Keller Matthew C, Miller Geoffrey
Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23219.
Behav Brain Sci. 2006 Aug;29(4):385-404; discussion 405-52. doi: 10.1017/S0140525X06009095.
Given that natural selection is so powerful at optimizing complex adaptations, why does it seem unable to eliminate genes (susceptibility alleles) that predispose to common, harmful, heritable mental disorders, such as schizophrenia or bipolar disorder? We assess three leading explanations for this apparent paradox from evolutionary genetic theory: (1) ancestral neutrality (susceptibility alleles were not harmful among ancestors), (2) balancing selection (susceptibility alleles sometimes increased fitness), and (3) polygenic mutation-selection balance (mental disorders reflect the inevitable mutational load on the thousands of genes underlying human behavior). The first two explanations are commonly assumed in psychiatric genetics and Darwinian psychiatry, while mutation-selection has often been discounted. All three models can explain persistent genetic variance in some traits under some conditions, but the first two have serious problems in explaining human mental disorders. Ancestral neutrality fails to explain low mental disorder frequencies and requires implausibly small selection coefficients against mental disorders given the data on the reproductive costs and impairment of mental disorders. Balancing selection (including spatio-temporal variation in selection, heterozygote advantage, antagonistic pleiotropy, and frequency-dependent selection) tends to favor environmentally contingent adaptations (which would show no heritability) or high-frequency alleles (which psychiatric genetics would have already found). Only polygenic mutation-selection balance seems consistent with the data on mental disorder prevalence rates, fitness costs, the likely rarity of susceptibility alleles, and the increased risks of mental disorders with brain trauma, inbreeding, and paternal age. This evolutionary genetic framework for mental disorders has wide-ranging implications for psychology, psychiatry, behavior genetics, molecular genetics, and evolutionary approaches to studying human behavior.
鉴于自然选择在优化复杂适应性方面如此强大，为什么它似乎无法消除那些易导致常见、有害且具有遗传性的精神障碍（如精神分裂症或双相情感障碍）的基因（易感性等位基因）呢？我们从进化遗传学理论评估了对这一明显悖论的三种主要解释：（1）祖先中性（易感性等位基因在祖先中并无危害），（2）平衡选择（易感性等位基因有时会提高适应性），以及（3）多基因突变 - 选择平衡（精神障碍反映了人类行为所涉及的数千个基因不可避免的突变负荷）。前两种解释在精神遗传学和达尔文精神病学中通常被假定，而突变 - 选择常常被忽视。所有这三种模型在某些条件下都能解释某些性状中持续存在的遗传变异，但前两种在解释人类精神障碍方面存在严重问题。祖先中性无法解释精神障碍的低发病率，并且鉴于精神障碍的生殖成本和损害的数据，需要难以置信的小选择系数来对抗精神障碍。平衡选择（包括选择的时空变化、杂合子优势、拮抗性多效性和频率依赖性选择）倾向于有利于环境依赖性适应（这将不显示遗传性）或高频等位基因（精神遗传学应该已经发现了）。只有多基因突变 - 选择平衡似乎与精神障碍患病率、适应性成本、易感性等位基因可能的稀有性以及脑外伤、近亲繁殖和父亲年龄导致精神障碍风险增加的数据一致。这种精神障碍的进化遗传框架对心理学、精神病学、行为遗传学、分子遗传学以及研究人类行为的进化方法具有广泛的影响。
