456 clones covering the effective genome approximately 10 times based on a genome size of 3.2 Gigabases (~1.6 Gb effective. Restriction digestion and PFGE analysis of 234 randomly chosen BACs indicated that 95% of the clones contained inserts, ranging from 60 to 180 kb with an average of 120 kb. Comparative sequence analysis of two homoeologous genomic regions harboring orthologs of the rice OsBRI1 locus, a low-copy gene encoding a putative protein kinase and associated with biomass, revealed that orthologous clones from homoeologous chromosomes can be unambiguously distinguished from each other and correctly assembled to respective fingerprint contigs. Thus, the data obtained not only provide genomic resources for further analysis of switchgrass genome, but also improve efforts for an accurate genome sequencing strategy. Conclusions The construction of the first switchgrass BAC library and comparative analysis of

  2. Targets of balancing selection in the human genome

    DEFF Research Database (Denmark)

    Andrés, Aida M; Hubisz, Melissa J; Indap, Amit

    2009-01-01

    to maintaining phenotypic variation in natural populations. Nevertheless, its prevalence and specific targets in the human genome remain largely unknown. We have analyzed the patterns of diversity and divergence of 13,400 genes in two human populations using an unbiased single-nucleotide polymorphism data set......, a genome-wide approach, and a method that incorporates demography in neutrality tests. We identified an unbiased catalog of genes with signatures of long-term balancing selection, which includes immunity genes as well as genes encoding keratins and membrane channels; the catalog also shows enrichment...... in functional categories involved in cellular structure. Patterns are mostly concordant in the two populations, with a small fraction of genes showing population-specific signatures of selection. Power considerations indicate that our findings represent a subset of all targets in the genome, suggesting...

  3. MIR retrotransposon sequences provide insulators to the human genome.

    Science.gov (United States)

    Wang, Jianrong; Vicente-García, Cristina; Seruggia, Davide; Moltó, Eduardo; Fernandez-Miñán, Ana; Neto, Ana; Lee, Elbert; Gómez-Skarmeta, José Luis; Montoliu, Lluís; Lunyak, Victoria V; Jordan, I King

    2015-08-11

    Insulators are regulatory elements that help to organize eukaryotic chromatin via enhancer-blocking and chromatin barrier activity. Although there are several examples of transposable element (TE)-derived insulators, the contribution of TEs to human insulators has not been systematically explored. Mammalian-wide interspersed repeats (MIRs) are a conserved family of TEs that have substantial regulatory capacity and share sequence characteristics with tRNA-related insulators. We sought to evaluate whether MIRs can serve as insulators in the human genome. We applied a bioinformatic screen using genome sequence and functional genomic data from CD4(+) T cells to identify a set of 1,178 predicted MIR insulators genome-wide. These predicted MIR insulators were computationally tested to serve as chromatin barriers and regulators of gene expression in CD4(+) T cells. The activity of predicted MIR insulators was experimentally validated using in vitro and in vivo enhancer-blocking assays. MIR insulators are enriched around genes of the T-cell receptor pathway and reside at T-cell-specific boundaries of repressive and active chromatin. A total of 58% of the MIR insulators predicted here show evidence of T-cell-specific chromatin barrier and gene regulatory activity. MIR insulators appear to be CCCTC-binding factor (CTCF) independent and show a distinct local chromatin environment with marked peaks for RNA Pol III and a number of histone modifications, suggesting that MIR insulators recruit transcriptional complexes and chromatin modifying enzymes in situ to help establish chromatin and regulatory domains in the human genome. The provisioning of insulators by MIRs across the human genome suggests a specific mechanism by which TE sequences can be used to modulate gene regulatory networks.

  4. A map of recent positive selection in the human genome.

    Directory of Open Access Journals (Sweden)

    Benjamin F Voight

    2006-03-01

    Full Text Available The identification of signals of very recent positive selection provides information about the adaptation of modern humans to local conditions. We report here on a genome-wide scan for signals of very recent positive selection in favor of variants that have not yet reached fixation. We describe a new analytical method for scanning single nucleotide polymorphism (SNP data for signals of recent selection, and apply this to data from the International HapMap Project. In all three continental groups we find widespread signals of recent positive selection. Most signals are region-specific, though a significant excess are shared across groups. Contrary to some earlier low resolution studies that suggested a paucity of recent selection in sub-Saharan Africans, we find that by some measures our strongest signals of selection are from the Yoruba population. Finally, since these signals indicate the existence of genetic variants that have substantially different fitnesses, they must indicate loci that are the source of significant phenotypic variation. Though the relevant phenotypes are generally not known, such loci should be of particular interest in mapping studies of complex traits. For this purpose we have developed a set of SNPs that can be used to tag the strongest approximately 250 signals of recent selection in each population.

  5. Enhancing Biology Instruction with the Human Genome Project

    Science.gov (United States)

    Buxeda, Rosa J.; Moore-Russo, Deborah A.

    2003-01-01

    The Human Genome Project (HGP) is a recent scientific milestone that has received notable attention. This article shows how a biology course is using the HGP to enhance students' experiences by providing awareness of cutting edge research, with information on new emerging career options, and with opportunities to consider ethical questions raised…

  6. The Human Genome Project: Biology, Computers, and Privacy.

    Science.gov (United States)

    Cutter, Mary Ann G.; Drexler, Edward; Gottesman, Kay S.; Goulding, Philip G.; McCullough, Laurence B.; McInerney, Joseph D.; Micikas, Lynda B.; Mural, Richard J.; Murray, Jeffrey C.; Zola, John

    This module, for high school teachers, is the second of two modules about the Human Genome Project (HGP) produced by the Biological Sciences Curriculum Study (BSCS). The first section of this module provides background information for teachers about the structure and objectives of the HGP, aspects of the science and technology that underlie the…

  7. Human Genome Project and cystic fibrosis--a symbiotic relationship.

    Science.gov (United States)

    Tolstoi, L G; Smith, C L

    1999-11-01

    When Watson and Crick determined the structure of DNA in 1953, a biological revolution began. One result of this revolution is the Human Genome Project. The primary goal of this international project is to obtain the complete nucleotide sequence of the human genome by the year 2005. Although molecular biologists and geneticists are most enthusiastic about the Human Genome Project, all areas of clinical medicine and fields of biology will be affected. Cystic fibrosis is the most common, inherited, lethal disease of white persons. In 1989, researchers located the cystic fibrosis gene on the long arm of chromosome 7 by a technique known as positional cloning. The most common mutation (a 3-base pair deletion) of the cystic fibrosis gene occurs in 70% of patients with cystic fibrosis. The knowledge gained from genetic research on cystic fibrosis will help researchers develop new therapies (e.g., gene) and improve standard therapies (e.g., pharmacologic) so that a patient's life span is increased and quality of life is improved. The purpose of this review is twofold. First, the article provides an overview of the Human Genome Project and its clinical significance in advancing interdisciplinary care for patients with cystic fibrosis. Second, the article includes a discussion of the genetic basis, pathophysiology, and management of cystic fibrosis.

  8. DOE Human Genome Program contractor-grantee workshop

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-01-01

    This volume contains the proceedings for the DOE Human Genome Program`s Contractor-Grantee Workshop V held in Sante Fe, New Mexico January 28, February 1, 1996. Presentations were divided into sessions entitled Sequencing; Mapping; Informatics; Ethical, Legal, and Social Issues; and Infrastructure. Reports of individual projects described herein are separately indexed and abstracted for the database.

  9. Human genome program report. Part 2, 1996 research abstracts

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-11-01

    This report contains Part 2 of a two-part report to reflect research and progress in the US Department of Energy Human Genome Program from 1994 through 1996, with specified updates made just before publication. Part 2 consists of 1996 research abstracts. Attention is focused on the following: sequencing; mapping; informatics; ethical, legal, and social issues; infrastructure; and small business innovation research.

  10. The human genome; you gain some, you lose some

    NARCIS (Netherlands)

    Kriek, Marjolein

    2007-01-01

    Copy number variations (CNVs) in the human genome are inherent in both evolutionary progression as well as the etiology of disease. The introduction of this thesis will review CNVs that appear to be neutral as well as CNVs that appear to be related to a phenotypic trait. This will be followed by a

  11. Reconsidering democracy - History of the human genome project

    NARCIS (Netherlands)

    Huijer, M

    What options are open for people-citizens, politicians, and other nonscientists-to become actively involved in and anticipate new directions in the life sciences? In addressing this question, this article focuses on the start of the Human Genome Project (1985-1990). By contrasting various models of

  12. Reconsidering democracy - History of the human genome project

    NARCIS (Netherlands)

    Huijer, M

    2003-01-01

    What options are open for people-citizens, politicians, and other nonscientists-to become actively involved in and anticipate new directions in the life sciences? In addressing this question, this article focuses on the start of the Human Genome Project (1985-1990). By contrasting various models of

  13. Human Genome Program Report. Part 2, 1996 Research Abstracts

    Science.gov (United States)

    1997-11-01

    This report contains Part 2 of a two-part report to reflect research and progress in the US Department of Energy Human Genome Program from 1994 through 1996, with specified updates made just before publication. Part 2 consists of 1996 research abstracts. Attention is focused on the following: sequencing; mapping; informatics; ethical, legal, and social issues; infrastructure; and small business innovation research.

  14. Human Genome Program Report. Part 1, Overview and Progress

    Science.gov (United States)

    1997-11-01

    This report contains Part 1 of a two-part report to reflect research and progress in the U.S. Department of Energy Human Genome Program from 1994 through 1996, with specified updates made just before publication. Part 1 consists of the program overview and report on progress.

  15. Human genome program report. Part 1, overview and progress

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-11-01

    This report contains Part 1 of a two-part report to reflect research and progress in the U.S. Department of Energy Human Genome Program from 1994 through 1996, with specified updates made just before publication. Part 1 consists of the program overview and report on progress.

  16. 78 FR 55752 - National Human Genome Research Institute; Notice of Closed Meetings

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    2013-09-11

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel; Clinical Sites for..., Scientific Review Branch, National Human Genome Research Institute, 5635 Fishers Lane, Suite 4076, MSC...

  17. 76 FR 28056 - National Human Genome Research Institute; Notice of Closed Meeting

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    2011-05-13

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed....), notice is hereby given of a meeting of the Board of Scientific Counselors, National Human Genome Research... individual intramural programs and projects conducted by the National Human Genome Research...

  18. 76 FR 35224 - National Human Genome Research Institute; Notice of Closed Meeting

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    2011-06-16

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed.... Day, PhD, Scientific Review Officer, CIR, National Human Genome Research Institute, National... . (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes...

  19. 76 FR 5390 - National Human Genome Research Institute; Notice of Closed Meeting

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    2011-01-31

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... privacy. Place: National Human Genome Research Institute Special Emphasis Panel; NHGRI Sample Repository..., National Human Genome Research Institute, 5635 Fishers Lane, Suite 4076, MSC 9306, Rockville, MD...

  20. 77 FR 58402 - National Human Genome Research Institute; Notice of Closed Meetings

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    2012-09-20

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel; R25 DAP Sept. 2012...: National Human Genome Research Institute, 5635 Fishers Lane, 3rd Floor Conference Room, Rockville, MD...

  1. 75 FR 62548 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2010-10-12

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed..., PhD, Scientific Review Officer, CIDR, National Human Genome Research Institute, National Institutes... . Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes...

  2. 76 FR 22112 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2011-04-20

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel, Special Emphasis Panel... Assistance Program Nos. 93.172, Human Genome Research, National Institutes of Health, HHS) Dated: April...

  3. 76 FR 19780 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2011-04-08

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... Officer, CIDR, National Human Genome Research Institute, National Institutes of Health, 5635 Fishers Lane... Assistance Program No. 93.172, Human Genome Research, National Institutes of Health, HHS) Dated: April...

  4. 75 FR 80509 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2010-12-22

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed..., PhD, Scientific Review Officer, CIDR, National Human Genome Research Institute, National Institutes..., Human Genome Research, National Institutes of Health, HHS) Dated: December 16, 2010. Jennifer S....

  5. 77 FR 8268 - National Human Genome Research Institute; Notice of Closed Meetings

    Science.gov (United States)

    2012-02-14

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed...:30 a.m. to 1 p.m. Agenda: To review and evaluate grant applications. Place: National Human Genome...). Contact Person: Camilla E. Day, Ph.D., Scientific Review Officer, CIDR, National Human Genome...

  6. 77 FR 20646 - National Human Genome Research Institute; Notice of Closed Meetings

    Science.gov (United States)

    2012-04-05

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel; Loan Repayment Program...: National Human Genome Research Institute, 5635 Fishers Lane, 3rd Floor Conference Room, Rockville, MD...

  7. 77 FR 59933 - National Human Genome Research Institute; Notice of Closed Meetings

    Science.gov (United States)

    2012-10-01

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel; ELSI CEERS RFA (SEP... Branch, National Human Genome Research Institute, 5635 Fishers Lane, Suite 4076, MSC 9306, Rockville,...

  8. 76 FR 66731 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2011-10-27

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel, DAP for CEGS-SEP. Date...@mail.nih.gov . (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome...

  9. 76 FR 66076 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2011-10-25

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed...: Camilla E. Day, PhD, Scientific Review Officer, CIDR, National Human Genome Research Institute, National..., Human Genome Research, National Institutes of Health, HHS) Dated: October 19, 2011. Jennifer S....

  10. 77 FR 64816 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2012-10-23

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed...: Camilla E. Day, Ph.D., Scientific Review Officer, CIDR, National Human Genome Research Institute, National... . (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes...

  11. 78 FR 56905 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2013-09-16

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel; H3AFRICA ELSI Research.... Place: National Human Genome Research Institute, Suite 3055, 5635 Fishers Lane, Rockville, MD...

  12. 78 FR 77477 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2013-12-23

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed...: Camilla E. Day, Ph.D., Scientific Review Officer, CIDR, National Human Genome Research Institute, National... . (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes...

  13. 76 FR 9031 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2011-02-16

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed..., PhD, Scientific Review Officer, CIDR, National Human Genome Research Institute, National Institutes... . (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes...

  14. 75 FR 13558 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2010-03-22

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed....), notice is hereby given of a meeting of the Board of Scientific Counselors, National Human Genome Research... individual intramural programs and projects conducted by the National Human Genome Research...

  15. 75 FR 8977 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2010-02-26

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed.... Nakamura, PhD, Scientific Review Officer, Scientific Review Branch, National Human Genome Research...-402-0838. (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome...

  16. 75 FR 2147 - National Human Genome Research Institute; Notice of Meetings

    Science.gov (United States)

    2010-01-14

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of....), notice is hereby given of meetings of the National Advisory Council for Human Genome Research. The... of Committee: National Advisory Council for Human Genome Research. Date: February 8-9, 2010....

  17. 77 FR 35991 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2012-06-15

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed...: Camilla E. Day, Ph.D., Scientific Review Officer, CIDR, National Human Genome Research Institute, National... . (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes...

  18. 78 FR 31953 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2013-05-28

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel; SEP-UDN Coordinating... applications. Place: National Human Genome Research Institute, 3rd Floor Conference Room, 3146, 5635...

  19. 75 FR 67380 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2010-11-02

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed...: Ken D. Nakamura, PhD, Scientific Review Officer, Scientific Review Branch, National Human Genome... Program Nos. 93.172, Human Genome Research, National Institutes of Health, HHS) Dated: October 26,...

  20. 75 FR 19984 - National Human Genome Research Institute; Notice of Closed Meetings

    Science.gov (United States)

    2010-04-16

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed...: Camilla E. Day, PhD, Scientific Review Officer, CIDR, National Human Genome Research Institute, National... Review Branch, National Human Genome Research Institute, National Institutes of Health, 5635 Fishers...

  1. 78 FR 11898 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2013-02-20

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed.... Day, Ph.D., Scientific Review Officer CIDR, National Human Genome Research Institute, National... . (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes...

  2. 78 FR 70063 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2013-11-22

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed....), notice is hereby given of a meeting of the Board of Scientific Counselors, National Human Genome Research... individual intramural programs and projects conducted by the NATIONAL HUMAN GENOME RESEARCH...

  3. 76 FR 36930 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2011-06-23

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel, DAP R-25. Date: July...@mail.nih.gov . (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome...

  4. 75 FR 8373 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2010-02-24

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel, GWAS Comparing Design... of Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes...

  5. 75 FR 60467 - National Human Genome Research Institute; Notice of Meeting

    Science.gov (United States)

    2010-09-30

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Meeting... hereby given of a meeting of the Board of Scientific Counselors, National Human Genome Research Institute... intramural programs and projects conducted by the National Human Genome Research Institute,...

  6. 78 FR 47715 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2013-08-06

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed...., Scientific Review Officer, CIDR, National Human Genome Research Institute, National Institutes of Health... Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes of Health,...

  7. 76 FR 50486 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2011-08-15

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed.... Day, PhD, Scientific Review Officer, CIDR, National Human Genome Research Institute, National... . (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes...

  8. 76 FR 10909 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2011-02-28

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed.... Nakamura, PhD, Scientific Review Officer, Scientific Review Branch, National Human Genome Research...-402-0838. (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome...

  9. 77 FR 50140 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2012-08-20

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed.... Day, Ph.D., Scientific Review Officer, CIDR, National Human Genome Research Institute, National... . (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes...

  10. 76 FR 17930 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2011-03-31

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... privacy. Name of Committee: National Human Genome Research Institute Special Emphasis Panel; Genetic... Branch, National Human Genome Research Institute, 5635 Fishers Lane, Suite 4076, MSC 9306, Rockville,...

  11. 77 FR 2304 - National Human Genome Research Institute; Notice of Meeting

    Science.gov (United States)

    2012-01-17

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Meeting... given that the National Human Genome Research Institute (NHGRI) will host a series of meetings to enable... for Human Genome Research. Background materials on the proposed reorganization and...

  12. 77 FR 2735 - National Human Genome Research Institute; Notice of Meetings

    Science.gov (United States)

    2012-01-19

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of....), notice is hereby given of meetings of the National Advisory Council for Human Genome Research. The... of Committee: National Advisory Council for Human Genome Research. Date: February 13-14, 2012....

  13. 78 FR 9707 - National Human Genome Research Institute; Notice of Closed Meetings

    Science.gov (United States)

    2013-02-11

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel; H3Africa (RM-006, RM... Human Genome Research Institute, 5635 Fishers Lane, Suite 4076, MSC 9306, Rockville, MD 20852, (301)...

  14. 77 FR 22332 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2012-04-13

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel, H3Africa Biorepository... applications. Place: National Human Genome Research Institute, 5635 Fishers Lane, 4076, Rockville, MD...

  15. 77 FR 74676 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2012-12-17

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... Person: Camilla E. Day, Ph.D., Scientific Review Officer, CIDR, National Human Genome Research Institute...@nih.gov . (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome...

  16. 77 FR 12604 - National Human Genome Research Institute; Notice of Closed Meetings

    Science.gov (United States)

    2012-03-01

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed.... >Name of Committee: National Human Genome Research Institute Special Emphasis Panel, CIDR Contract. Date...: National Human Genome Reseach Institute, 5635 Fishers Lane, Room 4076, Rockville, MD 20852,...

  17. 78 FR 21382 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2013-04-10

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed...:00 p.m. to 4:00 p.m. Agenda: To review and evaluate grant applications. Place: National Human Genome... Person: Camilla E. Day, PhD., Scientific Review Officer, CIDR, National Human Genome Research...

  18. 75 FR 56115 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2010-09-15

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel; CEGS DAP. Date... Assistance Program Nos. 93.172, Human Genome Research, National Institutes of Health, HHS) Dated: September...

  19. 75 FR 48977 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2010-08-12

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed.... Day, PhD, Scientific Review Officer, CIDR, National Human Genome Research Institute, National... . (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes...

  20. 76 FR 65204 - National Human Genome Research Institute; Notice of Meeting

    Science.gov (United States)

    2011-10-20

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Meeting... hereby given of a meeting of the Board of Scientific Counselors, National Human Genome Research Institute... intramural programs and projects conducted by the National Human Genome Research Institute,...

  1. 77 FR 31863 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2012-05-30

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel DAP R25 Eppig.... (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes...

  2. 77 FR 71604 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2012-12-03

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel. Date: January 11, 2013..., National Human Genome Research Institute, National Institutes of Health, 5635 Fishers Lane, Suite 4076,...

  3. 75 FR 46951 - National Human Genome Research Institute; Notice of Meeting

    Science.gov (United States)

    2010-08-04

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Meeting... hereby given of a meeting of the National Advisory Council for Human Genome Research. The meeting will be...: National Advisory Council for Human Genome Research. Date: September 13-14, 2010. Open: September 13,...

  4. 78 FR 107 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2013-01-02

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed...: National Human Genome Research Institute, 3rd Floor Conference Room, 5635 Fishers Lane, Rockville, MD 20851... Review Branch, National Human Genome Research Institute, National Institutes of Health, 5635 Fishers...

  5. 75 FR 32957 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2010-06-10

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel, Protein Resource RFA... of Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes...

  6. 75 FR 44800 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2010-07-29

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed....), notice is hereby given of a meeting of the National Advisory Council for Human Genome Research. The... Call). Contact Person: Mark S. Guyer, Director for Extramural Research, National Human Genome...

  7. 77 FR 64816 - National Human Genome Research Institute; Notice of Meeting

    Science.gov (United States)

    2012-10-23

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Meeting... hereby given of a meeting of the Board of Scientific Counselors, National Human Genome Research Institute... intramural programs and projects conducted by the National Human Genome Research Institute,...

