Frequent Loss and Alteration of the <i>MOXD2</i> Gene in Catarrhines and Whales: A Possible Connection with the Evolution of Olfaction

<div><p>The <i>MOXD2</i> gene encodes a membrane-bound monooxygenase similar to dopamine-β-hydroxylase, and has been proposed to be associated with olfaction. In this study, we analyzed <i>MOXD2</i> genes from 64 mammalian species, and identified loss-of-function mutations in apes (humans, Sumatran and Bornean orangutans, and five gibbon species from the four major gibbon genera), toothed whales (killer whales, bottlenose dolphins, finless porpoises, baijis, and sperm whales), and baleen whales (minke whales and fin whales). We also identified a shared 13-nt deletion in the last exon of Old World cercopithecine monkeys that results in conversion of a membrane-bound protein to a soluble form. We hypothesize that the frequent inactivation and alteration of <i>MOXD2</i> genes in catarrhines and whales may be associated with the evolution of olfaction in these clades.</p></div

Likelihood ratio tests of selective pressure on whale <i>MOXD2</i> gene^a.

a<p>Models in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104085#pone-0104085-t004" target="_blank">Table 4</a> were compared using likelihood ratio test.</p>b<p>Twice the difference in log likelihood values between the two models compared.</p>c<p>Degree of freedom.</p>d<p>***, <i>P</i><0.001; **, <i>P</i><0.01; *, <i>P</i><0.05; ns, not significant.</p

Likelihood ratio tests of selective pressure on catarrhine <i>MOXD2</i> gene^a.

a<p>Models in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104085#pone-0104085-t003" target="_blank">Table 3</a> were compared using likelihood ratio test.</p>b<p>Twice the difference in log likelihood values between the two models compared.</p>c<p>Degree of freedom.</p>d<p>***, <i>P</i><0.001; **, <i>P</i><0.01; *, <i>P</i><0.05; ns, not significant.</p

Molecular evolution of the <i>MOXD2</i> gene in catarrhines and whales.

<p>Molecular evolutionary histories of the <i>MOXD2</i> gene in catarrhines (A) and whales (B) are presented. Gene-disrupting mutations are indicated with arrowheads. dN/dS ratios (ω) estimated by the “free-ratio” model are presented on each branch. Asterisks indicate species of which coding sequences were used for the dN/dS analysis. e#, exon number; ins, insertion (followed by number of inserted residues); del, deletion (followed by number of deleted residues); ns, nonsense mutation; sa, splice acceptor mutation; sd, splice donor mutation.</p

Models and parameter estimates for likelihood ratio tests of selective pressure on whale <i>MOXD2</i> gene^a.

a<p>The sequence data file, tree files, control files, and main result files for the codeml analyses were provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104085#pone.0104085.s006" target="_blank">Data S3</a>.</p>b<p>The natural logarithm of the likelihood value.</p>c<p>Number of parameters.</p>d<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104085#pone-0104085-g006" target="_blank">Figure 6B</a>.</p

Complete deletion of the <i>MOXD2</i> gene in the sperm whale.

<p>Sequence comparison of the sperm whale (<i>Physeter macrocephalus</i>) (horizontal) and the bottlenose dolphin (<i>Tursiops truncatus</i>) (vertical) <i>MOXD2</i> gene loci is presented. In the sperm whale, the <i>MOXD2</i> genomic region was replaced with a repeat-rich segment (red box). The bottlenose dolphin <i>MGAM</i>, <i>MOXD2</i>, and <i>PRSS58</i> genes are marked at the right, with coding regions and introns in green and yellow, respectively. Gray horizontal lines indicate gaps in the bottlenose dolphin genome assembly “turTru2”.</p

Complete deletion of the <i>MOXD2</i> gene in gibbons.

<p>(A) Dot plots between the olive baboon <i>MOXD2</i>-<i>PRSS58</i> genomic locus and orthologous regions from five other primate species (the rhesus macaque, the northern white-cheeked gibbon, the western lowland gorilla, the chimpanzee, and the human) are depicted. The northern white-cheeked gibbon <i>MOXD2</i> gene is replaced by a translocated DNA fragment (red box). The locations of the <i>MOXD2</i> and <i>PRSS58</i> genes are indicated at the right (downward arrows), with coding regions and noncoding regions (introns and untranslated regions) in green and yellow, respectively. The human genomic segment containing <i>MOXD2</i> exons 12 and 13 was deleted after the human-chimpanzee divergence (red vertical line). Gray vertical lines in the rhesus macaque and the northern white-cheeked gibbon genomes mark short assembly gaps. Blue arrows indicate chromosome direction (from p- to q-telomere). (B) Deletion of <i>MOXD2</i> gene in four other gibbon species. WGS reads from the hoolock gibbon, the silvery gibbon, the pileated gibbon, the siamang, and the Bornean orangutan were mapped to the repeat-masked chimpanzee <i>MOXD2-PRSS58</i> genomic sequence. Where matched WGS read positions are marked with dots, the <i>MOXD2</i> gene region (red box) lacked matching gibbon WGS reads but not orangutan WGS reads, indicating that the region is missing in these four gibbon species. The locations of the <i>MOXD2</i> and <i>PRSS58</i> genes are indicated at the bottom with coding and noncoding regions in green and yellow, respectively. Parentheses indicate the genome assembly version and position for each species available from the UCSC Genome Browser database.</p

Phylogenetic tree of the species investigated in this study.

<p>The major groups are indicated either on the branch or to the right. Species with a mutated <i>MOXD2</i> gene are indicated by color: red, gene loss by gene deletion, exon deletion, or ORF-disrupting mutations; blue, C-terminal truncation due to a 13-nt deletion in the last exon. Numbers in parentheses correspond to those in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104085#pone-0104085-t001" target="_blank">Table 1</a>. K-Pg, Cretaceous-Paleogene boundary.</p