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1.
Nature ; 538(7624): 201-206, 2016 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-27654912

RESUMO

Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans.


Assuntos
Variação Genética/genética , Genoma Humano/genética , Genômica , Taxa de Mutação , Filogenia , Grupos Raciais/genética , Animais , Austrália , População Negra/genética , Conjuntos de Dados como Assunto , Genética Populacional , História Antiga , Migração Humana/história , Humanos , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Homem de Neandertal/genética , Nova Guiné , Análise de Sequência de DNA , Especificidade da Espécie , Fatores de Tempo
2.
Genome Res ; 28(1): 122-131, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29208628

RESUMO

Induced pluripotent stem cells (iPSCs) are an essential tool for studying cellular differentiation and cell types that are otherwise difficult to access. We investigated the use of iPSCs and iPSC-derived cells to study the impact of genetic variation on gene regulation across different cell types and as models for studies of complex disease. To do so, we established a panel of iPSCs from 58 well-studied Yoruba lymphoblastoid cell lines (LCLs); 14 of these lines were further differentiated into cardiomyocytes. We characterized regulatory variation across individuals and cell types by measuring gene expression levels, chromatin accessibility, and DNA methylation. Our analysis focused on a comparison of inter-individual regulatory variation across cell types. While most cell-type-specific regulatory quantitative trait loci (QTLs) lie in chromatin that is open only in the affected cell types, we found that 20% of cell-type-specific regulatory QTLs are in shared open chromatin. This observation motivated us to develop a deep neural network to predict open chromatin regions from DNA sequence alone. Using this approach, we were able to use the sequences of segregating haplotypes to predict the effects of common SNPs on cell-type-specific chromatin accessibility.


Assuntos
Diferenciação Celular , Montagem e Desmontagem da Cromatina , Cromatina/metabolismo , Metilação de DNA , Loci Gênicos , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/metabolismo , Linhagem Celular , Cromatina/genética , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologia
3.
Nat Rev Genet ; 13(7): 505-16, 2012 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-22705669

RESUMO

The hypothesis that differences in gene regulation have an important role in speciation and adaptation is more than 40 years old. With the advent of new sequencing technologies, we are able to characterize and study gene expression levels and associated regulatory mechanisms in a large number of individuals and species at an unprecedented resolution and scale. We have thus gained new insights into the evolutionary pressures that shape gene expression levels and have developed an appreciation for the relative importance of evolutionary changes in different regulatory genetic and epigenetic mechanisms. The current challenge is to link gene regulatory changes to adaptive evolution of complex phenotypes. Here we mainly focus on comparative studies in primates and how they are complemented by studies in model organisms.


Assuntos
Adaptação Biológica/fisiologia , Evolução Biológica , Epigênese Genética , Regulação da Expressão Gênica/fisiologia , Especiação Genética , Modelos Genéticos , Fisiologia Comparada/métodos , Primatas/genética , Adaptação Biológica/genética , Animais , Regulação da Expressão Gênica/genética , Seleção Genética , Especificidade da Espécie , Fatores de Transcrição/metabolismo
4.
Am J Hum Genet ; 89(6): 731-44, 2011 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-22152676

RESUMO

South Asia harbors one of the highest levels genetic diversity in Eurasia, which could be interpreted as a result of its long-term large effective population size and of admixture during its complex demographic history. In contrast to Pakistani populations, populations of Indian origin have been underrepresented in previous genomic scans of positive selection and population structure. Here we report data for more than 600,000 SNP markers genotyped in 142 samples from 30 ethnic groups in India. Combining our results with other available genome-wide data, we show that Indian populations are characterized by two major ancestry components, one of which is spread at comparable frequency and haplotype diversity in populations of South and West Asia and the Caucasus. The second component is more restricted to South Asia and accounts for more than 50% of the ancestry in Indian populations. Haplotype diversity associated with these South Asian ancestry components is significantly higher than that of the components dominating the West Eurasian ancestry palette. Modeling of the observed haplotype diversities suggests that both Indian ancestry components are older than the purported Indo-Aryan invasion 3,500 YBP. Consistent with the results of pairwise genetic distances among world regions, Indians share more ancestry signals with West than with East Eurasians. However, compared to Pakistani populations, a higher proportion of their genes show regionally specific signals of high haplotype homozygosity. Among such candidates of positive selection in India are MSTN and DOK5, both of which have potential implications in lipid metabolism and the etiology of type 2 diabetes.


