The long-term objective of the PI's research program is to discover and understand general principles of evolution in terms of molecular genetic mechanisms and driving forces. This is a rapidly progressing area, thanks to the technological revolution in molecular biology and genomics, rapid accumulation of genome sequences and functional genomic data, and most importantly, conceptual developments in various fields of biology. Genomic and systemic approaches to evolution are especially valuable, because the genomic approach allows assessing the generalities and relative contributions of individual mechanisms discovered and the systemic approach helps refocus the study of evolutionary processes from roles of individual genes/mutations to those of interactions among genes/mutations (and the environment), which are key to uncovering the inner workings and evolution of biological systems. The PI's lab studies evolutionary mechanisms from genomic and systemic perspectives using multiple model systems (mostly yeast and mammals) and a combination of theoretical modeling, computer simulation, integrative data analysis, laboratory experimental evolution, and molecular and genomic experimentation. This proposal centers on two related themes that are of fundamental importance to evolution: epistasis and pleiotropy. On the topic of epistasis, the PI and his team will characterize patterns of intragenic and intergenic epistasis by mapping fitness landscapes of representative genes and joint fitness landscapes of pairs of interacting genes, study the genetic background dependency of gene essentiality at the genomic scale, experimentally test the hypothesis that the existence and persistence of RNA editing is explained by evolutionary entrenchment, and attempt to resolve the apparently contradictory inferences of epistasis patterns from adaptive evolution and mutation accumulation. On the topic of pleiotropy, the PI and his team will map multi-environment fitness landscapes of representative genes to study general patterns of environmental pleiotropy of mutations, identify common loci of environmental adaptations, quantify the influence of pleiotropy on molecular adaptations in changing environments, and assess the impact of pleiotropy on the rate of phenotypic evolution and human aging and disease. Together, these projects promise to deepen the understanding of the genetic mechanisms and driving forces of evolution and shed light on disease mechanisms and prevalence.
This project examines evolutionary mechanisms from genomic and systemic perspectives, including studying a number of topics related to epistasis and pleiotropy. Because many of these topics are involved in human disease, are invoked in explaining disease prevalence, and/or help predict disease-causing mutations and mechanisms, understanding these phenomena sheds light on disease mechanisms and prevalence.