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Evolution of a new function by degenerative mutation in cephalochordate steroid receptors.

Bridgham JT, Brown JE, Rodríguez-Marí A, Catchen JM, Thornton JW - PLoS Genet. (2008)

Bottom Line: BfSR is specifically activated by estrogens and recognizes estrogen response elements (EREs) in DNA; BfER does not activate transcription in response to steroid hormones but binds EREs, where it competitively represses BfSR.These results corroborate previous findings that the ancestral steroid receptor was estrogen-sensitive and indicate that, after duplication, BfSR retained the ancestral function, while BfER evolved the capacity to negatively regulate BfSR.Our findings suggest that after duplication of genes whose functions depend on specific molecular interactions, high-probability degenerative mutations can yield novel functions, which are then exposed to positive or negative selection; in either case, the probability of neofunctionalization relative to gene loss is increased compared to existing models.

View Article: PubMed Central - PubMed

Affiliation: Center for Ecology and Evolutionary Biology, University of Oregon, Eugene, Oregon, United States of America.

ABSTRACT
Gene duplication is the predominant mechanism for the evolution of new genes. Major existing models of this process assume that duplicate genes are redundant; degenerative mutations in one copy can therefore accumulate close to neutrally, usually leading to loss from the genome. When gene products dimerize or interact with other molecules for their functions, however, degenerative mutations in one copy may produce repressor alleles that inhibit the function of the other and are therefore exposed to selection. Here, we describe the evolution of a duplicate repressor by simple degenerative mutations in the steroid hormone receptors (SRs), a biologically crucial vertebrate gene family. We isolated and characterized the SRs of the cephalochordate Branchiostoma floridae, which diverged from other chordates just after duplication of the ancestral SR. The B. floridae genome contains two SRs: BfER, an ortholog of the vertebrate estrogen receptors, and BfSR, an ortholog of the vertebrate receptors for androgens, progestins, and corticosteroids. BfSR is specifically activated by estrogens and recognizes estrogen response elements (EREs) in DNA; BfER does not activate transcription in response to steroid hormones but binds EREs, where it competitively represses BfSR. The two genes are partially coexpressed, particularly in ovary and testis, suggesting an ancient role in germ cell development. These results corroborate previous findings that the ancestral steroid receptor was estrogen-sensitive and indicate that, after duplication, BfSR retained the ancestral function, while BfER evolved the capacity to negatively regulate BfSR. Either of two historical mutations that occurred during BfER evolution is sufficient to generate a competitive repressor. Our findings suggest that after duplication of genes whose functions depend on specific molecular interactions, high-probability degenerative mutations can yield novel functions, which are then exposed to positive or negative selection; in either case, the probability of neofunctionalization relative to gene loss is increased compared to existing models.

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Cephalochordates have one ortholog each of the ER and kSR subfamilies.A) Sequence similarity of BfER and BfSR to each other and human steroid receptors. The percent of identical amino acid residues for each pairwise comparison is shown. DBD and LBD, DNA-binding and ligand-binding domains. B) Reduced phylogeny of the steroid receptor gene family. Numbers in parentheses refer to the number of sequences in each group used in the analysis. Estrogen-sensitive receptors, including the ancestral steroid receptor (AncSR1) are in blue; ketosteroid receptors are in yellow. Black triangle, loss of transcriptional activation; yellow triangle, gain of ketosteroid sensitivity in the vertebrate AR/PR/GR/MR clade. Support for each branch is shown as the approximate likelihood ratio (the ratio of the likelihood of the best tree with that node to the best tree without it), the chi-square likelihood confidence statistic for the node, and the Bayesian posterior probability. Nodes that place B. floridae receptors as orthologs of the ERs and kSRs are in red. Scale bar shows expected per-site substitution rate for branch lengths. Complete phylogenies and a list of genes, species, and accessions are in Figures S6, S7, S8 and Table S1. C) Conserved synteny between BfER-containing scaffold 42 and human chromosomes 14 and 6, which contain ERβ (ESR2) and ERα (ESR1), respectively. Green boxes with connecting lines indicate reciprocal BLAST best-hits between scaffold 42 in the B. floridae genome and human chromosome 14; purple boxes, orthologs between Bf scaffold 42 and human chromosome 6. Genes are shown in order with spacing approximately proportional to physical distance. BfER, ESR1, and ESR2 all share orthologous nearest neighbors (red lines).
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pgen-1000191-g002: Cephalochordates have one ortholog each of the ER and kSR subfamilies.A) Sequence similarity of BfER and BfSR to each other and human steroid receptors. The percent of identical amino acid residues for each pairwise comparison is shown. DBD and LBD, DNA-binding and ligand-binding domains. B) Reduced phylogeny of the steroid receptor gene family. Numbers in parentheses refer to the number of sequences in each group used in the analysis. Estrogen-sensitive receptors, including the ancestral steroid receptor (AncSR1) are in blue; ketosteroid receptors are in yellow. Black triangle, loss of transcriptional activation; yellow triangle, gain of ketosteroid sensitivity in the vertebrate AR/PR/GR/MR clade. Support for each branch is shown as the approximate likelihood ratio (the ratio of the likelihood of the best tree with that node to the best tree without it), the chi-square likelihood confidence statistic for the node, and the Bayesian posterior probability. Nodes that place B. floridae receptors as orthologs of the ERs and kSRs are in red. Scale bar shows expected per-site substitution rate for branch lengths. Complete phylogenies and a list of genes, species, and accessions are in Figures S6, S7, S8 and Table S1. C) Conserved synteny between BfER-containing scaffold 42 and human chromosomes 14 and 6, which contain ERβ (ESR2) and ERα (ESR1), respectively. Green boxes with connecting lines indicate reciprocal BLAST best-hits between scaffold 42 in the B. floridae genome and human chromosome 14; purple boxes, orthologs between Bf scaffold 42 and human chromosome 6. Genes are shown in order with spacing approximately proportional to physical distance. BfER, ESR1, and ESR2 all share orthologous nearest neighbors (red lines).

