Article

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

Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: .
Cell Reports (Impact Factor: 8.36). 09/2012; 2(4). DOI: 10.1016/j.celrep.2012.08.032
Source: PubMed

ABSTRACT Genotype-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.

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Available from: Michael Hiller, Aug 28, 2015
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    • "When a gene fails to map to a genome assembly, it is difficult to distinguish between true gene loss and an unresolved state due to low quality or missing sequencing product (Hiller et al., 2012). This problem is often exacerbated by the use of previously mis-assembled genomes to assemble new genome sequences. "
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    • "A recent proof-of-concept for this approach focused on the ability to synthesize vitamin C, an ancestral vertebrate trait that was lost in at least four independent mammalian lineages. A large phylogenetic tree aligning 27 sequenced mammalian genomes identified only a single gene that was lost in all of these and only these four lineages; this gene is indeed central to vitamin C synthesis (Hiller et al., 2012). It seems doubtful that such a straightforward strategy will be feasible for more complex multigenic traits, ones that emerged more recently in evolution, or ones for which large phylogenetic trees of gain and loss are not available. "
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