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ABSTRACT: Population mixture is an important process in biology. We present a suite of methods for learning about population mixtures, implemented in a software package called ADMIXTOOLS, that support formal tests for whether mixture occurred, and make it possible to infer proportions and dates of mixture. We also describe the development of a new single nucleotide polymorphism (SNP) array consisting of 629,433 sites with clearly documented ascertainment that was specifically designed for population genetic analyses, and that we genotyped in 934 individuals from 53 diverse populations. To illustrate the methods, we give a number of examples where they provide new insights about the history of human admixture. The most striking finding is a clear signal of admixture into northern Europe, with one ancestral population related to present day Basques and Sardinians, and the other related to present day populations of northeast Asia and the Americas. This likely reflects a history of admixture between Neolithic migrants and the indigenous Mesolithic population of Europe, consistent with recent analyses of ancient bones from Sweden and the sequencing of the genome of the Tyrolean 'Iceman'.
Genetics 09/2012; · 4.01 Impact Factor
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Matthias Meyer,
Martin Kircher,
Marie-Theres Gansauge,
Heng Li,
Fernando Racimo, Swapan Mallick,
Joshua G Schraiber,
Flora Jay,
Kay Prüfer,
Cesare de Filippo, [......],
Michael F Hammer,
Michael V Shunkov,
Anatoli P Derevianko,
Nick Patterson,
Aida M Andrés,
Evan E Eichler,
Montgomery Slatkin,
David Reich,
Janet Kelso,
Svante Pääbo
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ABSTRACT: We present a DNA library preparation method that has allowed us to reconstruct a high-coverage (30×) genome sequence of a Denisovan, an extinct relative of Neandertals. The quality of this genome allows a direct estimation of Denisovan heterozygosity indicating that genetic diversity in these archaic hominins was extremely low. It also allows tentative dating of the specimen on the basis of "missing evolution" in its genome, detailed measurements of Denisovan and Neandertal admixture into present-day human populations, and the generation of a near-complete catalog of genetic changes that swept to high frequency in modern humans since their divergence from Denisovans.
Science 08/2012; 338(6104):222-6. · 31.20 Impact Factor
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James X Sun,
Agnar Helgason,
Gisli Masson,
Sigríður Sunna Ebenesersdóttir,
Heng Li, Swapan Mallick,
Sante Gnerre,
Nick Patterson,
Augustine Kong,
David Reich,
Kari Stefansson
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ABSTRACT: Mutations are the raw material of evolution but have been difficult to study directly. We report the largest study of new mutations to date, comprising 2,058 germline changes discovered by analyzing 85,289 Icelanders at 2,477 microsatellites. The paternal-to-maternal mutation rate ratio is 3.3, and the rate in fathers doubles from age 20 to 58, whereas there is no association with age in mothers. Longer microsatellite alleles are more mutagenic and tend to decrease in length, whereas the opposite is seen for shorter alleles. We use these empirical observations to build a model that we apply to individuals for whom we have both genome sequence and microsatellite data, allowing us to estimate key parameters of evolution without calibration to the fossil record. We infer that the sequence mutation rate is 1.4-2.3 × 10(-8) mutations per base pair per generation (90% credible interval) and that human-chimpanzee speciation occurred 3.7-6.6 million years ago.
Nature Genetics 08/2012; 44(10):1161-5. · 35.53 Impact Factor
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Gaurav Bhatia,
Nick Patterson,
Bogdan Pasaniuc,
Noah Zaitlen,
Giulio Genovese,
Samuela Pollack, Swapan Mallick,
Simon Myers,
Arti Tandon,
Chris Spencer, [......],
Steve McCarroll,
Pardis Sabeti,
Guillaume Lettre,
Phil De Jager,
Joel Hirschhorn,
Xiaofeng Zhu,
Richard Cooper,
David Reich,
James G Wilson,
Alkes L Price
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ABSTRACT: The study of recent natural selection in human populations has important applications to human history and medicine. Positive natural selection drives the increase in beneficial alleles and plays a role in explaining diversity across human populations. By discovering traits subject to positive selection, we can better understand the population level response to environmental pressures including infectious disease. Our study examines unusual population differentiation between three large data sets to detect natural selection. The populations examined, African Americans, Nigerians, and Gambians, are genetically close to one another (F(ST) < 0.01 for all pairs), allowing us to detect selection even with moderate changes in allele frequency. We also develop a tree-based method to pinpoint the population in which selection occurred, incorporating information across populations. Our genome-wide significant results corroborate loci previously reported to be under selection in Africans including HBB and CD36. At the HLA locus on chromosome 6, results suggest the existence of multiple, independent targets of population-specific selective pressure. In addition, we report a genome-wide significant (p = 1.36 × 10(-11)) signal of selection in the prostate stem cell antigen (PSCA) gene. The most significantly differentiated marker in our analysis, rs2920283, is highly differentiated in both Africa and East Asia and has prior genome-wide significant associations to bladder and gastric cancers.
