Androgen receptor polyglutamine repeat number: models of selection and disease susceptibility

Evolutionary Applications

Calen P. Ryan¹ 

[1] Department of Biological Sciences, Simon Fraser University, Burnaby, BC, Canada

关键词: androgens;    balancing selection;    cancer;    disease susceptibility;    infertility;    sexual conflict;    tandem‐repeat accumulation;   

DOI  :  10.1111/j.1752-4571.2012.00275.x

来源: Wiley

【 摘 要 】

Abstract

Variation in polyglutamine repeat number in the androgen receptor (AR CAGn) is negatively correlated with the transcription of androgen-responsive genes and is associated with susceptibility to an extensive list of human disease. Only a small portion of the heritability for many of these diseases is explained by conventional SNP-based genome-wide association studies, and the forces shaping AR CAGn among humans remains largely unexplored. Here, we propose evolutionary models for understanding selection at the AR CAG locus, namely balancing selection, sexual conflict, accumulation-selection, and antagonistic pleiotropy. We evaluate these models by examining AR CAGn-linked susceptibility to eight extensively studied diseases representing the diverse physiological roles of androgens, and consider the costs of these diseases by their frequency and fitness effects. Five diseases could contribute to the distribution of AR CAGn observed among contemporary human populations. With support for disease susceptibilities associated with long and short AR CAGn, balancing selection provides a useful model for studying selection at this locus. Gender-specific differences AR CAGn health effects also support this locus as a candidate for sexual conflict over repeat number. Accompanied by the accumulation of AR CAGn in humans, these models help explain the distribution of repeat number in contemporary human populations.

【 授权许可】

CC BY-NC   
© 2012 The Authors. Evolutionary Applications published by Blackwell Publishing Ltd.

Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.