Assuntos
Estudo de Associação Genômica Ampla , Seleção Genética , Ásia , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Haplótipos , Hereditariedade , Humanos , Metabolismo dos Lipídeos/genética , Modelos Genéticos , Filogeografia , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal
5.
Hum Biol ; 85(1-3): 251-84, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24297229

RESUMO

Human pygmy populations inhabit different regions of the world, from Africa to Melanesia. In Asia, short-statured populations are often referred to as "negritos." Their short stature has been interpreted as a consequence of thermoregulatory, nutritional, and/or locomotory adaptations to life in tropical forests. A more recent hypothesis proposes that their stature is the outcome of a life history trade-off in high-mortality environments, where early reproduction is favored and, consequently, early sexual maturation and early growth cessation have coevolved. Some serological evidence of deficiencies in the growth hormone/insulin-like growth factor axis have been previously associated with pygmies' short stature. Using genome-wide single-nucleotide polymorphism genotype data, we first tested whether different negrito groups living in the Philippines and Papua New Guinea are closely related and then investigated genomic signals of recent positive selection in African, Asian, and Papuan pygmy populations. We found that negritos in the Philippines and Papua New Guinea are genetically more similar to their nonpygmy neighbors than to one another and have experienced positive selection at different genes. These results indicate that geographically distant pygmy groups are likely to have evolved their short stature independently. We also found that selection on common height variants is unlikely to explain their short stature and that different genes associated with growth, thyroid function, and sexual development are under selection in different pygmy groups.


Assuntos
Adaptação Fisiológica/genética , Povo Asiático/genética , Evolução Biológica , População Negra/genética , Estatura/genética , Genética Populacional , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Antropologia Física , Povo Asiático/etnologia , População Negra/etnologia , Estatura/etnologia , Variação Genética , Genótipo , Humanos , Havaiano Nativo ou Outro Ilhéu do Pacífico/etnologia , Papua Nova Guiné/etnologia , Fenótipo , Filipinas/etnologia , Polimorfismo de Nucleotídeo Único
6.
Science ; 380(6643): 360-361, 2023 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-37104588

RESUMO

A collection of mammalian genomes provides insights into human biology and evolution.


Assuntos
Evolução Biológica , Mamíferos , Animais , Humanos , Evolução Molecular , Genoma , Hominidae , Mamíferos/genética
7.
Mol Biol Evol ; 28(2): 1013-24, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20978040

RESUMO

The geographic origin and time of dispersal of Austroasiatic (AA) speakers, presently settled in south and southeast Asia, remains disputed. Two rival hypotheses, both assuming a demic component to the language dispersal, have been proposed. The first of these places the origin of Austroasiatic speakers in southeast Asia with a later dispersal to south Asia during the Neolithic, whereas the second hypothesis advocates pre-Neolithic origins and dispersal of this language family from south Asia. To test the two alternative models, this study combines the analysis of uniparentally inherited markers with 610,000 common single nucleotide polymorphism loci from the nuclear genome. Indian AA speakers have high frequencies of Y chromosome haplogroup O2a; our results show that this haplogroup has significantly higher diversity and coalescent time (17-28 thousand years ago) in southeast Asia, strongly supporting the first of the two hypotheses. Nevertheless, the results of principal component and "structure-like" analyses on autosomal loci also show that the population history of AA speakers in India is more complex, being characterized by two ancestral components-one represented in the pattern of Y chromosomal and EDAR results and the other by mitochondrial DNA diversity and genomic structure. We propose that AA speakers in India today are derived from dispersal from southeast Asia, followed by extensive sex-specific admixture with local Indian populations.


