Evolutionary genomics of human intellectual disability

Bernard Crespi,Steve Dorus,Kyle Summers

doi:10.1111/j.1752-4571.2009.00098.x

Bernard Crespi, Steve Dorus + Show 1 more

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https://doi.org/10.1111/j.1752-4571.2009.00098.x

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Abstract

Previous studies have postulated that X-linked and autosomal genes underlying human intellectual disability may have also mediated the evolution of human cognition. We have conducted the first comprehensive assessment of the extent and patterns of positive Darwinian selection on intellectual disability genes in humans. We report three main findings. First, as noted in some previous reports, intellectual disability genes with primary functions in the central nervous system exhibit a significant concentration to the X chromosome. Second, there was no evidence for a higher incidence of recent positive selection on X-linked than autosomal intellectual disability genes, nor was there a higher incidence of selection on such genes overall, compared to sets of control genes. However, the X-linked intellectual disability genes inferred to be subject to recent positive selection were concentrated in the Rho GTP-ase pathway, a key signaling pathway in neural development and function. Third, among all intellectual disability genes, there was evidence for a higher incidence of recent positive selection on genes involved in DNA repair, but not for genes involved in other functions. These results provide evidence that alterations to genes in the Rho GTP-ase and DNA-repair pathways may play especially-important roles in the evolution of human cognition and vulnerability to genetically-based intellectual disability.

Highlights

Human intellectual disability, formally defined as fullscale IQ of 70 and below (Kleefstra and Hamel 2005; Chelly et al 2006; Raymond 2006), is caused in many cases by rare, highly-penetrant loss-of-function mutations affecting a set of identified genes (Chiurazzi et al 2004; Inlow and Restifo 2004). Lehrke (1972, 1974) first suggested that such ‘mental retardation genes’, especially X-linked ones, might exhibit variants affecting ‘intelligence’ in nonclinical populations
A primary result of these tests is that there is no evidence for an enhanced signal of recent positive selection on intellectual disability genes considered as a whole, or for the subset of X-linked ones, despite the increased tendency of ascertained X-linked intellectual disability genes to exhibit functions in the central nervous system
Despite the apparent lack of enhanced signals of positive selection across all intellectual disability genes, two specific categories of intellectual disability genes, (i) X-linked genes in the Rho GTPase pathway (FGD1, FMR1, and OPHN1), and (ii) autosomal genes involved in DNA repair (FANCA, FANCC, NBS1, and XRCC8), show significantly increased frequencies of recent positive selection, from the HapMap analyses, compared to other categories

Summary

Introduction

Formally defined as fullscale IQ of 70 and below (Kleefstra and Hamel 2005; Chelly et al 2006; Raymond 2006), is caused in many cases by rare, highly-penetrant loss-of-function mutations affecting a set of identified genes (Chiurazzi et al 2004; Inlow and Restifo 2004). Lehrke (1972, 1974) first suggested that such ‘mental retardation genes’, especially X-linked ones, might exhibit variants affecting ‘intelligence’ (defined by clinicians in terms of IQ) in nonclinical populations. Lehrke (1972, 1974) first suggested that such ‘mental retardation genes’, especially X-linked ones, might exhibit variants affecting ‘intelligence’ (defined by clinicians in terms of IQ) in nonclinical populations This prediction was based on early studies showing an excess of males over females with intellectual disability, a wider distribution of IQ in males, and segregation patterns of intellectual disability within families, and it has since been reiterated by other authors as more evidence on the genetic bases of cognitive abilities and intellectual disability has become available (Turner and Partington 1991; Turner 1996; Lubs 1999; Neri and Opitz 2000; Spinath et al 2004; Ropers and Hamel 2005; Arden and Plomin 2006; Plomin et al 2006). The X chromosome a 2009 The Authors Journal compilation a 2009 Blackwell Publishing Ltd 3 (2010) 52–63

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