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DALL·E 2023-08-30 13.19.43 - a René Magritte painting of a futuristic city with building s

The Genetic Architecture of Human Complex Traits

Most human traits have a complex genetic basis, involving many genes and a multitude of genetic variants. What determines the number of such genes and variants, their frequencies in different populations, the magnitude of their effects, and their distribution across the genome? That is: what determines a trait's genetic architecture?

In our lab, we focus on how evolutionary processes shape the shape the genetic architecture of complex trait in humans. Since these processes are shared between all traits, we give particular emphasis on delineating similarities between the genetic architectures of all complex traits.

The Effects of Global Epistasis on Complex Traits and Protein Binding

It is not immediately obvious on what scale should we measure complex traits. For example, should we measure height in cm, as a percent of the mean height, or maybe by some transformation (like height squared)? To a first order approximation, scale doesn't matter with small enough effects. However, to a second order, it creates global epistasis - a systematic interaction between all genetic and environmental effects. This global epistasis can explain why effect sizes of genetic variants can be systematically larger in males vs. females (or vice versa).

We develop an approach to estimate effects and epistasis using order statistics, which are independent of scale. We apply this approach not only to complex traits, but also to detecting epistasis between amino acids on protein binding to ligands.

Selection on Complex Traits as a Driver of Speciation

Many mechanisms have been suggested for speciation - the process in which reproductive barriers are created between population that eventually lead to their separation into new species.

In collaboration with the Veller lab here at U Chicago, we propose a new mechanism for speciation, where selection on complex traits creates the reproductive barrier leading to speciation.

Accumulation of Mutation Load

Each individual carries many deleterious genetic variants in their genome. Mutational processes constantly introduce more deleterious variants, which Natural selection constantly purges from the population. How do changes in population size affect this process? Do smaller populations accumulate more deleterious variation?

We've shown that recent changes in population size have not affected mutation load, and are working on delineating their effect on the frequency distribution of genetic variants and thereby on the genetic architecture of complex traits.

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