The majority of aneuploid fetuses are spontaneously miscarried. Nevertheless, some aneuploid individuals survive despite the strong genetic insult. Here, we investigate if the survival probability of aneuploid fetuses is affected by the genome-wide burden of slightly deleterious variants. We analyzed two cohorts of live-born Down syndrome individuals (388 genotyped samples and 16 fibroblast transcriptomes) and observed a deficit of slightly deleterious variants on Chromosome 21 and decreased transcriptome-wide variation in the expression level of highly constrained genes. We interpret these results as signatures of embryonic selection, and propose a genetic handicap model whereby an individual bearing an extremely severe deleterious variant (such as aneuploidy) could escape embryonic lethality if the genome-wide burden of slightly deleterious variants is sufficiently low. This approach can be used to study the composition and effect of the numerous slightly deleterious variants in humans and model organisms.

大多数非整倍体胎儿是自然流产的。然而，尽管受到强烈的遗传损伤，一些非整倍体个体仍然存活。在这里，我们调查非整倍体胎儿的存活概率是否受到轻微有害变异的全基因组负担的影响。我们分析了两组活出生的唐氏综合症个体（388 个基因分型样本和 16 个成纤维细胞转录组），并观察到 ​​21 号染色体上轻微有害的变体缺乏，并且高度受限基因表达水平的转录组范围内的变异降低。我们将这些结果解释为胚胎选择的特征，并提出一个遗传障碍模型，如果轻微有害变体的全基因组负担足够低，则携带极其严重的有害变异（例如非整倍体）的个体可以逃脱胚胎致死率。这种方法可用于研究人类和模式生物中众多轻微有害变体的组成和影响。