  8. 76 FR 22407 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2011-04-21

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel; Loan Repayment Program....172, Human Genome Research, National Institutes of Health, HHS) Dated: April 12, 2011. Jennifer...

  9. 76 FR 79199 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2011-12-21

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed...., Scientific Review Officer, CIDR, National Human Genome Research Institute, National Institutes of Health... Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes of Health,...

  10. 77 FR 6810 - National Human Genome Research Institute; Notice of Closed Meetings

    Science.gov (United States)

    2012-02-09

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel; CIDR Contract Renewal... Branch, National Human Genome Research Institute, 5635 Fishers Lane, Suite 4076, MSC 9306, Rockville,...

  11. 75 FR 35821 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2010-06-23

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed..., Scientific Review Officer, CIDR, National Human Genome Research Institute, National Institutes of Health... Federal Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes of Health,...

  12. Human Cancer Models Initiative | Office of Cancer Genomics

    Science.gov (United States)

    The Human Cancer Models Initiative (HCMI) is an international consortium that is generating novel human tumor-derived culture models, which are annotated with genomic and clinical data. In an effort to advance cancer research and more fully understand how in vitro findings are related to clinical biology, HCMI-developed models and related data will be available as a community resource for cancer research.

  13. The linguistics of DNA. [HUMAN GENOME PROJECT

    Energy Technology Data Exchange (ETDEWEB)

    Searls, D.B. (Univ. of Pennsylvania, Philadelphia (United States))

    Discusses the structure of DNA and RNA and the mechanisms of transcription and translation in relation to the grammatical rules of language. The ultimate purpose is to design a grammar which can be used to write flexible, adaptive computer programs for searching nucleotide sequences, with the goal of being able to search large sequences for gene-coding regions. 11 refs., 16 figs.

  14. CRISPR/Cas9-mediated genome editing of Epstein-Barr virus in human cells.

    Science.gov (United States)

    Yuen, Kit-San; Chan, Chi-Ping; Wong, Nok-Hei Mickey; Ho, Chau-Ha; Ho, Ting-Hin; Lei, Ting; Deng, Wen; Tsao, Sai Wah; Chen, Honglin; Kok, Kin-Hang; Jin, Dong-Yan

    2015-03-01

    The CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated 9) system is a highly efficient and powerful tool for RNA-guided editing of the cellular genome. Whether CRISPR/Cas9 can also cleave the genome of DNA viruses such as Epstein-Barr virus (EBV), which undergo episomal replication in human cells, remains to be established. Here, we reported on CRISPR/Cas9-mediated editing of the EBV genome in human cells. Two guide RNAs (gRNAs) were used to direct a targeted deletion of 558 bp in the promoter region of BART (BamHI A rightward transcript) which encodes viral microRNAs (miRNAs). Targeted editing was achieved in several human epithelial cell lines latently infected with EBV, including nasopharyngeal carcinoma C666-1 cells. CRISPR/Cas9-mediated editing of the EBV genome was efficient. A recombinant virus with the desired deletion was obtained after puromycin selection of cells expressing Cas9 and gRNAs. No off-target cleavage was found by deep sequencing. The loss of BART miRNA expression and activity was verified, supporting the BART promoter as the major promoter of BART RNA. Although CRISPR/Cas9-mediated editing of the multicopy episome of EBV in infected HEK293 cells was mostly incomplete, viruses could be recovered and introduced into other cells at low m.o.i. Recombinant viruses with an edited genome could be further isolated through single-cell sorting. Finally, a DsRed selectable marker was successfully introduced into the EBV genome during the course of CRISPR/Cas9-mediated editing. Taken together, our work provided not only the first genetic evidence that the BART promoter drives the expression of the BART transcript, but also a new and efficient method for targeted editing of EBV genome in human cells.

  15. Integration of mouse and human genome-wide association data identifies KCNIP4 as an asthma gene

    NARCIS (Netherlands)

    Himes, Blanca E.; Sheppard, Keith; Berndt, Annerose; Leme, Adriana S.; Myers, Rachel A.; Gignoux, Christopher R.; Levin, Albert M.; Gauderman, W. James; Yang, James J.; Mathias, Rasika A.; Romieu, Isabelle; Torgerson, Dara G.; Roth, Lindsey A.; Huntsman, Scott; Eng, Celeste; Klanderman, Barbara; Ziniti, John; Senter-Sylvia, Jody; Szefler, Stanley J.; Lemanske, Robert F.; Zeiger, Robert S.; Strunk, Robert C.; Martinez, Fernando D.; Boushey, Homer; Chinchilli, Vernon M.; Israel, Elliot; Mauger, David; Koppelman, Gerard H.; Postma, Dirkje S.; Nieuwenhuis, Maartje A. E.; Vonk, Judith M.; Lima, John J.; Irvin, Charles G.; Peters, Stephen P.; Kubo, Michiaki; Tamari, Mayumi; Nakamura, Yusuke; Litonjua, Augusto A.; Tantisira, Kelan G.; Raby, Benjamin A.; Bleecker, Eugene R.; Meyers, Deborah A.; London, Stephanie J.; Barnes, Kathleen C.; Gilliland, Frank D.; Williams, L. Keoki; Burchard, Esteban G.; Nicolae, Dan L.; Ober, Carole; DeMeo, Dawn L.; Silverman, Edwin K.; Paigen, Beverly; Churchill, Gary; Shapiro, Steve D.; Weiss, Scott

    2013-01-01

    Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthm

  16. Comparative genetics. Systematic discovery of cap-independent translation sequences in human and viral genomes.

    Science.gov (United States)

    Weingarten-Gabbay, Shira; Elias-Kirma, Shani; Nir, Ronit; Gritsenko, Alexey A; Stern-Ginossar, Noam; Yakhini, Zohar; Weinberger, Adina; Segal, Eran

    2016-01-15

    To investigate gene specificity at the level of translation in both the human genome and viruses, we devised a high-throughput bicistronic assay to quantify cap-independent translation. We uncovered thousands of novel cap-independent translation sequences, and we provide insights on the landscape of translational regulation in both humans and viruses. We find extensive translational elements in the 3' untranslated region of human transcripts and the polyprotein region of uncapped RNA viruses. Through the characterization of regulatory elements underlying cap-independent translation activity, we identify potential mechanisms of secondary structure, short sequence motif, and base pairing with the 18S ribosomal RNA (rRNA). Furthermore, we systematically map the 18S rRNA regions for which reverse complementarity enhances translation. Thus, we make available insights into the mechanisms of translational control in humans and viruses.

  17. Definition of Soybean Genomic Regions That Control Seed Phytoestrogen Amounts

    Directory of Open Access Journals (Sweden)

    Kassem My A.

    2004-01-01

    Full Text Available Soybean seeds contain large amounts of isoflavones or phytoestrogens such as genistein, daidzein, and glycitein that display biological effects when ingested by humans and animals. In seeds, the total amount, and amount of each type, of isoflavone varies by 5 fold between cultivars and locations. Isoflavone content and quality are one key to the biological effects of soy foods, dietary supplements, and nutraceuticals. Previously we had identified 6 loci (QTL controlling isoflavone content using 150 DNA markers. This study aimed to identify and delimit loci underlying heritable variation in isoflavone content with additional DNA markers. We used a recombinant inbred line (RIL population ( n=100 derived from the cross of “Essex” by “Forrest,” two cultivars that contrast for isoflavone content. Seed isoflavone content of each RIL was determined by HPLC and compared against 240 polymorphic microsatellite markers by one-way analysis of variance. Two QTL that underlie seed isoflavone content were newly discovered. The additional markers confirmed and refined the positions of the six QTL already reported. The first new region anchored by the marker BARC-Satt063 was significantly associated with genistein ( P=0.009 , R 2 =29.5% and daidzein ( P=0.007 , R 2 =17.0% . The region is located on linkage group B2 and derived the beneficial allele from Essex. The second new region defined by the marker BARC-Satt129 was significantly associated with total glycitein ( P=0.0005 , R 2 =32.0% . The region is located on linkage group D1a+Q and also derived the beneficial allele from Essex. Jointly the eight loci can explain the heritable variation in isoflavone content. The loci may be used to stabilize seed isoflavone content by selection and to isolate the underlying genes.

  18. Genome sequence of the stramenopile Blastocystis, a human anaerobic parasite

    Science.gov (United States)

    2011-01-01

    Background Blastocystis is a highly prevalent anaerobic eukaryotic parasite of humans and animals that is associated with various gastrointestinal and extraintestinal disorders. Epidemiological studies have identified different subtypes but no one subtype has been definitively correlated with disease. Results Here we report the 18.8 Mb genome sequence of a Blastocystis subtype 7 isolate, which is the smallest stramenopile genome sequenced to date. The genome is highly compact and contains intriguing rearrangements. Comparisons with other available stramenopile genomes (plant pathogenic oomycete and diatom genomes) revealed effector proteins potentially involved in the adaptation to the intestinal environment, which were likely acquired via horizontal gene transfer. Moreover, Blastocystis living in anaerobic conditions harbors mitochondria-like organelles. An incomplete oxidative phosphorylation chain, a partial Krebs cycle, amino acid and fatty acid metabolisms and an iron-sulfur cluster assembly are all predicted to occur in these organelles. Predicted secretory proteins possess putative activities that may alter host physiology, such as proteases, protease-inhibitors, immunophilins and glycosyltransferases. This parasite also possesses the enzymatic machinery to tolerate oxidative bursts resulting from its own metabolism or induced by the host immune system. Conclusions This study provides insights into the genome architecture of this unusual stramenopile. It also proposes candidate genes with which to study the physiopathology of this parasite and thus may lead to further investigations into Blastocystis-host interactions. PMID:21439036

  19. Genomic and expression array profiling of chromosome 20q amplicon in human colon cancer cells

    Directory of Open Access Journals (Sweden)

    Carter Jennifer

    2005-01-01

    Full Text Available Background: Gain of the q arm of chromosome 20 in human colorectal cancer has been associated with poorer survival time and has been reported to increase in frequency from adenomas to metastasis. The increasing frequency of chromosome 20q amplification during colorectal cancer progression and the presence of this amplification in carcinomas of other tissue origin has lead us to hypothesize that 20q11-13 harbors one or more genes which, when over expressed promote tumor invasion and metastasis. Aims: Generate genomic and expression profiles of the 20q amplicon in human cancer cell lines in order to identify genes with increased copy number and expression. Materials and Methods: Utilizing genomic sequencing clones and amplification mapping data from our lab and other previous studies, BAC/ PAC tiling paths spanning the 20q amplicon and genomic microarrays were generated. Array-CGH on the custom array with human cancer cell line DNAs was performed to generate genomic profiles of the amplicon. Expression array analysis with RNA from these cell lines using commercial oligo microarrays generated expression profiles of the amplicon. The data were then combined in order to identify genes with increased copy number and expression. Results: Over expressed genes in regions of increased copy number were identified and a list of potential novel genetic tumor markers was assembled based on biological functions of these genes Conclusions: Performing high-resolution genomic microarray profiling in conjunction with expression analysis is an effective approach to identify potential tumor markers.

  20. Harnessing genomics to improve health in the Eastern Mediterranean Region – an executive course in genomics policy

    Directory of Open Access Journals (Sweden)

    Singer Peter A

    2005-01-01

    Full Text Available Abstract Background While innovations in medicine, science and technology have resulted in improved health and quality of life for many people, the benefits of modern medicine continue to elude millions of people in many parts of the world. To assess the potential of genomics to address health needs in EMR, the World Health Organization's Eastern Mediterranean Regional Office and the University of Toronto Joint Centre for Bioethics jointly organized a Genomics and Public Health Policy Executive Course, held September 20th–23rd, 2003, in Muscat, Oman. The 4-day course was sponsored by WHO-EMRO with additional support from the Canadian Program in Genomics and Global Health. The overall objective of the course was to collectively explore how to best harness genomics to improve health in the region. This article presents the course findings and recommendations for genomics policy in EMR. Methods The course brought together senior representatives from academia, biotechnology companies, regulatory bodies, media, voluntary, and legal organizations to engage in discussion. Topics covered included scientific advances in genomics, followed by innovations in business models, public sector perspectives, ethics, legal issues and national innovation systems. Results A set of recommendations, summarized below, was formulated for the Regional Office, the Member States and for individuals. • Advocacy for genomics and biotechnology for political leadership; • Networking between member states to share information, expertise, training, and regional cooperation in biotechnology; coordination of national surveys for assessment of health biotechnology innovation systems, science capacity, government policies, legislation and regulations, intellectual property policies, private sector activity; • Creation in each member country of an effective National Body on genomics, biotechnology and health to: - formulate national biotechnology strategies - raise

  1. A 1463 gene cattle-human comparative map with anchor points defined by human genome sequence coordinates.

    Science.gov (United States)

    Everts-van der Wind, Annelie; Kata, Srinivas R; Band, Mark R; Rebeiz, Mark; Larkin, Denis M; Everts, Robin E; Green, Cheryl A; Liu, Lei; Natarajan, Shreedhar; Goldammer, Tom; Lee, Jun Heon; McKay, Stephanie; Womack, James E; Lewin, Harris A

    2004-07-01

    A second-generation 5000 rad radiation hybrid (RH) map of the cattle genome was constructed primarily using cattle ESTs that were targeted to gaps in the existing cattle-human comparative map, as well as to sparsely populated map intervals. A total of 870 targeted markers were added, bringing the number of markers mapped on the RH(5000) panel to 1913. Of these, 1463 have significant BLASTN hits (E genes) were identified between the cattle and human genomes, of which 31 are newly discovered and 34 were extended singletons on the first-generation map. The new map represents an improvement of 20% genome-wide comparative coverage compared with the first-generation map. Analysis of gene content within human genome regions where there are gaps in the comparative map revealed gaps with both significantly greater and significantly lower gene content. The new, more detailed cattle-human comparative map provides an improved resource for the analysis of mammalian chromosome evolution, the identification of candidate genes for economically important traits, and for proper alignment of sequence contigs on cattle chromosomes. Copyright 2004 Cold Spring Harbor Laboratory Press ISSN

  2. Genomic responses in mouse models poorly mimic human inflammatory diseases.

    Science.gov (United States)

    Seok, Junhee; Warren, H Shaw; Cuenca, Alex G; Mindrinos, Michael N; Baker, Henry V; Xu, Weihong; Richards, Daniel R; McDonald-Smith, Grace P; Gao, Hong; Hennessy, Laura; Finnerty, Celeste C; López, Cecilia M; Honari, Shari; Moore, Ernest E; Minei, Joseph P; Cuschieri, Joseph; Bankey, Paul E; Johnson, Jeffrey L; Sperry, Jason; Nathens, Avery B; Billiar, Timothy R; West, Michael A; Jeschke, Marc G; Klein, Matthew B; Gamelli, Richard L; Gibran, Nicole S; Brownstein, Bernard H; Miller-Graziano, Carol; Calvano, Steve E; Mason, Philip H; Cobb, J Perren; Rahme, Laurence G; Lowry, Stephen F; Maier, Ronald V; Moldawer, Lyle L; Herndon, David N; Davis, Ronald W; Xiao, Wenzhong; Tompkins, Ronald G

    2013-02-26

    A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

  3. Genomic responses in mouse models poorly mimic human inflammatory diseases

    Science.gov (United States)

    Seok, Junhee; Warren, H. Shaw; Cuenca, Alex G.; Mindrinos, Michael N.; Baker, Henry V.; Xu, Weihong; Richards, Daniel R.; McDonald-Smith, Grace P.; Gao, Hong; Hennessy, Laura; Finnerty, Celeste C.; López, Cecilia M.; Honari, Shari; Moore, Ernest E.; Minei, Joseph P.; Cuschieri, Joseph; Bankey, Paul E.; Johnson, Jeffrey L.; Sperry, Jason; Nathens, Avery B.; Billiar, Timothy R.; West, Michael A.; Jeschke, Marc G.; Klein, Matthew B.; Gamelli, Richard L.; Gibran, Nicole S.; Brownstein, Bernard H.; Miller-Graziano, Carol; Calvano, Steve E.; Mason, Philip H.; Cobb, J. Perren; Rahme, Laurence G.; Lowry, Stephen F.; Maier, Ronald V.; Moldawer, Lyle L.; Herndon, David N.; Davis, Ronald W.; Xiao, Wenzhong; Tompkins, Ronald G.; Abouhamze, Amer; Balis, Ulysses G. J.; Camp, David G.; De, Asit K.; Harbrecht, Brian G.; Hayden, Douglas L.; Kaushal, Amit; O’Keefe, Grant E.; Kotz, Kenneth T.; Qian, Weijun; Schoenfeld, David A.; Shapiro, Michael B.; Silver, Geoffrey M.; Smith, Richard D.; Storey, John D.; Tibshirani, Robert; Toner, Mehmet; Wilhelmy, Julie; Wispelwey, Bram; Wong, Wing H

    2013-01-01

    A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases. PMID:23401516

  4. Trapping DNA replication origins from the human genome.

    Science.gov (United States)

    Eki, Toshihiko; Murakami, Yasufumi; Hanaoka, Fumio

    2013-04-17

    Synthesis of chromosomal DNA is initiated from multiple origins of replication in higher eukaryotes; however, little is known about these origins' structures. We isolated the origin-derived nascent DNAs from a human repair-deficient cell line by blocking the replication forks near the origins using two different origin-trapping methods (i.e., UV- or chemical crosslinker-treatment and cell synchronization in early S phase using DNA replication inhibitors). Single-stranded DNAs (of 0.5-3 kb) that accumulated after such treatments were labeled with bromodeoxyuridine (BrdU). BrdU-labeled DNA was immunopurified after fractionation by alkaline sucrose density gradient centrifugation and cloned by complementary-strand synthesis and PCR amplification. Competitive PCR revealed an increased abundance of DNA derived from known replication origins (c-myc and lamin B2 genes) in the nascent DNA fractions from the UV-treated or crosslinked cells. Nucleotide sequences of 85 and 208 kb were obtained from the two libraries (I and II) prepared from the UV-treated log-phase cells and early S phase arrested cells, respectively. The libraries differed from each other in their G+C composition and replication-related motif contents, suggesting that differences existed between the origin fragments isolated by the two different origin-trapping methods. The replication activities for seven out of 12 putative origin loci from the early-S phase cells were shown by competitive PCR. We mapped 117 (library I) and 172 (library II) putative origin loci to the human genome; approximately 60% and 50% of these loci were assigned to the G-band and intragenic regions, respectively. Analyses of the flanking sequences of the mapped loci suggested that the putative origin loci tended to associate with genes (including conserved sites) and DNase I hypersensitive sites; however, poor correlations were found between such loci and the CpG islands, transcription start sites, and K27-acetylated histone H3 peaks.

  5. Inference of distant genetic relations in humans using "1000 genomes".

    Science.gov (United States)

    Al-Khudhair, Ahmed; Qiu, Shuhao; Wyse, Meghan; Chowdhury, Shilpi; Cheng, Xi; Bekbolsynov, Dulat; Saha-Mandal, Arnab; Dutta, Rajib; Fedorova, Larisa; Fedorov, Alexei

    2015-01-07

    Nucleotide sequence differences on the whole-genome scale have been computed for 1,092 people from 14 populations publicly available by the 1000 Genomes Project. Total number of differences in genetic variants between 96,464 human pairs has been calculated. The distributions of these differences for individuals within European, Asian, or African origin were characterized by narrow unimodal peaks with mean values of 3.8, 3.5, and 5.1 million, respectively, and standard deviations of 0.1-0.03 million. The total numbers of genomic differences between pairs of all known relatives were found to be significantly lower than their respective population means and in reverse proportion to the distance of their consanguinity. By counting the total number of genomic differences it is possible to infer familial relations for people that share down to 6% of common loci identical-by-descent. Detection of familial relations can be radically improved when only very rare genetic variants are taken into account. Counting of total number of shared very rare single nucleotide polymorphisms (SNPs) from whole-genome sequences allows establishing distant familial relations for persons with eighth and ninth degrees of relationship. Using this analysis we predicted 271 distant familial pairwise relations among 1,092 individuals that have not been declared by 1000 Genomes Project. Particularly, among 89 British and 97 Chinese individuals we found three British-Chinese pairs with distant genetic relationships. Individuals from these pairs share identical-by-descent DNA fragments that represent 0.001%, 0.004%, and 0.01% of their genomes. With affordable whole-genome sequencing techniques, very rare SNPs should become important genetic markers for familial relationships and population stratification. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  6. Database of Periodic DNA Regions in Major Genomes

    Directory of Open Access Journals (Sweden)

    Felix E. Frenkel

    2017-01-01

    Full Text Available Summary. We analyzed several prokaryotic and eukaryotic genomes looking for the periodicity sequences availability and employing a new mathematical method. The method envisaged using the random position weight matrices and dynamic programming. Insertions and deletions were allowed inside periodicities, thus adding a novelty to the results we obtained. A periodicity length, one of the key periodicity features, varied from 2 to 50 nt. Totally over 60,000 periodicity sequences were found in 15 genomes including some chromosomes of the H. sapiens (partial, C. elegans, D. melanogaster, and A. thaliana genomes.

