Controlling for phylogenetic relatedness and evolutionary rates improves the discovery of associations between species’ phenotypic and genomic differences
Open accessAbstract
The growing number of sequenced genomes allows us now to address a key question in genetics and evolutionary biology: which genomic changes underlie particular phenotypic changes between species? Previously, we developed a computational framework called Forward Genomics that associates phenotypic to genomic differences by focusing on phenotypes that are independently lost in different lineages. However, our previous implementation had three main limitations. Here, we present two new Forward Genomics methods that overcome these limitations by (1) directly controlling for phylogenetic relatedness, (2) controlling for differences in evolutionary rates, and (3) computing a statistical significance. We demonstrate on large-scale simulated data and on real data that both new methods substantially improve the sensitivity to detect associations between phenotypic and genomic differences. We applied these new methods to detect genomic differences involved in the loss of vision in the blind mole rat and the cape golden mole, two independent subterranean mammals. Forward Genomics identified several genes that are enriched in functions related to eye development and the perception of light, as well as genes involved in the circadian rhythm. These new Forward Genomics methods represent a significant advance in our ability to discover the genomic basis underlying phenotypic differences between species. Source code: https://github.com/hillerlab/ForwardGenomics/.
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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 Prudent et al. 2016
The 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 [9]
The pGLS approach takes the phylogenetic relatedness of the species as given by the phylogenetic tree into account.
“This approach takes the phylogenetic relatedness of the species as given by the phylogenetic tree into account.”
From A genomics approach reveals insights into the importance of gene losses for mammalian adaptations (2018) · cites this paper as [9]
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Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool
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A genomics approach reveals insights into the importance of gene losses for mammalian adaptations
Sharma, V., Hecker, N., Roscito, J. G., Foerster, L., Langer, B. E., & Hiller, M. (2018) · Nature Communications · doi:10.1038/s41467-018-03667-1 · Cited by 237 · see citing works
Self-citationBayesian Detection of Convergent Rate Changes of Conserved Noncoding Elements on Phylogenetic Trees
Hu, Z., Sackton, T. B., Edwards, S. V., & Liu, J. S. (2019) · Molecular Biology and Evolution · doi:10.1093/molbev/msz049 · Cited by 69 · see citing works
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Vision-related convergent gene losses reveal SERPINE3’s unknown role in the eye
Indrischek, H., Hammer, J., Machate, A., Hecker, N., Kirilenko, B., Roscito, J., Hans, S., Norden, C., Brand, M., & Hiller, M. (2022) · eLife · doi:10.7554/elife.77999 · Cited by 21 · see citing works
Self-citation
- Authors
- Prudent, X., Parra, G., Schwede, P., Roscito, J. G., & Hiller, M.
- Affiliations
- Max Planck Institute for the Physics of Complex Systems (DE)
- Corresponding author
- Hiller, Michael
- Venue
- Molecular Biology and Evolution
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-05-24
- Volume
- 33
- Issue
- 8
- Pages
- 2135-2150
- ISSN
- 0737-4038 (ISSN-L)
- 1537-1719
- PMC
- PMC4948712
- OpenAlex
- W2405424609
- Cited by
- 71
- References
- 5
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 5 · 2023: 9 · 2022: 7 · 2021: 6 · 2020: 8 · 2019: 13 · 2018: 8 · 2017: 3 · 2016: 1
- FWCI
- 3.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Molecular Biology and Evolution (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo (2012/01319-8)
- Max-Planck-Gesellschaft
- Max-Planck-Institut für Physik Komplexer Systeme
- 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
- Physical Sciences › Earth and Planetary Sciences › Paleontology › Subterranean biodiversity and taxonomy
- Keywords
- phylogenetic control, evolutionary rate heterogeneity, vision loss, blind mole rat, subterranean mammals, eye development genes, circadian rhythm genes, statistical significance, comparative genomics
- MeSH terms
- Animals, Base Sequence, Computer Simulation, Biological Evolution, Genotype, Models, Genetic, Phenotype, Phylogeny, Evolution, Molecular, Computational Biology, Genomics, Genetic Speciation, Mutation Rate
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