In nature, we observe an abundance of both phenotypic and genetic variation. Phenotypic variation is
understood to be due to a combination of genetic and environmental factors, but the genetic component is
considered the primary tractable part of the system, and much of the remaining phenotypic variation is left
unexplained. In addition, a major problem in population genetics is that much genetic variation in not explained
by evolutionary forces of mutation, selection, and drift alone, including genetic variants that may be deleterious.
This unexplained abundance of both phenotypic and genetic variation reveals a major gap in our
understanding of how life works. Further, it has major implications for our understanding of the development of
complex diseases, which may appear to develop randomly because of our limited understanding of factors
influencing them. I therefore propose investigating differences in epigenetic regulation (‘epigenetic variation’)
as a unifying causal factor to account for unexplained phenotypic and genetic variation. I propose a set of
empirical and theoretical approaches to address both facets of this gap. First, I will use the roundworm
Caenorhabditis elegans to dissect the contribution of epigenetic variation to phenotypic variation in two key
reproductive traits following specific environmental perturbations in isogenic populations. These experiments
will be performed at the single-worm level (using single-worm RNA-seq and ATAC-seq) to test the hypothesis
that differences in reproductive traits are caused by differences in the epigenetic state of single individuals.
Second, I will extend population-genetic models to incorporate epigenetic variation to test the hypothesis that
epigenetic variation is a major contributor to the maintenance of genetic variation in populations over many
generations. These complementary approaches take advantage of the strengths of each type of system. With
C. elegans, it is straight-forward to generate large populations of genetically identical individuals, and these
differ for quantitative traits, making it an ideal system to understand the influence of epigenetic variation on
phenotypic variation. Using theoretical models, in contrast, facilitates the incorporation of genetic and
epigenetic variation simultaneously to ask how epigenetic variants affect genetic variation over timescales that
are not feasible to test experimentally. Collectively, this work will make important progress toward the long-
term goal of identifying proximate and ultimate mechanisms driving phenotypic and genetic variation.