  7. Database of Periodic DNA Regions in Major Genomes

    Science.gov (United States)

    2017-01-01

    Summary. We analyzed several prokaryotic and eukaryotic genomes looking for the periodicity sequences availability and employing a new mathematical method. The method envisaged using the random position weight matrices and dynamic programming. Insertions and deletions were allowed inside periodicities, thus adding a novelty to the results we obtained. A periodicity length, one of the key periodicity features, varied from 2 to 50 nt. Totally over 60,000 periodicity sequences were found in 15 genomes including some chromosomes of the H. sapiens (partial), C. elegans, D. melanogaster, and A. thaliana genomes. PMID:28182099

  8. Annotation of the protein coding regions of the equine genome

    DEFF Research Database (Denmark)

    Hestand, Matthew S.; Kalbfleisch, Theodore S.; Coleman, Stephen J.

    2015-01-01

    Current gene annotation of the horse genome is largely derived from in silico predictions and cross-species alignments. Only a small number of genes are annotated based on equine EST and mRNA sequences. To expand the number of equine genes annotated from equine experimental evidence, we sequenced m...... and appear to be small errors in the equine reference genome, since they are also identified as homozygous variants by genomic DNA resequencing of the reference horse. Taken together, we provide a resource of equine mRNA structures and protein coding variants that will enhance equine and cross...

  9. The mouse QTL map helps interpret human genome-wide association studies for HDL cholesterol.

    Science.gov (United States)

    Leduc, Magalie S; Lyons, Malcolm; Darvishi, Katayoon; Walsh, Kenneth; Sheehan, Susan; Amend, Sarah; Cox, Allison; Orho-Melander, Marju; Kathiresan, Sekar; Paigen, Beverly; Korstanje, Ron

    2011-06-01

    Genome-wide association (GWA) studies represent a powerful strategy for identifying susceptibility genes for complex diseases in human populations but results must be confirmed and replicated. Because of the close homology between mouse and human genomes, the mouse can be used to add evidence to genes suggested by human studies. We used the mouse quantitative trait loci (QTL) map to interpret results from a GWA study for genes associated with plasma HDL cholesterol levels. We first positioned single nucleotide polymorphisms (SNPs) from a human GWA study on the genomic map for mouse HDL QTL. We then used mouse bioinformatics, sequencing, and expression studies to add evidence for one well-known HDL gene (Abca1) and three newly identified genes (Galnt2, Wwox, and Cdh13), thus supporting the results of the human study. For GWA peaks that occur in human haplotype blocks with multiple genes, we examined the homologous regions in the mouse to prioritize the genes using expression, sequencing, and bioinformatics from the mouse model, showing that some genes were unlikely candidates and adding evidence for candidate genes Mvk and Mmab in one haplotype block and Fads1 and Fads2 in the second haplotype block. Our study highlights the value of mouse genetics for evaluating genes found in human GWA studies.

  10. Genome-wide signatures of 'rearrangement hotspots' within segmental duplications in humans.

    Directory of Open Access Journals (Sweden)

    Mohammed Uddin

    Full Text Available The primary objective of this study was to create a genome-wide high resolution map (i.e., >100 bp of 'rearrangement hotspots' which can facilitate the identification of regions capable of mediating de novo deletions or duplications in humans. A hierarchical method was employed to fragment segmental duplications (SDs into multiple smaller SD units. Combining an end space free pairwise alignment algorithm with a 'seed and extend' approach, we have exhaustively searched 409 million alignments to detect complex structural rearrangements within the reference-guided assembly of the NA18507 human genome (18× coverage, including the previously identified novel 4.8 Mb sequence from de novo assembly within this genome. We have identified 1,963 rearrangement hotspots within SDs which encompass 166 genes and display an enrichment of duplicated gene nucleotide variants (DNVs. These regions are correlated with increased non-allelic homologous recombination (NAHR event frequency which presumably represents the origin of copy number variations (CNVs and pathogenic duplications/deletions. Analysis revealed that 20% of the detected hotspots are clustered within the proximal and distal SD breakpoints flanked by the pathogenic deletions/duplications that have been mapped for 24 NAHR-mediated genomic disorders. FISH Validation of selected complex regions revealed 94% concordance with in silico localization of the highly homologous derivatives. Other results from this study indicate that intra-chromosomal recombination is enhanced in genic compared with agenic duplicated regions, and that gene desert regions comprising SDs may represent reservoirs for creation of novel genes. The generation of genome-wide signatures of 'rearrangement hotspots', which likely serve as templates for NAHR, may provide a powerful approach towards understanding the underlying mutational mechanism(s for development of constitutional and acquired diseases.

  11. Human genome education model project. Ethical, legal, and social implications of the human genome project: Education of interdisciplinary professionals

    Energy Technology Data Exchange (ETDEWEB)

    Weiss, J.O. [Alliance of Genetic Support Groups, Chevy Chase, MD (United States); Lapham, E.V. [Georgetown Univ., Washington, DC (United States). Child Development Center

    1996-12-31

    This meeting was held June 10, 1996 at Georgetown University. The purpose of this meeting was to provide a multidisciplinary forum for exchange of state-of-the-art information on the human genome education model. Topics of discussion include the following: psychosocial issues; ethical issues for professionals; legislative issues and update; and education issues.

  12. Abundance of ultramicro inversions within local alignments between human and chimpanzee genomes

    Directory of Open Access Journals (Sweden)

    Hara Yuichiro

    2011-10-01

    Full Text Available Abstract Background Chromosomal inversion is one of the most important mechanisms of evolution. Recent studies of comparative genomics have revealed that chromosomal inversions are abundant in the human genome. While such previously characterized inversions are large enough to be identified as a single alignment or a string of local alignments, the impact of ultramicro inversions, which are such short that the local alignments completely cover them, on evolution is still uncertain. Results In this study, we developed a method for identifying ultramicro inversions by scanning of local alignments. This technique achieved a high sensitivity and a very low rate of false positives. We identified 2,377 ultramicro inversions ranging from five to 125 bp within the orthologous alignments between the human and chimpanzee genomes. The false positive rate was estimated to be around 4%. Based on phylogenetic profiles using the primate outgroups, 479 ultramicro inversions were inferred to have specifically inverted in the human lineage. Ultramicro inversions exclusively involving adenine and thymine were the most frequent; 461 inversions (19.4% of the total. Furthermore, the density of ultramicro inversions in chromosome Y and the neighborhoods of transposable elements was higher than average. Sixty-five ultramicro inversions were identified within the exons of human protein-coding genes. Conclusions We defined ultramicro inversions as the inverted regions equal to or smaller than 125 bp buried within local alignments. Our observations suggest that ultramicro inversions are abundant among the human and chimpanzee genomes, and that location of the inversions correlated with the genome structural instability. Some of the ultramicro inversions may contribute to gene evolution. Our inversion-identification method is also applicable in the fine-tuning of genome alignments by distinguishing ultramicro inversions from nucleotide substitutions and indels.

  13. Unexpected observations after mapping LongSAGE tags to the human genome

    Directory of Open Access Journals (Sweden)

    Duret Laurent

    2007-05-01

    Full Text Available Abstract Background SAGE has been used widely to study the expression of known transcripts, but much less to annotate new transcribed regions. LongSAGE produces tags that are sufficiently long to be reliably mapped to a whole-genome sequence. Here we used this property to study the position of human LongSAGE tags obtained from all public libraries. We focused mainly on tags that do not map to known transcripts. Results Using a published error rate in SAGE libraries, we first removed the tags likely to result from sequencing errors. We then observed that an unexpectedly large number of the remaining tags still did not match the genome sequence. Some of these correspond to parts of human mRNAs, such as polyA tails, junctions between two exons and polymorphic regions of transcripts. Another non-negligible proportion can be attributed to contamination by murine transcripts and to residual sequencing errors. After filtering out our data with these screens to ensure that our dataset is highly reliable, we studied the tags that map once to the genome. 31% of these tags correspond to unannotated transcripts. The others map to known transcribed regions, but many of them (nearly half are located either in antisense or in new variants of these known transcripts. Conclusion We performed a comprehensive study of all publicly available human LongSAGE tags, and carefully verified the reliability of these data. We found the potential origin of many tags that did not match the human genome sequence. The properties of the remaining tags imply that the level of sequencing error may have been under-estimated. The frequency of tags matching once the genome sequence but not in an annotated exon suggests that the human transcriptome is much more complex than shown by the current human genome annotations, with many new splicing variants and antisense transcripts. SAGE data is appropriate to map new transcripts to the genome, as demonstrated by the high rate of cross

  14. Human genomics and microarrays: implications for the plastic surgeon.

    Science.gov (United States)

    Cole, Jana; Isik, Frank

    2002-09-01

    The Human Genome Project was launched in 1989 in an effort to sequence the entire span of human DNA. Although coding sequences are important in identifying mutations, the static order of DNA does not explain how a cell or organism may respond to normal and abnormal biological processes. By examining the mRNA content of a cell, researchers can determine which genes are being activated in response to a stimulus. Traditional methods in molecular biology generally work on a "one gene: one experiment" basis, which means that the throughput is very limited and the "whole picture" of gene function is hard to obtain. To study each of the 60,000 to 80,000 genes in the human genome under each biological circumstance is not practical. Recently, microarrays (also known as gene or DNA chips) have emerged; these allow for the simultaneous determination of expression for thousands of genes and analysis of genome-wide mRNA expression. The purpose of this article is twofold: first, to provide the clinical plastic surgeon with a working knowledge and understanding of the fields of genomics, microarrays, and bioinformatics and second, to present a case to illustrate how these technologies can be applied in the study of wound healing.

  15. The complete mitochondrial genomes for three Toxocara species of human and animal health significance

    Directory of Open Access Journals (Sweden)

    Wu Xiang-Yun

    2008-05-01

    Full Text Available Abstract Background Studying mitochondrial (mt genomics has important implications for various fundamental areas, including mt biochemistry, physiology and molecular biology. In addition, mt genome sequences have provided useful markers for investigating population genetic structures, systematics and phylogenetics of organisms. Toxocara canis, Toxocara cati and Toxocara malaysiensis cause significant health problems in animals and humans. Although they are of importance in human and animal health, no information on the mt genomes for any of Toxocara species is available. Results The sizes of the entire mt genome are 14,322 bp for T. canis, 14029 bp for T. cati and 14266 bp for T. malaysiensis, respectively. These circular genomes are amongst the largest reported to date for all secernentean nematodes. Their relatively large sizes relate mainly to an increased length in the AT-rich region. The mt genomes of the three Toxocara species all encode 12 proteins, two ribosomal RNAs and 22 transfer RNA genes, but lack the ATP synthetase subunit 8 gene, which is consistent with all other species of Nematode studied to date, with the exception of Trichinella spiralis. All genes are transcribed in the same direction and have a nucleotide composition high in A and T, but low in G and C. The contents of A+T of the complete genomes are 68.57% for T. canis, 69.95% for T. cati and 68.86% for T. malaysiensis, among which the A+T for T. canis is the lowest among all nematodes studied to date. The AT bias had a significant effect on both the codon usage pattern and amino acid composition of proteins. The mt genome structures for three Toxocara species, including genes and non-coding regions, are in the same order as for Ascaris suum and Anisakis simplex, but differ from Ancylostoma duodenale, Necator americanus and Caenorhabditis elegans only in the location of the AT-rich region, whereas there are substantial differences when compared with Onchocerca volvulus

  16. Meta-basic estimates the size of druggable human genome.

    Science.gov (United States)

    Plewczynski, Dariusz; Rychlewski, Leszek

    2009-06-01

    We present here the estimation of the upper limit of the number of molecular targets in the human genome that represent an opportunity for further therapeutic treatment. We select around approximately 6300 human proteins that are similar to sequences of known protein targets collected from DrugBank database. Our bioinformatics study estimates the size of 'druggable' human genome to be around 20% of human proteome, i.e. the number of the possible protein targets for small-molecule drug design in medicinal chemistry. We do not take into account any toxicity prediction, the three-dimensional characteristics of the active site in the predicted 'druggable' protein families, or detailed chemical analysis of known inhibitors/drugs. Instead we rely on remote homology detection method Meta-BASIC, which is based on sequence and structural similarity. The prepared dataset of all predicted protein targets from human genome presents the unique opportunity for developing and benchmarking various in silico chemo/bio-informatics methods in the context of the virtual high throughput screening.

  17. Genome sequencing of idiopathic pulmonary fibrosis in conjunction with a medical school human anatomy course.

    Science.gov (United States)

    Kumar, Akash; Dougherty, Max; Findlay, Gregory M; Geisheker, Madeleine; Klein, Jason; Lazar, John; Machkovech, Heather; Resnick, Jesse; Resnick, Rebecca; Salter, Alexander I; Talebi-Liasi, Faezeh; Arakawa, Christopher; Baudin, Jacob; Bogaard, Andrew; Salesky, Rebecca; Zhou, Qian; Smith, Kelly; Clark, John I; Shendure, Jay; Horwitz, Marshall S

    2014-01-01

    Even in cases where there is no obvious family history of disease, genome sequencing may contribute to clinical diagnosis and management. Clinical application of the genome has not yet become routine, however, in part because physicians are still learning how best to utilize such information. As an educational research exercise performed in conjunction with our medical school human anatomy course, we explored the potential utility of determining the whole genome sequence of a patient who had died following a clinical diagnosis of idiopathic pulmonary fibrosis (IPF). Medical students performed dissection and whole genome sequencing of the cadaver. Gross and microscopic findings were more consistent with the fibrosing variant of nonspecific interstitial pneumonia (NSIP), as opposed to IPF per se. Variants in genes causing Mendelian disorders predisposing to IPF were not detected. However, whole genome sequencing identified several common variants associated with IPF, including a single nucleotide polymorphism (SNP), rs35705950, located in the promoter region of the gene encoding mucin glycoprotein MUC5B. The MUC5B promoter polymorphism was recently found to markedly elevate risk for IPF, though a particular association with NSIP has not been previously reported, nor has its contribution to disease risk previously been evaluated in the genome-wide context of all genetic variants. We did not identify additional predicted functional variants in a region of linkage disequilibrium (LD) adjacent to MUC5B, nor did we discover other likely risk-contributing variants elsewhere in the genome. Whole genome sequencing thus corroborates the association of rs35705950 with MUC5B dysregulation and interstitial lung disease. This novel exercise additionally served a unique mission in bridging clinical and basic science education.

  18. Genome sequencing of idiopathic pulmonary fibrosis in conjunction with a medical school human anatomy course.

    Directory of Open Access Journals (Sweden)

    Akash Kumar

    Full Text Available Even in cases where there is no obvious family history of disease, genome sequencing may contribute to clinical diagnosis and management. Clinical application of the genome has not yet become routine, however, in part because physicians are still learning how best to utilize such information. As an educational research exercise performed in conjunction with our medical school human anatomy course, we explored the potential utility of determining the whole genome sequence of a patient who had died following a clinical diagnosis of idiopathic pulmonary fibrosis (IPF. Medical students performed dissection and whole genome sequencing of the cadaver. Gross and microscopic findings were more consistent with the fibrosing variant of nonspecific interstitial pneumonia (NSIP, as opposed to IPF per se. Variants in genes causing Mendelian disorders predisposing to IPF were not detected. However, whole genome sequencing identified several common variants associated with IPF, including a single nucleotide polymorphism (SNP, rs35705950, located in the promoter region of the gene encoding mucin glycoprotein MUC5B. The MUC5B promoter polymorphism was recently found to markedly elevate risk for IPF, though a particular association with NSIP has not been previously reported, nor has its contribution to disease risk previously been evaluated in the genome-wide context of all genetic variants. We did not identify additional predicted functional variants in a region of linkage disequilibrium (LD adjacent to MUC5B, nor did we discover other likely risk-contributing variants elsewhere in the genome. Whole genome sequencing thus corroborates the association of rs35705950 with MUC5B dysregulation and interstitial lung disease. This novel exercise additionally served a unique mission in bridging clinical and basic science education.

  19. The complete mitochondrial genomes of three cestode species of Taenia infecting animals and humans.

    Science.gov (United States)

    Liu, Guo-Hua; Lin, Rui-Qing; Li, Ming-Wei; Liu, Wei; Liu, Yi; Yuan, Zi-Guo; Song, Hui-Qun; Zhao, Guang-Hui; Zhang, Kou-Xing; Zhu, Xing-Quan

    2011-04-01

    Mitochondrial (mt) genome sequences provide useful markers for investigating population genetic structures, systematics and phylogenetics of organisms. Although Taenia multiceps, T. hydatigena, and T. taeniaeformis are common taeniid tapeworms of ruminants, pigs, dogs, or cats, causing significant economic losses, no published study on their mt genomes is available. The complete mt genomes of T. multiceps, T. hydatigena, and T. taeniaeformis were amplified in two overlapping fragments and then sequenced. The sizes of the entire mt genome were 13700 bp for T. multiceps, 13489 bp for T. hydatigena, and 13647 bp for T. taeniaeformis. Each of the three genomes contains 36 genes, consisting of 12 genes for proteins, 2 genes for rRNA, and 22 genes for tRNA, which are the same as the mt genomes of all other cestode species studied to date. All genes are transcribed in the same direction and have a nucleotide composition high in A and T. The contents of A+T of the complete genomes are 71.3% for T. multiceps, 70.8% for T. hydatigena, and 73.0% for T. taeniaeformis. The AT bias had a significant effect on both the codon usage pattern and amino acid composition of proteins. T. multiceps and T. hydatigena had two noncoding regions, but T. taeniaeformis had only one. Phylogenetic analyses based on concatenated amino acid sequences of 12 protein-coding genes revealed that T. multiceps, T. hydatigena, and T. taeniaeformis were more closely related to the other members of the Taenia genus, consistent with results of previous morphological and molecular studies. The present study determined the complete mt genome sequences for three Taenia species of animal and human health significance, providing useful markers for studying the systematics, population genetics, and molecular epidemiology of these cestode parasites of animals and humans.

  20. A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control.

    Science.gov (United States)

    Bartha, István; Carlson, Jonathan M; Brumme, Chanson J; McLaren, Paul J; Brumme, Zabrina L; John, Mina; Haas, David W; Martinez-Picado, Javier; Dalmau, Judith; López-Galíndez, Cecilio; Casado, Concepción; Rauch, Andri; Günthard, Huldrych F; Bernasconi, Enos; Vernazza, Pietro; Klimkait, Thomas; Yerly, Sabine; O'Brien, Stephen J; Listgarten, Jennifer; Pfeifer, Nico; Lippert, Christoph; Fusi, Nicolo; Kutalik, Zoltán; Allen, Todd M; Müller, Viktor; Harrigan, P Richard; Heckerman, David; Telenti, Amalio; Fellay, Jacques

    2013-10-29

    HIV-1 sequence diversity is affected by selection pressures arising from host genomic factors. Using paired human and viral data from 1071 individuals, we ran >3000 genome-wide scans, testing for associations between host DNA polymorphisms, HIV-1 sequence variation and plasma viral load (VL), while considering human and viral population structure. We observed significant human SNP associations to a total of 48 HIV-1 amino acid variants (pgenome-to-genome approach highlights sites of genomic conflict and is a strategy generally applicable to studies of host-pathogen interaction. DOI:http://dx.doi.org/10.7554/eLife.01123.001.

  1. The pathological consequences of impaired genome integrity in humans; disorders of the DNA replication machinery.

    Science.gov (United States)

    O'Driscoll, Mark

    2017-01-01

    Accurate and efficient replication of the human genome occurs in the context of an array of constitutional barriers, including regional topological constraints imposed by chromatin architecture and processes such as transcription, catenation of the helical polymer and spontaneously generated DNA lesions, including base modifications and strand breaks. DNA replication is fundamentally important for tissue development and homeostasis; differentiation programmes are intimately linked with stem cell division. Unsurprisingly, impairments of the DNA replication machinery can have catastrophic consequences for genome stability and cell division. Functional impacts on DNA replication and genome stability have long been known to play roles in malignant transformation through a variety of complex mechanisms, and significant further insights have been gained from studying model organisms in this context. Congenital hypomorphic defects in components of the DNA replication machinery have been and continue to be identified in humans. These disorders present with a wide range of clinical features. Indeed, in some instances, different mutations in the same gene underlie different clinical presentations. Understanding the origin and molecular basis of these features opens a window onto the range of developmental impacts of suboptimal DNA replication and genome instability in humans. Here, I will briefly overview the basic steps involved in DNA replication and the key concepts that have emerged from this area of research, before switching emphasis to the pathological consequences of defects within the DNA replication network; the human disorders. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  2. Genomes of cryptic chimpanzee Plasmodium species reveal key evolutionary events leading to human malaria.

    Science.gov (United States)

    Sundararaman, Sesh A; Plenderleith, Lindsey J; Liu, Weimin; Loy, Dorothy E; Learn, Gerald H; Li, Yingying; Shaw, Katharina S; Ayouba, Ahidjo; Peeters, Martine; Speede, Sheri; Shaw, George M; Bushman, Frederic D; Brisson, Dustin; Rayner, Julian C; Sharp, Paul M; Hahn, Beatrice H

    2016-03-22

    African apes harbour at least six Plasmodium species of the subgenus Laverania, one of which gave rise to human Plasmodium falciparum. Here we use a selective amplification strategy to sequence the genome of chimpanzee parasites classified as Plasmodium reichenowi and Plasmodium gaboni based on the subgenomic fragments. Genome-wide analyses show that these parasites indeed represent distinct species, with no evidence of cross-species mating. Both P. reichenowi and P. gaboni are 10-fold more diverse than P. falciparum, indicating a very recent origin of the human parasite. We also find a remarkable Laverania-specific expansion of a multigene family involved in erythrocyte remodelling, and show that a short region on chromosome 4, which encodes two essential invasion genes, was horizontally transferred into a recent P. falciparum ancestor. Our results validate the selective amplification strategy for characterizing cryptic pathogen species, and reveal evolutionary events that likely predisposed the precursor of P. falciparum to colonize humans.

