Slightly deleterious genomic variants and transcriptome perturbations in Down syndrome embryonic selection
- Konstantin Popadin1,2,3,4,
- Stephan Peischl4,5,
- Marco Garieri1,
- M. Reza Sailani6,
- Audrey Letourneau1,
- Federico Santoni1,
- Samuel W. Lukowski7,
- Georgii A. Bazykin8,9,
- Sergey Nikolaev1,
- Diogo Meyer10,
- Laurent Excoffier4,11,
- Alexandre Reymond2,12 and
- Stylianos E. Antonarakis1,12
- 1Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland;
- 2Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland;
- 3Immanuel Kant Baltic Federal University, Kaliningrad, 236041, Russia;
- 4Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland;
- 5Interfaculty Bioinformatics Unit, University of Bern, 3012 Bern, Switzerland;
- 6Stanford School of Medicine, Stanford University, Stanford, California 94305, USA;
- 7Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia;
- 8Institute for Information Transmission Problems (Kharkevich Institute) of the Russian Academy of Sciences, Moscow, 127051, Russia;
- 9Center for Data-Intensive Biomedicine and Biotechnology, Skolkovo Institute of Science and Technology, Skolkovo, 143026, Russia;
- 10Department of Genetics and Evolutionary Biology, University of Sao Paulo, 05508-090, Sao Paulo, Brazil;
- 11Institute for Ecology and Evolution, University of Bern, CH-3012 Bern, Switzerland
-
↵12 These authors contributed equally to this work.
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.
Footnotes
-
[Supplemental material is available for this article.]
-
Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.228411.117.
- Received July 29, 2017.
- Accepted November 20, 2017.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
