Applications of comparative evolution to human disease genetics

Abstract

Direct comparison of human diseases with model phenotypes allows exploration of key areas of human biology which are often inaccessible for practical or ethical reasons. We review recent developments in comparative evolutionary approaches for finding models for genetic disease, including high-throughput generation of gene/phenotype relationship data, the linking of orthologous genes and phenotypes across species, and statistical methods for linking human diseases to model phenotypes.

Figure 1

Components of comparative methods for rationally identifying human disease genes. Silhouettes are from PhyloPic (URL: http://phylopic.org/).

Figure 2

Components of statistical linking methods for rationally identifying human disease genes.

Figure 3

Recent applications of statistical linking methods to identify and treat human disease. A. Cha et al. 2012 used overlap between vasculature genes and genes linked to antifungal sensitivity in yeast to identify TBZ as a novel vascular disrupting agent. TBZ disassembled vasculature in Xenopus embryos (top panels) and slowed human fibrosarcoma tumor growth in mice (bottom panels). Adapted from Cha et al. 2012 [84]. B. Tardiff et al. 2013 overexpressed α-synuclein and screened for phenotype rescuing compounds. One such compound, NAB, in turn ameliorated neuronal proteinopathies in worm neurons. Adapted from Tardiff et al. 2013 [88]. C. Chan et al. 2014 identified divergent phenotypes in planarians and schistosomes in response to the small molecule PZQ. Ca_v, voltage-gated calcium channel; Na_v, voltage-gated sodium channel; HVA, high-voltage activated; LVA, low-voltage activated. Adapted from Chan et al. 2014 [90].