Distance from sub-Saharan Africa predicts mutational load in diverse human genomes

Abstract

The Out-of-Africa (OOA) dispersal ∼50,000 y ago is characterized by a series of founder events as modern humans expanded into multiple continents. Population genetics theory predicts an increase of mutational load in populations undergoing serial founder effects during range expansions. To test this hypothesis, we have sequenced full genomes and high-coverage exomes from seven geographically divergent human populations from Namibia, Congo, Algeria, Pakistan, Cambodia, Siberia, and Mexico. We find that individual genomes vary modestly in the overall number of predicted deleterious alleles. We show via spatially explicit simulations that the observed distribution of deleterious allele frequencies is consistent with the OOA dispersal, particularly under a model where deleterious mutations are recessive. We conclude that there is a strong signal of purifying selection at conserved genomic positions within Africa, but that many predicted deleterious mutations have evolved as if they were neutral during the expansion out of Africa. Under a model where selection is inversely related to dominance, we show that OOA populations are likely to have a higher mutation load due to increased allele frequencies of nearly neutral variants that are recessive or partially recessive. mutation | founder effect | range expansion | expansion load | purifying selection

Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum

“…The number and frequency of rare variants differs across populations, reflecting the degree of selection compounded by recent demography, including bottlenecks, split times, and migration between populations 8 . The ratio of deleterious to neutral alleles per individual increases as humans migrated out of Africa, consistent with negative selection against deleterious variants and serial founder effects that reduce the effective population size 9 . Conditional on a variant being ultra-rare, we observe a higher ratio of PTV to synonymous variants ( Figure 1b); recently arisen ultra-rare variants have had less time to be purged by negative selection, which is further magnified in populations that have undergone a recent bottleneck.…”

An Unexpectedly Complex Architecture for Skin Pigmentation in Africans

“…We mitigated technical artifacts from individuals genotyped on different arrays by subsetting haplotypes to variants genotyped only the array, resulting in four sets of haplotypes. We then imputed variants in 5 Mb windows for all 4 sets using the full 1000 Genomes phase 3 reference panel as well as 53 HGDP medium coverage genomes (Henn et al, 2016) with Impute2 (v2.2.2) for all runs. After imputing each array separately, we aggregated the data across windows and runs, including only sites that were imputed with an Impute2 info metric ≥ 0.8 across all sets and subset to sites with MAF ≥ 0.01.…”

The impact of recent population history on the deleterious mutation load in humans and close evolutionary relatives

“…3). In the two exceptions of which we are aware, one study performed no statistical test of significance [40] and the other used a test that we believe does not fully account for uncertainty [36] (see Box 1). Of course, other factors could potentially affect this summary (recessivity of deleterious mutations is considered below).…”