Analysis of genetic selection at insulin receptor substrate-2 gene loci.

Abstract

Type 2 diabetes mellitus (T2DM) is highly heritable and exhibits significant variability in prevalence between different populations. Prevalence of T2DM is higher in Asian and African relative to European populations. During evolution, traditional feast-famine cycles likely led to significant natural selection impacting metabolic genes. Human adaptation to environmental changes (food supply, lifestyle, climate, and geography) likely influenced differential selection of T2DM-associated genes. Together, insulin receptor substrate-1 and -2 (IRS1 and IRS2) genes encode the major ligands of insulin and IGF1 receptors. Irs2-deficient mice exhibit a T2DM phenotype with severe insulin resistance, and a common IRS2 polymorphism is associated with T2DM. Therefore, the present study sought evidence of natural selection at IRS2 loci. Data were sourced from the HapMap and 1000 Genomes projects, comprising four different populations with distinct ancestries: European, Yoruba, Han Chinese, and Japanese. A three-step method was applied to detect IRS2 locus selection. The long-range haplotype (LRH) test detected unusual extended haplotypes, the integrated haplotype score (iHS) detected selection, and Wright's F-statistics (particularly Wright's fixation index: FST) were calculated as a measure of population differentiation. The African population exhibited highly significant LRH findings (percentile >99.9, p = 0.005-0.0009), while both the European and African populations exhibited extreme positive iHS test scores ([iHS] >2.5). These findings indicate that genetic selection has occurred at the IRS2 locus, warranting further research into the adaptive evolution of metabolic disorder-associated genes. The online version contains supplementary material available at 10.1007/s40200-021-00745-y.