Mentions: Using a reciprocal BLAST search strategy, we identified two loci as steroid receptor orthologs in the completely sequenced genome of B. floridae. Coding sequences of both genes were determined using RACE (rapid amplification of cDNA ends) on RNA extracted from B. floridae adults, and full-length coding sequences were then isolated using the polymerase chain reaction. One of the B. floridae receptors has high amino acid identity to the human ERs, particularly in the DNA-binding domain, and much lower similarity to the AR, PR, GR, and MR. The other has approximately equal similarity to the ERs and the other SRs (Figure 2A, S1, S2).


Evolution of a new function by degenerative mutation in cephalochordate steroid receptors.

Bridgham JT, Brown JE, Rodríguez-Marí A, Catchen JM, Thornton JW - PLoS Genet. (2008)

Cephalochordates have one ortholog each of the ER and kSR subfamilies.A) Sequence similarity of BfER and BfSR to each other and human steroid receptors. The percent of identical amino acid residues for each pairwise comparison is shown. DBD and LBD, DNA-binding and ligand-binding domains. B) Reduced phylogeny of the steroid receptor gene family. Numbers in parentheses refer to the number of sequences in each group used in the analysis. Estrogen-sensitive receptors, including the ancestral steroid receptor (AncSR1) are in blue; ketosteroid receptors are in yellow. Black triangle, loss of transcriptional activation; yellow triangle, gain of ketosteroid sensitivity in the vertebrate AR/PR/GR/MR clade. Support for each branch is shown as the approximate likelihood ratio (the ratio of the likelihood of the best tree with that node to the best tree without it), the chi-square likelihood confidence statistic for the node, and the Bayesian posterior probability. Nodes that place B. floridae receptors as orthologs of the ERs and kSRs are in red. Scale bar shows expected per-site substitution rate for branch lengths. Complete phylogenies and a list of genes, species, and accessions are in Figures S6, S7, S8 and Table S1. C) Conserved synteny between BfER-containing scaffold 42 and human chromosomes 14 and 6, which contain ERβ (ESR2) and ERα (ESR1), respectively. Green boxes with connecting lines indicate reciprocal BLAST best-hits between scaffold 42 in the B. floridae genome and human chromosome 14; purple boxes, orthologs between Bf scaffold 42 and human chromosome 6. Genes are shown in order with spacing approximately proportional to physical distance. BfER, ESR1, and ESR2 all share orthologous nearest neighbors (red lines).
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pgen-1000191-g002: Cephalochordates have one ortholog each of the ER and kSR subfamilies.A) Sequence similarity of BfER and BfSR to each other and human steroid receptors. The percent of identical amino acid residues for each pairwise comparison is shown. DBD and LBD, DNA-binding and ligand-binding domains. B) Reduced phylogeny of the steroid receptor gene family. Numbers in parentheses refer to the number of sequences in each group used in the analysis. Estrogen-sensitive receptors, including the ancestral steroid receptor (AncSR1) are in blue; ketosteroid receptors are in yellow. Black triangle, loss of transcriptional activation; yellow triangle, gain of ketosteroid sensitivity in the vertebrate AR/PR/GR/MR clade. Support for each branch is shown as the approximate likelihood ratio (the ratio of the likelihood of the best tree with that node to the best tree without it), the chi-square likelihood confidence statistic for the node, and the Bayesian posterior probability. Nodes that place B. floridae receptors as orthologs of the ERs and kSRs are in red. Scale bar shows expected per-site substitution rate for branch lengths. Complete phylogenies and a list of genes, species, and accessions are in Figures S6, S7, S8 and Table S1. C) Conserved synteny between BfER-containing scaffold 42 and human chromosomes 14 and 6, which contain ERβ (ESR2) and ERα (ESR1), respectively. Green boxes with connecting lines indicate reciprocal BLAST best-hits between scaffold 42 in the B. floridae genome and human chromosome 14; purple boxes, orthologs between Bf scaffold 42 and human chromosome 6. Genes are shown in order with spacing approximately proportional to physical distance. BfER, ESR1, and ESR2 all share orthologous nearest neighbors (red lines).
Mentions: Using a reciprocal BLAST search strategy, we identified two loci as steroid receptor orthologs in the completely sequenced genome of B. floridae. Coding sequences of both genes were determined using RACE (rapid amplification of cDNA ends) on RNA extracted from B. floridae adults, and full-length coding sequences were then isolated using the polymerase chain reaction. One of the B. floridae receptors has high amino acid identity to the human ERs, particularly in the DNA-binding domain, and much lower similarity to the AR, PR, GR, and MR. The other has approximately equal similarity to the ERs and the other SRs (Figure 2A, S1, S2).