  3. Genome-wide association study identified CNP12587 region underlying height variation in Chinese females.

    Directory of Open Access Journals (Sweden)

    Yin-Ping Zhang

    Full Text Available INTRODUCTION: Human height is a highly heritable trait considered as an important factor for health. There has been limited success in identifying the genetic factors underlying height variation. We aim to identify sequence variants associated with adult height by a genome-wide association study of copy number variants (CNVs in Chinese. METHODS: Genome-wide CNV association analyses were conducted in 1,625 unrelated Chinese adults and sex specific subgroup for height variation, respectively. Height was measured with a stadiometer. Affymetrix SNP6.0 genotyping platform was used to identify copy number polymorphisms (CNPs. We constructed a genomic map containing 1,009 CNPs in Chinese individuals and performed a genome-wide association study of CNPs with height. RESULTS: We detected 10 significant association signals for height (p<0.05 in the whole population, 9 and 11 association signals for Chinese female and male population, respectively. A copy number polymorphism (CNP12587, chr18:54081842-54086942, p = 2.41 × 10(-4 was found to be significantly associated with height variation in Chinese females even after strict Bonferroni correction (p = 0.048. Confirmatory real time PCR experiments lent further support for CNV validation. Compared to female subjects with two copies of the CNP, carriers of three copies had an average of 8.1% decrease in height. An important candidate gene, ubiquitin-protein ligase NEDD4-like (NEDD4L, was detected at this region, which plays important roles in bone metabolism by binding to bone formation regulators. CONCLUSIONS: Our findings suggest the important genetic variants underlying height variation in Chinese.

  4. Scientists Spot 15 Regions of Human DNA Linked to Depression

    Science.gov (United States)

    ... Spot 15 Regions of Human DNA Linked to Depression Many are located near genes involved in brain ... identified 15 regions of human DNA associated with depression. These regions may contain genes that increase the ...

  5. Genome-wide landscapes of human local adaptation in Asia.

    Directory of Open Access Journals (Sweden)

    Wei Qian

    Full Text Available Genetic studies of human local adaptation have been facilitated greatly by recent advances in high-throughput genotyping and sequencing technologies. However, few studies have investigated local adaptation in Asian populations on a genome-wide scale and with a high geographic resolution. In this study, taking advantage of the dense population coverage in Southeast Asia, which is the part of the world least studied in term of natural selection, we depicted genome-wide landscapes of local adaptations in 63 Asian populations representing the majority of linguistic and ethnic groups in Asia. Using genome-wide data analysis, we discovered many genes showing signs of local adaptation or natural selection. Notable examples, such as FOXQ1, MAST2, and CDH4, were found to play a role in hair follicle development and human cancer, signal transduction, and tumor repression, respectively. These showed strong indications of natural selection in Philippine Negritos, a group of aboriginal hunter-gatherers living in the Philippines. MTTP, which has associations with metabolic syndrome, body mass index, and insulin regulation, showed a strong signature of selection in Southeast Asians, including Indonesians. Functional annotation analysis revealed that genes and genetic variants underlying natural selections were generally enriched in the functional category of alternative splicing. Specifically, many genes showing significant difference with respect to allele frequency between northern and southern Asian populations were found to be associated with human height and growth and various immune pathways. In summary, this study contributes to the overall understanding of human local adaptation in Asia and has identified both known and novel signatures of natural selection in the human genome.

  6. Statistical analysis of simple repeats in the human genome

    Science.gov (United States)

    Piazza, F.; Liò, P.

    2005-03-01

    The human genome contains repetitive DNA at different level of sequence length, number and dispersion. Highly repetitive DNA is particularly rich in homo- and di-nucleotide repeats, while middle repetitive DNA is rich of families of interspersed, mobile elements hundreds of base pairs (bp) long, among which belong the Alu families. A link between homo- and di-polymeric tracts and mobile elements has been recently highlighted. In particular, the mobility of Alu repeats, which form 10% of the human genome, has been correlated with the length of poly(A) tracts located at one end of the Alu. These tracts have a rigid and non-bendable structure and have an inhibitory effect on nucleosomes, which normally compact the DNA. We performed a statistical analysis of the genome-wide distribution of lengths and inter-tract separations of poly(X) and poly(XY) tracts in the human genome. Our study shows that in humans the length distributions of these sequences reflect the dynamics of their expansion and DNA replication. By means of general tools from linguistics, we show that the latter play the role of highly-significant content-bearing terms in the DNA text. Furthermore, we find that such tracts are positioned in a non-random fashion, with an apparent periodicity of 150 bases. This allows us to extend the link between repetitive, highly mobile elements such as Alus and low-complexity words in human DNA. More precisely, we show that Alus are sources of poly(X) tracts, which in turn affect in a subtle way the combination and diversification of gene expression and the fixation of multigene families.

  7. 78 FR 61851 - National Human Genome Research Institute; Notice of Closed Meeting

    Science.gov (United States)

    2013-10-04

    ... clearly unwarranted invasion of personal privacy. Name of Committee: National Human Genome Research... Human Genome Research Institute, 4076 Conference Room, 5635 Fishers Lane, Rockville, MD 20852... Domestic Assistance Program Nos. 93.172, Human Genome Research, National Institutes of Health, HHS)...

  8. Learning about the Human Genome. Part 2: Resources for Science Educators. ERIC Digest.

    Science.gov (United States)

    Haury, David L.

    This ERIC Digest identifies how the human genome project fits into the "National Science Education Standards" and lists Human Genome Project Web sites found on the World Wide Web. It is a resource companion to "Learning about the Human Genome. Part 1: Challenge to Science Educators" (Haury 2001). The Web resources and…

  9. 75 FR 51828 - National Human Genome Research Institute; Notice of Meetings

    Science.gov (United States)

    2010-08-23

    ... for Human Genome Research. The meetings will be open to the public as indicated below, with attendance..., PhD, Director for Extramural Research, National Human Genome Research Institute, 5635 Fishers Lane...: National Advisory Council for Human Genome Research. Date: May 16-17, 2011. Open: May 16, 2011, 8:30...

  10. Rapid extraction and preservation of genomic DNA from human samples.

    Science.gov (United States)

    Kalyanasundaram, D; Kim, J-H; Yeo, W-H; Oh, K; Lee, K-H; Kim, M-H; Ryew, S-M; Ahn, S-G; Gao, D; Cangelosi, G A; Chung, J-H

    2013-02-01

    Simple and rapid extraction of human genomic DNA remains a bottleneck for genome analysis and disease diagnosis. Current methods using microfilters require cumbersome, multiple handling steps in part because salt conditions must be controlled for attraction and elution of DNA in porous silica. We report a novel extraction method of human genomic DNA from buccal swab and saliva samples. DNA is attracted onto a gold-coated microchip by an electric field and capillary action while the captured DNA is eluted by thermal heating at 70 °C. A prototype device was designed to handle four microchips, and a compatible protocol was developed. The extracted DNA using microchips was characterized by qPCR for different sample volumes, using different lengths of PCR amplicon, and nuclear and mitochondrial genes. In comparison with a commercial kit, an equivalent yield of DNA extraction was achieved with fewer steps. Room-temperature preservation for 1 month was demonstrated for captured DNA, facilitating straightforward collection, delivery, and handling of genomic DNA in an environment-friendly protocol.

  11. Cynomolgus monkey testicular cDNAs for discovery of novel human genes in the human genome sequence

    Directory of Open Access Journals (Sweden)

    Terao Keiji

    2002-12-01

    Full Text Available Abstract Background In order to contribute to the establishment of a complete map of transcribed regions of the human genome, we constructed a testicular cDNA library for the cynomolgus monkey, and attempted to find novel transcripts for identification of their human homologues. Result The full-insert sequences of 512 cDNA clones were determined. Ultimately we found 302 non-redundant cDNAs carrying open reading frames of 300 bp-length or longer. Among them, 89 cDNAs were found not to be annotated previously in the Ensembl human database. After searching against the Ensembl mouse database, we also found 69 putative coding sequences have no homologous cDNAs in the annotated human and mouse genome sequences in Ensembl. We subsequently designed a DNA microarray including 396 non-redundant cDNAs (with and without open reading frames to examine the expression of the full-sequenced genes. With the testicular probe and a mixture of probes of 10 other tissues, 316 of 332 effective spots showed intense hybridized signals and 75 cDNAs were shown to be expressed very highly in the cynomolgus monkey testis, but not ubiquitously. Conclusions In this report, we determined 302 full-insert sequences of cynomolgus monkey cDNAs with enough length of open reading frames to discover novel transcripts as human homologues. Among 302 cDNA sequences, human homologues of 89 cDNAs have not been predicted in the annotated human genome sequence in the Ensembl. Additionally, we identified 75 dominantly expressed genes in testis among the full-sequenced clones by using a DNA microarray. Our cDNA clones and analytical results will be valuable resources for future functional genomic studies.

  12. Opening plenary speaker: Human genomics, precision medicine, and advancing human health.

    Science.gov (United States)

    Green, Eric D

    2016-08-01

    Starting with the launch of the Human Genome Project in 1990, the past quarter-century has brought spectacular achievements in genomics that dramatically empower the study of human biology and disease. The human genomics enterprise is now in the midst of an important transition, as the growing foundation of genomic knowledge is being used by researchers and clinicians to tackle increasingly complex problems in biomedicine. Of particular prominence is the use of revolutionary new DNA sequencing technologies for generating prodigious amounts of DNA sequence data to elucidate the complexities of genome structure, function, and evolution, as well as to unravel the genomic bases of rare and common diseases. Together, these developments are ushering in the era of genomic medicine. Augmenting the advances in human genomics have been innovations in technologies for measuring environmental and lifestyle information, electronic health records, and data science; together, these provide opportunities of unprecedented scale and scope for investigating the underpinnings of health and disease. To capitalize on these opportunities, U.S. President Barack Obama recently announced a major new research endeavor - the U.S. Precision Medicine Initiative. This bold effort will be framed around several key aims, which include accelerating the use of genomically informed approaches to cancer care, making important policy and regulatory changes, and establishing a large research cohort of >1 million volunteers to facilitate precision medicine research. The latter will include making the partnership with all participants a centerpiece feature in the cohort's design and development. The Precision Medicine Initiative represents a broad-based research program that will allow new approaches for individualized medical care to be rigorously tested, so as to establish a new evidence base for advancing clinical practice and, eventually, human health.

  13. Identification and annotation of promoter regions in microbial genome sequences on the basis of DNA stability

    Indian Academy of Sciences (India)

    Vetriselvi Rangannan; Manju Bansal

    2007-08-01

    Analysis of various predicted structural properties of promoter regions in prokaryotic as well as eukaryotic genomes had earlier indicated that they have several common features, such as lower stability, higher curvature and less bendability, when compared with their neighboring regions. Based on the difference in stability between neighboring upstream and downstream regions in the vicinity of experimentally determined transcription start sites, a promoter prediction algorithm has been developed to identify prokaryotic promoter sequences in whole genomes. The average free energy (E) over known promoter sequences and the difference (D) between E and the average free energy over the entire genome (G) are used to search for promoters in the genomic sequences. Using these cutoff values to predict promoter regions across entire Escherichia coli genome, we achieved a reliability of 70% when the predicted promoters were cross verified against the 960 transcription start sites (TSSs) listed in the Ecocyc database. Annotation of the whole E. coli genome for promoter region could be carried out with 49% accuracy. The method is quite general and it can be used to annotate the promoter regions of other prokaryotic genomes.

  14. Genomic discovery of potent chromatin insulators for human gene therapy.

    Science.gov (United States)

    Liu, Mingdong; Maurano, Matthew T; Wang, Hao; Qi, Heyuan; Song, Chao-Zhong; Navas, Patrick A; Emery, David W; Stamatoyannopoulos, John A; Stamatoyannopoulos, George

    2015-02-01

    Insertional mutagenesis and genotoxicity, which usually manifest as hematopoietic malignancy, represent major barriers to realizing the promise of gene therapy. Although insulator sequences that block transcriptional enhancers could mitigate or eliminate these risks, so far no human insulators with high functional potency have been identified. Here we describe a genomic approach for the identification of compact sequence elements that function as insulators. These elements are highly occupied by the insulator protein CTCF, are DNase I hypersensitive and represent only a small minority of the CTCF recognition sequences in the human genome. We show that the elements identified acted as potent enhancer blockers and substantially decreased the risk of tumor formation in a cancer-prone animal model. The elements are small, can be efficiently accommodated by viral vectors and have no detrimental effects on viral titers. The insulators we describe here are expected to increase the safety of gene therapy for genetic diseases.

  15. Genome Editing in Human Cells Using CRISPR/Cas Nucleases.

    Science.gov (United States)

    Wyvekens, Nicolas; Tsai, Shengdar Q; Joung, J Keith

    2015-10-01

    The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system has been broadly adopted for highly efficient genome editing in a variety of model organisms and human cell types. Unlike previous genome editing technologies such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), CRISPR/Cas technology does not require complex protein engineering and can be utilized by any researcher proficient in basic molecular biology and cell culture techniques. This unit describes protocols for design and cloning of vectors expressing single or multiplex gRNAs, for transient transfection of human cell lines, and for quantitation of mutation frequencies by T7 endonuclease I assay. These protocols also include guidance for using two improvements that increase the specificity of CRISPR/Cas nucleases: truncated gRNAs and dimeric RNA-guided FokI nucleases.

  16. GENOME EDITING IN HUMAN CELLS USING CRISPR/CAS NUCLEASES

    Science.gov (United States)

    Wyvekens, Nicolas; Tsai, Shengdar; Joung, J. Keith

    2016-01-01

    The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system has been broadly adopted for highly efficient genome editing in a variety of model organisms and human cell types. Unlike previous genome editing technologies such as Zinc Finger Nucleases (ZFNs) and Transcription Activator-Like Effector Nucleases (TALENs), the CRISPR/Cas technology does not require complex protein engineering and can be utilized by any researcher proficient in basic molecular biology and cell culture techniques. Here we describe protocols for design and cloning of vectors expressing single or multiplex gRNAs, for transient transfection of human cell lines, and for quantitation of mutation frequencies by T7 Endonuclease I assay. These protocols also include guidance for using two improvements that increase the specificity of CRISPR/Cas nucleases: truncated gRNAs and dimeric RNA-guided FokI nucleases. PMID:26423589

  17. Life Sciences Division and Center for Human Genome Studies

    Energy Technology Data Exchange (ETDEWEB)

    Spitzmiller, D.; Bradbury, M.; Cram, S. (comps.)

    1992-05-01

    This report summarizes the research and development activities of Los Alamos National Laboratories Life Sciences Division and biological aspects of the Center for Human Genome Studies for the calendar year 1991. Selected research highlights include: yeast artificial chromosome libraries from flow sorted human chromosomes 16 and 21; distances between the antigen binding sites of three murine antibody subclasses measured using neutron and x-ray scattering; NFCR 10th anniversary highlights; kinase-mediated differences found in the cell cycle regulation of normal and transformed cells; and detecting mutations that cause Gaucher's disease by denaturing gradient gel electrophoresis. Project descriptions include: genomic structure and regulation, molecular structure, cytometry, cell growth and differentiation, radiation biology and carcinogenesis, and pulmonary biology.

  18. Concise review: Human cell engineering: cellular reprogramming and genome editing.

    Science.gov (United States)

    Mali, Prashant; Cheng, Linzhao

    2012-01-01

    Cell engineering is defined here as the collective ability to both reset and edit the genome of a mammalian cell. Until recently, this had been extremely challenging to achieve as nontransformed human cells are significantly refractory to both these processes. The recent success in reprogramming somatic cells into induced pluripotent stem cells that are self-renewable in culture, coupled with our increasing ability to effect precise and predesigned genomic editing, now readily permits cellular changes at both the genetic and epigenetic levels. These dual capabilities also make possible the generation of genetically matched, disease-free stem cells from patients for regenerative medicine. The objective of this review is to summarize the key enabling developments on these two rapidly evolving research fronts in human cell engineering, highlight unresolved issues, and outline potential future research directions.

  19. Genomic regions associated with necrotic enteritis resistance in Fayoumi and White Leghorn chickens

    Science.gov (United States)

    In this study, we used two breeds of chicken to identify genomic regions corresponding to necrotic enteritis (NE) resistance. We scanned the genomes of a resistant and susceptible line of Fayoumi and White Leghorn chicken using a chicken 60K Illumina SNP panel. A total of 235 loci with divergently ...

  20. Comparative Genomic Analysis of Human Fungal Pathogens Causing Paracoccidioidomycosis

    OpenAIRE

    Desjardins, Christopher A; Champion, Mia D.; Holder, Jason W.; Muszewska, Anna; Goldberg, Jonathan; Bailao, Alexandre M.; Brigido, Marcelo de Macedo; Silva Ferreira, Marcia Eliana da; Garcia, Ana Maria; Grynberg, Marcin; Gujja, Sharvari; Heiman, David I.; Henn, Matthew R.; Kodira, Chinnappa D.; Leon-Narvaez, Henry

    2011-01-01

    Paracoccidioides is a fungal pathogen and the cause of paracoccidioidomycosis, a health-threatening human systemic mycosis endemic to Latin America. Infection by Paracoccidioides, a dimorphic fungus in the order Onygenales, is coupled with a thermally regulated transition from a soil-dwelling filamentous form to a yeast-like pathogenic form. To better understand the genetic basis of growth and pathogenicity in Paracoccidioides, we sequenced the genomes of two strains of Paracoccidioides brasi...

  1. Detection of extracellular genomic DNA scaffold in human thrombus

    DEFF Research Database (Denmark)

    Oklu, Rahmi; Albadawi, Hassan; Watkins, Michael T

    2012-01-01

    PURPOSE: Mechanisms underlying transition of a thrombus susceptible to tissue plasminogen activator (TPA) fibrinolysis to one that is resistant is unclear. Demonstration of a new possible thrombus scaffold may open new avenues of research in thrombolysis and may provide mechanistic insight...... thrombi. CONCLUSIONS: Extensive detection of genomic DNA associated with histones in the extracellular matrix of human and mouse thrombi suggest the presence of a new thrombus-associated scaffold....

  2. Human gene encoding prostacyclin synthase (PTGIS): Genomic organization, chromosomal localization, and promoter activity

    Energy Technology Data Exchange (ETDEWEB)

    Yokoyama, Chieko; Yabuki, Tomoko; Inoue, Hiroyasu [National Cardiovascular Center Research Institute, Osaka (Japan)] [and others

    1996-09-01

    The prostacyclin synthase gene isolated from human genomic libraries (PTGIS) consists of 10 exons spanning approximately 60 kb. All the splice donor and acceptor sites conform to the GT/AG rule. Genomic Southern blot and fluorescence in situ hybridization analyses revealed that the human prostacyclin synthase gene is present as a single copy per haploid genome and is localized on chromosome 20q13.11-q13.13. The 1.5-kb sequence of the 5{prime} of the translational initiation site contained both GC-rich and pyrimidine-rich regions and consensus sequences of the transcription factor recognition sites such as Sp1, AP-2, the interferon-{gamma} response element, GATA, NF-{kappa}B, the CACCC box, and the glucocorticoid response element. The core binding sequence (GAGACC) of the shear stress responsive element was also found in the 5{prime}-flanking region of the gene. The major product of the primer extension analysis suggested that the transcription of the gene started from the positions around 49 bp upstream of the translational initiation codon. Transient transfection experiments using human aortic and bovine arterial endothelial cells demonstrated that the GC-rich region (positions -145 to -10) possessed a significant promoter activity. The 6-kb downstream sequence of the translational termination codon contained multiple polyadenylation signals, Alu repeat sequences, and the consensus sequence of the primate-repetitive DNA element, MER1. Two sizes of the prostacyclin synthase mRNAs (approximately 6 and 3.3 kb) were detected with the human aorta and lung. RNA blot hybridization analysis using the 3{prime}-untranslated region as probe indicated that the sizes of the 3{prime}-flanking regions were different in the major 6-kb and minor 3.3-kb mRNAs. 54 refs., 7 figs.

  3. Localising loci underlying complex trait variation using Regional Genomic Relationship Mapping.

    Directory of Open Access Journals (Sweden)

    Yoshitaka Nagamine

    Full Text Available The limited proportion of complex trait variance identified in genome-wide association studies may reflect the limited power of single SNP analyses to detect either rare causative alleles or those of small effect. Motivated by studies that demonstrate that loci contributing to trait variation may contain a number of different alleles, we have developed an analytical approach termed Regional Genomic Relationship Mapping that, like linkage-based family methods, integrates variance contributed by founder gametes within a pedigree. This approach takes advantage of very distant (and unrecorded relationships, and this greatly increases the power of the method, compared with traditional pedigree-based linkage analyses. By integrating variance contributed by founder gametes in the population, our approach provides an estimate of the Regional Heritability attributable to a small genomic region (e.g. 100 SNP window covering ca. 1 Mb of DNA in a 300000 SNP GWAS and has the power to detect regions containing multiple alleles that individually contribute too little variance to be detectable by GWAS as well as regions with single common GWAS-detectable SNPs. We use genome-wide SNP array data to obtain both a genome-wide relationship matrix and regional relationship ("identity by state" or IBS matrices for sequential regions across the genome. We then estimate a heritability for each region sequentially in our genome-wide scan. We demonstrate by simulation and with real data that, when compared to traditional ("individual SNP" GWAS, our method uncovers new loci that explain additional trait variation. We analysed data from three Southern European populations and from Orkney for exemplar traits - serum uric acid concentration and height. We show that regional heritability estimates are correlated with results from genome-wide association analysis but can capture more of the genetic variance segregating in the population and identify additional trait loci.

