Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
ReviewArthropod CYPomes illustrate the tempo and mode in P450 evolution
Introduction
The P450 gene superfamily is large enough that after transcriptome and proteome became the logical followers of genome in the biological discourse, the term CYPome was introduced in the literature [1]. As this issue is dedicated to Klaus Ruckpaul and his contributions to the P450 field, it seems appropriate to celebrate by joining in the use of this evocative term. The explosion of new knowledge on CYPomes brought about by the sequencing of various genomes is impacting the field of P450 research in many ways. The sheer number of P450 genes, the size of the CYPomes, is baffling (Nelson, this issue). Humans have a CYPome of 57 P450 genes and 58 pseudogenes, distributed in 18 CYP families, but the mouse has a CYPome of 102 P450 genes and nearly 90 pseudogenes. The human CYP2D6 “debrisoquine hydroxylase” gene has nine CYP2D paralogs in the mouse [2]. The number of P450 genes is therefore highly variable over evolutionary time, even over the very short 90 million years (MY) that separate human and mouse.
This highly dynamic nature of the P450 superfamily shown by the difference between humans and mouse is neither just curious nor just obvious. Beyond the implications of P450 diversity for our reliance on “model” species in research, particularly risk assessment in toxicology, the origins of P450 diversity are of great interest intrinsically. Because it is so large, the P450 superfamily can serve as a model for gene family evolution, perhaps one where knowledge of specific functions of P450 can bring deeper insights into the mechanism of gene family evolution. Therefore, while it is certainly presumptuous to paraphrase the title of G. G. Simpson's famous book on evolution for this paper, both the tempo (rates) and the mode (patterns and mechanisms) of evolution of the CYPomes are fascinating and still poorly understood.
Here, I will examine the dynamics of P450 evolution in the light of current concepts of gene family evolution. I will first describe the diversity of CYPomes using arthropods (mainly insects) as examples, then attempt to describe how the processes of gene duplications in the P450 family have shaped its diversity. I close with a discussion of mitochondrial P450 that are surprisingly diverse in their own right, with insects and vertebrates having found different ways to metabolize xenobiotics within this organelle.
Section snippets
P450 diversity in arthropods
By all estimates, the number of arthropod species and of insects in particular is larger than that of other animals, fungi and plants combined. Coleoptera (beetles) and Lepidoptera (moths and butterflies) together make up more than half of all insect species [3]. The diversity of P450 genes in arthropods has been documented gradually over the last 10 years, with an increasing number of genomes available for study. This rich dataset allows us to study the patterns of evolution of the P450
CYPome diversity: Past and present
In the theoretical scheme shown in Fig. 4, the diversity of CYP families in a typical organism is represented over evolutionary time. In this scheme, many will recognize the typical way that the fossil record is illustrated. The vertical axis represents time, an arrow pointing up to the present, and the horizontal axis represents diversity, such as the prevalence of a certain type of fossil at a particular time in the past. Typically, each group of fossils or clade is represented by an
Neofunctionalization and subfunctionalization
The fate of duplicated genes has been extensively studied [21]. Although one would assume that duplicated genes are initially identical and redundant, this is rarely exactly true (size of the duplicated segment, position effect, allelic sampling) [36] so that the two members of a duplicated pair do not have formally the same probability to have the same fate. However, it is statistically very difficult to detect asymmetric rates of duplicate gene divergence [36]. Gene death
Mitochondrial P450s
It is somewhat paradoxical that during the early historical development of P450 research until the late 1970s, the number of mammalian mitochondrial P450s involved in specific physiological functions was greater than that of microsomal xenobiotic metabolizing P450s (the “3MC-inducible” and “phenobarbital-inducible” types). This view of P450 diversity has changed dramatically, but the idea that mitochondrial P450s are restricted to specific physiological or endocrine functions is still widely
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