Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
PLoS Genet ; 17(2): e1009273, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33571193

RESUMO

Epidemiological studies of obesity, Type-2 diabetes (T2D), cardiovascular diseases and several common cancers have revealed an increased risk in Native Hawaiians compared to European- or Asian-Americans living in the Hawaiian islands. However, there remains a gap in our understanding of the genetic factors that affect the health of Native Hawaiians. To fill this gap, we studied the genetic risk factors at both the chromosomal and sub-chromosomal scales using genome-wide SNP array data on ~4,000 Native Hawaiians from the Multiethnic Cohort. We estimated the genomic proportion of Native Hawaiian ancestry ("global ancestry," which we presumed to be Polynesian in origin), as well as this ancestral component along each chromosome ("local ancestry") and tested their respective association with binary and quantitative cardiometabolic traits. After attempting to adjust for non-genetic covariates evaluated through questionnaires, we found that per 10% increase in global Polynesian genetic ancestry, there is a respective 8.6%, and 11.0% increase in the odds of being diabetic (P = 1.65×10-4) and having heart failure (P = 2.18×10-4), as well as a 0.059 s.d. increase in BMI (P = 1.04×10-10). When testing the association of local Polynesian ancestry with risk of disease or biomarkers, we identified a chr6 region associated with T2D. This association was driven by an uniquely prevalent variant in Polynesian ancestry individuals. However, we could not replicate this finding in an independent Polynesian cohort from Samoa due to the small sample size of the replication cohort. In conclusion, we showed that Polynesian ancestry, which likely capture both genetic and lifestyle risk factors, is associated with an increased risk of obesity, Type-2 diabetes, and heart failure, and that larger cohorts of Polynesian ancestry individuals will be needed to replicate the putative association on chr6 with T2D.

2.
Circ Genom Precis Med ; 13(5): 424-434, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32815737

RESUMO

BACKGROUND: To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry. METHODS: We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3634), compared findings with additional populations and White HCM cohorts (n=6179), and performed in vitro functional studies. RESULTS: Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (pathogenic/likely pathogenic: 18%, P<0.0001) but an excess of variants of uncertain significance (24%, P<0.0001), as compared to Whites (pathogenic/likely pathogenic: 31%, excess of variants of uncertain significance: 7%). Two missense variants in thin filament encoding genes were commonly seen in Singaporean HCM (TNNI3:p.R79C, disease allele frequency [AF]=0.018; TNNT2:p.R286H, disease AF=0.022) and are enriched in Singaporean HCM when compared with Asian controls (TNNI3:p.R79C, Singaporean controls AF=0.0055, P=0.0057, genome aggregation database-East Asian AF=0.0062, P=0.0086; TNNT2:p.R286H, Singaporean controls AF=0.0017, P<0.0001, genome aggregation database-East Asian AF=0.0009, P<0.0001). Both these variants have conflicting annotations in ClinVar and are of low penetrance (TNNI3:p.R79C, 0.7%; TNNT2:p.R286H, 2.7%) but are predicted to be deleterious by computational tools. In population controls, TNNI3:p.R79C carriers had significantly thicker left ventricular walls compared with noncarriers while its etiological fraction is limited (0.70 [95% CI, 0.35-0.86]) and thus TNNI3:p.R79C is considered variant of uncertain significance. Mutant TNNT2:p.R286H iPSC-CMs (induced pluripotent stem cells derived cardiomyocytes) show hypercontractility, increased metabolic requirements, and cellular hypertrophy and the etiological fraction (0.93 [95% CI, 0.83-0.97]) support the likely pathogenicity of TNNT2:p.R286H. CONCLUSIONS: As compared with Whites, Chinese HCM patients commonly have low penetrance risk alleles in TNNT2 or TNNI3 but exhibit few clinically actionable HCM variants overall. This highlights the need for greater study of HCM genetics in non-White populations.

