A “Forward Genomics” Approach Links Genotype to Phenotype using Independent Phenotypic Losses among Related Species

SummaryGenotype-phenotype mapping is hampered by countless genomic changes between species. We introduce a computational “forward genomics” strategy that—given only an independently lost phenotype and whole genomes—matches genomic and phenotypic loss patterns to associate specific genomic regions with this phenotype. We conducted genome-wide screens for two metabolic phenotypes. First, our approach correctly matches the inactivated Gulo gene exactly with the species that lost the ability to synthesize vitamin C. Second, we attribute naturally low biliary phospholipid levels in guinea pigs and horses to the inactivated phospholipid transporter Abcb4. Human ABCB4 mutations also result in low phospholipid levels but lead to severe liver disease, suggesting compensatory mechanisms in guinea pig and horse. Our simulation studies, counts of independent changes in existing phenotype surveys, and the forthcoming availability of many new genomes all suggest that forward genomics can be applied to many phenotypes, including those relevant for human evolution and disease.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Matching independent phenotypic losses with ancestral genomic information erosion ► Gulo gene loss uniquely matches to “loss of vitamin C synthesis” in mammals ► Abcb4 gene loss matches “low biliary phospholipid levels” in guinea pig & horse ► Broad applicability of the approach from simulation and phenotype measurements