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

Konstantin Popadin; Stephan Peischl; Marco Garieri; M Reza Sailani; Audrey Letourneau; Federico Santoni; Samuel W Lukowski; Georgii A Bazykin; Sergey Nikolaev; Diogo Meyer; Laurent Excoffier; Alexandre Reymond; Stylianos E Antonarakis

doi:10.1101/gr.228411.117

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

Genome Res. 2018 Jan;28(1):1-10. doi: 10.1101/gr.228411.117. Epub 2017 Dec 13.

Authors

Konstantin Popadin^{1

2

3

4}, Stephan Peischl^{4

5}, Marco Garieri¹, M Reza Sailani⁶, Audrey Letourneau¹, Federico Santoni¹, Samuel W Lukowski⁷, Georgii A Bazykin^{8

9}, Sergey Nikolaev¹, Diogo Meyer¹⁰, Laurent Excoffier^{4

11}, Alexandre Reymond², Stylianos E Antonarakis¹

Affiliations

¹ Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.
² Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland.
³ Immanuel Kant Baltic Federal University, Kaliningrad, 236041, Russia.
⁴ Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
⁵ Interfaculty Bioinformatics Unit, University of Bern, 3012 Bern, Switzerland.
⁶ Stanford School of Medicine, Stanford University, Stanford, California 94305, USA.
⁷ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.
⁸ Institute for Information Transmission Problems (Kharkevich Institute) of the Russian Academy of Sciences, Moscow, 127051, Russia.
⁹ Center for Data-Intensive Biomedicine and Biotechnology, Skolkovo Institute of Science and Technology, Skolkovo, 143026, Russia.
¹⁰ Department of Genetics and Evolutionary Biology, University of Sao Paulo, 05508-090, Sao Paulo, Brazil.
¹¹ Institute for Ecology and Evolution, University of Bern, CH-3012 Bern, Switzerland.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Abortion, Spontaneous
Aneuploidy*
Chromosomes, Human, Pair 21 / genetics*
Down Syndrome* / embryology
Down Syndrome* / genetics
Female
Genotype*
Humans
Pregnancy
Transcriptome*

Grants and funding

249968/ERC_/European Research Council/International