309V Poster Online - Virtual Posters
Tuesday June 07, 11:00 AM - 3:00 PM

Authors:
Chris Kyriazis ¹; Emma Wade ^1,2; Maria Izabel Cavassim ¹; Kirk Lohmueller ¹

Affiliations:
1) UCLA, Los Angeles, CA; 2) Mississippi State University, Starkville, MS

Keywords:
Natural selection

Early genetic studies indicated that some mutations, when homozygous, will result in lethality or sterility. While the presence of such recessive lethal mutations is now clearly established, quantifying what proportion of new mutations are recessive lethal has been much more challenging because population genetic studies of the distribution of fitness effects (DFE) may be underpowered to detect such mutations. To overcome this challenge, here we present an alternative approach for quantifying the fraction of new mutations that are recessive lethal. Specifically, we use mutation-selection-drift balance models in concert with previously published estimates of segregating recessive lethals in humans and Drosophila. Our approach shows a very small fraction of new nonsynonymous mutations (<1%) in Drosophila and humans are likely to be recessive lethal. We then we use forward-in-time simulations of human coding sequence with DFEs, mutation rates, and demographic models inferred from the literature, combined with a range of plausible dominance coefficients to validate our model. We find that, under nearly all parameter combinations, existing DFEs of nonsynonymous mutations with an additional 1% of mutations being recessive lethal can explain observed levels of inbreeding depression in humans. Our work validates molecular population genetic estimates of the DFE by showing that these DFEs can recapitulate reductions in fitness measured in an orthogonal manner. Further, this analysis places limits on the proportion of recessive lethal mutations, which has implications for studying inbreeding depression in a variety of species.