Joseph Lachance

Evolutionary history and adaptation from high-coverage whole-genome sequences of diverse African hunter-gatherers

To reconstruct modern human evolutionary history and identify loci that have shaped hunter-gatherer adaptation, we sequenced the whole genomes of five individuals in each of three different hunter-gatherer populations at > 60× coverage: Pygmies from Cameroon and Khoesan-speaking Hadza and Sandawe from Tanzania. We identify 13.4 million variants, substantially increasing the set of known human variation. We found evidence of archaic introgression in all three populations, and the distribution of time to most recent common ancestors from these regions is similar to that observed for introgressed regions in Europeans. Additionally, we identify numerous loci that harbor signatures of local adaptation, including genes involved in immunity, metabolism, olfactory and taste perception, reproduction, and wound healing. Within the Pygmy population, we identify multiple highly differentiated loci that play a role in growth and anterior pituitary function and are associated with height.

The genetic prehistory of southern Africa

Southern and eastern African populations that speak non-Bantu languages with click consonants are known to harbour some of the most ancient genetic lineages in humans, but their relationships are poorly understood. Here, we report data from 23 populations analysed at over half a million single-nucleotide polymorphisms, using a genome-wide array designed for studying human history. The southern African Khoisan fall into two genetic groups, loosely corresponding to the northwestern and southeastern Kalahari, which we show separated within the last 30,000 years. We find that all individuals derive at least a few percent of their genomes from admixture with non-Khoisan populations that began ∼1,200 years ago. In addition, the East African Hadza and Sandawe derive a fraction of their ancestry from admixture with a population related to the Khoisan, supporting the hypothesis of an ancient link between southern and eastern Africa.

A recent bottleneck of Y chromosome diversity coincides with a global change in culture

It is commonly thought that human genetic diversity in non-African populations was shaped primarily by an out-of-Africa dispersal 50-100 thousand yr ago (kya). Here, we present a study of 456 geographically diverse high-coverage Y chromosome sequences, including 299 newly reported samples. Applying ancient DNA calibration, we date the Y-chromosomal most recent common ancestor (MRCA) in Africa at 254 (95% CI 192-307) kya and detect a cluster of major non-African founder haplogroups in a narrow time interval at 47-52 kya, consistent with a rapid initial colonization model of Eurasia and Oceania after the out-of-Africa bottleneck. In contrast to demographic reconstructions based on mtDNA, we infer a second strong bottleneck in Y-chromosome lineages dating to the last 10 ky. We hypothesize that this bottleneck is caused by cultural changes affecting variance of reproductive success among males.

SNP ascertainment bias in population genetic analyses: Why it is important, and how to correct it

Whole genome sequencing and SNP genotyping arrays can paint strikingly different pictures of demographic history and natural selection. This is because genotyping arrays contain biased sets of pre‐ascertained SNPs. In this short review, we use comparisons between high‐coverage whole genome sequences of African hunter‐gatherers and data from genotyping arrays to highlight how SNP ascertainment bias distorts population genetic inferences. Sample sizes and the populations in which SNPs are discovered affect the characteristics of observed variants. We find that SNPs on genotyping arrays tend to be older and present in multiple populations. In addition, genotyping arrays cause allele frequency distributions to be shifted towards intermediate frequency alleles, and estimates of linkage disequilibrium are modified. Since population genetic analyses depend on allele frequencies, it is imperative that researchers are aware of the effects of SNP ascertainment bias. With this in mind, we describe multiple ways to correct for SNP ascertainment bias.

Genomic analyses inform on migration events during the peopling of Eurasia

High-coverage whole-genome sequence studies have so far focused on a limited number of geographically restricted populations, or been targeted at specific diseases, such as cancer. Nevertheless, the availability of high-resolution genomic data has led to the development of new methodologies for inferring population history and refuelled the debate on the mutation rate in humans. Here we present the Estonian Biocentre Human Genome Diversity Panel (EGDP), a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations, which we group into diversity and selection sets. We analyse this dataset to refine estimates of continent-wide patterns of heterozygosity, long- and short-distance gene flow, archaic admixture, and changes in effective population size through time as well as for signals of positive or balancing selection. We find a genetic signature in present-day Papuans that suggests that at least 2% of their genome originates from an early and largely extinct expansion of anatomically modern humans (AMHs) out of Africa. Together with evidence from the western Asian fossil record, and admixture between AMHs and Neanderthals predating the main Eurasian expansion, our results contribute to the mounting evidence for the presence of AMHs out of Africa earlier than 75,000 years ago.

The genetics of sex chromosomes: evolution and implications for hybrid incompatibility.

Heteromorphic sex chromosomes, where one sex has two different types of sex chromosomes, face very different evolutionary consequences than do autosomes. Two important features of sex chromosomes arise from being present in only one copy in one of the sexes: dosage compensation and the meiotic silencing of sex chromosomes. Other differences arise because sex chromosomes spend unequal amounts of time in each sex. Thus, the impact of evolutionary processes (mutation, selection, genetic drift, and meiotic drive) differs substantially between each sex chromosome, and between the sex chromosomes and the autosomes. Sex chromosomes also play a disproportionate role in Haldanes rule and other important patterns related to hybrid incompatibility, and thus speciation. We review the consequences of sex chromosomes on hybrid incompatibility. A theme running through this review is that epigenetic processes, notably those related to chromatin, may be more important to the evolution of sex chromosomes and the evolution of hybrid incompatibility than previously recognized.

