Abstract
Glutathione S-Transferases (GSTs) are phase II detoxification enzymes that may have evolved in response to changes of environmental substrates. GST genes formed a multigene family and in mammals, there are six classes known as Alpha, Mu, Omega, Pi, Theta, and Zeta. Recent studies in phase I detoxification system specifically the cytochrome P450s provided a general explanation on why genes from a common origin such as those in a multigene family have both phylogenetically stable and unstable genes. Genes that participate in core functions of organisms such as development and physiology are stable whereas genes that play a role in detoxification are unstable and evolve in a process known as birth-death evolution, which is characterised by frequent gene gains and losses. The generality of the birth-death model at explaining the evolution of detoxification enzymes beyond the phase I enzyme has not been comprehensively explored. This work utilized 383 Gst genes and 300 pseudogenes across 22 mammalian species to study gene gains and losses. GSTs vary greatly in their phylogenetic stability despite their overall sequence similarity. Stable Gst genes from Omega and Zeta classes do not show fluctuation in gene numbers from human to opossum. These genes play a role in biosynthesis related functions. Unstable genes that include Alpha, Mu, Pi and Theta undergo frequent gene gain and loss in a process known as birth-death evolution. Gene members of these four classes are well known for their roles in detoxification. Our positive selection screen identified five positively selected sites in mouse GSTA3. Previous studies showed two of these sites (108H and 208E) were biochemically tested as important residues that conferred catalytic activity against the toxic aflatoxin B1-8,9-epoxide. The functional significance against aflatoxin of the remaining three positively selected sites warrant further investigation.
Highlights
Genes that adopt a particular canonical protein fold and share amino acid sequence similarity above a certain threshold are grouped into a multigene family [1]
To explore the generality of the model put forward by previous studies in explaining the patterns of gene gains and losses beyond just the phase I cytochrome P450 monooxygenases (P450s), we examined in detail the evolution of phase II Glutathione S-transferases and restrict the choice of species to include only 22 mammals with genomes assembled at the chromosome level [4, 5]
An attempt to annotate this genome for Glutathione S-Transferases (GST) only showed one complete GST found whereas all the other genes were broken into shorter contigs; the platypus genome was removed from further analysis
Summary
Genes that adopt a particular canonical protein fold and share amino acid sequence similarity above a certain threshold are grouped into a multigene family [1]. The definition of ‘phylogenetic instability’ may be loosely defined but studies on stable versus unstable genes have relied on a sharp distinction between gene classes from the same multigene family that showed very different gene copy number variation when analysed on a specific evolution timeframe [2]. The term birth-death evolution describes unstable genes that undergo frequent duplications and loses. Genes in rapid birth-death evolution have more opportunities for neofunctionalization, subfunctionalization and pseudogenization [3]
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