Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.
Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland.
Genome Res. 2018 Jan;28(1):1-10. doi: 10.1101/gr.228411.117. Epub 2017 Dec 13.
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会自然流产。然而，尽管受到强烈的遗传损伤，一些非整倍体个体仍能存活下来。在这里，我们研究了非整倍体胎儿的存活概率是否受到全基因组轻度有害变异负担的影响。我们分析了两组活产唐氏综合征个体（388 个基因分型样本和 16 个成纤维细胞转录组），并观察到 21 号染色体上轻度有害变异的缺失和高度受限基因表达水平的全转录组变异减少。我们将这些结果解释为胚胎选择的特征，并提出了一种遗传障碍模型，即如果全基因组轻度有害变异负担足够低，携带极其严重有害变异（如非整倍体）的个体可能会逃避胚胎致死性。这种方法可用于研究人类和模式生物中大量轻度有害变异的组成和影响。