Assuntos
Emigração e Imigração , Variação Genética , Genética Populacional , Idioma , Sudeste Asiático , Cromossomos Humanos Y , DNA Mitocondrial/genética , Humanos , Índia
8.
Hum Genet ; 131(5): 665-74, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22057783

RESUMO

We have investigated whether regions of the genome showing signs of positive selection in scans based on haplotype structure also show evidence of positive selection when sequence-based tests are applied, whether the target of selection can be localized more precisely, and whether such extra evidence can lead to increased biological insights. We used two tools: simulations under neutrality or selection, and experimental investigation of two regions identified by the HapMap2 project as putatively selected in human populations. Simulations suggested that neutral and selected regions should be readily distinguished and that it should be possible to localize the selected variant to within 40 kb at least half of the time. Re-sequencing of two ~300 kb regions (chr4:158Mb and chr10:22Mb) lacking known targets of selection in HapMap CHB individuals provided strong evidence for positive selection within each and suggested the micro-RNA gene hsa-miR-548c as the best candidate target in one region, and changes in regulation of the sperm protein gene SPAG6 in the other.


Assuntos
Genoma Humano , Seleção Genética , Análise de Sequência de DNA , Genótipo , Projeto HapMap , Haplótipos , Humanos , Modelos Biológicos , Polimorfismo Genético
9.
Nat Commun ; 11(1): 2420, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415101

RESUMO

Archetypal human pluripotent stem cells (hPSC) are widely considered to be equivalent in developmental status to mouse epiblast stem cells, which correspond to pluripotent cells at a late post-implantation stage of embryogenesis. Heterogeneity within hPSC cultures complicates this interspecies comparison. Here we show that a subpopulation of archetypal hPSC enriched for high self-renewal capacity (ESR) has distinct properties relative to the bulk of the population, including a cell cycle with a very low G1 fraction and a metabolomic profile that reflects a combination of oxidative phosphorylation and glycolysis. ESR cells are pluripotent and capable of differentiation into primordial germ cell-like cells. Global DNA methylation levels in the ESR subpopulation are lower than those in mouse epiblast stem cells. Chromatin accessibility analysis revealed a unique set of open chromatin sites in ESR cells. RNA-seq at the subpopulation and single cell levels shows that, unlike mouse epiblast stem cells, the ESR subset of hPSC displays no lineage priming, and that it can be clearly distinguished from gastrulating and extraembryonic cell populations in the primate embryo. ESR hPSC correspond to an earlier stage of post-implantation development than mouse epiblast stem cells.


Assuntos
Células-Tronco Embrionárias/citologia , Camadas Germinativas/citologia , Células-Tronco Pluripotentes/citologia , Animais , Diferenciação Celular , Cromatina/metabolismo , Metilação de DNA , Epigenoma , Citometria de Fluxo , Técnica Indireta de Fluorescência para Anticorpo , Fase G1 , Camadas Germinativas/metabolismo , Glicólise , Humanos , Sistema de Sinalização das MAP Quinases , Metabolômica , Camundongos , Mitocôndrias/metabolismo , Fosforilação Oxidativa , RNA-Seq , Transdução de Sinais
10.
Science ; 349(6253): aab3761, 2015 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-26249230

RESUMO

In order to explore the diversity and selective signatures of duplication and deletion human copy-number variants (CNVs), we sequenced 236 individuals from 125 distinct human populations. We observed that duplications exhibit fundamentally different population genetic and selective signatures than deletions and are more likely to be stratified between human populations. Through reconstruction of the ancestral human genome, we identify megabases of DNA lost in different human lineages and pinpoint large duplications that introgressed from the extinct Denisova lineage now found at high frequency exclusively in Oceanic populations. We find that the proportion of CNV base pairs to single-nucleotide-variant base pairs is greater among non-Africans than it is among African populations, but we conclude that this difference is likely due to unique aspects of non-African population history as opposed to differences in CNV load.