The American Journal of Human Genetics 09/2011; 89(3):368-81. · 10.60 Impact Factor
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David Reich,
Richard E Green,
Martin Kircher,
Johannes Krause,
Nick Patterson,
Eric Y Durand,
Bence Viola,
Adrian W Briggs,
Udo Stenzel,
Philip L F Johnson, [......],
Evan E Eichler,
Mark Stoneking,
Michael Richards,
Sahra Talamo,
Michael V Shunkov,
Anatoli P Derevianko,
Jean-Jacques Hublin,
Janet Kelso,
Montgomery Slatkin,
Svante Pääbo
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ABSTRACT: Using DNA extracted from a finger bone found in Denisova Cave in southern Siberia, we have sequenced the genome of an archaic hominin to about 1.9-fold coverage. This individual is from a group that shares a common origin with Neanderthals. This population was not involved in the putative gene flow from Neanderthals into Eurasians; however, the data suggest that it contributed 4-6% of its genetic material to the genomes of present-day Melanesians. We designate this hominin population 'Denisovans' and suggest that it may have been widespread in Asia during the Late Pleistocene epoch. A tooth found in Denisova Cave carries a mitochondrial genome highly similar to that of the finger bone. This tooth shares no derived morphological features with Neanderthals or modern humans, further indicating that Denisovans have an evolutionary history distinct from Neanderthals and modern humans.
Nature 12/2010; 468(7327):1053-60. · 36.28 Impact Factor
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ABSTRACT: To elucidate the history of living and extinct elephantids, we generated 39,763 bp of aligned nuclear DNA sequence across 375 loci for African savanna elephant, African forest elephant, Asian elephant, the extinct American mastodon, and the woolly mammoth. Our data establish that the Asian elephant is the closest living relative of the extinct mammoth in the nuclear genome, extending previous findings from mitochondrial DNA analyses. We also find that savanna and forest elephants, which some have argued are the same species, are as or more divergent in the nuclear genome as mammoths and Asian elephants, which are considered to be distinct genera, thus resolving a long-standing debate about the appropriate taxonomic classification of the African elephants. Finally, we document a much larger effective population size in forest elephants compared with the other elephantid taxa, likely reflecting species differences in ancient geographic structure and range and differences in life history traits such as variance in male reproductive success.
PLoS Biology 01/2010; 8(12):e1000564. · 11.45 Impact Factor
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ABSTRACT: Several studies have found evidence for more positive selection on the chimpanzee lineage compared with the human lineage since the two species split. A potential concern, however, is that these findings may simply reflect artifacts of the data: inaccuracies in the underlying chimpanzee genome sequence, which is of lower quality than human. To test this hypothesis, we generated de novo genome assemblies of chimpanzee and macaque and aligned them with human. We also implemented a novel bioinformatic procedure for producing alignments of closely related species that uses synteny information to remove misassembled and misaligned regions, and sequence quality scores to remove nucleotides that are less reliable. We applied this procedure to re-examine 59 genes recently identified as candidates for positive selection in chimpanzees. The great majority of these signals disappear after application of our new bioinformatic procedure. We also carried out laboratory-based resequencing of 10 of the regions in multiple chimpanzees and humans, and found that our alignments were correct wherever there was a conflict with the published results. These findings throw into question previous findings that there has been more positive selection in chimpanzees than in humans since the two species diverged. Our study also highlights the challenges of searching the extreme tails of distributions for signals of natural selection. Inaccuracies in the genome sequence at even a tiny fraction of genes can produce false-positive signals, which make it difficult to identify loci that have genuinely been targets of selection.
Genome Research 06/2009; 19(5):922-33. · 13.61 Impact Factor
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ABSTRACT: Population geneticists often study small numbers of carefully chosen loci, but it has become possible to obtain orders of magnitude for more data from overlaps of genome sequences. Here, we generate tens of millions of base pairs of multiple sequence alignments from combinations of three western chimpanzees, three central chimpanzees, an eastern chimpanzee, a bonobo, a human, an orangutan, and a macaque. Analysis provides a more precise understanding of demographic history than was previously available. We show that bonobos and common chimpanzees were separated approximately 1,290,000 years ago, western and other common chimpanzees approximately 510,000 years ago, and eastern and central chimpanzees at least 50,000 years ago. We infer that the central chimpanzee population size increased by at least a factor of 4 since its separation from western chimpanzees, while the western chimpanzee effective population size decreased. Surprisingly, in about one percent of the genome, the genetic relationships between humans, chimpanzees, and bonobos appear to be different from the species relationships. We used PCR-based resequencing to confirm 11 regions where chimpanzees and bonobos are not most closely related. Study of such loci should provide information about the period of time 5-7 million years ago when the ancestors of humans separated from those of the chimpanzees.
PLoS Genetics 05/2008; 4(4):e1000057. · 8.69 Impact Factor