  4. Human genome-guided identification of memory-modulating drugs.

    Science.gov (United States)

    Papassotiropoulos, Andreas; Gerhards, Christiane; Heck, Angela; Ackermann, Sandra; Aerni, Amanda; Schicktanz, Nathalie; Auschra, Bianca; Demougin, Philippe; Mumme, Eva; Elbert, Thomas; Ertl, Verena; Gschwind, Leo; Hanser, Edveena; Huynh, Kim-Dung; Jessen, Frank; Kolassa, Iris-Tatjana; Milnik, Annette; Paganetti, Paolo; Spalek, Klara; Vogler, Christian; Muhs, Andreas; Pfeifer, Andrea; de Quervain, Dominique J-F

    2013-11-12

    In the last decade there has been an exponential increase in knowledge about the genetic basis of complex human traits, including neuropsychiatric disorders. It is not clear, however, to what extent this knowledge can be used as a starting point for drug identification, one of the central hopes of the human genome project. The aim of the present study was to identify memory-modulating compounds through the use of human genetic information. We performed a multinational collaborative study, which included assessment of aversive memory--a trait central to posttraumatic stress disorder--and a gene-set analysis in healthy individuals. We identified 20 potential drug target genes in two genomewide-corrected gene sets: the neuroactive ligand-receptor interaction and the long-term depression gene set. In a subsequent double-blind, placebo-controlled study in healthy volunteers, we aimed at providing a proof of concept for the genome-guided identification of memory modulating compounds. Pharmacological intervention at the neuroactive ligand-receptor interaction gene set led to significant reduction of aversive memory. The findings demonstrate that genome information, along with appropriate data mining methodology, can be used as a starting point for the identification of memory-modulating compounds.

  5. The human genome: Some assembly required. Final report

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1994-12-31

    The Human Genome Project promises to be one of the most rewarding endeavors in modern biology. The cost and the ethical and social implications, however, have made this project the source of considerable debate both in the scientific community and in the public at large. The 1994 Graduate Student Symposium addresses the scientific merits of the project, the technical issues involved in accomplishing the task, as well as the medical and social issues which stem from the wealth of knowledge which the Human Genome Project will help create. To this end, speakers were brought together who represent the diverse areas of expertise characteristic of this multidisciplinary project. The keynote speaker addresses the project`s motivations and goals in the larger context of biological and medical sciences. The first two sessions address relevant technical issues, data collection with a focus on high-throughput sequencing methods and data analysis with an emphasis on identification of coding sequences. The third session explores recent advances in the understanding of genetic diseases and possible routes to treatment. Finally, the last session addresses some of the ethical, social and legal issues which will undoubtedly arise from having a detailed knowledge of the human genome.

  6. Characterization of the flamenco region of the Drosophila melanogaster genome.

    Science.gov (United States)

    Robert, V; Prud'homme, N; Kim, A; Bucheton, A; Pélisson, A

    2001-06-01

    The flamenco gene, located at 20A1-3 in the beta-heterochromatin of the Drosophila X chromosome, is a major regulator of the gypsy/mdg4 endogenous retrovirus. As a first step to characterize this gene, approximately 100 kb of genomic DNA flanking a P-element-induced mutation of flamenco was isolated. This DNA is located in a sequencing gap of the Celera Genomics project, i.e., one of those parts of the genome in which the "shotgun" sequence could not be assembled, probably because it contains long stretches of repetitive DNA, especially on the proximal side of the P insertion point. Deficiency mapping indicated that sequences required for the normal flamenco function are located >130 kb proximal to the insertion site. The distal part of the cloned DNA does, nevertheless, contain several unique sequences, including at least four different transcription units. Dip1, the closest one to the P-element insertion point, might be a good candidate for a gypsy regulator, since it putatively encodes a nuclear protein containing two double-stranded RNA-binding domains. However, transgenes containing dip1 genomic DNA were not able to rescue flamenco mutant flies. The possible nature of the missing flamenco sequences is discussed.

  7. Annotation of the protein coding regions of the equine genome

    DEFF Research Database (Denmark)

    Hestand, Matthew S.; Kalbfleisch, Theodore S.; Coleman, Stephen J.;

    2015-01-01

    Current gene annotation of the horse genome is largely derived from in silico predictions and cross-species alignments. Only a small number of genes are annotated based on equine EST and mRNA sequences. To expand the number of equine genes annotated from equine experimental evidence, we sequenced...

  8. Targeted enrichment of genomic DNA regions for next generation sequencing

    NARCIS (Netherlands)

    Mertens, F.; El-Sharawy, A.; Sauer, S.; Van Helvoort, J.; Van der Zaag, P.J.; Franke, A.; Nilsson, M.; Lehrach. H.; Brookes, A.

    2011-01-01

    In this review we discuss the latest targeted enrichment methods, and aspects of their utilization along with second generation sequencing for complex genome analysis. In doing so we provide an overview of issues involved in detecting genetic variation, for which targeted enrichment has become a pow

  9. Structured RNAs and synteny regions in the pig genome

    DEFF Research Database (Denmark)

    Anthon, Christian; Tafer, Hakim; Havgaard, Jakob H

    2014-01-01

    for Laurasiatheria (pig, cow, dolphin, horse, cat, dog, hedgehog). CONCLUSIONS: We have obtained one of the most comprehensive annotations for structured ncRNAs of a mammalian genome, which is likely to play central roles in both health modelling and production. The core annotation is available in Ensembl 70...

  10. Core and region-enriched networks of behaviorally regulated genes and the singing genome

    Science.gov (United States)

    Whitney, Osceola; Pfenning, Andreas R.; Howard, Jason T.; Blatti, Charles A; Liu, Fang; Ward, James M.; Wang, Rui; Audet, Jean-Nicolas; Kellis, Manolis; Mukherjee, Sayan; Sinha, Saurabh; Hartemink, Alexander J.; West, Anne E.; Jarvis, Erich D.

    2015-01-01

    Songbirds represent an important model organism for elucidating molecular mechanisms that link genes with complex behaviors, in part because they have discrete vocal learning circuits that have parallels with those that mediate human speech. We found that ~10% of the genes in the avian genome were regulated by singing, and we found a striking regional diversity of both basal and singing-induced programs in the four key song nuclei of the zebra finch, a vocal learning songbird. The region-enriched patterns were a result of distinct combinations of region-enriched transcription factors (TFs), their binding motifs, and presinging acetylation of histone 3 at lysine 27 (H3K27ac) enhancer activity in the regulatory regions of the associated genes. RNA interference manipulations validated the role of the calcium-response transcription factor (CaRF) in regulating genes preferentially expressed in specific song nuclei in response to singing. Thus, differential combinatorial binding of a small group of activity-regulated TFs and predefined epigenetic enhancer activity influences the anatomical diversity of behaviorally regulated gene networks. PMID:25504732

  11. Subfunction partitioning, the teleost radiation and the annotation of the human genome.

    Science.gov (United States)

    Postlethwait, John; Amores, Angel; Cresko, William; Singer, Amy; Yan, Yi-Lin

    2004-10-01

    Half of all vertebrate species are teleost fish. What accounts for this explosion of biodiversity? Recent evidence and advances in evolutionary theory suggest that genomic features could have played a significant role in the teleost radiation. This review examines evidence for an ancient whole-genome duplication (tetraploidization) event that probably occurred just before the teleost radiation. The partitioning of ancestral subfunctions between gene copies arising from this duplication could have contributed to the genetic isolation of populations, to lineage-specific diversification of developmental programs, and ultimately to phenotypic variation among teleost fish. Beyond its importance for understanding mechanisms that generate biodiversity, the partitioning of subfunctions between teleost co-orthologs of human genes can facilitate the identification of tissue-specific conserved noncoding regions and can simplify the analysis of ancestral gene functions obscured by pleiotropy or haploinsufficiency. Applying these principles on a genomic scale can accelerate the functional annotation of the human genome and understanding of the roles of human genes in health and disease.

  12. Large-insert BAC/YAC libraries for selective re-isolation of genomic regions by homologous recombination in yeast.

    Science.gov (United States)

    Zeng, C; Kouprina, N; Zhu, B; Cairo, A; Hoek, M; Cross, G; Osoegawa, K; Larionov, V; de Jong, P

    2001-09-01

    We constructed representative large-insert bacterial artificial chromosome (BAC) libraries of two human pathogens (Trypanosoma brucei and Giardia lamblia) using a new hybrid vector, pTARBAC1, containing a yeast artificial chromosome (YAC) cassette (a yeast selectable marker and a centromere). The cassette allows transferring of BACs into yeast for their further modification. Furthermore, the new hybrid vector provides the opportunity to re-isolate each DNA insert without construction of a new library of random clones. Digestion of a BAC DNA by an endonuclease that has no recognition site in the vector, but which deletes most of the internal insert sequence and leaves the unique flanking sequences, converts a BAC into a TAR vector, thus allowing direct gene isolation. Cotransformation of a TAR vector and genomic DNA into yeast spheroplasts, and subsequent recombination between the TAR vector's flanking ends and a specific genomic fragment, allows rescue of the fragment as a circular YAC/BAC molecule. Here we prove a new cloning strategy by re-isolation of randomly chosen genomic fragments of different size from T. brucei cloned in BACs. We conclude that genomic regions of unicellular eukaryotes can be easily re-isolated using this technique, which provides an opportunity to study evolution of these genomes and the role of genome instability in pathogenicity.

  13. Standardized metadata for human pathogen/vector genomic sequences.

    Directory of Open Access Journals (Sweden)

    Vivien G Dugan

    Full Text Available High throughput sequencing has accelerated the determination of genome sequences for thousands of human infectious disease pathogens and dozens of their vectors. The scale and scope of these data are enabling genotype-phenotype association studies to identify genetic determinants of pathogen virulence and drug/insecticide resistance, and phylogenetic studies to track the origin and spread of disease outbreaks. To maximize the utility of genomic sequences for these purposes, it is essential that metadata about the pathogen/vector isolate characteristics be collected and made available in organized, clear, and consistent formats. Here we report the development of the GSCID/BRC Project and Sample Application Standard, developed by representatives of the Genome Sequencing Centers for Infectious Diseases (GSCIDs, the Bioinformatics Resource Centers (BRCs for Infectious Diseases, and the U.S. National Institute of Allergy and Infectious Diseases (NIAID, part of the National Institutes of Health (NIH, informed by interactions with numerous collaborating scientists. It includes mapping to terms from other data standards initiatives, including the Genomic Standards Consortium's minimal information (MIxS and NCBI's BioSample/BioProjects checklists and the Ontology for Biomedical Investigations (OBI. The standard includes data fields about characteristics of the organism or environmental source of the specimen, spatial-temporal information about the specimen isolation event, phenotypic characteristics of the pathogen/vector isolated, and project leadership and support. By modeling metadata fields into an ontology-based semantic framework and reusing existing ontologies and minimum information checklists, the application standard can be extended to support additional project-specific data fields and integrated with other data represented with comparable standards. The use of this metadata standard by all ongoing and future GSCID sequencing projects will

  14. Predicting human genetic interactions from cancer genome evolution.

    Directory of Open Access Journals (Sweden)

    Xiaowen Lu

    Full Text Available Synthetic Lethal (SL genetic interactions play a key role in various types of biological research, ranging from understanding genotype-phenotype relationships to identifying drug-targets against cancer. Despite recent advances in empirical measuring SL interactions in human cells, the human genetic interaction map is far from complete. Here, we present a novel approach to predict this map by exploiting patterns in cancer genome evolution. First, we show that empirically determined SL interactions are reflected in various gene presence, absence, and duplication patterns in hundreds of cancer genomes. The most evident pattern that we discovered is that when one member of an SL interaction gene pair is lost, the other gene tends not to be lost, i.e. the absence of co-loss. This observation is in line with expectation, because the loss of an SL interacting pair will be lethal to the cancer cell. SL interactions are also reflected in gene expression profiles, such as an under representation of cases where the genes in an SL pair are both under expressed, and an over representation of cases where one gene of an SL pair is under expressed, while the other one is over expressed. We integrated the various previously unknown cancer genome patterns and the gene expression patterns into a computational model to identify SL pairs. This simple, genome-wide model achieves a high prediction power (AUC = 0.75 for known genetic interactions. It allows us to present for the first time a comprehensive genome-wide list of SL interactions with a high estimated prediction precision, covering up to 591,000 gene pairs. This unique list can potentially be used in various application areas ranging from biotechnology to medical genetics.

  15. Frequency and Correlation of Nearest Neighboring Nucleotides in Human Genome

    Science.gov (United States)

    Jin, Neng-zhi; Liu, Zi-xian; Qiu, Wen-yuan

    2009-02-01

    Zipf's approach in linguistics is utilized to analyze the statistical features of frequency and correlation of 16 nearest neighboring nucleotides (AA, AC, AG, ..., TT) in 12 human chromosomes (Y, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, and 12). It is found that these statistical features of nearest neighboring nucleotides in human genome: (i) the frequency distribution is a linear function, and (ii) the correlation distribution is an inverse function. The coefficients of the linear function and inverse function depend on the GC content. It proposes the correlation distribution of nearest neighboring nucleotides for the first time and extends the descriptor about nearest neighboring nucleotides.

  16. A genome-wide analysis of genetic diversity in Trypanosoma cruzi intergenic regions.

    Directory of Open Access Journals (Sweden)

    Leonardo G Panunzi

    2014-05-01

    Full Text Available BACKGROUND: Trypanosoma cruzi is the causal agent of Chagas Disease. Recently, the genomes of representative strains from two major evolutionary lineages were sequenced, allowing the construction of a detailed genetic diversity map for this important parasite. However this map is focused on coding regions of the genome, leaving a vast space of regulatory regions uncharacterized in terms of their evolutionary conservation and/or divergence. METHODOLOGY: Using data from the hybrid CL Brener and Sylvio X10 genomes (from the TcVI and TcI Discrete Typing Units, respectively, we identified intergenic regions that share a common evolutionary ancestry, and are present in both CL Brener haplotypes (TcII-like and TcIII-like and in the TcI genome; as well as intergenic regions that were conserved in only two of the three genomes/haplotypes analyzed. The genetic diversity in these regions was characterized in terms of the accumulation of indels and nucleotide changes. PRINCIPAL FINDINGS: Based on this analysis we have identified i a core of highly conserved intergenic regions, which remained essentially unchanged in independently evolving lineages; ii intergenic regions that show high diversity in spite of still retaining their corresponding upstream and downstream coding sequences; iii a number of defined sequence motifs that are shared by a number of unrelated intergenic regions. A fraction of indels explains the diversification of some intergenic regions by the expansion/contraction of microsatellite-like repeats.

  17. Estimation of (co)variances for genomic regions of flexible sizes

    DEFF Research Database (Denmark)

    Sørensen, Lars P; Janss, Luc; Madsen, Per;

    2012-01-01

    traits such as mammary disease traits in dairy cattle. METHODS: Data on progeny means of six traits related to mastitis resistance in dairy cattle (general mastitis resistance and five pathogen-specific mastitis resistance traits) were analyzed using a bivariate Bayesian SNP-based genomic model......)variances of mastitis resistance traits in dairy cattle using multivariate genomic models......., per chromosome, and in regions of 100 SNP on a chromosome. RESULTS: Genomic proportions of the total variance differed between traits. Genomic correlations were lower than pedigree-based genetic correlations and they were highest between general mastitis and pathogen-specific traits because...

  18. Differentially Methylated Genomic Regions in Birth-Weight Discordant Twin Pairs

    DEFF Research Database (Denmark)

    Chen, Mubo; Baumbach, Jan; Vandin, Fabio

    2016-01-01

    twin pairs to find evidence for such “programming” effects, but no significant results emerged. We further investigated this issue using a new computational approach: Instead of probing single genomic sites for significant alterations in epigenetic marks, we scan for differentially methylated genomic...... regions. Whole genome DNA methylation levels were measured in whole blood from 150 pairs of adult identical twins discordant for birth-weight. Intrapair differential DNA methylation was associated with qualitative (large or small) and quantitative (percentage) birth-weight discordance at each genomic site...

  19. A matter of life or death: how microsatellites emerge in and vanish from the human genome.

    Science.gov (United States)

    Kelkar, Yogeshwar D; Eckert, Kristin A; Chiaromonte, Francesca; Makova, Kateryna D

    2011-12-01

    Microsatellites--tandem repeats of short DNA motifs--are abundant in the human genome and have high mutation rates. While microsatellite instability is implicated in numerous genetic diseases, the molecular processes involved in their emergence and disappearance are still not well understood. Microsatellites are hypothesized to follow a life cycle, wherein they are born and expand into adulthood, until their degradation and death. Here we identified microsatellite births/deaths in human, chimpanzee, and orangutan genomes, using macaque and marmoset as outgroups. We inferred mutations causing births/deaths based on parsimony, and investigated local genomic environments affecting them. We also studied birth/death patterns within transposable elements (Alus and L1s), coding regions, and disease-associated loci. We observed that substitutions were the predominant cause for births of short microsatellites, while insertions and deletions were important for births of longer microsatellites. Substitutions were the cause for deaths of microsatellites of virtually all lengths. AT-rich L1 sequences exhibited elevated frequency of births/deaths over their entire length, while GC-rich Alus only in their 3' poly(A) tails and middle A-stretches, with differences depending on transposable element integration timing. Births/deaths were strongly selected against in coding regions. Births/deaths occurred in genomic regions with high substitution rates, protomicrosatellite content, and L1 density, but low GC content and Alu density. The majority of the 17 disease-associated microsatellites examined are evolutionarily ancient (were acquired by the common ancestor of simians). Our genome-wide investigation of microsatellite life cycle has fundamental applications for predicting the susceptibility of birth/death of microsatellites, including many disease-causing loci.

  20. [Genetic individuality and the universal declaration on the human genome and human rights].

    Science.gov (United States)

    Siqueiros, Jesús M; Saruwatari, Garbiñe; Oliva-Sánchez, Pablo Francisco

    2012-01-01

    In this article we explore the epistemic and ontological relationship between science and law through the concept of individual in the Universal Declaration of the Human Genome and Human Rights. We argue for a better understanding of this relationship in order to foresee ethical and social consequences derived from Law adopting concepts with a strong scientific meaning.

  1. Human and non-human primate genomes share hotspots of positive selection.

    Directory of Open Access Journals (Sweden)

    David Enard

    2010-02-01

    Full Text Available Among primates, genome-wide analysis of recent positive selection is currently limited to the human species because it requires extensive sampling of genotypic data from many individuals. The extent to which genes positively selected in human also present adaptive changes in other primates therefore remains unknown. This question is important because a gene that has been positively selected independently in the human and in other primate lineages may be less likely to be involved in human specific phenotypic changes such as dietary habits or cognitive abilities. To answer this question, we analysed heterozygous Single Nucleotide Polymorphisms (SNPs in the genomes of single human, chimpanzee, orangutan, and macaque individuals using a new method aiming to identify selective sweeps genome-wide. We found an unexpectedly high number of orthologous genes exhibiting signatures of a selective sweep simultaneously in several primate species, suggesting the presence of hotspots of positive selection. A similar significant excess is evident when comparing genes positively selected during recent human evolution with genes subjected to positive selection in their coding sequence in other primate lineages and identified using a different test. These findings are further supported by comparing several published human genome scans for positive selection with our findings in non-human primate genomes. We thus provide extensive evidence that the co-occurrence of positive selection in humans and in other primates at the same genetic loci can be measured with only four species, an indication that it may be a widespread phenomenon. The identification of positive selection in humans alongside other primates is a powerful tool to outline those genes that were selected uniquely during recent human evolution.

  2. Los Alamos Science: The Human Genome Project. Number 20, 1992

    Energy Technology Data Exchange (ETDEWEB)

    Cooper, N G; Shea, N [eds.

    1992-01-01

    This article provides a broad overview of the Human Genome Project, with particular emphasis on work being done at Los Alamos. It tries to emphasize the scientific aspects of the project, compared to the more speculative information presented in the popular press. There is a brief introduction to modern genetics, including a review of classic work. There is a broad overview of the Genome Project, describing what the project is, what are some of its major five-year goals, what are major technological challenges ahead of the project, and what can the field of biology, as well as society expect to see as benefits from this project. Specific results on the efforts directed at mapping chromosomes 16 and 5 are discussed. A brief introduction to DNA libraries is presented, bearing in mind that Los Alamos has housed such libraries for many years prior to the Genome Project. Information on efforts to do applied computational work related to the project are discussed, as well as experimental efforts to do rapid DNA sequencing by means of single-molecule detection using applied spectroscopic methods. The article introduces the Los Alamos staff which are working on the Genome Project, and concludes with brief discussions on ethical, legal, and social implications of this work; a brief glimpse of genetics as it may be practiced in the next century; and a glossary of relevant terms.

  3. Los Alamos Science: The Human Genome Project. Number 20, 1992

    Science.gov (United States)

    Cooper, N. G.; Shea, N. eds.