Assuntos
Variações do Número de Cópias de DNA , Evolução Molecular , Duplicação Gênica , Genoma Humano/genética , População/genética , Deleção de Sequência , Animais , População Negra/classificação , População Negra/genética , Hominidae/genética , Humanos , Havaiano Nativo ou Outro Ilhéu do Pacífico/classificação , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Filogenia , Polimorfismo de Nucleotídeo Único , Seleção Genética
11.
PLoS One ; 9(5): e98076, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24847810

RESUMO

Following the dispersal out of Africa, where hominins evolved in warm environments for millions of years, our species has colonised different climate zones of the world, including high latitudes and cold environments. The extent to which human habitation in (sub-)Arctic regions has been enabled by cultural buffering, short-term acclimatization and genetic adaptations is not clearly understood. Present day indigenous populations of Siberia show a number of phenotypic features, such as increased basal metabolic rate, low serum lipid levels and increased blood pressure that have been attributed to adaptation to the extreme cold climate. In this study we introduce a dataset of 200 individuals from ten indigenous Siberian populations that were genotyped for 730,525 SNPs across the genome to identify genes and non-coding regions that have undergone unusually rapid allele frequency and long-range haplotype homozygosity change in the recent past. At least three distinct population clusters could be identified among the Siberians, each of which showed a number of unique signals of selection. A region on chromosome 11 (chr11:66-69 Mb) contained the largest amount of clustering of significant signals and also the strongest signals in all the different selection tests performed. We present a list of candidate cold adaption genes that showed significant signals of positive selection with our strongest signals associated with genes involved in energy regulation and metabolism (CPT1A, LRP5, THADA) and vascular smooth muscle contraction (PRKG1). By employing a new method that paints phased chromosome chunks by their ancestry we distinguish local Siberian-specific long-range haplotype signals from those introduced by admixture.


Assuntos
Aclimatação/genética , Clima Frio , Genômica , Grupos Populacionais/genética , Evolução Molecular , Humanos , Polimorfismo de Nucleotídeo Único , Grupos Populacionais/etnologia , Seleção Genética , Sibéria/etnologia
12.
Science ; 335(6070): 823-8, 2012 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-22344438

RESUMO

Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease-causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies.


Assuntos
Variação Genética , Genoma Humano , Proteínas/genética , Doença/genética , Expressão Gênica , Frequência do Gene , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Seleção Genética
13.
Eur J Hum Genet ; 18(3): 354-63, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19809480

RESUMO

Islam is the second most practiced religion in India, next to Hinduism. It is still unclear whether the spread of Islam in India has been only a cultural transformation or is associated with detectable levels of gene flow. To estimate the contribution of West Asian and Arabian admixture to Indian Muslims, we assessed genetic variation in mtDNA, Y-chromosomal and LCT/MCM6 markers in 472, 431 and 476 samples, respectively, representing six Muslim communities from different geographical regions of India. We found that most of the Indian Muslim populations received their major genetic input from geographically close non-Muslim populations. However, low levels of likely sub-Saharan African, Arabian and West Asian admixture were also observed among Indian Muslims in the form of L0a2a2 mtDNA and E1b1b1a and J(*)(xJ2) Y-chromosomal lineages. The distinction between Iranian and Arabian sources was difficult to make with mtDNA and the Y chromosome, as the estimates were highly correlated because of similar gene pool compositions in the sources. In contrast, the LCT/MCM6 locus, which shows a clear distinction between the two sources, enabled us to rule out significant gene flow from Arabia. Overall, our results support a model according to which the spread of Islam in India was predominantly cultural conversion associated with minor but still detectable levels of gene flow from outside, primarily from Iran and Central Asia, rather than directly from the Arabian Peninsula.


Assuntos
Genética Populacional , Islamismo , Filogenia , África Subsaariana/etnologia , Cromossomos Humanos Y/genética , DNA Mitocondrial/genética , Frequência do Gene/genética , Pool Gênico , Loci Gênicos/genética , Variação Genética , Geografia , Haplótipos/genética , Humanos , Índia , Irã (Geográfico) , Oriente Médio/etnologia , Análise de Componente Principal
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