The cytochrome P450 genesis locus: the origin and evolution of animal cytochrome P450s

Abstract

The neighbourhoods of cytochrome P450 (CYP) genes in deuterostome genomes, as well as those of the cnidarians Nematostella vectensis and Acropora digitifera and the placozoan Trichoplax adhaerens were examined to find clues concerning the evolution of CYP genes in animals. CYP genes created by the 2R whole genome duplications in chordates have been identified. Both microsynteny and macrosynteny were used to identify genes that coexisted near CYP genes in the animal ancestor. We show that all 11 CYP clans began in a common gene environment. The evidence implies the existence of a single locus, which we term the 'cytochrome P450 genesis locus', where one progenitor CYP gene duplicated to create a tandem set of genes that were precursors of the 11 animal CYP clans: CYP Clans 2, 3,4,7,19,20,26,46,51,74 and mitochondrial. These early CYP genes existed side by side before the origin of cnidarians, possibly with a few additional genes interspersed. The Hox gene cluster, WNT genes, an NK gene cluster and at least one ARF gene were close neighbours to this original CYP locus. According to this evolutionary scenario, the CYP74 clan originated from animals and not from land plants nor from a common ancestor of plants and animals. The CYP7 and CYP19 families that are chordate-specific belong to CYP clans that seem to have originated in the CYP genesis locus as well, even though this requires many gene losses to explain their current distribution. The approach to uncovering the CYP genesis locus overcomes confounding effects because of gene conversion, sequence divergence, gene birth and death, and opens the way to understanding the biodiversity of CYP genes, families and subfamilies, which in animals has been obscured by more than 600 Myr of evolution.

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Evolution of the mineralocorticoid receptor: sequence, structure and function

“…The insight that the MR and GR were kin has been important for applying information about each receptor to understanding mineralocorticoid and glucocorticoid responses in normal physiology and in treatment of endocrine-dependent diseases. With the current explosive increase in genomic sequences, in which thousands of human genomes can be studied for mutations, we can expect new insights into the molecular basis for diseases dependent on the MR, GR and their ligands (Markov et al 2009, Hawkins et al 2012, Nelson et al 2013, de Kloet 2014, Gomez-Sanchez & Gomez-Sanchez 2014, Fuller 2015, Rossier et al 2015, de Kloet et al 2016, Jaisser & Farman 2016.…”

Human cytochromes P450 in health and disease

“…CYP20A1 is fascinating because this gene is highly conserved from genomes of the sea anemone and sponge to the human; therefore, CYP20 is one of the original 11 P450 clans (cf. Nelson et al [165]). CYP20A1 mRNA expression is present in human liver, as well as the nasopharynx [166] and CNS regions such as substantia nigra, hippocampus and amygdala [167].…”

Comparative metabolism as a key driver of wildlife species sensitivity to human and veterinary pharmaceuticals

“…More broadly, many Phase I biotransformations of lipophilic xenobiotics are carried out by microsomal monooxygenases, located in the endoplasmic reticulum of the liver and other organs [7]. The haem protein cytochrome P450 provides the active centre of these enzymes and has huge diversity, with 37 cytochrome P450 families currently identified across many animal species [8]. It is hypothesized that the P450 superfamily has undergone repeated rounds of expansion by genome duplication, whereby approximately one and a half billion years ago, the first expansion gave rise to the P450 families primarily involved in metabolizing endogenous fatty acids, cholesterol and its derivatives (CYP4 and CYP11 families) which likely played a key role in maintaining the eukaryotic cell membrane integrity.…”

“…A final major expansion of several P450 families involved in xenobiotic metabolism (including CYP2, CYP3, CYP4 and CYP6), began about 400 Ma. This most recent expansion is thought to have been driven by first the emergence of aquatic organisms onto land, associated with eating toxic plant allelochemicals ('animal-plant warfare'), together with exposure of terrestrial organisms to hydrocarbon-based combustion products in the atmosphere [8][9][10][11][12].…”