Unifying approaches from statistical genetics and phylogenetics for mapping phenotypes in structured populations

Abstract

In both statistical genetics and phylogenetics, a major goal is to identify correlations between genetic loci or other aspects of the phenotype or environment and a focal trait. In these two fields, there are sophisticated but disparate statistical traditions aimed at these tasks. The disconnect between their respective approaches is becoming untenable as questions in medicine, conservation biology, and evolutionary biology increasingly rely on integrating data from within and among species and once clear conceptual divisions are becoming increasingly blurred. To help bridge this divide, we derive a general model describing the covariance between the genetic contributions to the quantitative phenotypes of different individuals. Taking this approach shows that standard models in both statistical genetics (e.g., Genome-Wide Association Studies; GWAS) and phylogenetic comparative biology (e.g., phylogenetic regression) can be interpreted as special cases of this more general quantitative-genetic model. The fact that these models share the same core architecture means that we can build a unified understanding of the strengths and limitations of different methods for controlling for genetic structure when testing for associations. We develop intuition for why and when spurious correlations may occur using analytical theory and conduct population genetic and phylogenetic simulations of quantitative traits to provide to a detailed analysis of the general regression model, in which both standard GWAS methods and phylogenetic regression are subsumed. This enables us to take methodological advances from one field and apply them in the other. We demonstrate this by showing how a standard GWAS technique---including both the genetic relatedness matrix (GRM) as well as its leading eigenvectors, corresponding the principal components (PCs) of the genotype matrix, in a regression model---can mitigate spurious correlations in phylogenetic analyses. As a case study of this, we re-examine an analysis testing for co-evolution of expression levels between genes across a fungal phylogeny, and show that including principal components as covariates decreases the false positive rate while simultaneously increasing the true positive rate. More generally, this work provides a foundation for more integrative approaches for understanding the genetic architecture of phenotypes and how evolutionary processes shape it.