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1.
Science ; 365(6456)2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31467194

RESUMO

Twin and family studies have shown that same-sex sexual behavior is partly genetically influenced, but previous searches for specific genes involved have been underpowered. We performed a genome-wide association study (GWAS) on 477,522 individuals, revealing five loci significantly associated with same-sex sexual behavior. In aggregate, all tested genetic variants accounted for 8 to 25% of variation in same-sex sexual behavior, only partially overlapped between males and females, and do not allow meaningful prediction of an individual's sexual behavior. Comparing these GWAS results with those for the proportion of same-sex to total number of sexual partners among nonheterosexuals suggests that there is no single continuum from opposite-sex to same-sex sexual behavior. Overall, our findings provide insights into the genetics underlying same-sex sexual behavior and underscore the complexity of sexuality.

2.
Nat Genet ; 51(2): 245-257, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643258

RESUMO

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.


Assuntos
Comportamento/fisiologia , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudos de Casos e Controles , Feminino , Genética Comportamental/métodos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
3.
Genome Res ; 28(7): 1039-1052, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29773658

RESUMO

Current approaches to detect and characterize mosaic chromosomal aneuploidy are limited by sensitivity, efficiency, cost, or the need to culture cells. We describe the mosaic aneuploidy detection by massively parallel sequencing (MAD-seq) capture assay and the MADSEQ analytical approach that allow low (<10%) levels of mosaicism for chromosomal aneuploidy or regional loss of heterozygosity to be detected, assigned to a meiotic or mitotic origin, and quantified as a proportion of the cells in the sample. We show results from a multi-ethnic MAD-seq (meMAD-seq) capture design that works equally well in populations of diverse racial and ethnic origins and how the MADSEQ analytical approach can be applied to exome or whole-genome sequencing data, revealing previously unrecognized aneuploidy or copy number neutral loss of heterozygosity in samples studied by the 1000 Genomes Project, cell lines from public repositories, and one of the Illumina Platinum Genomes samples. We have made the meMAD-seq capture design and MADSEQ analytical software open for unrestricted use, with the goal that they can be applied in clinical samples to allow new insights into the unrecognized prevalence of mosaic chromosomal aneuploidy in humans and its phenotypic associations.


Assuntos
Cromossomos/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Aneuploidia , Exoma/genética , Feminino , Genoma/genética , Humanos , Masculino , Mosaicismo , Software
4.
Hum Mol Genet ; 27(11): 2025-2038, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29659830

RESUMO

The ratio of the length of the index finger to that of the ring finger (2D:4D) is sexually dimorphic and is commonly used as a non-invasive biomarker of prenatal androgen exposure. Most association studies of 2D:4D ratio with a diverse range of sex-specific traits have typically involved small sample sizes and have been difficult to replicate, raising questions around the utility and precise meaning of the measure. In the largest genome-wide association meta-analysis of 2D:4D ratio to date (N = 15 661, with replication N = 75 821), we identified 11 loci (9 novel) explaining 3.8% of the variance in mean 2D:4D ratio. We also found weak evidence for association (ß = 0.06; P = 0.02) between 2D:4D ratio and sensitivity to testosterone [length of the CAG microsatellite repeat in the androgen receptor (AR) gene] in females only. Furthermore, genetic variants associated with (adult) testosterone levels and/or sex hormone-binding globulin were not associated with 2D:4D ratio in our sample. Although we were unable to find strong evidence from our genetic study to support the hypothesis that 2D:4D ratio is a direct biomarker of prenatal exposure to androgens in healthy individuals, our findings do not explicitly exclude this possibility, and pathways involving testosterone may become apparent as the size of the discovery sample increases further. Our findings provide new insight into the underlying biology shaping 2D:4D variation in the general population.

5.
Nat Commun ; 8(1): 303, 2017 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-28827725

RESUMO

Heterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations across multiple generations. Using exome sequences from 3222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1.45 ± 0.05 × 10-8 per base pair per generation in autosomal coding sequence, with a corresponding non-crossover gene conversion rate of 8.75 ± 0.05 × 10-6 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent-offspring trios, suggesting that post-zygotic mutations contribute little to the human germ-line mutation rate. We find frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5' CCG 3' to 5' CTG 3' context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.Estimates of human mutation rates differ substantially based on the approach. Here, the authors present a multi-generational estimate from the autozygous segment in a non-European population that gives insight into the contribution of post-zygotic mutations and population-specific mutational processes.