3.
Hum Mol Genet ; 29(13): 2275-2284, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32491157

RESUMO

Statistical imputation applied to genome-wide array data is the most cost-effective approach to complete the catalog of genetic variation in a study population. However, imputed genotypes in underrepresented populations incur greater inaccuracies due to ascertainment bias and a lack of representation among reference individuals, further contributing to the obstacles to study these populations. Here we examined the consequences due to the lack of representation by genotyping in a large number of self-reported Native Hawaiians (N = 3693) a functionally important, Polynesian-specific variant in the CREBRF gene, rs373863828. We found the derived allele was significantly associated with several adiposity traits with large effects (e.g. ~ 1.28 kg/m2 per allele in body mass index as the most significant; P = 7.5 × 10-5), consistent with the original findings in Samoans. Due to the current absence of Polynesian representation in publicly accessible reference sequences, rs373863828 or its proxies could not be tested through imputation using these existing resources. Moreover, the association signals at the entire CREBRF locus could not be captured by alternative approaches, such as admixture mapping. In contrast, highly accurate imputation can be achieved even if a small number (<200) of internally constructed Polynesian reference individuals were available; this would increase sample size and improve the statistical evidence of associations. Taken together, our results suggest the alarming possibility that lack of representation in reference panels could inhibit discovery of functionally important loci such as CREBRF. Yet, they could be easily detected and prioritized with improved representation of diverse populations in sequencing studies.

4.
Am J Hum Genet ; 107(1): 60-71, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32533944

RESUMO

Adult height is one of the earliest putative examples of polygenic adaptation in humans. However, this conclusion was recently challenged because residual uncorrected stratification from large-scale consortium studies was considered responsible for the previously noted genetic difference. It thus remains an open question whether height loci exhibit signals of polygenic adaptation in any human population. We re-examined this question, focusing on one of the shortest European populations, the Sardinians, in addition to mainland European populations. We utilized height-associated loci from the Biobank Japan (BBJ) dataset to further alleviate concerns of biased ascertainment of GWAS loci and showed that the Sardinians remain significantly shorter than expected under neutrality (∼0.22 standard deviation shorter than Utah residents with ancestry from northern and western Europe [CEU] on the basis of polygenic height scores, p = 3.89 × 10-4). We also found the trajectory of polygenic height scores between the Sardinian and the British populations diverged over at least the last 10,000 years (p = 0.0082), consistent with a signature of polygenic adaptation driven primarily by the Sardinian population. Although the polygenic score-based analysis showed a much subtler signature in mainland European populations, we found a clear and robust adaptive signature in the UK population by using a haplotype-based statistic, the trait singleton density score (tSDS), driven by the height-increasing alleles (p = 9.1 × 10-4). In summary, by ascertaining height loci in a distant East Asian population, we further supported the evidence of polygenic adaptation at height-associated loci among the Sardinians. In mainland Europeans, the adaptive signature was detected in haplotype-based analysis but not in polygenic score-based analysis.


Assuntos
Adaptação Fisiológica/genética , Estatura/genética , Herança Multifatorial/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Bancos de Espécimes Biológicos , Grupo com Ancestrais do Continente Europeu/genética , Genética Populacional/métodos , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Haplótipos/genética , Humanos , Itália , Japão , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Seleção Genética/genética
5.
Nat Commun ; 11(1): 939, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32094358

RESUMO

The island of Sardinia has been of particular interest to geneticists for decades. The current model for Sardinia's genetic history describes the island as harboring a founder population that was established largely from the Neolithic peoples of southern Europe and remained isolated from later Bronze Age expansions on the mainland. To evaluate this model, we generate genome-wide ancient DNA data for 70 individuals from 21 Sardinian archaeological sites spanning the Middle Neolithic through the Medieval period. The earliest individuals show a strong affinity to western Mediterranean Neolithic populations, followed by an extended period of genetic continuity on the island through the Nuragic period (second millennium BCE). Beginning with individuals from Phoenician/Punic sites (first millennium BCE), we observe spatially-varying signals of admixture with sources principally from the eastern and northern Mediterranean. Overall, our analysis sheds light on the genetic history of Sardinia, revealing how relationships to mainland populations shifted over time.


