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


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, Sep 29, 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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    ABSTRACT: The genomic and developmental complexity of vertebrates is commonly attributed to two rounds of whole genome duplications which occurred at the base of the vertebrate radiation. These duplications led to the rise of several, multi-gene families of developmental proteins like the fibroblast growth factors (FGFs); a signaling protein family which functions at various stages of embryonic development. One of the major FGF assemblages arising from these duplications is the FGF8 subfamily, which includes FGF8, FGF17, and FGF18 in tetrapods. While FGF8 and FGF18 are found in all tetrapods and are critical for embryonic survival, genomic analyses suggest putative loss of FGF17 in various lineages ranging from frogs and fish, to the chicken. This study utilizes 27 avian genomes in conjunction with molecular analyses of chicken embryos to confirm the loss of FGF17 in chicken as a true, biological occurrence. FGF17 is also missing in the turkey, black grouse, Japanese quail and northern bobwhite genomes. These species, along with chicken, form a monophyletic clade in the order Galliformes. Four additional species, members of the clade Passeroidea, within the order Passeriformes, are also missing FGF17. Additionally, analysis of intact FGF17 in other avian lineages reveals that it is still under strong purifying selection, despite being seemingly dispensable. Thus, FGF17 likely represents a molecular spandrel arising from a genome duplication event and due to its high connectivity with FGF8/FGF18, and potential for interference with their function, is retained under strong purifying selection, despite itself not having a strong selective advantage. Copyright © 2015. Published by Elsevier B.V.
    Gene 03/2015; 563(2). DOI:10.1016/j.gene.2015.03.027 · 2.14 Impact Factor
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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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    Frontiers in Neuroendocrinology 10/2013; 35(1). DOI:10.1016/j.yfrne.2013.09.004 · 7.04 Impact Factor
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    ABSTRACT: Evolutionary genetics has entered an unprecedented era of discovery, catalyzed in large part by the development of technologies that provide information about genome sequence and function. An important benefit is the ability to move beyond a handful of model organisms in lab settings to identify the genetic basis for evolutionarily interesting traits in many organisms in natural settings. Other benefits are the abilities to identify causal mutations and validate their phenotypic consequences more readily and in many more species. Genomic technologies have reinvigorated interest in some of the most fundamental and persistent questions in evolutionary genetics, revealed previously unsuspected evolutionary phenomena, and opened the door to a wide range of new questions.
    Annual Review of Ecology Evolution and Systematics 11/2012; 44(1). DOI:10.1146/annurev-ecolsys-110512-135828 · 10.56 Impact Factor
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