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“Superior Genome” May Allow Down Syndrome Fetuses to Survive Pregnancy with Average Life Expectancy of 60 Years--Authors Propose That Embryonic Selection for Reduced Burden of Slightly Deleterious Variants Permits Survival of Extremely Deleterious Variant

Trisomy 21 is a serious genetic disorder, with four pregnancies out of five not reaching term naturally if the fetus is affected. However, 20% of conceptuses with Down's syndrome are born live, grow up and many live into their 60s and 70s (the average life span is 60). How is this possible? Researchers from the Universities of Geneva (UNIGE) and Lausanne (UNIL) have found that children born with Down's syndrome have an “excellent” genome – “better” in terms of certain measurable criteria (gene variation, gene regulation, gene expression), in fact, than the average genome of people without the genetic abnormality. It is possible that this “higher-quality” genome offsets the disabilities caused by the extra chromosome, helping the fetus to survive and the child to grow and develop. In their abstract of an article published in the January 2018 issue of Genome Research, the researchers say the following. “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.” The Genome Research article is titled “Slightly Deleterious Genomic Variants and Transcriptome Perturbations in Down Syndrome Embryonic Selection." "The genome consists of all the genetic material that makes up an individual," explains Stylianos Antonarakis, MD, the honorary professor in UNIGE's Faculty of Medicine who led the research. "It's the genome that determines what becomes of a person, and makes him or her grow up and grow old, with or without disease. Some genomes are of better quality than others, and can also be less exposed to illnesses such as cancer." Basing their work on the hypothesis of the quality of the genome, the geneticists tested the gene variation, gene regulation, and gene expression of 380 individuals with Down's syndrome and compared the results to those of people without the genetic disorder.


The first test consisted of observing the presence of rare variants, i.e., potentially harmful genetic mutations, in people with Down's. It is known that a chromosome can have different rare variants in its two copies. In a person with Down's, however, the rare mutations are identical for all three copies of chromosome 21 and limited in number, thereby reducing the total of potentially deleterious variants.


In a next step, the geneticists have studied the regulation of genes on chromosome 21. Each gene has switches that regulate its expression either positively or negatively. Because people with Down's have three chromosomes 21, most of these genes are overexpressed. "But we discovered that people with Down syndrome have more regulators that diminish the expression of the 21 genes, making it possible to compensate for the surplus induced by the third copy," says Konstantin Popadin, PhD, a researcher at UNIL's Center for Integrative Genomics.


Finally, the researchers focused on the variation gene expression for the chromosomes of the entire genome. Each gene expression on a scale from 0 to 100 forms part of a global spread curve, with the median of 50 being considered the ideal expression.

"For a normal genome, the expressions oscillate between 30 and 70, while for a person with Down's syndrome, the curve is narrower around the peak that is very close to 50 for genes on all the chromosomes," continues Professor Antonarakis.

"In other words, this means that the genome of someone with Down's leans towards the average - optimal functioning." Indeed, the smaller the gene expression variations are, the better the genome.


The UNIGE and UNIL geneticists were thus able to test the three functions of genomes of people suffering from Down's syndrome. "The research has shown that for a child with Down's to survive pregnancy and then grow, his or her genome must be of a higher quality so that it can compensate for the disabilities caused by the extra copy of chromosome 21,” concludes Dr. Popadin. These conclusions may also apply to other serious genetic disorders where pregnancies reach full term.

[Press release] [Genome Research abstract]