Model-based analyses of whole-genome data reveal a complex evolutionary history involving archaic introgression in Central African Pygmies.

Comparisons of whole-genome sequences from ancient and contemporary samples have pointed to several instances of archaic admixture through interbreeding between the ancestors of modern non-Africans and now extinct hominids such as Neanderthals and Denisovans. One implication of these findings is that some adaptive features in contemporary humans may have entered the population via gene flow with archaic forms in Eurasia. Within Africa, fossil evidence suggests that anatomically modern humans (AMH) and various archaic forms coexisted for much of the last 200,000 yr; however, the absence of ancient DNA in Africa has limited our ability to make a direct comparison between archaic and modern human genomes. Here, we use statistical inference based on high coverage whole-genome data (greater than 60×) from contemporary African Pygmy hunter-gatherers as an alternative means to study the evolutionary history of the genus Homo. Using whole-genome simulations that consider demographic histories that include both isolation and gene flow with neighboring farming populations, our inference method rejects the hypothesis that the ancestors of AMH were genetically isolated in Africa, thus providing the first whole genome-level evidence of African archaic admixture. Our inferences also suggest a complex human evolutionary history in Africa, which involves at least a single admixture event from an unknown archaic population into the ancestors of AMH, likely within the last 30,000 yr.

Biased Gene Conversion Skews Allele Frequencies in Human Populations, Increasing the Disease Burden of Recessive Alleles

Gene conversion results in the nonreciprocal transfer of genetic information between two recombining sequences, and there is evidence that this process is biased toward G and C alleles. However, the strength of GC-biased gene conversion (gBGC) in human populations and its effects on hereditary disease have yet to be assessed on a genomic scale. Using high-coverage whole-genome sequences of African hunter-gatherers, agricultural populations, and primate outgroups, we quantified the effects of GC-biased gene conversion on population genomic data sets. We find that genetic distances (FST and population branch statistics) are modified by gBGC. In addition, the site frequency spectrum is left-shifted when ancestral alleles are favored by gBGC and right-shifted when derived alleles are favored by gBGC. Allele frequency shifts due to gBGC mimic the effects of natural selection. As expected, these effects are strongest in high-recombination regions of the human genome. By comparing the relative rates of fixation of unbiased and biased sites, the strength of gene conversion was estimated to be on the order of Nb ≈ 0.05 to 0.09. We also find that derived alleles favored by gBGC are much more likely to be homozygous than derived alleles at unbiased SNPs (+42.2% to 62.8%). This results in a curse of the converted, whereby gBGC causes substantial increases in hereditary disease risks. Taken together, our findings reveal that GC-biased gene conversion has important population genetic and public health implications.

Long-Term Adaptation of Epistatic Genetic Networks

Abstract Gene networks are likely to govern most traits in nature. Mutations at these genes often show functional epistatic interactions that lead to complex genetic architectures and variable fitness effects in different genetic backgrounds. Understanding how epistatic genetic systems evolve in nature remains one of the great challenges in evolutionary biology. Here we combine an analytical framework with individual-based simulations to generate novel predictions about long-term adaptation of epistatic networks. We find that relative to traits governed by independently evolving genes, adaptation with epistatic gene networks is often characterized by longer waiting times to selective sweeps, lower standing genetic variation, and larger fitness effects of adaptive mutations. This may cause epistatic networks to either adapt more slowly or more quickly relative to a nonepistatic system. Interestingly, epistatic networks may adapt faster even when epistatic effects of mutations are on average deleterious. Further, we study the evolution of epistatic properties of adaptive mutations in gene networks. Our results show that adaptive mutations with small fitness effects typically evolve positive synergistic interactions, whereas adaptive mutations with large fitness effects evolve positive synergistic and negative antagonistic interactions at approximately equal frequencies. These results provide testable predictions for adaptation of traits governed by epistatic networks and the evolution of epistasis within networks.

Apparent Variation in Neanderthal Admixture among African Populations is Consistent with Gene Flow from non-African Populations

Recent studies have found evidence of introgression from Neanderthals into modern humans outside of sub-Saharan Africa. Given the geographic range of Neanderthals, the findings have been interpreted as evidence of gene exchange between Neanderthals and modern humans descended from the Out-of-Africa (OOA) migration. Here, we examine an alternative interpretation in which the introgression occurred earlier within Africa, between ancestors or relatives of Neanderthals and a subset of African modern humans who were the ancestors of those involved in the OOA migration. Under the alternative model, if the population structure among present-day Africans predates the OOA migration, we might find some African populations show a signal of Neanderthal introgression whereas others do not. To test this alternative model, we compiled a whole-genome data set including 38 sub-Saharan Africans from eight populations and 25 non-African individuals from five populations. We assessed differences in the amount of Neanderthal-like single-nucleotide polymorphism alleles among these populations and observed up to 1.5% difference in the number of Neanderthal-like alleles among African populations. Further analyses suggest that these differences are likely due to recent non-African admixture in these populations. After accounting for recent non-African admixture, our results do not support the alternative model of older (e.g., >100 kya) admixture between modern humans and Neanderthal-like hominids within Africa.