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PLoS One
2015 Jan 01;107:e0134084. doi: 10.1371/journal.pone.0134084.
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Evolutionary Analyses and Natural Selection of Betaine-Homocysteine S-Methyltransferase (BHMT) and BHMT2 Genes.
Ganu RS
,
Ishida Y
,
Koutmos M
,
Kolokotronis SO
,
Roca AL
,
Garrow TA
,
Schook LB
.
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Betaine-homocysteine S-methyltransferase (BHMT) and BHMT2 convert homocysteine to methionine using betaine and S-methylmethionine, respectively, as methyl donor substrates. Increased levels of homocysteine in blood are associated with cardiovascular disease. Given their role in human health and nutrition, we identified BHMT and BHMT2 genes and proteins from 38 species of deuterostomes including human and non-human primates. We aligned the genes to look for signatures of selection, to infer evolutionary rates and events across lineages, and to identify the evolutionary timing of a gene duplication event that gave rise to two genes, BHMT and BHMT2. We found that BHMT was present in the genomes of the sea urchin, amphibians, reptiles, birds and mammals; BHMT2 was present only across mammals. BHMT and BHMT2 were present in tandem in the genomes of all monotreme, marsupial and placental species examined. Evolutionary rates were accelerated for BHMT2 relative to BHMT. Selective pressure varied across lineages, with the highest dN/dS ratios for BHMT and BHMT2 occurring immediately following the gene duplication event, as determined using GA Branch analysis. Nine codons were found to display signatures suggestive of positive selection; these contribute to the enzymatic or oligomerization domains, suggesting involvement in enzyme function. Gene duplication likely occurred after the divergence of mammals from other vertebrates but prior to the divergence of extant mammalian subclasses, followed by two deletions in BHMT2 that affect oligomerization and methyl donor specificity. The faster evolutionary rate of BHMT2 overall suggests that selective constraints were reduced relative to BHMT. The dN/dS ratios in both BHMT and BHMT2 was highest following the gene duplication, suggesting that purifying selection played a lesser role as the two paralogs diverged in function.
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Fig 1. Phylogeny of BHMT and BHMT2 peptide sequences across deuterostome species.The phylogeny was inferred from an amino acid alignment using maximum likelihood implemented in RAxML [31]. Bootstrap supports are indicated at nodes and were based on 500 pseudoreplicates. We have labeled non-mammalian BHMT, mammalian BHMT and mammalian BHMT2. Note that a duplication event resulted in the appearance of BHMT2 at the base of the mammalian lineage, since BHMT and BHMT2 are both present in all extant placental mammals. The relatively long branches in BHMT2 following the duplication event suggest an accelerated evolutionary rate following a change in evolutionary constraints related to the functional divergence between BHMT and BHMT2.
Fig 2. Mapping of amino acids with signatures of positive selection on the structure of BHMT.Cartoon representation of human BHMT with the four monomers in blue, green, yellow and red. The amino acids with signatures of positive selection (K139, L142, M149, I223, N247, N290, S330, Y363) are displayed as balls and sticks.
Fig 3. Ratio of substitutions per site across a phylogeny of BHMT and BHMT2 coding sequences.The phylogenetic relationships across taxa were constrained based on known evolutionary relationships (http://tolweb.org) [29]. GA Branch analysis selected a model with six classes of dN/dS; next to the color code is indicated the percent proportion of branches in the tree in each class (as a percentage of total tree length measured in expected substitutions per site per unit time). The arrows point to the branches with the highest values of dN/dS, indicating that selective constraints were most relaxed immediately after gene duplication in the lineage ancestral to all living mammals. Relatively higher positive selection, or relatively lower purifying selection, may have affected both BHMT and BHMT2 in the evolutionary interval that immediately followed gene duplication.
Fig 4. Identity (multipip) plot comparing DNA sequences across species, using human BHMT as a reference.Features present within human BHMT are shown at the top of the figure, with the key shown below the figure Sequences compared [43] are those of BHMT (B1) or BHMT2 (B2) for the species listed; the horizontal lines depict the regions of BHMT or BHMT2 for each species that are similar to human BHMT, with the vertical positioning of the line proportionate to the percentage of similarity. Blank regions indicate that sequence similarity was below 50% or that genome coverage was not available for the non-human species. Note that as the evolutionary distance between species increases, the similarity of their sequences decreases; and that B1 and B2 sequences within the same species are not conserved, reflecting their origins in an ancient duplication at the root of the mammalian divergence. The coding regions (exon 2 through exon 8) are highly conserved.
Fig 5. Identity (multipip) plot comparing DNA sequences across species, using human BHMT2 as a reference.Features present within human BHMT2 are shown at the top of the figure, with the key shown below the figure Sequences compared [43] are those of BHMT (B1) or BHMT2 (B2) for the species listed; the horizontal lines depict the regions or BHMT or BHMT2 for each species that are similar to human BHMT2, with the vertical positioning of the line proportionate to the percentage of similarity. Blank regions indicate that sequence similarity was below 50% or that genome coverage was not available for the non-human species. Note that as the evolutionary distance between species increases, the similarity of their sequences decreases; and that B2 and B1 sequences within the same species are not conserved, reflecting their origins in a duplication at the root of the mammalian divergence. The coding regions within the exons shown are highly conserved.
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