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Review
. 2017 Apr:69:174-186.
doi: 10.1016/j.reprotox.2017.03.003. Epub 2017 Mar 4.

Applying evolutionary genetics to developmental toxicology and risk assessment

Maxwell C K Leung  1 , Andrew C Procter  2 , Jared V Goldstone  3 , Jonathan Foox  4 , Robert DeSalle  4 , Carolyn J Mattingly  5 , Mark E Siddall  4 , Alicia R Timme-Laragy  6
Affiliations
Review

Applying evolutionary genetics to developmental toxicology and risk assessment

Maxwell C K Leung et al. Reprod Toxicol. 2017 Apr.

Abstract

Evolutionary thinking continues to challenge our views on health and disease. Yet, there is a communication gap between evolutionary biologists and toxicologists in recognizing the connections among developmental pathways, high-throughput screening, and birth defects in humans. To increase our capability in identifying potential developmental toxicants in humans, we propose to apply evolutionary genetics to improve the experimental design and data interpretation with various in vitro and whole-organism models. We review five molecular systems of stress response and update 18 consensual cell-cell signaling pathways that are the hallmark for early development, organogenesis, and differentiation; and revisit the principles of teratology in light of recent advances in high-throughput screening, big data techniques, and systems toxicology. Multiscale systems modeling plays an integral role in the evolutionary approach to cross-species extrapolation. Phylogenetic analysis and comparative bioinformatics are both valuable tools in identifying and validating the molecular initiating events that account for adverse developmental outcomes in humans. The discordance of susceptibility between test species and humans (ontogeny) reflects their differences in evolutionary history (phylogeny). This synthesis not only can lead to novel applications in developmental toxicity and risk assessment, but also can pave the way for applying an evo-devo perspective to the study of developmental origins of health and disease.

Keywords: Birth defects; Developmental toxicology; Evo-Devo; Evolutionary genetics; High-throughput screening; Signaling pathways; Systems toxicology.

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Conflict of interest statement

Conflict of interest: The authors declare they have no actual or potential competing financial interests.

Figures

Figure 1
Figure 1. Discovery from Natural Selection: Thalidomide-induced limb deformities in D. rerio and G. gallus in comparison with forelimb atrophy in A. means, R. cucullatus, and T. rex
Limb deformities (phocomelia) can be observed with exposure to thalidomide in (A, B) D. rerio, (C, D) G. gallus, and humans. In the course of evolution, a similar developmental outcome (forelimb atrophy) is stabilized to better adapt to ecological niches in (E) two-toed amphiuma (Amphiuma means), a native species of salamanders in North Carolina; (F) flightless birds, such as the dodos (Raphus cucullatus); and (G) the family Tyrannosauridae and subfamily Carnotaurinae of theropod dinosaurs, such as Tyrannosaurus rex (Guinard 2015). The images were used with permission of (A–D) the American Association for the Advancement of Science (Ito et al. 2010), and (F) Michael Hanson (Yale University); and taken in (E) the North Carolina Museum of Natural Sciences, Raleigh, NC, and (G) the National Museum of Natural History, Smithsonian Institution, Washington, D.C.
Figure 2
Figure 2. Evolutionary origins of stress response and developmental pathways
Stress response and developmental pathways (Table 1 and 2) are highly interconnected, and both have diversified in the course of evolution at different time points. For example, the estrogen receptor evolved before the diversification of animals; the androgen receptor evolved at a much later time point (Reitzel and Tarrant 2010; Kassahn et al. 2011). The species divergence times were calculated using the TimeTree knowledgebase (Hedges et al. 2006, 2015).
Figure 3
Figure 3. Number of PubMed Articles Between 2000 and 2015 for nine model organisms and humans for seven consensual cell-cell signaling pathways in early development
Rats, mouse, and rabbits―the three conventional models in teratology―share the last common ancestor with humans approximately 90 million years ago (TimeTree knowledgebase; Hedges et al. 2006, 2015). Citations of all 209,241 articles are provided in Supplementary Material, Excel Workbook S1.
Figure 4
Figure 4. Evolutionary approach to cross-species extrapolation
Adverse Outcome Pathway (AOP) is a useful framework to integrate a large volume of toxicity data from research literature and high-throughput screening for predicting developmental toxicity in humans. An adverse outcome can be linked to a molecular initiating event (MIE) that involves a developmental toxicant and a molecular target. Risk assessment can be started with the bioinformatics analysis (green) of (1) an AOP to predict MIEs and target genes and (2) phylogenetic analysis of putative protein interactions. Multiscale systems models (3) can be built to examine the spatio-temporal dynamics of developmental patterning. The results of computer simulations can be cross-validated in vitro, in vivo, and in silico using (4) cell culture models, (5) whole-organism models, and (6) functional genomics. This approach can improve the design and data interpretation with different experimental models (blue), thereby increasing the capability in identifying potential developmental toxicants in humans.
Figure 5
Figure 5. Statistical tests for phylogenetic congruence, protein co-evolution, and natural selection
(A) Phylogenetic congruence tests measure and visualize the extent to which tree topologies differ. These tests can be used to provide evidence for differing patterns of evolution among genes, as well as gene duplication, horizontal gene transfer, or other nonvertical inheritance. Phylogenetic congruence tests may be classified as character congruence tests, of which the incongruence length difference test is most well-known, and topological congruence tests, including the tanglegram shown here (the gene A and B topologies are congruent). (B) Tests for protein co-evolution measure the coordinated changes that occur in pairs of proteins or protein residues, typically to maintain or refine catalytic or ligand-binding interactions (between protein C and D; modified from de Juan et al. 2013). (C) dN/dS is an indicator of natural selection acting on a genetic locus. It is the ratio of mutations that change amino acids (nonsynonymous mutations) to those that do not (synonymous mutations). If selection is absent, and mutations are caused by random genetic drift, dN/dS = 1. dN/dS > 1 suggests positive directional selection, indicating adaptation of gene E in those species (red lineages in the tree). dN/dS < 1 suggests balancing selection, such that mutations of gene E are reducing the fitness of those species (orange through blue lineages).
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