The role of mutation rate variation and genetic diversity in the architecture of human disease

TL;DR

This study investigates how mutation rate variation and genetic diversity influence whether genes are involved in human disease, finding that these factors play a minor role in disease association.

Contribution

The paper provides empirical evidence that mutation rate and genetic diversity have limited impact on disease gene involvement, challenging previous assumptions.

Findings

Disease genes are longer than non-disease genes.

Disease genes are located in regions with low mutation rates.

Genetic diversity is higher in disease genes, even after controlling for mutation rate.

Abstract

We have investigated the role that the mutation rate and the structure of genetic variation at a locus play in determining whether a gene is involved in disease. We predict that the mutation rate and its genetic diversity should be higher in genes associated with disease, unless all genes that could cause disease have already been identified. Consistent with our predictions we find that genes associated with Mendelian and complex disease are substantially longer than non-disease genes. However, we find that both Mendelian and complex disease genes are found in regions of the genome with relatively low mutation rates, as inferred from intron divergence between humans and chimpanzees. Complex disease gene are predicted to have higher rates of non-synonymous mutation than non-disease genes, but the opposite pattern is found in Mendelian disease genes. Finally, we find that disease genes are in regions of significantly elevated genetic diversity, even when variation in the rate of mutation is controlled for. The effect is small nevertheless. Our results suggest that variation in the genic mutation rate and the genetic architecture of the locus play a minor role in determining whether a gene is associated with disease.