Biology subjects

David Reich

Publications and source records attributed to David Reich.

11 recordsLinked to original sources

bioRxiv2016

No evidence for unknown archaic ancestry in South Asia

Genomic studies have documented a contribution of archaic Neanderthals and Denisovans to non-Africans1,2. Recently Mondal et al.3 published a major dataset--the largest whole genome sequencing study of diverse South Asians to date--including 60 mainland groups and 10 indigenous Andamanese. They reported analyses claiming that nearly all South Asians harbor ancestry from an unknown archaic human population that is neither Neanderthal nor Denisovan. However, the statistics cited in support of this conclusion do not replicate in other data sets, and in fact contradict the conclusion.\n\nThe main evidence cited by Mondal et al. is statistics suggesting that indigenous Andamanese and mainland Indian groups share fewer alleles with sub-Saharan Africans than they do with Europeans and East Asians; such statistics have previously been reported in Australasians, for whom they represent key evide ...

Genomics↗

bioRxiv2016

A genomic view of the peopling of the Americas

Whole-genome studies have documented that most Native American ancestry stems from a single population that diversified within the continent more than twelve thousand years ago. However, this shared ancestry hides a more complex history whereby at least four distinct streams of Eurasian migration have contributed to present-day and prehistoric Native American populations. Whole genome studies enhanced by technological breakthroughs in ancient DNA now provide evidence of a sequence of events involving initial migration from a structured Northeast Asian source population, followed by a divergence into northern and southern Native American lineages. During the Holocene, new migrations from Asia introduced the Saqqaq/Dorset Paleoeskimo population to the North American Arctic ~4,500 years ago, ancestry that is potentially connected with ancestry found in Athabaskan-speakers today. This was then followed by a major new population turnover in the high Arctic involving Thule-related peoples who are the ancestors of present-day Inuit. We highlight several open questions that could be addressed through future genomic research.

Evolutionary Biology↗

bioRxiv2016

The promise of disease gene discovery in South Asia

The more than 1.5 billion people who live in South Asia are correctly viewed not as a single large population, but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identify 81 unique groups, of which 14 have estimated census sizes of more than a million, that descend from founder events more extreme than those in Ashkenazi Jews and Finns, both of which have high rates of recessive disease due to founder events. We identify multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an under-appreciated opportunity for reducing disease burden among South Asians through the discovery of and testing for recessive disease genes.

Evolutionary Biology↗

bioRxiv2015

The contribution of rare variation to prostate cancer heritability

Although genome-wide association studies (GWAS) have found more than a hundred common susceptibility alleles for prostate cancer, the GWAS reported variants jointly explain only 33% of risk to siblings, leaving the majority of the familial risk unexplained. We use targeted sequencing of 63 known GWAS risk regions in 9,237 men from four ancestries (African, Latino, Japanese, and European) to explore the role of low-frequency variation in risk for prostate cancer. We find that the sequenced variants explain significantly more of the variance in the trait than the known GWAS variants, thus showing that part of the missing familial risk lies in poorly tagged causal variants at known risk regions. We report evidence for genetic heterogeneity in SNP effect sizes across different ancestries. We also partition heritability by minor allele frequency (MAF) spectrum using variance components methods, and find that a large fraction of heritability (0.12, s.e. 0.05; 95% CI [0.03, 0.21]) is explained by rare variants (MAF<0.01) in men of African ancestry. We use the heritability attributable to rare variants to estimate the coupling between selection and allelic effects at 0.48 (95% CI of [0.19, 0.78]) under the Eyre-Walker model. These results imply that natural selection has driven down the frequency of many prostate cancer risk alleles over evolutionary history. Overall our results show that a substantial fraction of the risk for prostate cancer in men of African ancestry lies in rare variants at known risk loci and suggests that rare variants make a significant contribution to heritability of common traits.

Genetics↗

bioRxiv2015

Calibrating the Human Mutation Rate via Ancestral Recombination Density in Diploid Genomes

The human mutation rate is an essential parameter for studying the evolution of our species, interpreting present-day genetic variation, and understanding the incidence of genetic disease. Nevertheless, our current estimates of the rate are uncertain. Most notably, recent approaches based on counting de novo mutations in family pedigrees have yielded significantly smaller values than classical methods based on sequence divergence. Here, we propose a new method that uses the fine-scale human recombination map to calibrate the rate of accumulation of mutations. By comparing local heterozygosity levels in diploid genomes to the genetic distance scale over which these levels change, we are able to estimate a long-term mutation rate averaged over hundreds or thousands of generations. We infer a rate of 1.61 {+/-} 0.13 x 10-8 mutations per base per generation, which falls in between phylogenetic and pedigree-based estimates, and we suggest possible mechanisms to reconcile our estimate with previous studies. Our results support intermediate-age divergences among human populations and between humans and other great apes.

Genetics↗

bioRxiv2014

The genetic ancestry of African, Latino, and European Americans across the United States.