    1992-01-01

    This document provides a broad overview of the Human Genome Project, with particular emphasis on work being done at Los Alamos. It tries to emphasize the scientific aspects of the project, compared to the more speculative information presented in the popular press. There is a brief introduction to modern genetics, including a review of classic work. There is a broad overview of the Genome Project, describing what the project is, what are some of its major five-year goals, what are major technological challenges ahead of the project, and what can the field of biology, as well as society expect to see as benefits from this project. Specific results on the efforts directed at mapping chromosomes 16 and 5 are discussed. A brief introduction to DNA libraries is presented, bearing in mind that Los Alamos has housed such libraries for many years prior to the Genome Project. Information on efforts to do applied computational work related to the project are discussed, as well as experimental efforts to do rapid DNA sequencing by means of single-molecule detection using applied spectroscopic methods. The article introduces the Los Alamos staff which are working on the Genome Project, and concludes with brief discussions on ethical, legal, and social implications of this work; a brief glimpse of genetics as it may be practiced in the next century; and a glossary of relevant terms.

  4. Experimental annotation of the human genome using microarray technology.

    Science.gov (United States)

    Shoemaker, D D; Schadt, E E; Armour, C D; He, Y D; Garrett-Engele, P; McDonagh, P D; Loerch, P M; Leonardson, A; Lum, P Y; Cavet, G; Wu, L F; Altschuler, S J; Edwards, S; King, J; Tsang, J S; Schimmack, G; Schelter, J M; Koch, J; Ziman, M; Marton, M J; Li, B; Cundiff, P; Ward, T; Castle, J; Krolewski, M; Meyer, M R; Mao, M; Burchard, J; Kidd, M J; Dai, H; Phillips, J W; Linsley, P S; Stoughton, R; Scherer, S; Boguski, M S

    2001-02-15

    The most important product of the sequencing of a genome is a complete, accurate catalogue of genes and their products, primarily messenger RNA transcripts and their cognate proteins. Such a catalogue cannot be constructed by computational annotation alone; it requires experimental validation on a genome scale. Using 'exon' and 'tiling' arrays fabricated by ink-jet oligonucleotide synthesis, we devised an experimental approach to validate and refine computational gene predictions and define full-length transcripts on the basis of co-regulated expression of their exons. These methods can provide more accurate gene numbers and allow the detection of mRNA splice variants and identification of the tissue- and disease-specific conditions under which genes are expressed. We apply our technique to chromosome 22q under 69 experimental condition pairs, and to the entire human genome under two experimental conditions. We discuss implications for more comprehensive, consistent and reliable genome annotation, more efficient, full-length complementary DNA cloning strategies and application to complex diseases.

  5. Interspecies comparative genome hybridization and interspecies representational difference analysis reveal gross DNA differences between humans and great apes.

    Science.gov (United States)

    Toder, R; Xia, Y; Bausch, E

    1998-09-01

    Comparative chromosome G-/R-banding, comparative gene mapping and chromosome painting techniques have demonstrated that only few chromosomal rearrangements occurred during great ape and human evolution. Interspecies comparative genome hybridization (CGH), used here in this study, between human, gorilla and pygmy chimpanzee revealed species-specific regions in all three species. In contrast to the human, a far more complex distribution of species-specific blocks was detected with CGH in gorilla and pygmy chimpanzee. Most of these blocks coincide with already described heterochromatic regions on gorilla and chimpanzee chromosomes. Representational difference analysis (RDA) was used to subtract the complex genome of gorilla against human in order to enrich gorilla-specific DNA sequences. Gorilla-specific clones isolated with this technique revealed a 32-bp repeat unit. These clones were mapped by fluorescence in situ hybridization (FISH) to the telomeric regions of gorilla chromosomes that had been shown by interspecies CGH to contain species-specific sequences.

  6. Genomic comparison of multi-drug resistant invasive and colonizing Acinetobacter baumannii isolated from diverse human body sites reveals genomic plasticity

    Directory of Open Access Journals (Sweden)

    Hsiao William W

    2011-06-01

    Full Text Available Abstract Background Acinetobacter baumannii has recently emerged as a significant global pathogen, with a surprisingly rapid acquisition of antibiotic resistance and spread within hospitals and health care institutions. This study examines the genomic content of three A. baumannii strains isolated from distinct body sites. Isolates from blood, peri-anal, and wound sources were examined in an attempt to identify genetic features that could be correlated to each isolation source. Results Pulsed-field gel electrophoresis, multi-locus sequence typing and antibiotic resistance profiles demonstrated genotypic and phenotypic variation. Each isolate was sequenced to high-quality draft status, which allowed for comparative genomic analyses with existing A. baumannii genomes. A high resolution, whole genome alignment method detailed the phylogenetic relationships of sequenced A. baumannii and found no correlation between phylogeny and body site of isolation. This method identified genomic regions unique to both those isolates found on the surface of the skin or in wounds, termed colonization isolates, and those identified from body fluids, termed invasive isolates; these regions may play a role in the pathogenesis and spread of this important pathogen. A PCR-based screen of 74 A. baumanii isolates demonstrated that these unique genes are not exclusive to either phenotype or isolation source; however, a conserved genomic region exclusive to all sequenced A. baumannii was identified and verified. Conclusions The results of the comparative genome analysis and PCR assay show that A. baumannii is a diverse and genomically variable pathogen that appears to have the potential to cause a range of human disease regardless of the isolation source.

  7. Detection of regulatory SNPs in human genome using ChIP-seq ENCODE data.

    Science.gov (United States)

    Bryzgalov, Leonid O; Antontseva, Elena V; Matveeva, Marina Yu; Shilov, Alexander G; Kashina, Elena V; Mordvinov, Viatcheslav A; Merkulova, Tatyana I

    2013-01-01

    A vast amount of SNPs derived from genome-wide association studies are represented by non-coding ones, therefore exacerbating the need for effective identification of regulatory SNPs (rSNPs) among them. However, this task remains challenging since the regulatory part of the human genome is annotated much poorly as opposed to coding regions. Here we describe an approach aggregating the whole set of ENCODE ChIP-seq data in order to search for rSNPs, and provide the experimental evidence of its efficiency. Its algorithm is based on the assumption that the enrichment of a genomic region with transcription factor binding loci (ChIP-seq peaks) indicates its regulatory function, and thereby SNPs located in this region are more likely to influence transcription regulation. To ensure that the approach preferably selects functionally meaningful SNPs, we performed enrichment analysis of several human SNP datasets associated with phenotypic manifestations. It was shown that all samples are significantly enriched with SNPs falling into the regions of multiple ChIP-seq peaks as compared with the randomly selected SNPs. For experimental verification, 40 SNPs falling into overlapping regions of at least 7 TF binding loci were selected from OMIM. The effect of SNPs on the binding of the DNA fragments containing them to the nuclear proteins from four human cell lines (HepG2, HeLaS3, HCT-116, and K562) has been tested by EMSA. A radical change in the binding pattern has been observed for 29 SNPs, besides, 6 more SNPs also demonstrated less pronounced changes. Taken together, the results demonstrate the effective way to search for potential rSNPs with the aid of ChIP-seq data provided by ENCODE project.

  8. Genomic structure, characterization, and identification of the promotor of the human IL-8 receptor A gene

    Energy Technology Data Exchange (ETDEWEB)

    Sprenger, H.; Lloyd, A.R.; Meyer, R.G.; Johnston, J.A.; Kelvin, D.J. [National Cancer Institute, Frederick, MA (United States)

    1994-09-15

    Two unique but homologous receptors for the neutrophil chemoattractant IL-8 have been cloned (designated IL-8RA and IL-8RB), each of which binds IL-8 with high affinity. IL-8RA mRNA expression was found to be regulated by granulocyte-CSF and LPS. In an attempt to understand the tissue-specific expression and to identify transcriptional regulatory elements, the authors have cloned, sequenced, and characterized the human IL-8RA gene. A {lambda}-DASH clone encoding the entire human IL-8RA gene was isolated by screening a genomic library with a PCR-generated cDNA. After mapping, subcloning, and sequencing several restriction fragments, a 9.2-kb continuous DNA sequence was obtained. As the sizes of the published cDNA (1.9 kb) and the mRNA determined by Northern blot analysis (2.1 kb) were not in agreement, a full-length cDNA was cloned by using a modified rapid amplification of cDNA ends technique. They identified a 5{prime}-untranslated region of 119 bp. After comparison with the genomic sequence, they found the gene consisted of two exons interrupted by an intron of 1.7 kb. A 1050-bp ORF was encoded entirely in the second exon together with a 834-bp 3{prime}-untranslated region. The immediate GC-rich 5{prime}-flanking region upstream of exon 1 could serve as a constitutively active promoter in chloramphenicolacetyl-transferase-expression assays. Expression analysis of additional upstream regions suggested the presence of silencer elements between positions -841 and -280. In conclusion, cloning a full-length cDNA permitted cloning of the human IL-8RA gene, identification of the genomic structure, and characterization of the promoter region. 45 refs., 6 figs.

  9. Identifying genomic regions for fine-mapping using genome scan meta-analysis (GSMA) to identify the minimum regions of maximum significance (MRMS) across populations.

    Science.gov (United States)

    Cooper, Margaret E; Goldstein, Toby H; Maher, Brion S; Marazita, Mary L

    2005-12-30

    In order to detect linkage of the simulated complex disease Kofendrerd Personality Disorder across studies from multiple populations, we performed a genome scan meta-analysis (GSMA). Using the 7-cM microsatellite map, nonparametric multipoint linkage analyses were performed separately on each of the four simulated populations independently to determine p-values. The genome of each population was divided into 20-cM bin regions, and each bin was rank-ordered based on the most significant linkage p-value for that population in that region. The bin ranks were then averaged across all four studies to determine the most significant 20-cM regions over all studies. Statistical significance of the averaged bin ranks was determined from a normal distribution of randomly assigned rank averages. To narrow the region of interest for fine-mapping, the meta-analysis was repeated two additional times, with each of the 20-cM bins offset by 7 cM and 13 cM, respectively, creating regions of overlap with the original method. The 6-7 cM shared regions, where the highest averaged 20-cM bins from each of the three offsets overlap, designated the minimum region of maximum significance (MRMS). Application of the GSMA-MRMS method revealed genome wide significance (p-values refer to the average rank assigned to the bin) at regions including or adjacent to all of the simulated disease loci: chromosome 1 (p value value value < 0.05 for 7-14 cM, the region adjacent to D4). This GSMA analysis approach demonstrates the power of linkage meta-analysis to detect multiple genes simultaneously for a complex disorder. The MRMS method enhances this powerful tool to focus on more localized regions of linkage.

  10. CGHScan: finding variable regions using high-density microarray comparative genomic hybridization data

    Directory of Open Access Journals (Sweden)

    Rajashekara Gireesh

    2006-04-01

    Full Text Available Abstract Background Comparative genomic hybridization can rapidly identify chromosomal regions that vary between organisms and tissues. This technique has been applied to detecting differences between normal and cancerous tissues in eukaryotes as well as genomic variability in microbial strains and species. The density of oligonucleotide probes available on current microarray platforms is particularly well-suited for comparisons of organisms with smaller genomes like bacteria and yeast where an entire genome can be assayed on a single microarray with high resolution. Available methods for analyzing these experiments typically confine analyses to data from pre-defined annotated genome features, such as entire genes. Many of these methods are ill suited for datasets with the number of measurements typical of high-density microarrays. Results We present an algorithm for analyzing microarray hybridization data to aid identification of regions that vary between an unsequenced genome and a sequenced reference genome. The program, CGHScan, uses an iterative random walk approach integrating multi-layered significance testing to detect these regions from comparative genomic hybridization data. The algorithm tolerates a high level of noise in measurements of individual probe intensities and is relatively insensitive to the choice of method for normalizing probe intensity values and identifying probes that differ between samples. When applied to comparative genomic hybridization data from a published experiment, CGHScan identified eight of nine known deletions in a Brucella ovis strain as compared to Brucella melitensis. The same result was obtained using two different normalization methods and two different scores to classify data for individual probes as representing conserved or variable genomic regions. The undetected region is a small (58 base pair deletion that is below the resolution of CGHScan given the array design employed in the study

  11. Complete Genome Sequence of Human Respiratory Syncytial Virus from Lanzhou, China

    OpenAIRE

    Zhu, Chuanfeng; Fu, Shengfang; Zhou, Xv; Yu, Li

    2017-01-01

    ABSTRACT A complete genome of human respiratory syncytial virus was sequenced and analyzed. Phylogenetic analysis showed that the full-length human respiratory syncytial virus (HRSV) genome sequence belongs to gene type NA1. We sequenced the genome in order to create the full-length cDNA infectious clone and develop vaccines against HRSV.

  12. 78 FR 64222 - National Human Genome Research Institute; Notice of Closed Meetings

    Science.gov (United States)

    2013-10-28

    ... Committee, CEGS-- Initiative to Maximize Research Education in Genomics. Date: November 7-8, 2013. Time: 8..., Ph.D., Scientific Review Officer, Office of Scientific Review, National Human Genome Research...: Camilla E. Day, Ph.D., Scientific Review Officer, CIDR, National Human Genome Research Institute, National...

  13. Engineered chromosome-based genetic mapping establishes a 3.7-Mb critical genomic region for Down syndrome-associated heart defects in mice

    OpenAIRE

    Liu, Chunhong; Morishima, Masae; Jiang,Xiaoling; Yu, Tao; Meng, Kai; Ray, Debjit; Pao, Annie; Ye, Ping; Parmacek, Michael S.; Yu, Y. Eugene

    2013-01-01

    Trisomy 21 (Down syndrome, DS) is the most common human genetic anomaly associated with heart defects. Based on evolutionary conservation, DS-associated heart defects have been modeled in mice. By generating and analyzing mouse mutants carrying different genomic rearrangements in human chromosome 21 (Hsa21) syntenic regions, we found the triplication of the Tiam1-Kcnj6 region on mouse chromosome 16 (Mmu16) resulted in DS-related cardiovascular abnormalities. In this study, we developed two ta...

  14. Animal models for human contiguous gene syndromes and other genomic disorders

    Directory of Open Access Journals (Sweden)

    Katherina Walz

    2004-01-01

    Full Text Available Genomic disorders refer to a group of syndromes caused by DNA rearrangements, such as deletions and duplications, which result in an alteration of normal gene dosage. The chromosomal rearrangements are usually relatively small and often difficult to detect cytogenetically. In a subset of such conditions the rearrangements comprise multiple unrelated contiguous genes that are physically linked and thus have been referred to as contiguous gene syndromes (CGS. In general, each syndrome presents a complex clinical phenotype that has been attributed generally to dosage sensitive gene(s present in the responsible chromosomal interval. A common mechanism for CGS resulting from interstitial deletion/duplication has recently been elucidated. The DNA rearrangements result from nonallelic homologous recombination (NAHR utilizing flanking low-copy repeats (LCRs as recombination substrates. The resulting rearrangements often involve the same genomic region, a common deletion or duplication, making it difficult to assign a specific phenotype or endophenotype to a single responsible gene. The human and mouse genome sequencing projects, in conjunction with the ability to engineer mouse chromosome rearrangements, have enabled the production of mouse models for CGS and genomic disorders. In this review we present an overview of different techniques utilized to generate mouse models for selected genomic disorders. These models foment novel insights into the specific genes that convey the phenotype by dosage and/or position effects and provide opportunities to explore therapeutic options.

  15. Marked variation in predicted and observed variability of tandem repeat loci across the human genome

    Directory of Open Access Journals (Sweden)

    Shields Denis C

    2008-04-01

    Full Text Available Abstract Background Tandem repeat (TR variants in the human genome play key roles in a number of diseases. However, current models predicting variability are based on limited training sets. We conducted a systematic analysis of TRs of unit lengths 2–12 nucleotides in Whole Genome Shotgun (WGS sequences to define the extent of variation of 209,214 unique repeat loci throughout the genome. Results We applied a multivariate statistical model to predict TR variability. Predicted heterozygosity correlated with heterozygosity in the CEPH polymorphism database (correlation ρ = 0.29, p Conclusion Variability among 2–12-mer TRs in the genome can be modeled by a few parameters, which do not markedly differ according to unit length, consistent with a common mechanism for the generation of variability among such TRs. Analysis of the distributions of observed and predicted variants across the genome showed a general concordance, indicating that the repeat variation dataset does not exhibit strong regional ascertainment biases. This revealed a deficit of variant repeats in chromosomes 19 and Y – likely to reflect a reduction in 2-mer repeats in the former and a reduced level of recombination in the latter – and excesses in chromosomes 6, 13, 20 and 21.

  16. 76 FR 3917 - National Human Genome Research Institute; Notice of Closed Meeting

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    2011-01-21

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... privacy. Name of Committee: National Human Genome Research Institute Special Emphasis Panel, TRND--RFP... Person: Rudy O. Pozzatti, PhD, Scientific Review Officer, Scientific Review Branch, National Human...

  17. 77 FR 5035 - National Human Genome Research Institute; Notice of Closed Meetings

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    2012-02-01

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel Sequencing Technology..., Rockville, MD 20852, (301) 402-0838, nakamurk@mail.nih.gov . Name of Committee: National Human...

  18. 78 FR 47715 - National Human Genome Research Institute; Notice of Meeting

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    2013-08-06

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Meeting... hereby given of a meeting of the National Advisory Council for Human Genome Research. The meeting will be... unwarranted invasion of personal privacy. Name of Committee: National Advisory Council for Human...

  19. 76 FR 29772 - National Human Genome Research Institute; Notice of Closed Meetings

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    2011-05-23

    ... HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Notice of Closed... of Committee: National Human Genome Research Institute Special Emphasis Panel; ELSI-SEP. Date: June...: Rudy O. Pozzatti, PhD, Scientific Review Officer, Office of Scientific Review, National Human...

  20. Changes in the human mitochondrial genome after treatment of malignant disease

    Energy Technology Data Exchange (ETDEWEB)

    Wardell, Theresa M.; Ferguson, Elaine; Chinnery, Patrick F.; Borthwick, Gillian M.; Taylor, Robert W.; Jackson, Graham; Craft, Alan; Lightowlers, Robert N.; Howell, Neil; Turnbull, Douglass M

    2003-04-09

    Mitochondrial DNA (mtDNA) is the only extrachromosomal DNA in human cells. The mitochondrial genome encodes essential information for the synthesis of the mitochondrial respiratory chain. Inherited defects of this genome are an important cause of human disease. In addition, the mitochondrial genome seems to be particularly prone to DNA damage and acquired mutations may have a role in ageing, cancer and neurodegeneration. We wished to determine if radiotherapy and chemotherapy used in the treatment of cancer could induce changes in the mitochondrial genome. Such changes would be an important genetic marker of DNA damage and may explain some of the adverse effects of treatment. We studied samples from patients who had received radiotherapy and chemotherapy for point mutations within the mtDNA control region, and for large-scale deletions. In blood samples from patients, we found a significantly increased number of point mutations compared to the control subjects. In muscle biopsies from 7 of 8 patients whom had received whole body irradiation as well as chemotherapy, the level of a specific mtDNA deletion was significantly greater than in control subjects. Our studies have shown that in patients who have been treated for cancer there is an increased level of mtDNA damage.

  1. Regional and cellular gene expression changes in human Huntington's disease brain

    OpenAIRE

    2006-01-01

    Huntington's disease (HD) pathology is well understood at a histological level but a comprehensive molecular analysis of the effect of the disease in the human brain has not previously been available. To elucidate the molecular phenotype of HD on a genome-wide scale, we compared mRNA profiles from 44 human HD brains with those from 36 unaffected controls using microarray analysis. Four brain regions were analyzed: caudate nucleus, cerebellum, prefrontal association cortex [Brodmann's area 9 (...

  2. Genomic variation landscape of the human gut microbiome

    DEFF Research Database (Denmark)

    Schloissnig, Siegfried; Arumugam, Manimozhiyan; Sunagawa, Shinichi

    2013-01-01

    Whereas large-scale efforts have rapidly advanced the understanding and practical impact of human genomic variation, the practical impact of variation is largely unexplored in the human microbiome. We therefore developed a framework for metagenomic variation analysis and applied it to 252 faecal...... metagenomes of 207 individuals from Europe and North America. Using 7.4 billion reads aligned to 101 reference species, we detected 10.3 million single nucleotide polymorphisms (SNPs), 107,991 short insertions/deletions, and 1,051 structural variants. The average ratio of non-synonymous to synonymous...... polymorphism rates of 0.11 was more variable between gut microbial species than across human hosts. Subjects sampled at varying time intervals exhibited individuality and temporal stability of SNP variation patterns, despite considerable composition changes of their gut microbiota. This indicates...

  3. Human body region enhancement method based on Kinect infrared imaging

    Science.gov (United States)

    Yang, Lei; Fan, Yubo; Song, Xiaowei; Cai, Wenjing

    2016-10-01

    To effectively improve the low contrast of human body region in the infrared images, a combing method of several enhancement methods is utilized to enhance the human body region. Firstly, for the infrared images acquired by Kinect, in order to improve the overall contrast of the infrared images, an Optimal Contrast-Tone Mapping (OCTM) method with multi-iterations is applied to balance the contrast of low-luminosity infrared images. Secondly, to enhance the human body region better, a Level Set algorithm is employed to improve the contour edges of human body region. Finally, to further improve the human body region in infrared images, Laplacian Pyramid decomposition is adopted to enhance the contour-improved human body region. Meanwhile, the background area without human body region is processed by bilateral filtering to improve the overall effect. With theoretical analysis and experimental verification, the results show that the proposed method could effectively enhance the human body region of such infrared images.

