On differentiating selective and neutral evolutionary processes

Jensen, Abstract At the founding of population genetics in the early 20th century, S. Wright and R.A. Fisher developed much of the mathematical framework underlying the study of population-level processes dictating variation observed within- and between-species. However, as evidenced by decades of published interactions, they held strongly differing views regarding the relative importance of adaptive vs. non-adaptive processes in driving evolution. As pointed out by J. Crow (2008), these issues were not really resolved, but "rather they were abandoned in favor of more tractable studies." With the proposal of the Neutral Theory by M. Kimura and T. Ohta, the relative contribution of stochastic effects, as earlier advocated by S. Wright, received renewed attention. In the following decades, further theoretical development as well as the availability of large-scale sequencing data have indeed overwhelmingly justified the important role of genetic drift. However, subsequent research related to linked, rather than direct, selection effects have re-ignited previous debates. The primary difficulty in addressing this question has historically stemmed from our lack of an appropriate evolutionary baseline model - that is, a model jointly incorporating constantly and commonly acting evolutionary processes. This would necessarily include genetic drift as modulated by a realistic demographic history, as well as a realistic distribution of fitness effects summarizing the pervasive effects of both direct and linked purifying selection. Without this baseline model incorporating these evolutionary processes that are certain to be occurring, it is simply not feasible to accurately quantify the episodic frequency with which rarer processes (e.g., positive and balancing selection) may be further acting to shape patterns of polymorphism and divergence. During our current funding period, we have addressed this decades old limitation by developing population genetic theory and methodology to jointly estimate the parameters underlying such a baseline model, and we have applied these developments to a number of critical species (including humans, genetic model systems such as Drosophila melanogaster, and critical pathogens including influenza A virus and SARS-CoV- 2). These developments have been made in parallel for organisms well fit by Kingman coalescent assumptions (e.g., mammals) as well as those with highly skewed progeny distributions which necessitate a more generalized multiple-merger coalescent framework (e.g., viruses). In this renewal, I propose to build upon this baseline modeling to additionally infer, identify, and estimate the genomic contributions of the episodic processes of positive and balancing selection, and to extend our evolutionary baseline inference across the primate clade.