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A "forward genomics" approach links genotype to phenotype using independent phenotypic losses among related species.

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.

Pubmed ID: 23022484

Authors

  • Hiller M
  • Schaar BT
  • Indjeian VB
  • Kingsley DM
  • Hagey LR
  • Bejerano G

Journal

Cell reports

Publication Data

October 25, 2012

Associated Grants

  • Agency: NICHD NIH HHS, Id: R01 HD059862
  • Agency: NHGRI NIH HHS, Id: R01 HG005058
  • Agency: NICHD NIH HHS, Id: R01HD059862
  • Agency: NHGRI NIH HHS, Id: R01HG005058
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Ascorbic Acid
  • Computational Biology
  • Exons
  • Gene Expression Profiling
  • Genomics
  • Genotype
  • Guinea Pigs
  • Horses
  • Humans
  • Mice
  • Molecular Sequence Data
  • Mutation
  • P-Glycoproteins
  • Phenotype
  • Phospholipids