Assuntos
DNA Antigo , DNA Mitocondrial/genética , Genética Populacional/história , Migração Humana , Modelos Genéticos , Arqueologia/métodos , Restos Mortais , Cromossomos Humanos X/genética , Cromossomos Humanos Y/genética , Conjuntos de Dados como Assunto , Feminino , História do Século XV , História do Século XVI , História do Século XVII , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , História Antiga , História Medieval , Humanos , Itália , Masculino , Análise de Sequência de DNA
7.
Nature ; 572(7769): 323-328, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31367044

RESUMO

Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of rare coding variants in clinically relevant quantitative cardiometabolic traits. Exome-wide association studies for 64 quantitative traits identified 26 newly associated deleterious alleles. Of these 26 alleles, 19 are either unique to or more than 20 times more frequent in Finnish individuals than in other Europeans and show geographical clustering comparable to Mendelian disease mutations that are characteristic of the Finnish population. We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Variação Genética/genética , Locos de Características Quantitativas/genética , Sequenciamento Completo do Exoma , Alelos , HDL-Colesterol/genética , Análise por Conglomerados , Determinação de Ponto Final , Finlândia , Mapeamento Geográfico , Humanos , Herança Multifatorial/genética , Reprodutibilidade dos Testes
8.
Mol Biol Evol ; 35(11): 2736-2750, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30169787

RESUMO

As are most non-European populations, the Han Chinese are relatively understudied in population and medical genetics studies. From low-coverage whole-genome sequencing of 11,670 Han Chinese women we present a catalog of 25,057,223 variants, including 548,401 novel variants that are seen at least 10 times in our data set. Individuals from this data set came from 24 out of 33 administrative divisions across China (including 19 provinces, 4 municipalities, and 1 autonomous region), thus allowing us to study population structure, genetic ancestry, and local adaptation in Han Chinese. We identified previously unrecognized population structure along the East-West axis of China, demonstrated a general pattern of isolation-by-distance among Han Chinese, and reported unique regional signals of admixture, such as European influences among the Northwestern provinces of China. Furthermore, we identified a number of highly differentiated, putatively adaptive, loci (e.g., MTHFR, ADH7, and FADS, among others) that may be driven by immune response, climate, and diet in the Han Chinese. Finally, we have made available allele frequency estimates stratified by administrative divisions across China in the Geography of Genetic Variant browser for the broader community. By leveraging the largest currently available genetic data set for Han Chinese, we have gained insights into the history and population structure of the world's largest ethnic group.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Evolução Biológica , Variação Genética , Adaptação Biológica , Animais , Estudos de Casos e Controles , China , Transtorno Depressivo Maior/genética , Feminino , Frequência do Gene , Humanos , Homem de Neandertal/genética , Filogeografia , Seleção Genética
9.
Nat Genet ; 50(10): 1426-1434, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30224645

RESUMO

The population of the Mediterranean island of Sardinia has made important contributions to genome-wide association studies of complex disease traits and, based on ancient DNA studies of mainland Europe, Sardinia is hypothesized to be a unique refuge for early Neolithic ancestry. To provide new insights on the genetic history of this flagship population, we analyzed 3,514 whole-genome sequenced individuals from Sardinia. Sardinian samples show elevated levels of shared ancestry with Basque individuals, especially samples from the more historically isolated regions of Sardinia. Our analysis also uniquely illuminates how levels of genetic similarity with mainland ancient DNA samples varies subtly across the island. Together, our results indicate that within-island substructure and sex-biased processes have substantially impacted the genetic history of Sardinia. These results give new insight into the demography of ancestral Sardinians and help further the understanding of sharing of disease risk alleles between Sardinia and mainland populations.


