B3912 - Measurement of Genic Constraint via Reproductive Success - 01/11/2021

B number: 
Principal applicant name: 
Eugene Gardner | MRC Epidemiology Unit, University of Cambridge (United Kingdom)
Title of project: 
Measurement of Genic Constraint via Reproductive Success
Proposal summary: 

New genetic variants arise in the germline due to mutation. While the majority are genetically neutral and have no effect on organismal 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 perhaps the most predictive for coding variation. Genes that are depleted of deleterious genetic variation (DGV) due to negative selection are said to be “constrained”. Why most genes are under significant constraint remains a mystery, but in recent work using data from the UK Biobank we identified a link between DGV burden within constrained genes and increased childlessness.

We also found that a combination of having a partner at home and presence of various mental health disorders played a significant role in the relationship between DGV and childlessness. We hypothesized that DGV burden is associated with behaviours attributable to mental health disorders that in turn decrease the likelihood of finding a reproductive partner. However, we were unable to test this hypothesis due to limitations in the phenotyping of our original data. Using the rich, longitudinal phenotyping and genetic data provided by ALSPAC, we now wish to explore how individual feelings about having children, mental health disorders, and behaviours interact to create selective pressure on DGV within constrained genes.

Impact of research: 
My hope is that our research will be used to develop a better understanding of why some genes are depleted for deleterious genetic variation and the mechanisms of how deleterious genetic variation burden leads to increased childlessness.
Date proposal received: 
Monday, 18 October, 2021
Date proposal approved: 
Tuesday, 26 October, 2021
Genetics, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Cognitive impairment, Fertility/infertility, Mental health, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Computer simulations/modelling/algorithms, DNA sequencing, Gene mapping, Statistical methods, Ageing, Birth outcomes, Parenting, Sex differences, Statistical methods, Childhood - childcare, childhood adversity, Cognition - cognitive function, Development, Genetic epidemiology, Genetics, Genomics, Growth, Offspring