Use with caution: developmental systems divergence and potential pitfalls of animal models

Abstract

Transgenic animal models have played an important role in elucidating gene functions and the molecular basis development, physiology, behavior, and pathogenesis. Transgenic models have been so successful that they have become a standard tool in molecular genetics and biomedical studies and are being used to fulfill one of the main goals of the post-genomic era: to assign functions to each gene in the genome. However, the assumption that gene functions and genetic systems are conserved between models and humans is taken for granted, often in spite of evidence that gene functions and networks diverge during evolution. In this review, I discuss some mechanisms that generate functional divergence and highlight recent examples demonstrating that gene functions and regulatory networks diverge through time. These examples suggest that annotation of gene functions based solely on mutant phenotypes in animal models, as well as assumptions of conserved functions between species, can be wrong. Therefore, animal models of gene function and human disease may not provide appropriate information, particularly for rapidly evolving genes and systems.

Figure 1

Gene regulatory networks for heart development in Drosophila (top) and vertebrates (middle); shared linkages are shown at the bottom. A core set of regulatory genes are used in common between insect and vertebrates and are linked in a similar way in conserved subcircuits of the gene network. Gray boxes highlight different ways that the same two nodes of the network are linked in Drosophila and vertebrates. Orthologs of many regulatory genes in vertebrate heart formation are not known in Drosophila. Image used with permission from [72].

Figure 2

β-globin gene family evolution in eutherian mammals. Two successive duplications of a proto-ε gene gave rise to the γ and η genes in the stem-lineage of eutherian mammals after their divergence from marsupials. Consequently, the full complement of embryonic globin genes (hemoglobin ε, γ and η) was present in the common ancestor of the eutherian mammals. The η gene was lost in the common ancestor of Xenarthrans and Afrotherians, and the γ gene was lost in Xenarthrans after divergence from the Afrotherians. The η and γ genes were independently lost in the Euarchontoglires and Laurasiatherians, respectively. Crosses indicate lineage-specific gene losses. Image used with permission from [87].

Figure 3

Evolution of a novel nuclear localization signal (NLS) in PLCZ1. (a) Logo of the X-Y linker region from 31 species of amniotes. In this representation of a multiple sequence alignment the conservation of amino acid residues in the protein are indicated by the height of the column (Bit Score) while the conservation of specific amino acids in at that site are shown by the height of letters within columns. Note that conservation is generally poor. (b) Superimposed structural models of human (blue) and mouse (red) PLCZ1 proteins. Note that while the structure of human and mouse PLCZ1 proteins are generally the same, the X-Y linker region is much longer in humans leading to a longer disordered loop than in mouse. The mouse NLS is shown as red spheres and the human pre-NLS is shown as blue spheres.