Assuntos
Variação Genética , Genética Populacional , Filogenia , Estudos de Casos e Controles , Demografia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , História Antiga , Migração Humana/estatística & dados numéricos , Humanos , Itália/epidemiologia , Estudos Longitudinais , Masculino , Região do Mediterrâneo/epidemiologia
10.
Hum Mol Genet ; 25(24): 5321-5331, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27798100

RESUMO

The Taiwan Biobank (TWB) aims to build a nationwide research database that integrates genomic/epigenomic profiles, lifestyle patterns, dietary habits, environmental exposure history and long-term health outcomes of 300,000 residents of Taiwan. We describe here an investigation of the population structure of Han Chinese on this Pacific island using genotype data of 591,048 SNPs in an initial freeze of 10,801 unrelated TWB participants. In addition to the North-South cline reported in other Han Chinese populations, we find the Taiwanese Han Chinese clustered into three cline groups: 5% were of northern Han Chinese ancestry, 79.9% were of southern Han Chinese ancestry, and 14.5% belonged to a third (T) group. We also find that this T group is genetically distinct from neighbouring Southeast Asians and Austronesian tribes but similar to other southern Han Chinese. Interestingly, high degree of LD between HLA haplotype A*33:03-B*58:01, an MHC allele being of pathological relevance, and SNPs across the MHC region was observed in subjects with T origin, but not in other Han Chinese. This suggested the T group individuals may have experienced evolutionary events independent from the other southern Han Chinese. Based on the newly-discovered population structure, we detect different loci susceptible to type II diabetes in individuals with southern and northern Han Chinese ancestries. Finally, as one of the largest dataset currently available for the Chinese population, genome-wide statistics for the 10,810 subjects are made publicly accessible through Taiwan View (https://taiwanview.twbiobank.org.tw/index; date last accessed October 14, 2016) to encourage future genetic research and collaborations with the island Taiwan.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Genética Populacional , Polimorfismo de Nucleotídeo Único/genética , Bancos de Espécimes Biológicos , China , Feminino , Genótipo , Antígenos HLA-A/genética , Haplótipos/genética , Humanos , Desequilíbrio de Ligação , Masculino , Taiwan
12.
G3 (Bethesda) ; 6(5): 1287-96, 2016 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-26935417

RESUMO

Identity-by-descent (IBD) is a fundamental concept in genetics with many applications. In a common definition, two haplotypes are said to share an IBD segment if that segment is inherited from a recent shared common ancestor without intervening recombination. Segments several cM long can be efficiently detected by a number of algorithms using high-density SNP array data from a population sample, and there are currently efforts to detect shorter segments from sequencing. Here, we study a problem of identifiability: because existing approaches detect IBD based on contiguous segments of identity-by-state, inferred long segments of IBD may arise from the conflation of smaller, nearby IBD segments. We quantified this effect using coalescent simulations, finding that significant proportions of inferred segments 1-2 cM long are results of conflations of two or more shorter segments, each at least 0.2 cM or longer, under demographic scenarios typical for modern humans for all programs tested. The impact of such conflation is much smaller for longer (> 2 cM) segments. This biases the inferred IBD segment length distribution, and so can affect downstream inferences that depend on the assumption that each segment of IBD derives from a single common ancestor. As an example, we present and analyze an estimator of the de novo mutation rate using IBD segments, and demonstrate that unmodeled conflation leads to underestimates of the ages of the common ancestors on these segments, and hence a significant overestimate of the mutation rate. Understanding the conflation effect in detail will make its correction in future methods more tractable.


Assuntos
Genética Populacional , Genoma Humano , Modelos Genéticos , Algoritmos , Simulação por Computador , Genótipo , Haplótipos , Humanos , Mutação , Taxa de Mutação , Recombinação Genética
13.
PLoS Genet ; 11(10): e1005378, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26426971

RESUMO

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.


