The growing number of sequenced genomes allows us now to address a key question in genetics and evolutionary biology: What is the genomic basis that underlies phenotypic differences between species? We developed a computational framework called Forward Genomics that associates phenotypic to genomic differences by focusing on phenotypes that are repeatedly lost in independent lineages. Here, we present two new Forward Genomics methods that (i) control for the phylogenetic relatedness between the species of interest, (ii) control for differences in evolutionary rates and (iii) compute the significance of the association between phenotypic and genomic differences. We systematically compare these methods on simulated and on real data and demonstrate that the new methods significantly improve the sensitivity to detect such associations.
We use these methods to discover genomic loci that underlie the degeneration of the visual system in blind subterranean mammals. This genome-wide screen identifies many loci that are enriched in functions related to eye development and the perception of light as well as loci associated with eye diseases in human. In addition, we find genomic loci with a function in the circadian rhythm, which might be an adaptation to the subterranean environment.
The Forward Genomics framework has broad applicability to many other phenotypic differences. The new methods presented here significantly advance our ability to discover the genomic basis underlying phenotypic differences between species, which will contribute our understanding of how nature’s phenotypic diversity has evolved.