A “forward genomics” approach links genotype to phenotype using independent phenotypic losses among related species
Open accessAbstract
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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The Forward Genomics method tests the significance of the Pearson correlation between normalized substitutions and hypothetical phenotypic states on each branch.
“The “Forward Genomics” method (Hiller et al. 2012; Prudent et al. 2016) tests the significance of the Pearson correlation between normalized substitutions and hypothetical phenotypic states on each branch.”
From Bayesian Detection of Convergent Rate Changes of Conserved Noncoding Elements on Phylogenetic Trees (2019) · cites this paper as Hiller et al. 2012
The Experimental Procedures section (“Screening for conserved regions that evolve faster in species lacking a trait”; page unavailable) describes a different test: it compares percent identity between trait-loss and trait-preserving species and counts species that violate a 1% separation. It does not describe testing a Pearson correlation between branch-level normalized substitutions and hypothetical phenotypic states. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredThe original forward genomics approach searches for genomic regions that have a higher nucleotide divergence in species that share an independently evolved phenotype.
“While the original forward genomics approach searches for genomic regions that have a higher nucleotide divergence in species that share an independently evolved phenotype6,9”
From A genomics approach reveals insights into the importance of gene losses for mammalian adaptations (2018) · cites this paper as [6]
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Self-citation
- Authors
- Hiller, M., Schaar, B. T., Indjeian, V. B., Kingsley, D. M., Hagey, L. R., & Bejerano, G.
- Affiliations
- Stanford University (US)
- Howard Hughes Medical Institute (US)
- University of California San Diego (US)
- Corresponding author
- Hiller, Michael
- Bejerano, Gill
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 2
- Issue
- 4
- Pages
- 817-823
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC3572205
- OpenAlex
- W2076189890
- Cited by
- 144
- References
- 4
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 12 · 2023: 15 · 2022: 7 · 2021: 8 · 2020: 10 · 2019: 22 · 2018: 11 · 2017: 9 · 2016: 10 · 2015: 11 · 2014: 2 · 2013: 8
- FWCI
- 2.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Broad Institute
- National Human Genome Research Institute (R01HG005058)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD059862)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- genotype-phenotype mapping, scurvy, guinea pig, horses, ABCB4, compensatory mechanisms, genome-wide screen
- MeSH terms
- Animals, Ascorbic Acid, Exons, Genotype, Guinea Pigs, Horses, Humans, Molecular Sequence Data, Mutation, Phenotype, Phospholipids, ATP Binding Cassette Transporter, Subfamily B, Computational Biology, Gene Expression Profiling, Genomics, Mice
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