Assuntos
Índice de Massa Corporal , Tamanho Corporal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adulto , Fatores Etários , Idoso , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Caracteres Sexuais , Relação Cintura-Quadril
14.
Nat Genet ; 47(11): 1352-1356, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26366551

RESUMO

We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent in Sardinia (0.87% versus <0.01% elsewhere) and in the homozygous state causes Laron syndrome involving short stature. We find that this variant reduces height in heterozygotes by an average of 4.2 cm (-0.64 s.d.). The other variant, in the imprinted KCNQ1 gene (minor allele frequency (MAF) = 7.7% in Sardinia versus <1% elsewhere) reduces height by an average of 1.83 cm (-0.31 s.d.) when maternally inherited. Additionally, polygenic scores indicate that known height-decreasing alleles are at systematically higher frequencies in Sardinians than would be expected by genetic drift. The findings are consistent with selection for shorter stature in Sardinia and a suggestive human example of the proposed 'island effect' reducing the size of large mammals.


Assuntos
Estatura/genética , Variação Genética , Síndrome de Laron/genética , Seleção Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Transporte/genética , Feminino , Efeito Fundador , Frequência do Gene , Estudo de Associação Genômica Ampla/métodos , Genótipo , Haplótipos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Ilhas , Itália , Canal de Potássio KCNQ1/genética , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Nat Genet ; 47(11): 1272-1281, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26366554

RESUMO

We report ∼17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, ∼76,000 variants common in our sample (frequency >5%) are rare elsewhere (<0.5% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels and 19 signals, including 2 new loci, for inflammatory markers. The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population.


Assuntos
Biomarcadores/sangue , Variação Genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Lipídeos/sangue , Análise de Sequência de DNA/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Efeito Fundador , Frequência do Gene , Genética Populacional , Genótipo , Geografia , Haplótipos , Humanos , Mediadores da Inflamação/sangue , Itália , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
16.
Sci Rep ; 4: 4666, 2014 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-24763138

RESUMO

A pyrographically decorated gourd, dated to the French Revolution period, has been alleged to contain a handkerchief dipped into the blood of the French king Louis XVI (1754-1793) after his beheading but recent analyses of living males from two Bourbon branches cast doubts on its authenticity. We sequenced the complete genome of the DNA contained in the gourd at low coverage (~2.5×) with coding sequences enriched at a higher ~7.3× coverage. We found that the ancestry of the gourd's genome does not seem compatible with Louis XVI's known ancestry. From a functional perspective, we did not find an excess of alleles contributing to height despite being described as the tallest person in Court. In addition, the eye colour prediction supported brown eyes, while Louis XVI had blue eyes. This is the first draft genome generated from a person who lived in a recent historical period; however, our results suggest that this sample may not correspond to the alleged king.


Assuntos
DNA , Genoma Humano , Genômica , Alelos , Contaminação por DNA , Exoma , Genética Forense , França , Humanos , Metagenômica , Fenótipo , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável
17.
Am J Hum Genet ; 94(5): 710-20, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24768551

RESUMO

Finnish samples have been extensively utilized in studying single-gene disorders, where the founder effect has clearly aided in discovery, and more recently in genome-wide association studies of complex traits, where the founder effect has had less obvious impacts. As the field starts to explore rare variants' contribution to polygenic traits, it is of great importance to characterize and confirm the Finnish founder effect in sequencing data and to assess its implications for rare-variant association studies. Here, we employ forward simulation, guided by empirical deep resequencing data, to model the genetic architecture of quantitative polygenic traits in both the general European and the Finnish populations simultaneously. We demonstrate that power of rare-variant association tests is higher in the Finnish population, especially when variants' phenotypic effects are tightly coupled with fitness effects and therefore reflect a greater contribution of rarer variants. SKAT-O, variable-threshold tests, and single-variant tests are more powerful than other rare-variant methods in the Finnish population across a range of genetic models. We also compare the relative power and efficiency of exome array genotyping to those of high-coverage exome sequencing. At a fixed cost, less expensive genotyping strategies have far greater power than sequencing; in a fixed number of samples, however, genotyping arrays miss a substantial portion of genetic signals detected in sequencing, even in the Finnish founder population. As genetic studies probe sequence variation at greater depth in more diverse populations, our simulation approach provides a framework for evaluating various study designs for gene discovery.


