Population Genetics of Rare Variants and Complex Diseases

TL;DR

This paper explores how natural selection and demographic history influence genetic variation in human populations, revealing that deleterious variants often persist at low frequencies and may contribute to complex diseases.

Contribution

It provides a comprehensive analysis of natural selection signatures in complex disease genes and uses simulations to understand the age and frequency of deleterious variants in human populations.

Findings

Genes linked to complex diseases show stronger purifying selection signatures.

Deleterious variants can persist at low frequencies due to population bottlenecks and growth.

Many rare alleles are young and potentially contribute to disease susceptibility.

Abstract

Identifying drivers of complex traits from the noisy signals of genetic variation obtained from high throughput genome sequencing technologies is a central challenge faced by human geneticists today. We hypothesize that the variants involved in complex diseases are likely to exhibit non-neutral evolutionary signatures. Uncovering the evolutionary history of all variants is therefore of intrinsic interest for complex disease research. However, doing so necessitates the simultaneous elucidation of the targets of natural selection and population-specific demographic history. Here we characterize the action of natural selection operating across complex disease categories, and use population genetic simulations to evaluate the expected patterns of genetic variation in large samples. We focus on populations that have experienced historical bottlenecks followed by explosive growth (consistent with most human populations), and describe the differences between evolutionarily deleterious mutations and those that are neutral. Genes associated with several complex disease categories exhibit stronger signatures of purifying selection than non-disease genes. In addition, loci identified through genome-wide association studies of complex traits also exhibit signatures consistent with being in regions recurrently targeted by purifying selection. Through simulations, we show that population bottlenecks and rapid growth enables deleterious rare variants to persist at low frequencies just as long as neutral variants, but low frequency and common variants tend to be much younger than neutral variants. This has resulted in a large proportion of modern-day rare alleles that have a deleterious effect on function, and that potentially contribute to disease susceptibility.