  4. Sex-biased evolutionary forces shape genomic patterns of human diversity.

    Directory of Open Access Journals (Sweden)

    Michael F Hammer

    Full Text Available Comparisons of levels of variability on the autosomes and X chromosome can be used to test hypotheses about factors influencing patterns of genomic variation. While a tremendous amount of nucleotide sequence data from across the genome is now available for multiple human populations, there has been no systematic effort to examine relative levels of neutral polymorphism on the X chromosome versus autosomes. We analyzed approximately 210 kb of DNA sequencing data representing 40 independent noncoding regions on the autosomes and X chromosome from each of 90 humans from six geographically diverse populations. We correct for differences in mutation rates between males and females by considering the ratio of within-human diversity to human-orangutan divergence. We find that relative levels of genetic variation are higher than expected on the X chromosome in all six human populations. We test a number of alternative hypotheses to explain the excess polymorphism on the X chromosome, including models of background selection, changes in population size, and sex-specific migration in a structured population. While each of these processes may have a small effect on the relative ratio of X-linked to autosomal diversity, our results point to a systematic difference between the sexes in the variance in reproductive success; namely, the widespread effects of polygyny in human populations. We conclude that factors leading to a lower male versus female effective population size must be considered as important demographic variables in efforts to construct models of human demographic history and for understanding the forces shaping patterns of human genomic variability.

  5. Genome-Wide Identification of Regulatory Sequences Undergoing Accelerated Evolution in the Human Genome.

    Science.gov (United States)

    Dong, Xinran; Wang, Xiao; Zhang, Feng; Tian, Weidong

    2016-10-01

    Accelerated evolution of regulatory sequence can alter the expression pattern of target genes, and cause phenotypic changes. In this study, we used DNase I hypersensitive sites (DHSs) to annotate putative regulatory sequences in the human genome, and conducted a genome-wide analysis of the effects of accelerated evolution on regulatory sequences. Working under the assumption that local ancient repeat elements of DHSs are under neutral evolution, we discovered that ∼0.44% of DHSs are under accelerated evolution (ace-DHSs). We found that ace-DHSs tend to be more active than background DHSs, and are strongly associated with epigenetic marks of active transcription. The target genes of ace-DHSs are significantly enriched in neuron-related functions, and their expression levels are positively selected in the human brain. Thus, these lines of evidences strongly suggest that accelerated evolution on regulatory sequences plays important role in the evolution of human-specific phenotypes. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  6. Sequencing the CHO DXB11 genome reveals regional variations in genomic stability and haploidy

    DEFF Research Database (Denmark)

    Kaas, Christian Schrøder; Kristensen, Claus; Betenbaugh, Michael J.

    2015-01-01

    Background: The DHFR negative CHO DXB11 cell line (also known as DUX-B11 and DUKX) was historically the first CHO cell line to be used for large scale production of heterologous proteins and is still used for production of a number of complex proteins.  Results: Here we present the genomic sequen...

  7. Hi-C-constrained physical models of human chromosomes recover functionally-related properties of genome organization

    CERN Document Server

    Di Stefano, Marco; Lien, Tonje G; Hovig, Eivind; Micheletti, Cristian

    2016-01-01

    Combining genome-wide structural models with phenomenological data is at the forefront of efforts to understand the organizational principles regulating the human genome. Here, we use chromosome-chromosome contact data as knowledge-based constraints for large-scale three-dimensional models of the human diploid genome. The resulting models remain minimally entangled and acquire several functional features that are observed in vivo and that were never used as input for the model. We find, for instance, that gene-rich, active regions are drawn towards the nuclear center, while gene poor and lamina-associated domains are pushed to the periphery. These and other properties persist upon adding local contact constraints, suggesting their compatibility with non-local constraints for the genome organization. The results show that suitable combinations of data analysis and physical modelling can expose the unexpectedly rich functionally-related properties implicit in chromosome-chromosome contact data. Specific directi...

  8. Host susceptibility to periodontitis: mapping murine genomic regions.

    Science.gov (United States)

    Shusterman, A; Durrant, C; Mott, R; Polak, D; Schaefer, A; Weiss, E I; Iraqi, F A; Houri-Haddad, Y

    2013-05-01

    Host susceptibility to periodontal infection is controlled by genetic factors. As a step toward identifying and cloning these factors, we generated an A/J x BALB/cJ F2 mouse resource population. A genome-wide search for Quantitative Trait Loci (QTL) associated with periodontitis was performed. We aimed to quantify the phenotypic response of the progenies to periodontitis by microCT analysis, to perform a genome-wide search for QTL associated with periodontitis, and, finally, to suggest candidate genes for periodontitis. We were able to produce 408 F2 mice. All mice were co-infected with Porphyromonas gingivalis and Fusobacterium nucleatum bacteria. Six weeks following infection, alveolar bone loss was quantified by computerized tomography (microCT) technology. We found normal distribution of the phenotype, with 2 highly significant QTL on chromosomes 5 and 3. A third significant QTL was found on chromosome 1. Candidate genes were suggested, such as Toll-like receptors (TLR) 1 and 6, chemokines, and bone-remodeling genes (enamelin, ameloblastin, and amelotin). This report shows that periodontitis in mice is a polygenic trait with highly significant mapped QTL.

  9. Genome-wide nucleosome map and cytosine methylation levels of an ancient human genome

    DEFF Research Database (Denmark)

    Pedersen, Jakob Skou; Valen, Eivind; Velazquez, Amhed Missael Vargas;

    2014-01-01

    data generated from hair shafts of a 4000-yr-old Paleo-Eskimo belonging to the Saqqaq culture, we generate the first ancient nucleosome map coupled with a genome-wide survey of cytosine methylation levels. The validity of both nucleosome map and methylation levels were confirmed by the recovery...... of the expected signals at promoter regions, exon/intron boundaries, and CTCF sites. The top-scoring nucleosome calls revealed distinct DNA positioning biases, attesting to nucleotide-level accuracy. The ancient methylation levels exhibited high conservation over time, clustering closely with modern hair tissues...

  10. Genomic connectivity networks based on the BrainSpan atlas of the developing human brain

    Science.gov (United States)

    Mahfouz, Ahmed; Ziats, Mark N.; Rennert, Owen M.; Lelieveldt, Boudewijn P. F.; Reinders, Marcel J. T.

    2014-03-01

    The human brain comprises systems of networks that span the molecular, cellular, anatomic and functional levels. Molecular studies of the developing brain have focused on elucidating networks among gene products that may drive cellular brain development by functioning together in biological pathways. On the other hand, studies of the brain connectome attempt to determine how anatomically distinct brain regions are connected to each other, either anatomically (diffusion tensor imaging) or functionally (functional MRI and EEG), and how they change over development. A global examination of the relationship between gene expression and connectivity in the developing human brain is necessary to understand how the genetic signature of different brain regions instructs connections to other regions. Furthermore, analyzing the development of connectivity networks based on the spatio-temporal dynamics of gene expression provides a new insight into the effect of neurodevelopmental disease genes on brain networks. In this work, we construct connectivity networks between brain regions based on the similarity of their gene expression signature, termed "Genomic Connectivity Networks" (GCNs). Genomic connectivity networks were constructed using data from the BrainSpan Transcriptional Atlas of the Developing Human Brain. Our goal was to understand how the genetic signatures of anatomically distinct brain regions relate to each other across development. We assessed the neurodevelopmental changes in connectivity patterns of brain regions when networks were constructed with genes implicated in the neurodevelopmental disorder autism (autism spectrum disorder; ASD). Using graph theory metrics to characterize the GCNs, we show that ASD-GCNs are relatively less connected later in development with the cerebellum showing a very distinct expression of ASD-associated genes compared to other brain regions.

  11. The Human Genome Diversity (HGD) Project. Summary document

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1993-12-31

    In 1991 a group of human geneticists and molecular biologists proposed to the scientific community that a world wide survey be undertaken of variation in the human genome. To aid their considerations, the committee therefore decided to hold a small series of international workshops to explore the major scientific issues involved. The intention was to define a framework for the project which could provide a basis for much wider and more detailed discussion and planning--it was recognized that the successful implementation of the proposed project, which has come to be known as the Human Genome Diversity (HGD) Project, would not only involve scientists but also various national and international non-scientific groups all of which should contribute to the project`s development. The international HGD workshop held in Sardinia in September 1993 was the last in the initial series of planning workshops. As such it not only explored new ground but also pulled together into a more coherent form much of the formal and informal discussion that had taken place in the preceding two years. This report presents the deliberations of the Sardinia workshop within a consideration of the overall development of the HGD Project to date.

  12. Comparative genomics of the neglected human malaria parasite Plasmodium vivax

    Science.gov (United States)

    Carlton, Jane M.; Adams, John H.; Silva, Joana C.; Bidwell, Shelby L.; Lorenzi, Hernan; Caler, Elisabet; Crabtree, Jonathan; Angiuoli, Samuel V.; Merino, Emilio F.; Amedeo, Paolo; Cheng, Qin; Coulson, Richard M. R.; Crabb, Brendan S.; del Portillo, Hernando A.; Essien, Kobby; Feldblyum, Tamara V.; Fernandez-Becerra, Carmen; Gilson, Paul R.; Gueye, Amy H.; Guo, Xiang; Kang’a, Simon; Kooij, Taco W. A.; Korsinczky, Michael; Meyer, Esmeralda V.-S.; Nene, Vish; Paulsen, Ian; White, Owen; Ralph, Stuart A.; Ren, Qinghu; Sargeant, Tobias J.; Salzberg, Steven L.; Stoeckert, Christian J.; Sullivan, Steven A.; Yamamoto, Marcio Massao; Hoffman, Stephen L.; Wortman, Jennifer R.; Gardner, Malcolm J.; Galinski, Mary R.; Barnwell, John W.; Fraser-Liggett, Claire M.

    2008-01-01

    The human malaria parasite Plasmodium vivax is responsible for 25-40% of the ~515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated in the laboratory except in non-human primates. We determined the genome sequence of P. vivax in order to shed light on its distinctive biologic features, and as a means to drive development of new drugs and vaccines. Here we describe the synteny and isochore structure of P. vivax chromosomes, and show that the parasite resembles other malaria parasites in gene content and metabolic potential, but possesses novel gene families and potential alternate invasion pathways not recognized previously. Completion of the P. vivax genome provides the scientific community with a valuable resource that can be used to advance scientific investigation into this neglected species. PMID:18843361

  13. Dynamic association of NUP98 with the human genome.

    Directory of Open Access Journals (Sweden)

    Yun Liang

    Full Text Available Faithful execution of developmental gene expression programs occurs at multiple levels and involves many different components such as transcription factors, histone-modification enzymes, and mRNA processing proteins. Recent evidence suggests that nucleoporins, well known components that control nucleo-cytoplasmic trafficking, have wide-ranging functions in developmental gene regulation that potentially extend beyond their role in nuclear transport. Whether the unexpected role of nuclear pore proteins in transcription regulation, which initially has been described in fungi and flies, also applies to human cells is unknown. Here we show at a genome-wide level that the nuclear pore protein NUP98 associates with developmentally regulated genes active during human embryonic stem cell differentiation. Overexpression of a dominant negative fragment of NUP98 levels decreases expression levels of NUP98-bound genes. In addition, we identify two modes of developmental gene regulation by NUP98 that are differentiated by the spatial localization of NUP98 target genes. Genes in the initial stage of developmental induction can associate with NUP98 that is embedded in the nuclear pores at the nuclear periphery. Alternatively, genes that are highly induced can interact with NUP98 in the nuclear interior, away from the nuclear pores. This work demonstrates for the first time that NUP98 dynamically associates with the human genome during differentiation, revealing a role of a nuclear pore protein in regulating developmental gene expression programs.

  14. Insertion and deletion mutagenesis of the human cytomegalovirus genome

    Energy Technology Data Exchange (ETDEWEB)

    Spaete, R.R.; Mocarski, E.S.

    1987-10-01

    Studies on human cytomegalovirus (CMV) have been limited by a paucity of molecular genetic techniques available for manipulating the viral genome. The authors have developed methods for site-specific insertion and deletion mutagenesis of CMV utilizing a modified Escherichia coli lacZ gene as a genetic marker. The lacZ gene was placed under the control of the major ..beta.. gene regulatory signals and inserted into the viral genome by homologous recombination, disrupting one of two copies of this ..beta.. gene within the L-component repeats of CMV DNA. They observed high-level expression of ..beta..-galactosidase by the recombinant in a temporally authentic manner, with levels of this enzyme approaching 1% of total protein in infected cells. Thus, CMV is an efficient vector for high-level expression of foreign gene products in human cells. Using back selection of lacZ-deficient virus in the presence of the chromogenic substrate 5-bromo-4-chloro-3-indolyl ..beta..-D-galactoside, they generated random endpoint deletion mutants. Analysis of these mutant revealed that CMV DNA sequences flanking the insert had been removed, thereby establishing this approach as a means of determining whether sequences flanking a lacZ insertion are dispensable for viral growth. In an initial test of the methods, they have shown that 7800 base pairs of one copy of L-component repeat sequences can be deleted without affecting viral growth in human fibroblasts.

  15. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions.

    Directory of Open Access Journals (Sweden)

    Soumya Raychaudhuri

    2009-06-01

    Full Text Available Translating a set of disease regions into insight about pathogenic mechanisms requires not only the ability to identify the key disease genes within them, but also the biological relationships among those key genes. Here we describe a statistical method, Gene Relationships Among Implicated Loci (GRAIL, that takes a list of disease regions and automatically assesses the degree of relatedness of implicated genes using 250,000 PubMed abstracts. We first evaluated GRAIL by assessing its ability to identify subsets of highly related genes in common pathways from validated lipid and height SNP associations from recent genome-wide studies. We then tested GRAIL, by assessing its ability to separate true disease regions from many false positive disease regions in two separate practical applications in human genetics. First, we took 74 nominally associated Crohn's disease SNPs and applied GRAIL to identify a subset of 13 SNPs with highly related genes. Of these, ten convincingly validated in follow-up genotyping; genotyping results for the remaining three were inconclusive. Next, we applied GRAIL to 165 rare deletion events seen in schizophrenia cases (less than one-third of which are contributing to disease risk. We demonstrate that GRAIL is able to identify a subset of 16 deletions containing highly related genes; many of these genes are expressed in the central nervous system and play a role in neuronal synapses. GRAIL offers a statistically robust approach to identifying functionally related genes from across multiple disease regions--that likely represent key disease pathways. An online version of this method is available for public use (http://www.broad.mit.edu/mpg/grail/.

  16. Differential DNA methylation regions in cytokine and transcription factor genomic loci associate with childhood physical aggression.

    Directory of Open Access Journals (Sweden)

    Nadine Provençal

    Full Text Available BACKGROUND: Animal and human studies suggest that inflammation is associated with behavioral disorders including aggression. We have recently shown that physical aggression of boys during childhood is strongly associated with reduced plasma levels of cytokines IL-1α, IL-4, IL-6, IL-8 and IL-10, later in early adulthood. This study tests the hypothesis that there is an association between differential DNA methylation regions in cytokine genes in T cells and monocytes DNA in adult subjects and a trajectory of physical aggression from childhood to adolescence. METHODOLOGY/PRINCIPAL FINDINGS: We compared the methylation profiles of the entire genomic loci encompassing the IL-1α, IL-6, IL-4, IL-10 and IL-8 and three of their regulatory transcription factors (TF NFkB1, NFAT5 and STAT6 genes in adult males on a chronic physical aggression trajectory (CPA and males with the same background who followed a normal physical aggression trajectory (control group from childhood to adolescence. We used the method of methylated DNA immunoprecipitation with comprehensive cytokine gene loci and TF loci microarray hybridization, statistical analysis and false discovery rate correction. We found differentially methylated regions to associate with CPA in both the cytokine loci as well as in their transcription factors loci analyzed. Some of these differentially methylated regions were located in known regulatory regions whereas others, to our knowledge, were previously unknown as regulatory areas. However, using the ENCODE database, we were able to identify key regulatory elements in many of these regions that indicate that they might be involved in the regulation of cytokine expression. CONCLUSIONS: We provide here the first evidence for an association between differential DNA methylation in cytokines and their regulators in T cells and monocytes and male physical aggression.

  17. HUMAN CANCER IS A PARASITE SPREAD VIA INTRUSION IN GENOME

    Directory of Open Access Journals (Sweden)

    Sergey N. Rumyantsev

    2013-03-01

    Full Text Available The present article is devoted to further development of new paradigm about the biology of human cancer: the hypothesis of parasitic nature, origin and evolution of the phenomenon. The study included integrative reconsidering, and reinterpretation of the make-ups, traits and processes existing both in human and animal cancers. It was demonstrated that human cancer possesses nearly analogous set of traits characteristic of transmissible animal cancer. Undoubted analogies are seen in the prevalence, clinical exposure, progression of disease, origin of causative agents, immune response against invasion and especially in the intrinsic deviations of the leading traits of cancerous cells. Both human and animal cancers are highly exceptional pathogens. But in contrast to contagious animal cancers the cells of of human cancer can not pass between individuals as usual infectious agents. Exhaustive evidence of the parasitic nature and evolutionary origin of human cancer was revealed and interpreted. In contrast to animal cancer formed of solitary cell lineage, human cancer consists of a couple of lineages constructed under different genetic regulations and performed different structural and physiological functions. The complex make-up of cancer composition remains stable over sequential propagation. The subsistence of human cancer regularly includes obligatory interchange of its successive forms. Human cancer possesses its own biological watch and the ability to gobble its victim, transmit via the intrusion of the genome, perform intercommunications within the tumor components and between the dispersed subunits of cancer. Such intrinsic traits characterize human cancer as a primitively structured parasite that can be classified in Class Mammalians, Species Genomeintruder malevolent (G.malevolent.

  18. The developmental brain gene NPAS3 contains the largest number of accelerated regulatory sequences in the human genome.

    Science.gov (United States)

    Kamm, Gretel B; Pisciottano, Francisco; Kliger, Rafi; Franchini, Lucía F

    2013-05-01

    To identify the evolutionary genetic novelties that contributed to shape human-specific traits such as the use of a complex language, long-term planning and exceptional learning abilities is one of the ultimate frontiers of modern biology. Evolutionary signatures of functional shifts could be detected by comparing noncoding regions that are highly conserved across mammals or primates and rapidly accumulated nucleotide substitutions only in the lineage leading to humans. As gene loci densely populated with human-accelerated elements (HAEs) are more likely to have contributed to human-specific novelties, we sought to identify the transcriptional units and genomic 1 Mb intervals of the entire human genome carrying the highest number of HAEs. To this end, we took advantage of four available data sets of human genomic accelerated regions obtained through different comparisons and algorithms and performed a meta-analysis of the combined data. We found that the brain developmental transcription factor neuronal PAS domain-containing protein 3 (NPAS3) contains the largest cluster of noncoding-accelerated regions in the human genome with up to 14 elements that are highly conserved in mammals, including primates, but carry human-specific nucleotide substitutions. We then tested the ability of the 14 HAEs identified at the NPAS3 locus to act as transcriptional regulatory sequences in a reporter expression assay performed in transgenic zebrafish. We found that 11 out of the 14 HAEs present in NPAS3 act as transcriptional enhancers during development, particularly within the nervous system. As NPAS3 is known to play a crucial role during mammalian brain development, our results indicate that the high density of HAEs present in the human NPAS3 locus could have modified the spatiotemporal expression pattern of NPAS3 in the developing human brain and, therefore, contributed to human brain evolution.

  19. Identifying genomic regions for fine-mapping using genome scan meta-analysis (GSMA to identify the minimum regions of maximum significance (MRMS across populations

    Directory of Open Access Journals (Sweden)

    Maher Brion S

    2005-12-01

    Full Text Available Abstract In order to detect linkage of the simulated complex disease Kofendrerd Personality Disorder across studies from multiple populations, we performed a genome scan meta-analysis (GSMA. Using the 7-cM microsatellite map, nonparametric multipoint linkage analyses were performed separately on each of the four simulated populations independently to determine p-values. The genome of each population was divided into 20-cM bin regions, and each bin was rank-ordered based on the most significant linkage p-value for that population in that region. The bin ranks were then averaged across all four studies to determine the most significant 20-cM regions over all studies. Statistical significance of the averaged bin ranks was determined from a normal distribution of randomly assigned rank averages. To narrow the region of interest for fine-mapping, the meta-analysis was repeated two additional times, with each of the 20-cM bins offset by 7 cM and 13 cM, respectively, creating regions of overlap with the original method. The 6–7 cM shared regions, where the highest averaged 20-cM bins from each of the three offsets overlap, designated the minimum region of maximum significance (MRMS. Application of the GSMA-MRMS method revealed genome wide significance (p-values refer to the average rank assigned to the bin at regions including or adjacent to all of the simulated disease loci: chromosome 1 (p p-value p-value p-value

  20. A co-evolutionary arms race: trypanosomes shaping the human genome, humans shaping the trypanosome genome

    OpenAIRE

    Capewell, Paul; Cooper, Anneli; Clucas, Caroline; Weir, William; MacLeod, Annette

    2014-01-01

    Trypanosoma brucei is the causative agent of African sleeping sickness in humans and one of several pathogens that cause the related veterinary disease Nagana. A complex co-evolution has occurred between these parasites and primates that led to the emergence of trypanosome-specific defences and counter-measures. The first line of defence in humans and several other catarrhine primates is the trypanolytic protein apolipoprotein-L1 (APOL1) found within two serum protein complexes, trypanosome l...