Assuntos
Simulação por Computador , Grupo com Ancestrais do Continente Europeu/genética , Efeito Fundador , Modelos Genéticos , População/genética , Diabetes Mellitus Tipo 2/genética , Exoma/genética , Finlândia , Humanos , Herança Multifatorial/genética
18.
Nature ; 507(7491): 225-8, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24463515

RESUMO

Ancient genomic sequences have started to reveal the origin and the demographic impact of farmers from the Neolithic period spreading into Europe. The adoption of farming, stock breeding and sedentary societies during the Neolithic may have resulted in adaptive changes in genes associated with immunity and diet. However, the limited data available from earlier hunter-gatherers preclude an understanding of the selective processes associated with this crucial transition to agriculture in recent human evolution. Here we sequence an approximately 7,000-year-old Mesolithic skeleton discovered at the La Braña-Arintero site in León, Spain, to retrieve a complete pre-agricultural European human genome. Analysis of this genome in the context of other ancient samples suggests the existence of a common ancient genomic signature across western and central Eurasia from the Upper Paleolithic to the Mesolithic. The La Braña individual carries ancestral alleles in several skin pigmentation genes, suggesting that the light skin of modern Europeans was not yet ubiquitous in Mesolithic times. Moreover, we provide evidence that a significant number of derived, putatively adaptive variants associated with pathogen resistance in modern Europeans were already present in this hunter-gatherer.


Assuntos
Alelos , Grupo com Ancestrais do Continente Europeu/genética , Fósseis , Imunidade/genética , Pigmentação/genética , Agricultura/história , Evolução Biológica , Cavernas , Cor de Olho/genética , Genoma Humano/genética , Genômica , História Antiga , Humanos , Intolerância à Lactose/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Análise de Componente Principal , Esqueleto , Pigmentação da Pele/genética , Espanha/etnologia
19.
Nat Genet ; 45(6): 690-6, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23583978

RESUMO

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.


Assuntos
Afro-Americanos/genética , Índice de Massa Corporal , Obesidade/genética , Estudos de Casos e Controles , Frequência do Gene , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Obesidade/etnologia , Polimorfismo de Nucleotídeo Único
20.
Nat Genet ; 44(9): 1015-9, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22902787

RESUMO

Strong signatures of positive selection at newly arising genetic variants are well documented in humans(1-8), but this form of selection may not be widespread in recent human evolution(9). Because many human traits are highly polygenic and partly determined by common, ancient genetic variation, an alternative model for rapid genetic adaptation has been proposed: weak selection acting on many pre-existing (standing) genetic variants, or polygenic adaptation(10-12). By studying height, a classic polygenic trait, we demonstrate the first human signature of widespread selection on standing variation. We show that frequencies of alleles associated with increased height, both at known loci and genome wide, are systematically elevated in Northern Europeans compared with Southern Europeans (P < 4.3 × 10(-4)). This pattern mirrors intra-European height differences and is not confounded by ancestry or other ascertainment biases. The systematic frequency differences are consistent with the presence of widespread weak selection (selection coefficients ∼10(-3)-10(-5) per allele) rather than genetic drift alone (P < 10(-15)).


Assuntos
Estatura/genética , Grupo com Ancestrais do Continente Europeu/genética , Variação Genética/fisiologia , Polimorfismo de Nucleotídeo Único , Seleção Genética/fisiologia , Adulto , Estatura/etnologia , Estudos de Coortes , Europa (Continente)/epidemiologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Frequência do Gene , Genética Populacional , Estudo de Associação Genômica Ampla , Humanos , Funções Verossimilhança , Masculino , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA