Abstract
Understanding the relationship between natural selection and phenotypic variation has been a long-standing challenge in human population genetics. With the emergence of biobank-scale datasets, along with new statistical metrics to approximate strength of purifying selection at the variant level, it is now possible to correlate a proxy of individual relative fitness with a range of medical phenotypes. We calculated a per-individual deleterious load score by summing the total number of derived alleles per individual after incorporating a weight that approximates strength of purifying selection. We assessed four methods for the weight, including GERP, phyloP, CADD, and fitcons. By quantitatively tracking each of these scores with the site frequency spectrum, we identified phyloP as the most appropriate weight. The phyloP-weighted load score was then calculated across 15,129,142 variants in 335,161 individuals from the UK Biobank and tested for association on 1,380 medical phenotypes. After accounting for multiple test correction, we observed a strong association of the load score amongst coding sites only on 27 traits including body mass, adiposity and metabolic rate. We further observed that the association signals were driven by common variants (derived allele frequency > 5%) with high phyloP score (phyloP > 2). Finally, through permutation analyses, we showed that the load score amongst coding sites had an excess of nominally significant associations on many medical phenotypes. These results suggest a broad impact of deleterious load on medical phenotypes and highlight the deleterious load score as a tool to disentangle the complex relationship between natural selection and medical phenotypes.
Highlights
One of the primary questions of interest in the study of human population genetics is the relation between natural selection and the evolution of human phenotypes, from quantitative traits to complex disease
This study aims to augment our understanding of the complex relation between natural selection and human phenotypic variation
Multiple methods have been developed to characterize purifying selection, including methods that predict deleterious selection acting on the level of a single allele, methods that measure evolutionary conservation and methods that predict the effect of an allele on molecular function (CADD [17], DANN [18], GenoCanyon [19], Eigen and EigenPC [20])
Summary
One of the primary questions of interest in the study of human population genetics is the relation between natural selection and the evolution of human phenotypes, from quantitative traits to complex disease. With the emergence of biobank-scale datasets, along with new statistical metrics to approximate strength of purifying selection at the variant level, it is possible to both estimate the net impact of deleterious mutations for each individual in a large population sample and correlate it to a range of medical phenotypes exhibited by that individual. This provides an opportunity to simultaneously study the genetics of individuals within a relatively homogenous population and the potential impact of natural selection on annotated phenotypes. When compared to the mean of the population, this per-individual load score can be interpreted as a component of the relative fitness of each individual
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