Assuntos
Genética Populacional/métodos , Genoma Humano/genética , Taxa de Mutação , Mutação , Exoma/genética , Mutação em Linhagem Germinativa , Heterozigoto , Homozigoto , Humanos , Polimorfismo Genético
6.
Nat Commun ; 8: 14994, 2017 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-28440270

RESUMO

In humans, males have lower recombination rates than females over the majority of the genome, but the opposite is usually true near the telomeres. These broad-scale differences have been known for decades, yet little is known about differences at the fine scale. By combining data sets, we have collected recombination events from over 100,000 meioses and have constructed sex-specific genetic maps at a previously unachievable resolution. Here we show that, although a substantial fraction of the genome shows some degree of sexually dimorphic recombination, the vast majority of hotspots are shared between the sexes, with only a small number of putative sex-specific hotspots. Wavelet analysis indicates that most of the differences can be attributed to the fine scale, and that variation in rate between the sexes can mostly be explained by differences in hotspot magnitude, rather than location. Nonetheless, known recombination-associated genomic features, such as THE1B repeat elements, show systematic differences between the sexes.


Assuntos
Mapeamento Cromossômico/métodos , Troca Genética/genética , Recombinação Homóloga/genética , Meiose/genética , Feminino , Genoma Humano/genética , Genômica/métodos , Humanos , Masculino , Fatores Sexuais
7.
G3 (Bethesda) ; 6(11): 3517-3524, 2016 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-27591755

RESUMO

Meiotic recombination in mammals has been shown to largely cluster into hotspots, which are targeted by the chromatin modifier PRDM9. The canid family, including wolves and dogs, has undergone a series of disrupting mutations in this gene, rendering PRDM9 inactive. Given the importance of PRDM9, it is of great interest to learn how its absence in the dog genome affects patterns of recombination placement. We have used genotypes from domestic dog pedigrees to generate sex-specific genetic maps of recombination in this species. On a broad scale, we find that placement of recombination events in dogs is consistent with that in mice and apes, in that the majority of recombination occurs toward the telomeres in males, while female crossing over is more frequent and evenly spread along chromosomes. It has been previously suggested that dog recombination is more uniform in distribution than that of humans; however, we found that recombination in dogs is less uniform than in humans. We examined the distribution of recombination within the genome, and found that recombination is elevated immediately upstream of the transcription start site and around CpG islands, in agreement with previous studies, but that this effect is stronger in male dogs. We also found evidence for positive crossover interference influencing the spacing between recombination events in dogs, as has been observed in other species including humans and mice. Overall our data suggests that dogs have similar broad scale properties of recombination to humans, while fine scale recombination is similar to other species lacking PRDM9.

8.
Nat Genet ; 48(6): 593-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27111036

RESUMO

We report the sequences of 1,244 human Y chromosomes randomly ascertained from 26 worldwide populations by the 1000 Genomes Project. We discovered more than 65,000 variants, including single-nucleotide variants, multiple-nucleotide variants, insertions and deletions, short tandem repeats, and copy number variants. Of these, copy number variants contribute the greatest predicted functional impact. We constructed a calibrated phylogenetic tree on the basis of binary single-nucleotide variants and projected the more complex variants onto it, estimating the number of mutations for each class. Our phylogeny shows bursts of extreme expansion in male numbers that have occurred independently among each of the five continental superpopulations examined, at times of known migrations and technological innovations.


Assuntos
Cromossomos Humanos Y , Demografia , Haplótipos , Humanos , Masculino , Mutação , Filogenia , Polimorfismo de Nucleotídeo Único
9.
Nature ; 526(7571): 75-81, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26432246

RESUMO

Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.