Over the past 500 years, North America has been the site of ongoing mixing of Native Americans, European settlers, and Africans brought largely by the Trans-Atlantic slave trade, shaping the early history of what became the United States. We studied the genetic ancestry of 5,269 self-described African Americans, 8,663 Latinos, and 148,789 European Americans who are 23andMe customers and show that the legacy of these historical interactions is visible in the genetic ancestry of present-day Americans. We document pervasive mixed ancestry and asymmetrical male and female ancestry contributions in all groups studied. We show that regional ancestry differences reflect historical events, such as early Spanish colonization, waves of immigration from many regions of Europe, and forced relocation of Native Americans within the US. This study sheds light on the fine-scale differences in ancestry within and across the United States, and informs our understanding of the relationship between racial and ethnic identities and genetic ancestry.

Genetics↗

bioRxiv2014

Non-crossover gene conversions show strong GC bias and unexpected clustering in humans

Although the past decade has seen tremendous progress in our understanding of fine-scale recombination, little is known about non-crossover (NCO) gene conversion. We report the first genome-wide study of NCO events in humans. Using SNP array data from 98 meioses, we identified 103 sites affected by NCO, of which 50/52 were confirmed in sequence data. Overlap with double strand break (DSB) hotspots indicates that the events are likely of meiotic origin. We estimate that a site is involved in a NCO at a rate of 5.7x10-6/bp/generation, consistent with sperm-typing studies, and infer that tract lengths span at least an order of magnitude. Observed NCO events show strong allelic bias at heterozygous AT/GC SNPs, with 68% (58-78%) transmitting GC alleles (P=5x10-4). Strikingly, in 4 of 15 regions for which there are also resequencing data, multiple disjoint NCO tracts cluster in close proximity (~20-30 kb), a phenomenon not previously seen in mammals.

Genetics↗

bioRxiv2014

Reconstructing Austronesian population history in Island Southeast Asia

Austronesian languages are spread across half the globe, from Easter Island to Madagascar. Evidence from linguistics and archaeology indicates that the \"Austronesian expansion,\" which began 4-5 thousand years ago, likely had roots in Taiwan, but the ancestry of present-day Austronesian-speaking populations remains controversial. Here, focusing primarily on Island Southeast Asia, we analyze genome-wide data from 56 populations using new methods for tracing ancestral gene flow. We show that all sampled Austronesian groups harbor ancestry that is more closely related to aboriginal Taiwanese than to any present-day mainland population. Surprisingly, western Island Southeast Asian populations have also inherited ancestry from a source nested within the variation of present-day populations speaking Austro-Asiatic languages, which have historically been nearly exclusive to the mainland. Thus, either there was once a substantial Austro-Asiatic presence in Island Southeast Asia, or Austronesian speakers migrated to and through the mainland, admixing there before continuing to western Indonesia.

Genetics↗

bioRxiv2014

Response to a population bottleneck can be used to infer recessive selection

Here we present the first genome wide statistical test for recessive selection. This test uses explicitly non-equilibrium demographic differences between populations to infer the mode of selection. By analyzing the transient response to a population bottleneck and subsequent re-expansion, we qualitatively distinguish between alleles under additive and recessive selection. We analyze the response of the average number of deleterious mutations per haploid individual and describe time dependence of this quantity. We introduce a statistic, BR, to compare the number of mutations in different populations and detail its functional dependence on the strength of selection and the intensity of the population bottleneck. This test can be used to detect the predominant mode of selection on the genome wide or regional level, as well as among a sufficiently large set of medically or functionally relevant alleles.

Evolutionary Biology↗

bioRxiv2014

Towards a new history and geography of human genes informed by ancient DNA

Genetic information contains a record of the history of our species, and technological advances have transformed our ability to access this record. Many studies have used genome-wide data from populations today to learn about the peopling of the globe and subsequent adaptation to local conditions. Implicit in this research is the assumption that the geographic locations of people today are informative about the geographic locations of their ancestors in the distant past. However, it is now clear that long-range migration, admixture and population replacement have been the rule rather than the exception in human history. In light of this, we argue that it is time to critically re-evaluate current views of the peopling of the globe and the importance of natural selection in determining the geographic distribution of phenotypes. We specifically highlight the transformative potential of ancient DNA. By accessing the genetic make-up of populations living at archaeologically-known times and places, ancient DNA makes it possible to directly track migrations and responses to natural selection.

Evolutionary Biology↗

bioRxiv2014

No evidence that natural selection has been less effective at removing deleterious mutations in Europeans than in West Africans

Non-African populations have experienced major bottlenecks in the time since their split from West Africans, which has led to the hypothesis that natural selection to remove weakly deleterious mutations may have been less effective in non-Africans. To directly test this hypothesis, we measure the per-genome accumulation of deleterious mutations across diverse humans. We fail to detect any significant differences, but find that archaic Denisovans accumulated non-synonymous mutations at a higher rate than modern humans, consistent with the longer separation time of modern and archaic humans. We also revisit the empirical patterns that have been interpreted as evidence for less effective removal of deleterious mutations in non-Africans than in West Africans, and show they are not driven by differences in selection after population separation, but by neutral evolution.

Evolutionary Biology↗