Assessing the role played by purifying selection on a susceptibility allele to late-onset disease (SALOD) is crucial to understanding the puzzling allelic spectrum of a disease, because most alleles are recent and rare. This fact is surprising because it suggests that alleles are under purifying selection while those that are involved in post-menopause mortality are often considered neutral in the genetic literature. The aim of this article is to use an evolutionary demography model to assess the magnitude of selection on SALODs while accounting for epidemiological and sociocultural factors. We develop an age-structured population model allowing for the calculation of SALOD selection coefficients (1) for a large and realistic parameter space for disease onset, (2) in a two-sex model in which men can reproduce in old age and (3) for situations in which child survival depends on maternal, paternal and grandmaternal care. The results show that SALODs are under purifying selection for most known age-at-onset distributions of late-onset genetic diseases. Estimates regarding various genes involved in susceptibility to cancer or Huntington’s disease demonstrate that negative selection largely overcomes the effects of drift in most human populations. This is also probably true for neurodegenerative or polycystic kidney diseases, although sociocultural factors modulate the effect of selection in these cases. We conclude that neutrality is probably the exception among alleles that have a deleterious effect in old age and that accounting for sociocultural factors is required to understand the full extent of the force of selection shaping senescence in humans.

评估纯化选择对迟发性疾病 (SALOD) 易感性等位基因所起的作用对于理解疾病令人费解的等位基因谱至关重要，因为大多数等位基因是最近出现的且罕见。这一事实令人惊讶，因为它表明等位基因处于纯化选择之下，而那些与绝经后死亡率有关的基因在遗传文献中通常被认为是中性的。本文的目的是在考虑流行病学和社会文化因素的同时，使用进化人口统计学模型评估 SALOD 的选择程度。我们开发了一个年龄结构的人口模型，允许计算 SALOD 选择系数 (1) 用于疾病发作的大而现实的参数空间，(2) 在男性可以在老年生育的双性模式中，以及 (3) 在儿童生存依赖于母亲、父亲和祖母照顾的情况下。结果表明，SALOD 正在针对大多数已知的迟发性遗传病的发病年龄分布进行纯化选择。对与癌症或亨廷顿氏病易感性有关的各种基因的估计表明，负选择在很大程度上克服了大多数人群中漂移的影响。这也可能适用于神经退行性或多囊肾病，尽管社会文化因素会调节这些病例中选择的影响。