Bottom Line: BfSR is specifically activated by estrogens and recognizes estrogen response elements (EREs) in DNA; BfER does not activate transcription in response to steroid hormones but binds EREs, where it competitively represses BfSR.These results corroborate previous findings that the ancestral steroid receptor was estrogen-sensitive and indicate that, after duplication, BfSR retained the ancestral function, while BfER evolved the capacity to negatively regulate BfSR.Our findings suggest that after duplication of genes whose functions depend on specific molecular interactions, high-probability degenerative mutations can yield novel functions, which are then exposed to positive or negative selection; in either case, the probability of neofunctionalization relative to gene loss is increased compared to existing models.

View Article: PubMed Central - PubMed

Affiliation: Center for Ecology and Evolutionary Biology, University of Oregon, Eugene, Oregon, United States of America.

ABSTRACT
Gene duplication is the predominant mechanism for the evolution of new genes. Major existing models of this process assume that duplicate genes are redundant; degenerative mutations in one copy can therefore accumulate close to neutrally, usually leading to loss from the genome. When gene products dimerize or interact with other molecules for their functions, however, degenerative mutations in one copy may produce repressor alleles that inhibit the function of the other and are therefore exposed to selection. Here, we describe the evolution of a duplicate repressor by simple degenerative mutations in the steroid hormone receptors (SRs), a biologically crucial vertebrate gene family. We isolated and characterized the SRs of the cephalochordate Branchiostoma floridae, which diverged from other chordates just after duplication of the ancestral SR. The B. floridae genome contains two SRs: BfER, an ortholog of the vertebrate estrogen receptors, and BfSR, an ortholog of the vertebrate receptors for androgens, progestins, and corticosteroids. BfSR is specifically activated by estrogens and recognizes estrogen response elements (EREs) in DNA; BfER does not activate transcription in response to steroid hormones but binds EREs, where it competitively represses BfSR. The two genes are partially coexpressed, particularly in ovary and testis, suggesting an ancient role in germ cell development. These results corroborate previous findings that the ancestral steroid receptor was estrogen-sensitive and indicate that, after duplication, BfSR retained the ancestral function, while BfER evolved the capacity to negatively regulate BfSR. Either of two historical mutations that occurred during BfER evolution is sufficient to generate a competitive repressor. Our findings suggest that after duplication of genes whose functions depend on specific molecular interactions, high-probability degenerative mutations can yield novel functions, which are then exposed to positive or negative selection; in either case, the probability of neofunctionalization relative to gene loss is increased compared to existing models.

Show MeSH