共查询到20条相似文献,搜索用时 31 毫秒
1.
AP Gregory CA Dendrou KE Attfield A Haghikia DK Xifara F Butter G Poschmann G Kaur L Lambert OA Leach S Prömel D Punwani JH Felce SJ Davis R Gold FC Nielsen RM Siegel M Mann JI Bell G McVean L Fugger 《Nature》2012,488(7412):508-511
Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS), it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation. 相似文献
2.
Large recurrent microdeletions associated with schizophrenia 总被引:1,自引:0,他引:1
Stefansson H Rujescu D Cichon S Pietiläinen OP Ingason A Steinberg S Fossdal R Sigurdsson E Sigmundsson T Buizer-Voskamp JE Hansen T Jakobsen KD Muglia P Francks C Matthews PM Gylfason A Halldorsson BV Gudbjartsson D Thorgeirsson TE Sigurdsson A Jonasdottir A Jonasdottir A Bjornsson A Mattiasdottir S Blondal T Haraldsson M Magnusdottir BB Giegling I Möller HJ Hartmann A Shianna KV Ge D Need AC Crombie C Fraser G Walker N Lonnqvist J Suvisaari J Tuulio-Henriksson A Paunio T Toulopoulou T 《Nature》2008,455(7210):232-236
Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia. 相似文献
3.
Some people inherit an unfortunate combination of genetic sequences, such that exposure to an external trigger causes their immune response to turn on their own tissues. Although mutations in a single gene can cause autoimmunity, most autoimmune diseases are associated with several sequence variants. Marked advances in genetic resources and tools are now making it possible to identify the sequence variants that contribute to autoimmune diseases--promising a better understanding of how we normally remain tolerant of our own tissue components, and how this goes wrong in autoimmune disease. 相似文献
4.
A map of human genome variation from population-scale sequencing 总被引:2,自引:0,他引:2
Genomes Project Consortium 《Nature》2010,467(7319):1061-1073
The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10(-8) per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research. 相似文献
5.
Gudbjartsson DF Arnar DO Helgadottir A Gretarsdottir S Holm H Sigurdsson A Jonasdottir A Baker A Thorleifsson G Kristjansson K Palsson A Blondal T Sulem P Backman VM Hardarson GA Palsdottir E Helgason A Sigurjonsdottir R Sverrisson JT Kostulas K Ng MC Baum L So WY Wong KS Chan JC Furie KL Greenberg SM Sale M Kelly P MacRae CA Smith EE Rosand J Hillert J Ma RC Ellinor PT Thorgeirsson G Gulcher JR Kong A Thorsteinsdottir U Stefansson K 《Nature》2007,448(7151):353-357
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart. 相似文献
6.
An SNP map of human chromosome 22 总被引:35,自引:0,他引:35
Mullikin JC Hunt SE Cole CG Mortimore BJ Rice CM Burton J Matthews LH Pavitt R Plumb RW Sims SK Ainscough RM Attwood J Bailey JM Barlow K Bruskiewich RM Butcher PN Carter NP Chen Y Clee CM Coggill PC Davies J Davies RM Dawson E Francis MD Joy AA Lamble RG Langford CF Macarthy J Mall V Moreland A Overton-Larty EK Ross MT Smith LC Steward CA Sulston JE Tinsley EJ Turney KJ Willey DL Wilson GD McMurray AA Dunham I Rogers J Bentley DR 《Nature》2000,407(6803):516-520
The human genome sequence will provide a reference for measuring DNA sequence variation in human populations. Sequence variants are responsible for the genetic component of individuality, including complex characteristics such as disease susceptibility and drug response. Most sequence variants are single nucleotide polymorphisms (SNPs), where two alternate bases occur at one position. Comparison of any two genomes reveals around 1 SNP per kilobase. A sufficiently dense map of SNPs would allow the detection of sequence variants responsible for particular characteristics on the basis that they are associated with a specific SNP allele. Here we have evaluated large-scale sequencing approaches to obtaining SNPs, and have constructed a map of 2,730 SNPs on human chromosome 22. Most of the SNPs are within 25 kilobases of a transcribed exon, and are valuable for association studies. We have scaled up the process, detecting over 65,000 SNPs in the genome as part of The SNP Consortium programme, which is on target to build a map of 1 SNP every 5 kilobases that is integrated with the human genome sequence and that is freely available in the public domain. 相似文献
7.
Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility 总被引:30,自引:0,他引:30
C Julier R N Hyer J Davies F Merlin P Soularue L Briant G Cathelineau I Deschamps J I Rotter P Froguel 《Nature》1991,354(6349):155-159
A class of alleles at the VNTR (variable number of tandem repeat) locus in the 5' region of the insulin gene (INS) on chromosome 11p is associated with increased risk of insulin-dependent diabetes mellitus (IDDM), but family studies have failed to demonstrate linkage. INS is thought to contribute to IDDM susceptibility but this view has been difficult to reconcile with the lack of linkage evidence. We thus investigated polymorphisms of INS and neighbouring loci in random diabetics, IDDM multiplex families and controls. HLA-DR4-positive diabetics showed an increased risk associated with common variants at polymorphic sites in a 19-kilobase segment spanned by the 5' INS VNTR and the third intron of the gene for insulin-like growth factor II (IGF2). As INS is the major candidate gene from this region, diabetic and control sequence were compared to identify all INS polymorphisms that could contribute to disease susceptibility. In multiplex families the IDDM-associated alleles were transmitted preferentially to HLA-DR4-positive diabetic offspring from heterozygous parents. The effect was strongest in paternal meioses, suggesting a possible role for maternal imprinting. Our results strongly support the existence of a gene or genes affecting HLA-DR4 IDDM susceptibility which is located in a 19-kilobase region of INS-IGF2. Our results also suggest new ways to map susceptibility loci in other common diseases. 相似文献
8.
Somatic variants of murine immunoglobulin lambda light chains 总被引:26,自引:0,他引:26
Studies of the murine lambda light chains produced by myeloma cells provided the first evidence for somatic point mutation of germ-line variable (V) region genes. An examination of the variable regions of 19 lambda 1 chains revealed seven which differed from a common sequence by one to three amino acid substitutions. Subsequently, one of these presumed somatic variants of the single lambda 1 V gene was characterized by DNA sequence analysis of the rearranged functional gene. The predicted DNA sequence alteration was observed and no silent mutation was evident. These studies of lambda chain variants suggested that the hypervariable, complementarity-determining regions (CDRs) ht be a preferred site of somatic mutation because all seven characterized variants contained substitutions only in these regions. By contrast, comparisons of closely related kappa chain variable region amino acid sequences, and more recently VK and VH genes, have suggested that somatic mutation probably occurs in codons for both framework and CDR residues. To examine this apparent discrepancy between the sites of somatic mutations in lambda and kappa genes, we have determined the nucleotide sequence of two lambda 1 gene from hybridomas and a lambda 2 gene from a myeloma. These sequences demonstrate that somatic mutation in lambda genes can occur in both the framework and CDR residues. 相似文献
9.
The International HapMap Project 总被引:1,自引:0,他引:1
International HapMap Consortium 《Nature》2003,426(6968):789-796
The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention. 相似文献
10.
一些基因变异已被发现与阿尔茨海默病典型表型脑脊液相关,但这些发现忽略了小效应风险的变体、基因座内部关联以及与外部环境之间的相互关系.为此,作者利用基于功能网络和基于通路信息的方法从系统生物学角度对遗传变异进行识别.将反映阿尔茨海默症早期病理特点的CSF t-tau作为表型,在全基因组关联分析的基础上提出一种基于权重调整的PageRank网络功能模块挖掘策略.该策略不仅挖掘到广泛研究的与t-tau相关的遗传变异,挖掘到的子网也富集在如神经退行性疾病,神经系统和信号转导等通路中,表明在系统生物学层面,策略识别的特征优先子网与表型具有一定的功能关联. 相似文献
11.
