Slightly deleterious genomic variants and transcriptome perturbations in Down syndrome embryonic selection

Area of Science:

• Genetics
• Developmental Biology
• Human Evolution

Background:

• Aneuploidy, such as in Down syndrome, often leads to miscarriage.
• However, some aneuploid individuals survive, indicating complex regulatory mechanisms.
• The role of genome-wide variant burden in aneuploid survival is not well understood.

Purpose of the Study:

• To investigate if the genome-wide burden of slightly deleterious variants influences the survival probability of aneuploid fetuses.
• To explore the impact of genetic load on embryonic selection in Down syndrome.

Main Methods:

• Analysis of two cohorts of live-born Down syndrome individuals (388 genotyped samples, 16 fibroblast transcriptomes).
• Examination of variant burden on Chromosome 21 and transcriptome-wide variation in gene expression.
• Application of a genetic handicap model to interpret findings.

Main Results:

• Observed a deficit of slightly deleterious variants on Chromosome 21 in Down syndrome individuals.
• Found decreased transcriptome-wide variation in the expression of highly constrained genes.
• Identified signatures consistent with embryonic selection.

Conclusions:

• Survival of aneuploid fetuses may depend on a low genome-wide burden of slightly deleterious variants.
• Proposes a genetic handicap model where reduced genetic load can mitigate the lethality of severe genetic insults like aneuploidy.
• Suggests this framework can advance the study of deleterious variants in humans and model organisms.