Dear all, just a gentle reminder the next seminar will take place this Wednesday, the details are below. We look forward to seeing you all. Best wishes, Petr Danecek --------------------------------- Title: Investigating the Genetics of Sexual Reproduction in 200,000 Humans Speaker: Eugene Gardner Date and time: *Wednesday 23/03/2022 - 17:20 *Location: MFF UK, Malostranské nám. 25*, lecture hall S9 ** * Abstract:Why genes in the human genome are under significant constraint remains a mystery. New genetic variants arise in the germline due to mutation. While the majority are genetically neutral and have no effect on phenotype, some variants confer either an advantage and proceed towards fixation via positive selection, or a disadvantage and are removed from the gene pool by negative selection. The context of where a given variant arises in the genome strongly predicts whether it is eliminated or becomes fixed, with the function of the gene impacted among the most predictive for coding variation. Genes that are depleted of deleterious genetic variation (DGV) due to negative selection are said to be “constrained”. Depending on the method of calculation and dataset used, the human genome contains ~3,000 such genes. While genes associated with dominant diseases such as developmental disorders are among the most constrained genes in the human genome, well-characterised gene-disease pairs only comprise ~35% of all genes determined to be under significant constraint. Based on the principles of evolution, it can be assumed that natural selection shapes genic constraint by reducing an individual’s ability to pass on their genes via sexual reproduction. As part of recent work, using sequencing data for 200,000 humans from the UK Biobank Study, we have shown that genetic variants that damage these genes are associated with markedly reduced reproductive success, primarily due to increased childlessness, with a stronger effect in males than in females. We provided evidence that increased childlessness is likely mediated by genetically associated cognitive and behavioural traits, which may mean male carriers are less likely to find reproductive partners. This reduction in reproductive success may account for 20% of purifying selection against heterozygous variants that ablate protein-coding genes. While this genetic association could only account for a very minor fraction of the overall likelihood of being childless (less than 1%), especially when compared to more influential sociodemographic factors, it may influence how genes evolve over time.