Assuntos
Variação Genética/genética , Genoma Humano/genética , Mapeamento Físico do Cromossomo , Sequência de Aminoácidos , Predisposição Genética para Doença , Genética Médica , Genética Populacional , Estudo de Associação Genômica Ampla , Genômica , Genótipo , Haplótipos/genética , Homozigoto , Humanos , Dados de Sequência Molecular , Taxa de Mutação , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Análise de Sequência de DNA , Deleção de Sequência/genética
10.
Nature ; 526(7571): 68-74, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26432245

RESUMO

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.


Assuntos
Variação Genética/genética , Genética Populacional/normas , Genoma Humano/genética , Genômica/normas , Internacionalidade , Conjuntos de Dados como Assunto , Demografia , Suscetibilidade a Doenças , Exoma/genética , Genética Médica , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL/genética , Mapeamento Físico do Cromossomo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Doenças Raras/genética , Padrões de Referência , Análise de Sequência de DNA
11.
Oncotarget ; 6(28): 24627-35, 2015 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-26384365

RESUMO

Aging is associated with an increased risk of cancer, possibly in part because of an age-related increase in mutations in normal tissues. Due to their extremely low abundance, somatic mutations in normal tissues frequently escape detection. Tumors, as clonal expansions of single cells, can provide information about the somatic mutations present in these cells prior to tumorigenesis. Here, we used data from The Cancer Genome Atlas (TCGA), to systematically study the frequency and spectrum of somatic mutations in a total of 6,969 patients and 34 different tumor types as a function of the age of the patient. After using linear modeling to control for the age structure of different tumor types, we found that the number of identified somatic mutations increases exponentially with age. Using additional data from the literature, we found that accumulation of somatic mutations is associated with cell division rate, cancer risk and cigarette smoking, with the latter also associated with a distinct spectrum of mutations. Our results confirm that aging is associated with the accumulation of somatic mutations, and strongly suggest that the level of genome instability of normal cells, modified by both endogenous and environmental factors, is the main risk factor for cancer.


Assuntos
Envelhecimento/genética , Biomarcadores Tumorais/genética , Genoma Humano , Mutação , Neoplasias/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Senescência Celular , Biologia Computacional , Análise Mutacional de DNA , Bases de Dados Genéticas , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Instabilidade Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Fenótipo , Fatores de Risco , Fumar/efeitos adversos , Fumar/genética , Adulto Jovem
12.
Nat Commun ; 6: 6260, 2015 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-25695863

RESUMO

Recombination plays a fundamental role in meiosis, ensuring the proper segregation of chromosomes and contributing to genetic diversity by generating novel combinations of alleles. Here, we use data derived from direct-to-consumer genetic testing to investigate patterns of recombination in over 4,200 families. Our analysis reveals a number of sex differences in the distribution of recombination. We find the fraction of male events occurring within hotspots to be 4.6% higher than for females. We confirm that the recombination rate increases with maternal age, while hotspot usage decreases, with no such effects observed in males. Finally, we show that the placement of female recombination events appears to become increasingly deregulated with maternal age, with an increasing fraction of events observed within closer proximity to each other than would be expected under simple models of crossover interference.


Assuntos
Troca Genética , Idade Materna , Adulto , Fatores Etários , Feminino , Humanos , Masculino
13.
Mol Genet Genomic Med ; 3(6): 558-69, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26740948

RESUMO

We explored potential genetic risk factors implicated in nonalcoholic fatty liver disease (NAFLD) within a Caribbean-Hispanic population in New York City. A total of 316 individuals including 40 subjects with biopsy-proven NAFLD, 24 ethnically matched non-NAFLD controls, and a 252 ethnically mixed random sampling of Bronx County, New York were analyzed. Genotype analysis was performed to determine allelic frequencies of 74 known single-nucleotide polymorphisms (SNPs) associated with NAFLD risk based on previous genome-wide association study (GWAS) and candidate gene studies. Additionally, the entire coding region of PNPLA3, a gene showing the strongest association to NAFLD was subjected to Sanger sequencing. Results suggest that both rare and common DNA variations in PNPLA3 and SAMM50 may be correlated with NAFLD in this small population study, while common DNA variations in CHUK and ERLIN1, may have a protective interaction. Common SNPs in ENPP1 and ABCC2 have suggestive association with fatty liver, but with less compelling significance. In conclusion, Hispanic patients of Caribbean ancestry may have different interactions with NAFLD genetic modifiers; therefore, further investigation with a larger sample size, into this Caribbean-Hispanic population is warranted.

