ABI Innovation: Beyond dN/dS: Population Genetics, Genome Structure, and Protein Structure

University Of Wyoming, Laramie WY

Investigators

Abstract

Full genome sequences, including the sequence for all protein-encoding genes, now exist for many different species. Within these sequences lie the molecular underpinnings of species differentiation. Presently it is not possible to systematically compare homologous genes from different species and predict which have changed function. New mechanistic models that describe the underlying population genetic, evolutionary, and biochemical processes and constraints on amino acid change between species will be developed and applied to genome comparisons, including to the divergence between humans and chimpanzees. Additionally, the project will provide educational opportunities for undergraduate and graduate students as well as postdoctoral training. Further, a popular video, interactive educational website, and poster-based museum exhibit on comparative genomics will be produced to explain the concepts of comparative genomic analysis to a popular science audience. The project involves collaboration with the American Museum of Natural History and researchers at University of Otago in New Zealand. Current widely used approaches in comparative genomics simply look for a statistical excess of nucleotide changes that change the encoded amino acid, normalized by the expectation from synonymous nucleotide changes (the ratio of nonsynonymous to synonymous nucleotide substitution rates), but do not look at amino acid biochemistry or structural biology. They also do not consider genome structure (linkage) or population genetic considerations of the probability of fixation of an amino acid change. This research will develop approaches that explicitly consider the linkage of sites on chromosomes in a population genetic model and in different ways, also consider the biochemical and structural context of amino acid changes. The new models will be used initially in comparisons of the human and chimpanzee genome protein coding set and will subsequently be implemented in a phylogenetic context to enable comparison of gene families from multiple species. Potential downstream applications of this modeling approach that enables better mechanistic understanding of lineage-specific evolution include prediction of proteins or pathways where functions have changed. This can point to proteins and pathways that make a species unique as well as validating when model organisms are likely to be good models for particular molecular systems. Information related to this project will be available at http://www.wyomingbioinformatics.org/LiberlesGroup.