  1. Frequency and Correlation of Nearest Neighboring Nucleotides in Human Genome

    Institute of Scientific and Technical Information of China (English)

    Neng-zhi Jin; Zi-xian Liu; Wen-yuan Qiu

    2009-01-01

    Zipf's approach in linguistics is utilized to analyze the statistical features of frequency and mosomes (Y, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, and 12). It is found that these statistical features of nearest neighboring nucleotides in human genome: (ⅰ) the frequency distribution is a linear function, and (ⅱ) the correlation distribution is an inverse function. The coeffi-cients of the linear function and inverse function depend on the GC content. It proposes the correlation distribution of nearest neighboring nucleotides for the first time and extends the descriptor about nearest neighboring nucleotides.

  2. Attenuation of Sindbis virus neurovirulence by using defined mutations in nontranslated regions of the genome RNA

    NARCIS (Netherlands)

    Kuhn, R J; Griffin, D E; Zhang, H; Niesters, Hubert G. M.; Strauss, J H

    1992-01-01

    We examined a panel of Sindbis virus mutants containing defined mutations in the 5' nontranslated region of the genome RNA, in the 3' nontranslated region, or in both for their growth in cultured cells and virulence in newborn mice. In cultured cells, these viruses all had defects in RNA synthesis a

  3. Distinct Contributions of Replication and Transcription to Mutation Rate Variation of Human Genomes

    KAUST Repository

    Cui, Peng

    2012-03-23

    Here, we evaluate the contribution of two major biological processes—DNA replication and transcription—to mutation rate variation in human genomes. Based on analysis of the public human tissue transcriptomics data, high-resolution replicating map of Hela cells and dbSNP data, we present significant correlations between expression breadth, replication time in local regions and SNP density. SNP density of tissue-specific (TS) genes is significantly higher than that of housekeeping (HK) genes. TS genes tend to locate in late-replicating genomic regions and genes in such regions have a higher SNP density compared to those in early-replication regions. In addition, SNP density is found to be positively correlated with expression level among HK genes. We conclude that the process of DNA replication generates stronger mutational pressure than transcription-associated biological processes do, resulting in an increase of mutation rate in TS genes while having weaker effects on HK genes. In contrast, transcription-associated processes are mainly responsible for the accumulation of mutations in highly-expressed HK genes.

  4. The evolution of signaling complexity suggests a mechanism for reducing the genomic search space in human association studies.

    Science.gov (United States)

    Irizarry, K J L; Merriman, B; Bahamonde, M E; Wong, M-L; Licinio, J

    2005-01-01

    The size complexity of the human genome has been traditionally viewed as an obstacle that frustrates efforts aimed at identifying the genetic correlates of complex human phenotypes. As such complex phenotypes are attributed to the combined action of numerous genomic loci, attempts to identify the underlying multi-locus interactions may produce a combinatorial sum of false positives that drown out the real signal. Faced with such grim prospects for successfully identifying the genetic basis of complex phenotypes, many geneticists simply disregard epistatic interactions altogether. However, the emerging picture from systems biology is that the cellular programs encoded by the genome utilize nested signaling hierarchies to integrate a number of loosely coupled, semiautonomous, and functionally distinct genetic networks. The current view of these modules is that connections encoding inter-module signaling are relatively sparse, while the gene-to-gene (protein-to-protein) interactions within a particular module are typically denser. We believe that each of these modules is encoded by a finite set of discontinuous, sequence-specific, genomic intervals that are functionally linked to association rules, which correlate directly to features in the environment. Furthermore, because these environmental association rules have evolved incrementally over time, we explore theoretical models of cellular evolution to better understand the role of evolution in genomic complexity. Specifically, we present a conceptual framework for (1) reducing genomic complexity by partitioning the genome into subsets composed of functionally distinct genetic modules and (2) improving the selection of coding region SNPs, which results in an increased probability of identifying functionally relevant SNPs. Additionally, we introduce the notion of 'genomic closure,' which provides a quantitative measure of how functionally insulated a specific genetic module might be from the influence of the rest of

  5. Genomic imprinting and human psychology: cognition, behavior and pathology.

    Science.gov (United States)

    Goos, Lisa M; Ragsdale, Gillian

    2008-01-01

    Imprinted genes expressed in the brain are numerous and it has become clear that they play an important role in nervous system development and function. The significant influence of genomic imprinting during development sets the stage for structural and physiological variations affecting psychological function and behaviour, as well as other physiological systems mediating health and well-being. However, our understanding of the role of imprinted genes in behaviour lags far behind our understanding of their roles in perinatal growth and development. Knowledge of genomic imprinting remains limited among behavioral scientists and clinicians and research regarding the influence of imprinted genes on normal cognitive processes and the most common forms of neuropathology has been limited to date. In this chapter, we will explore how knowledge of genomic imprinting can be used to inform our study of normal human cognitive and behavioral processes as well as their disruption. Behavioural analyses of rare imprinted disorders, such as Prader-Willi and Angelman syndromes, provide insight regarding the phenotypic impact of imprinted genes in the brain, and can be used to guide the study of normal behaviour as well as more common but etiologically complex disorders such as ADHD and autism. Furthermore, hypotheses regarding the evolutionary development of imprinted genes can be used to derive predictions about their role in normal behavioural variation, such as that observed in food-related and social interactions.

  6. A library of TAL effector nucleases spanning the human genome.

    Science.gov (United States)

    Kim, Yongsub; Kweon, Jiyeon; Kim, Annie; Chon, Jae Kyung; Yoo, Ji Yeon; Kim, Hye Joo; Kim, Sojung; Lee, Choongil; Jeong, Euihwan; Chung, Eugene; Kim, Doyoung; Lee, Mi Seon; Go, Eun Mi; Song, Hye Jung; Kim, Hwangbeom; Cho, Namjin; Bang, Duhee; Kim, Seokjoong; Kim, Jin-Soo

    2013-03-01

    Transcription activator-like (TAL) effector nucleases (TALENs) can be readily engineered to bind specific genomic loci, enabling the introduction of precise genetic modifications such as gene knockouts and additions. Here we present a genome-scale collection of TALENs for efficient and scalable gene targeting in human cells. We chose target sites that did not have highly similar sequences elsewhere in the genome to avoid off-target mutations and assembled TALEN plasmids for 18,740 protein-coding genes using a high-throughput Golden-Gate cloning system. A pilot test involving 124 genes showed that all TALENs were active and disrupted their target genes at high frequencies, although two of these TALENs became active only after their target sites were partially demethylated using an inhibitor of DNA methyltransferase. We used our TALEN library to generate single- and double-gene-knockout cells in which NF-κB signaling pathways were disrupted. Compared with cells treated with short interfering RNAs, these cells showed unambiguous suppression of signal transduction.

  7. A hybrid approach for de novo human genome sequence assembly and phasing.

    Science.gov (United States)

    Mostovoy, Yulia; Levy-Sakin, Michal; Lam, Jessica; Lam, Ernest T; Hastie, Alex R; Marks, Patrick; Lee, Joyce; Chu, Catherine; Lin, Chin; Džakula, Željko; Cao, Han; Schlebusch, Stephen A; Giorda, Kristina; Schnall-Levin, Michael; Wall, Jeffrey D; Kwok, Pui-Yan

    2016-07-01

    Despite tremendous progress in genome sequencing, the basic goal of producing a phased (haplotype-resolved) genome sequence with end-to-end contiguity for each chromosome at reasonable cost and effort is still unrealized. In this study, we describe an approach to performing de novo genome assembly and experimental phasing by integrating the data from Illumina short-read sequencing, 10X Genomics linked-read sequencing, and BioNano Genomics genome mapping to yield a high-quality, phased, de novo assembled human genome.

  8. Exploring human disease using the Rat Genome Database

    Directory of Open Access Journals (Sweden)

    Mary Shimoyama

    2016-10-01

    Full Text Available Rattus norvegicus, the laboratory rat, has been a crucial model for studies of the environmental and genetic factors associated with human diseases for over 150 years. It is the primary model organism for toxicology and pharmacology studies, and has features that make it the model of choice in many complex-disease studies. Since 1999, the Rat Genome Database (RGD; http://rgd.mcw.edu has been the premier resource for genomic, genetic, phenotype and strain data for the laboratory rat. The primary role of RGD is to curate rat data and validate orthologous relationships with human and mouse genes, and make these data available for incorporation into other major databases such as NCBI, Ensembl and UniProt. RGD also provides official nomenclature for rat genes, quantitative trait loci, strains and genetic markers, as well as unique identifiers. The RGD team adds enormous value to these basic data elements through functional and disease annotations, the analysis and visual presentation of pathways, and the integration of phenotype measurement data for strains used as disease models. Because much of the rat research community focuses on understanding human diseases, RGD provides a number of datasets and software tools that allow users to easily explore and make disease-related connections among these datasets. RGD also provides comprehensive human and mouse data for comparative purposes, illustrating the value of the rat in translational research. This article introduces RGD and its suite of tools and datasets to researchers – within and beyond the rat community – who are particularly interested in leveraging rat-based insights to understand human diseases.

  9. Exploring human disease using the Rat Genome Database

    Science.gov (United States)

    Laulederkind, Stanley J. F.; De Pons, Jeff; Nigam, Rajni; Smith, Jennifer R.; Tutaj, Marek; Petri, Victoria; Hayman, G. Thomas; Wang, Shur-Jen; Ghiasvand, Omid; Thota, Jyothi; Dwinell, Melinda R.

    2016-01-01

    ABSTRACT Rattus norvegicus, the laboratory rat, has been a crucial model for studies of the environmental and genetic factors associated with human diseases for over 150 years. It is the primary model organism for toxicology and pharmacology studies, and has features that make it the model of choice in many complex-disease studies. Since 1999, the Rat Genome Database (RGD; http://rgd.mcw.edu) has been the premier resource for genomic, genetic, phenotype and strain data for the laboratory rat. The primary role of RGD is to curate rat data and validate orthologous relationships with human and mouse genes, and make these data available for incorporation into other major databases such as NCBI, Ensembl and UniProt. RGD also provides official nomenclature for rat genes, quantitative trait loci, strains and genetic markers, as well as unique identifiers. The RGD team adds enormous value to these basic data elements through functional and disease annotations, the analysis and visual presentation of pathways, and the integration of phenotype measurement data for strains used as disease models. Because much of the rat research community focuses on understanding human diseases, RGD provides a number of datasets and software tools that allow users to easily explore and make disease-related connections among these datasets. RGD also provides comprehensive human and mouse data for comparative purposes, illustrating the value of the rat in translational research. This article introduces RGD and its suite of tools and datasets to researchers – within and beyond the rat community – who are particularly interested in leveraging rat-based insights to understand human diseases. PMID:27736745

  10. Identification of copy number variants defining genomic differences among major human groups.

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    Lluís Armengol

    Full Text Available BACKGROUND: Understanding the genetic contribution to phenotype variation of human groups is necessary to elucidate differences in disease predisposition and response to pharmaceutical treatments in different human populations. METHODOLOGY/PRINCIPAL FINDINGS: We have investigated the genome-wide profile of structural variation on pooled samples from the three populations studied in the HapMap project by comparative genome hybridization (CGH in different array platforms. We have identified and experimentally validated 33 genomic loci that show significant copy number differences from one population to the other. Interestingly, we found an enrichment of genes related to environment adaptation (immune response, lipid metabolism and extracellular space within these regions and the study of expression data revealed that more than half of the copy number variants (CNVs translate into gene-expression differences among populations, suggesting that they could have functional consequences. In addition, the identification of single nucleotide polymorphisms (SNPs that are in linkage disequilibrium with the copy number alleles allowed us to detect evidences of population differentiation and recent selection at the nucleotide variation level. CONCLUSIONS: Overall, our results provide a comprehensive view of relevant copy number changes that might play a role in phenotypic differences among major human populations, and generate a list of interesting candidates for future studies.

  11. The influence of genomic context on mutation patterns in the human genome inferred from rare variants.

    Science.gov (United States)

    Schaibley, Valerie M; Zawistowski, Matthew; Wegmann, Daniel; Ehm, Margaret G; Nelson, Matthew R; St Jean, Pamela L; Abecasis, Gonçalo R; Novembre, John; Zöllner, Sebastian; Li, Jun Z

    2013-12-01

    Understanding patterns of spontaneous mutations is of fundamental interest in studies of human genome evolution and genetic disease. Here, we used extremely rare variants in humans to model the molecular spectrum of single-nucleotide mutations. Compared to common variants in humans and human-chimpanzee fixed differences (substitutions), rare variants, on average, arose more recently in the human lineage and are less affected by the potentially confounding effects of natural selection, population demographic history, and biased gene conversion. We analyzed variants obtained from a population-based sequencing study of 202 genes in >14,000 individuals. We observed considerable variability in the per-gene mutation rate, which was correlated with local GC content, but not recombination rate. Using >20,000 variants with a derived allele frequency ≤ 10(-4), we examined the effect of local GC content and recombination rate on individual variant subtypes and performed comparisons with common variants and substitutions. The influence of local GC content on rare variants differed from that on common variants or substitutions, and the differences varied by variant subtype. Furthermore, recombination rate and recombination hotspots have little effect on rare variants of any subtype, yet both have a relatively strong impact on multiple variant subtypes in common variants and substitutions. This observation is consistent with the effect of biased gene conversion or selection-dependent processes. Our results highlight the distinct biases inherent in the initial mutation patterns and subsequent evolutionary processes that affect segregating variants.

  12. Documenting genomics: Applying archival theory to preserving the records of the Human Genome Project.

    Science.gov (United States)

    Shaw, Jennifer

    2016-02-01

    The Human Genome Archive Project (HGAP) aimed to preserve the documentary heritage of the UK's contribution to the Human Genome Project (HGP) by using archival theory to develop a suitable methodology for capturing the results of modern, collaborative science. After assessing past projects and different archival theories, the HGAP used an approach based on the theory of documentation strategy to try to capture the records of a scientific project that had an influence beyond the purely scientific sphere. The HGAP was an archival survey that ran for two years. It led to ninety scientists being contacted and has, so far, led to six collections being deposited in the Wellcome Library, with additional collections being deposited in other UK repositories. In applying documentation strategy the HGAP was attempting to move away from traditional archival approaches to science, which have generally focused on retired Nobel Prize winners. It has been partially successful in this aim, having managed to secure collections from people who are not 'big names', but who made an important contribution to the HGP. However, the attempt to redress the gender imbalance in scientific collections and to improve record-keeping in scientific organisations has continued to be difficult to achieve.

  13. Transcription Restores DNA Repair to Heterochromatin, Determining Regional Mutation Rates in Cancer Genomes

    Directory of Open Access Journals (Sweden)

    Christina L. Zheng

    2014-11-01

    Full Text Available Somatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs arising in an XPC−/− background. XPC−/− cells lack global genome nucleotide excision repair (GG-NER, thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk.

  14. Gametic phase estimation over large genomic regions using an adaptive window approach

    Directory of Open Access Journals (Sweden)

    Excoffier Laurent

    2003-11-01

    Full Text Available Abstract The authors present ELB, an easy to programme and computationally fast algorithm for inferring gametic phase in population samples of multilocus genotypes. Phase updates are made on the basis of a window of neighbouring loci, and the window size varies according to the local level of linkage disequilibrium. Thus, ELB is particularly well suited to problems involving many loci and/or relatively large genomic regions, including those with variable recombination rate. The authors have simulated population samples of single nucleotide polymorphism genotypes with varying levels of recombination and marker density, and find that ELB provides better local estimation of gametic phase than the PHASE or HTYPER programs, while its global accuracy is broadly similar. The relative improvement in local accuracy increases both with increasing recombination and with increasing marker density. Short tandem repeat (STR, or microsatellite simulation studies demonstrate ELB's superiority over PHASE both globally and locally. Missing data are handled by ELB; simulations show that phase recovery is virtually unaffected by up to 2 per cent of missing data, but that phase estimation is noticeably impaired beyond this amount. The authors also applied ELB to datasets obtained from random pairings of 42 human X chromosomes typed at 97 diallelic markers in a 200 kb low-recombination region. Once again, they found ELB to have consistently better local accuracy than PHASE or HTYPER, while its global accuracy was close to the best.

  15. An Aboriginal Australian genome reveals separate human dispersals into Asia.

    Science.gov (United States)

    Rasmussen, Morten; Guo, Xiaosen; Wang, Yong; Lohmueller, Kirk E; Rasmussen, Simon; Albrechtsen, Anders; Skotte, Line; Lindgreen, Stinus; Metspalu, Mait; Jombart, Thibaut; Kivisild, Toomas; Zhai, Weiwei; Eriksson, Anders; Manica, Andrea; Orlando, Ludovic; De La Vega, Francisco M; Tridico, Silvana; Metspalu, Ene; Nielsen, Kasper; Ávila-Arcos, María C; Moreno-Mayar, J Víctor; Muller, Craig; Dortch, Joe; Gilbert, M Thomas P; Lund, Ole; Wesolowska, Agata; Karmin, Monika; Weinert, Lucy A; Wang, Bo; Li, Jun; Tai, Shuaishuai; Xiao, Fei; Hanihara, Tsunehiko; van Driem, George; Jha, Aashish R; Ricaut, François-Xavier; de Knijff, Peter; Migliano, Andrea B; Gallego Romero, Irene; Kristiansen, Karsten; Lambert, David M; Brunak, Søren; Forster, Peter; Brinkmann, Bernd; Nehlich, Olaf; Bunce, Michael; Richards, Michael; Gupta, Ramneek; Bustamante, Carlos D; Krogh, Anders; Foley, Robert A; Lahr, Marta M; Balloux, Francois; Sicheritz-Pontén, Thomas; Villems, Richard; Nielsen, Rasmus; Wang, Jun; Willerslev, Eske

    2011-10-07

    We present an Aboriginal Australian genomic sequence obtained from a 100-year-old lock of hair donated by an Aboriginal man from southern Western Australia in the early 20th century. We detect no evidence of European admixture and estimate contamination levels to be below 0.5%. We show that Aboriginal Australians are descendants of an early human dispersal into eastern Asia, possibly 62,000 to 75,000 years ago. This dispersal is separate from the one that gave rise to modern Asians 25,000 to 38,000 years ago. We also find evidence of gene flow between populations of the two dispersal waves prior to the divergence of Native Americans from modern Asian ancestors. Our findings support the hypothesis that present-day Aboriginal Australians descend from the earliest humans to occupy Australia, likely representing one of the oldest continuous populations outside Africa.

  16. The UK Human Genome Mapping Project online computing service.

    Science.gov (United States)

    Rysavy, F R; Bishop, M J; Gibbs, G P; Williams, G W

    1992-04-01

    This paper presents an overview of computing and networking facilities developed by the Medical Research Council to provide online computing support to the Human Genome Mapping Project (HGMP) in the UK. The facility is connected to a number of other computing facilities in various centres of genetics and molecular biology research excellence, either directly via high-speed links or through national and international wide-area networks. The paper describes the design and implementation of the current system, a 'client/server' network of Sun, IBM, DEC and Apple servers, gateways and workstations. A short outline of online computing services currently delivered by this system to the UK human genetics research community is also provided. More information about the services and their availability could be obtained by a direct approach to the UK HGMP-RC.

  17. Regions of homozygosity in the porcine genome: consequence of demography and the recombination landscape.

    Directory of Open Access Journals (Sweden)

    Mirte Bosse

    Full Text Available Inbreeding has long been recognized as a primary cause of fitness reduction in both wild and domesticated populations. Consanguineous matings cause inheritance of haplotypes that are identical by descent (IBD and result in homozygous stretches along the genome of the offspring. Size and position of regions of homozygosity (ROHs are expected to correlate with genomic features such as GC content and recombination rate, but also direction of selection. Thus, ROHs should be non-randomly distributed across the genome. Therefore, demographic history may not fully predict the effects of inbreeding. The porcine genome has a relatively heterogeneous distribution of recombination rate, making Sus scrofa an excellent model to study the influence of both recombination landscape and demography on genomic variation. This study utilizes next-generation sequencing data for the analysis of genomic ROH patterns, using a comparative sliding window approach. We present an in-depth study of genomic variation based on three different parameters: nucleotide diversity outside ROHs, the number of ROHs in the genome, and the average ROH size. We identified an abundance of ROHs in all genomes of multiple pigs from commercial breeds and wild populations from Eurasia. Size and number of ROHs are in agreement with known demography of the populations, with population bottlenecks highly increasing ROH occurrence. Nucleotide diversity outside ROHs is high in populations derived from a large ancient population, regardless of current population size. In addition, we show an unequal genomic ROH distribution, with strong correlations of ROH size and abundance with recombination rate and GC content. Global gene content does not correlate with ROH frequency, but some ROH hotspots do contain positive selected genes in commercial lines and wild populations. This study highlights the importance of the influence of demography and recombination on homozygosity in the genome to understand

  18. De Novo Identification of Regulatory Regions in Intergenic Spaces of Prokaryotic Genomes

    Energy Technology Data Exchange (ETDEWEB)

    Chain, P; Garcia, E; Mcloughlin, K; Ovcharenko, I

    2007-02-20

    This project was begun to implement, test, and experimentally validate the results of a novel algorithm for genome-wide identification of candidate transcription-fa