14.
Genome Biol ; 15(3): R25, 2014 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-24995881

RESUMO

BACKGROUND: Obsessive-compulsive disorder (OCD), a severe mental disease manifested in time-consuming repetition of behaviors, affects 1 to 3% of the human population. While highly heritable, complex genetics has hampered attempts to elucidate OCD etiology. Dogs suffer from naturally occurring compulsive disorders that closely model human OCD, manifested as an excessive repetition of normal canine behaviors that only partially responds to drug therapy. The limited diversity within dog breeds makes identifying underlying genetic factors easier. RESULTS: We use genome-wide association of 87 Doberman Pinscher cases and 63 controls to identify genomic loci associated with OCD and sequence these regions in 8 affected dogs from high-risk breeds and 8 breed-matched controls. We find 119 variants in evolutionarily conserved sites that are specific to dogs with OCD. These case-only variants are significantly more common in high OCD risk breeds compared to breeds with no known psychiatric problems. Four genes, all with synaptic function, have the most case-only variation: neuronal cadherin (CDH2), catenin alpha2 (CTNNA2), ataxin-1 (ATXN1), and plasma glutamate carboxypeptidase (PGCP). In the 2 Mb gene desert between the cadherin genes CDH2 and DSC3, we find two different variants found only in dogs with OCD that disrupt the same highly conserved regulatory element. These variants cause significant changes in gene expression in a human neuroblastoma cell line, likely due to disrupted transcription factor binding. CONCLUSIONS: The limited genetic diversity of dog breeds facilitates identification of genes, functional variants and regulatory pathways underlying complex psychiatric disorders that are mechanistically similar in dogs and humans.


Assuntos
Carboxipeptidases/genética , Cateninas/genética , Desmocolinas/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Transtorno Obsessivo-Compulsivo/genética , Sequências Reguladoras de Ácido Nucleico/genética , Animais , Animais Endogâmicos , Ataxina-1 , Ataxinas , Cães , Estudo de Associação Genômica Ampla
15.
Genome Biol ; 15(6): R88, 2014 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-24980144

RESUMO

BACKGROUND: Population differentiation has proved to be effective for identifying loci under geographically localized positive selection, and has the potential to identify loci subject to balancing selection. We have previously investigated the pattern of genetic differentiation among human populations at 36.8 million genomic variants to identify sites in the genome showing high frequency differences. Here, we extend this dataset to include additional variants, survey sites with low levels of differentiation, and evaluate the extent to which highly differentiated sites are likely to result from selective or other processes. RESULTS: We demonstrate that while sites with low differentiation represent sampling effects rather than balancing selection, sites showing extremely high population differentiation are enriched for positive selection events and that one half may be the result of classic selective sweeps. Among these, we rediscover known examples, where we actually identify the established functional SNP, and discover novel examples including the genes ABCA12, CALD1 and ZNF804, which we speculate may be linked to adaptations in skin, calcium metabolism and defense, respectively. CONCLUSIONS: We identify known and many novel candidate regions for geographically restricted positive selection, and suggest several directions for further research.


Assuntos
Genoma Humano , Mutação INDEL , Polimorfismo de Nucleotídeo Único , Frequência do Gene , Deriva Genética , Humanos , Seleção Genética , Análise de Sequência de DNA
16.
PLoS Genet ; 10(5): e1004402, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24875834

RESUMO

DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.


Assuntos
Fatores Etários , Transtornos Globais do Desenvolvimento Infantil/genética , Metilação de DNA/genética , Epigênese Genética , Mosaicismo , Adulto , Transtornos Globais do Desenvolvimento Infantil/patologia , Aberrações Cromossômicas , Feminino , Perfilação da Expressão Gênica , Genoma Humano , Haplótipos , Humanos , Masculino , Relações Materno-Fetais , Pessoa de Meia-Idade , Gravidez
17.
Nat Commun ; 5: 3956, 2014 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-24853639

