What caused the great expansion of gene families prone to deleterious mutations in vertebrates?
Giulia Malaguti, Institut Curie, Paris, France

Gene families implicated in cancers and other genetic diseases have been greatly expanded by duplication during vertebrate evolution. In particular, their expansion can be traced back to two rounds of whole-genome duplication (WGD) that occurred at the onset of jawed vertebrates. However, the duplication of these genes is expected to lead to an enhanced susceptibility to genetic diseases, and thus the retention of these deleterious gene duplicates represents an evolutionary puzzle from a natural selection perspective. To quantitatively analyze this striking evolutionary outcome, I have expanded classical population genetics models to reveal the non-adaptive mechanism through which such deleterious ohnologs (WGD-duplicated genes) could have been retained in the vertebrate genome. At first, a deterministic haploid model is solved, focusing on the fixation of gene duplicates following either a single gene small scale duplication (SSD) or a whole genome duplication (WGD). Then, extensions to diploid genotypes are considered, and population size effects and the impact of positive selection are analyzed through a stochastic approach. The results demonstrate, consistently with available human cancer genome data, that WGD duplicates prone to dominant deleterious mutations are indirectly selected through purifying selection in post-WGD species, arisen through the ploidy incompatibility between post-WGD individuals and the rest of the pre-WGD population. To further investigate the influence of the mode of duplication on the retention of genes prone to dominant deleterious mutations, I have applied advanced inference methods to investigate causal pathways and quantify direct and indirect effects. This analysis brings further supporting evidences for the importance of the direct role of the susceptibility to dominant deleterious mutations, among other a priori possible genomic properties, on ohnolog retention.

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