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The Resilience of the Down's Syndrome Genome

Infographic characterizing Down syndrome phenotypes and health risks.

Image courtesy of Villa Medica

Research project summary and purpose

Down syndrome (DS) is often caused by three copies of chromosome 21, called trisomy. Individuals with DS are born with a variety of different abnormal phenotypes, summarized in Figure 1. DS fetuses have up to an 80% miscarriage rate. In this project, researchers investigate the nature of miscarriages in DS fetuses and whether certain levels of genomic stability are more advantageous for the 20% of fetuses that survive. Specifically, the team examines the slightly deleterious variant (SDV) load of the genome of an individual with trisomy 21. SDVs are indicators of potential disease-causing mutations, such as those seen with trisomy.

In this paper, Popadin et al. hypothesize that an individual with DS will likely have fewer genome-wide SDVs due to the severe nature of the SDVs present in trisomic chromosome 21. An overall lower SDV load across the genome will improve a fetus' chance of survival. The researchers name this hypothesis "the genetic handicap model" because the genome of an individual with DS is handicapped by the trisomy, but universally stable. They predict that this stable DS genome is selected for in trisomy 21 fetal survival.

Genomics Technology

The researchers analyzed 388 genotyped samples and 16 transcriptome samples of Down syndrome individuals. The samples were prepared using the Illumina mRNAseq and TruSeq RNA Sample Preparation kits. The data were analyzed using Illumina HiSeq 2000 technology using paired-end sequencing.

Take Home Message

Popadin et al. discovered that an individual with Down's syndrome has a more stable genome that consists of a universally reduced number of slightly deleterious variants. The smaller load of deleterious variants allows for fetal survival despite the extra copy of chromosome 21.


Overall, I found this project to reveal a novel facet of genomics research. Rather than characterizing potentially pathogenic genes, Popadin et al. examines the entire genome of trisomic individuals and relates the variant load to fertility. This project introduces a new, compelling perspective to the progress of DS genomics research by providing an explanation as to why some individuals may survive with trisomy. This perspective of a genome-wide examination provides insight into the complex, interacting nature of the human genome. It is important to understand the relatedness of genes and how they influence disease etiology and outcome.

It would be interesting to apply this approach to women undergoing fertility treatments. Perhaps the presence of fetal slightly deleterious variants could serve as an explanation for infertility and inform physicians on how to best assist infertile women.


News article: The Resilience of the Down's Syndrome Genome Available from Technology Networks

Paper: Popadin K, Peischl S, Garieri M, Sailani MR, et al., 2017. Slightly deleterious genomic variants and transcriptome perturbations in Down syndrome embryonic selection. Genome Research. 28:1-10. Available from Genome Research

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