RESUMO

Horizontal gene transfer is an important driver of bacterial evolution, but genetic exchange in the core genome of clonal species, including the major pathogen Staphylococcus aureus, is incompletely understood. Here we reveal widespread homologous recombination in S. aureus at the species level, in contrast to its near-complete absence between closely related strains. We discover a patchwork of hotspots and coldspots at fine scales falling against a backdrop of broad-scale trends in rate variation. Over megabases, homoplasy rates fluctuate 1.9-fold, peaking towards the origin-of-replication. Over kilobases, we find core recombination hotspots of up to 2.5-fold enrichment situated near fault lines in the genome associated with mobile elements. The strongest hotspots include regions flanking conjugative transposon ICE6013, the staphylococcal cassette chromosome (SCC) and genomic island νSaα. Mobile element-driven core genome transfer represents an opportunity for adaptation and challenges our understanding of the recombination landscape in predominantly clonal pathogens, with important implications for genotype-phenotype mapping.


Assuntos
Elementos de DNA Transponíveis/genética , Genoma Bacteriano/genética , Recombinação Genética , Staphylococcus aureus/genética , Cromossomos Bacterianos/genética , Transferência Genética Horizontal/genética , Variação Genética , Funções Verossimilhança , Desequilíbrio de Ligação/genética , Filogenia , Especificidade da Espécie , Staphylococcus aureus/isolamento & purificação
18.
PLoS Genet ; 9(12): e1003984, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24348265

RESUMO

The identification of the H3K4 trimethylase, PRDM9, as the gene responsible for recombination hotspot localization has provided considerable insight into the mechanisms by which recombination is initiated in mammals. However, uniquely amongst mammals, canids appear to lack a functional version of PRDM9 and may therefore provide a model for understanding recombination that occurs in the absence of PRDM9, and thus how PRDM9 functions to shape the recombination landscape. We have constructed a fine-scale genetic map from patterns of linkage disequilibrium assessed using high-throughput sequence data from 51 free-ranging dogs, Canis lupus familiaris. While broad-scale properties of recombination appear similar to other mammalian species, our fine-scale estimates indicate that canine highly elevated recombination rates are observed in the vicinity of CpG rich regions including gene promoter regions, but show little association with H3K4 trimethylation marks identified in spermatocytes. By comparison to genomic data from the Andean fox, Lycalopex culpaeus, we show that biased gene conversion is a plausible mechanism by which the high CpG content of the dog genome could have occurred.


Assuntos
Evolução Molecular , Conversão Gênica , Regiões Promotoras Genéticas , Recombinação Genética , Animais , Mapeamento Cromossômico , Ilhas de CpG , Cães , Estudos de Associação Genética , Genoma , Histona-Lisina N-Metiltransferase/genética , Desequilíbrio de Ligação
19.
Science ; 339(6127): 1578-82, 2013 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-23413192

RESUMO

Instances in which natural selection maintains genetic variation in a population over millions of years are thought to be extremely rare. We conducted a genome-wide scan for long-lived balancing selection by looking for combinations of SNPs shared between humans and chimpanzees. In addition to the major histocompatibility complex, we identified 125 regions in which the same haplotypes are segregating in the two species, all but two of which are noncoding. In six cases, there is evidence for an ancestral polymorphism that persisted to the present in humans and chimpanzees. Regions with shared haplotypes are significantly enriched for membrane glycoproteins, and a similar trend is seen among shared coding polymorphisms. These findings indicate that ancient balancing selection has shaped human variation and point to genes involved in host-pathogen interactions as common targets.


Assuntos
Genoma Humano/genética , Interações Hospedeiro-Patógeno/genética , Pan troglodytes/genética , Seleção Genética , Animais , Sequência de Bases , Estudos de Associação Genética , Haplótipos , Humanos , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único
20.
Nature ; 491(7422): 56-65, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23128226

RESUMO

By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations.


Assuntos
Variação Genética/genética , Genética Populacional , Genoma Humano/genética , Genômica , Alelos , Sítios de Ligação/genética , Sequência Conservada/genética , Grupos de Populações Continentais/genética , Evolução Molecular , Genética Médica , Estudo de Associação Genômica Ampla , Haplótipos/genética , Humanos , Motivos de Nucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Deleção de Sequência/genética , Fatores de Transcrição/metabolismo
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