De novo mutations revealed by whole-exome sequencing are strongly associated with autism 总被引:1,自引:0,他引:1
Sanders SJ Murtha MT Gupta AR Murdoch JD Raubeson MJ Willsey AJ Ercan-Sencicek AG DiLullo NM Parikshak NN Stein JL Walker MF Ober GT Teran NA Song Y El-Fishawy P Murtha RC Choi M Overton JD Bjornson RD Carriero NJ Meyer KA Bilguvar K Mane SM Sestan N Lifton RP Günel M Roeder K Geschwind DH Devlin B State MW 《Nature》2012,485(7397):237-241
Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance. 相似文献
12.
Hundreds of variants clustered in genomic loci and biological pathways affect human height 总被引:2,自引:0,他引:2
Lango Allen H Estrada K Lettre G Berndt SI Weedon MN Rivadeneira F Willer CJ Jackson AU Vedantam S Raychaudhuri S Ferreira T Wood AR Weyant RJ Segrè AV Speliotes EK Wheeler E Soranzo N Park JH Yang J Gudbjartsson D Heard-Costa NL Randall JC Qi L Vernon Smith A Mägi R Pastinen T Liang L Heid IM Luan J Thorleifsson G Winkler TW Goddard ME Sin Lo K Palmer C Workalemahu T Aulchenko YS Johansson A Zillikens MC Feitosa MF Esko T Johnson T Ketkar S Kraft P Mangino M Prokopenko I Absher D Albrecht E 《Nature》2010,467(7317):832-838
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P?0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways. 相似文献
13.
Easton DF Pooley KA Dunning AM Pharoah PD Thompson D Ballinger DG Struewing JP Morrison J Field H Luben R Wareham N Ahmed S Healey CS Bowman R;SEARCH collaborators Meyer KB Haiman CA Kolonel LK Henderson BE Le Marchand L Brennan P Sangrajrang S Gaborieau V Odefrey F Shen CY Wu PE Wang HC Eccles D Evans DG Peto J Fletcher O Johnson N Seal S Stratton MR Rahman N Chenevix-Trench G Bojesen SE Nordestgaard BG Axelsson CK Garcia-Closas M Brinton L Chanock S Lissowska J Peplonska B Nevanlinna H 《Nature》2007,447(7148):1087-1093
Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2 > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10(-7)). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach. 相似文献
14.
The mahogany protein is a receptor involved in suppression of obesity 总被引:13,自引:0,他引:13
Nagle DL McGrail SH Vitale J Woolf EA Dussault BJ DiRocco L Holmgren L Montagno J Bork P Huszar D Fairchild-Huntress V Ge P Keilty J Ebeling C Baldini L Gilchrist J Burn P Carlson GA Moore KJ 《Nature》1999,398(6723):148-152
Genetic studies have shown that mutations within the mahogany locus suppress the pleiotropic phenotypes, including obesity, of the agouti-lethal-yellow mutant. Here we identify the mahogany gene and its product; this study, to our knowledge, represents the first positional cloning of a suppressor gene in the mouse. Expression of the mahogany gene is broad; however, in situ hybridization analysis emphasizes the importance of its expression in the ventromedial hypothalamic nucleus, a region that is intimately involved in the regulation of body weight and feeding. We present new genetic studies that indicate that the mahogany locus does not suppress the obese phenotype of the melanocortin-4-receptor null allele or those of the monogenic obese models (Lep(db), tub and Cpe(fat)). However, mahogany can suppress diet-induced obesity, the mechanism of which is likely to have implications for therapeutic intervention in common human obesity. The amino-acid sequence of the mahogany protein suggests that it is a large, single-transmembrane-domain receptor-like molecule, with a short cytoplasmic tail containing a site that is conserved between Caenorhabditis elegans and mammals. We propose two potential, alternative modes of action for mahogany: one draws parallels with the mechanism of action of low-affinity proteoglycan receptors such as fibroblast growth factor and transforming growth factor-beta, and the other suggests that mahogany itself is a signalling receptor. 相似文献
15.
Yokoyama S Woods SL Boyle GM Aoude LG MacGregor S Zismann V Gartside M Cust AE Haq R Harland M Taylor JC Duffy DL Holohan K Dutton-Regester K Palmer JM Bonazzi V Stark MS Symmons J Law MH Schmidt C Lanagan C O'Connor L Holland EA Schmid H Maskiell JA Jetann J Ferguson M Jenkins MA Kefford RF Giles GG Armstrong BK Aitken JF Hopper JL Whiteman DC Pharoah PD Easton DF Dunning AM Newton-Bishop JA Montgomery GW Martin NG Mann GJ Bishop DT Tsao H Trent JM Fisher DE Hayward NK Brown KM 《Nature》2011,480(7375):99-103
16.
Thorgeirsson TE Geller F Sulem P Rafnar T Wiste A Magnusson KP Manolescu A Thorleifsson G Stefansson H Ingason A Stacey SN Bergthorsson JT Thorlacius S Gudmundsson J Jonsson T Jakobsdottir M Saemundsdottir J Olafsdottir O Gudmundsson LJ Bjornsdottir G Kristjansson K Skuladottir H Isaksson HJ Gudbjartsson T Jones GT Mueller T Gottsäter A Flex A Aben KK de Vegt F Mulders PF Isla D Vidal MJ Asin L Saez B Murillo L Blondal T Kolbeinsson H Stefansson JG Hansdottir I Runarsdottir V Pola R Lindblad B 《Nature》2008,452(7187):638-642
Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene-environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases. 相似文献
17.
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis 总被引:1,自引:0,他引:1
International Multiple Sclerosis Genetics Consortium;Wellcome Trust Case Control Consortium Sawcer S Hellenthal G Pirinen M Spencer CC Patsopoulos NA Moutsianas L Dilthey A Su Z Freeman C Hunt SE Edkins S Gray E Booth DR Potter SC Goris A Band G Oturai AB Strange A Saarela J Bellenguez C Fontaine B Gillman M Hemmer B Gwilliam R Zipp F Jayakumar A Martin R Leslie S Hawkins S Giannoulatou E D'alfonso S Blackburn H Martinelli Boneschi F Liddle J Harbo HF Perez ML Spurkland A Waller MJ Mycko MP 《Nature》2011,476(7359):214-219
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis. 相似文献
18.
Mills RE Walter K Stewart C Handsaker RE Chen K Alkan C Abyzov A Yoon SC Ye K Cheetham RK Chinwalla A Conrad DF Fu Y Grubert F Hajirasouliha I Hormozdiari F Iakoucheva LM Iqbal Z Kang S Kidd JM Konkel MK Korn J Khurana E Kural D Lam HY Leng J Li R Li Y Lin CY Luo R Mu XJ Nemesh J Peckham HE Rausch T Scally A Shi X Stromberg MP Stütz AM Urban AE Walker JA Wu J Zhang Y Zhang ZD Batzer MA Ding L Marth GT McVean G Sebat J Snyder M Wang J Ye K Eichler EE Gerstein MB Hurles ME Lee C McCarroll SA 《Nature》2011,470(7332):59-65
Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies. 相似文献
19.
A second generation human haplotype map of over 3.1 million SNPs 总被引:2,自引:0,他引:2
International HapMap Consortium Frazer KA Ballinger DG Cox DR Hinds DA Stuve LL Gibbs RA Belmont JW Boudreau A Hardenbol P Leal SM Pasternak S Wheeler DA Willis TD Yu F Yang H Zeng C Gao Y Hu H Hu W Li C Lin W Liu S Pan H Tang X Wang J Wang W Yu J Zhang B Zhang Q Zhao H Zhao H Zhou J Gabriel SB Barry R Blumenstiel B Camargo A Defelice M Faggart M Goyette M Gupta S Moore J Nguyen H Onofrio RC Parkin M Roy J Stahl E Winchester E Ziaugra L Altshuler D Shen Y Yao Z Huang W Chu X He Y Jin L Liu Y 《Nature》2007,449(7164):851-861
We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations. 相似文献