The deleterious mutation load is insensitive to recent population history

TL;DR

This study shows that recent human population changes have had minimal impact on the average burden of deleterious mutations and the contribution of rare variants to complex traits, despite significant demographic shifts.

Contribution

The paper provides a population genetic model and empirical evidence demonstrating that recent demographic events have little effect on genetic load and the role of rare variants in complex traits.

Findings

Recent demographic history has little impact on genetic load.

African American and European American individuals carry similar burdens of damaging mutations.

Rare variants contribute modestly to genetic variance in most complex traits.

Abstract

Human populations have undergone dramatic changes in population size in the past 100,000 years, including a severe bottleneck of non-African populations and recent explosive population growth. There is currently great interest in how these demographic events may have affected the burden of deleterious mutations in individuals and the allele frequency spectrum of disease mutations in populations. Here we use population genetic models to show that--contrary to previous conjectures--recent human demography has likely had very little impact on the average burden of deleterious mutations carried by individuals. This prediction is supported by exome sequence data showing that African American and European American individuals carry very similar burdens of damaging mutations. We next consider whether recent population growth has increased the importance of very rare mutations in complex traits. Our analysis predicts that for most classes of disease variants, rare alleles are unlikely to contribute a large fraction of the total genetic variance, and that the impact of recent growth is likely to be modest. However, for diseases that have a direct impact on fitness, strongly deleterious rare mutations likely do play important roles, and the impact of very rare mutations will be far greater as a result of recent growth. In summary, demographic history has dramatically impacted patterns of variation in different human populations, but these changes have likely had little impact on either genetic load or on the importance of rare variants for most complex traits.