Limits...
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.

Show MeSH
Effect of degenerative mutations on the function of a duplicate gene that depends on molecular interactions.A) In the classic model, duplicate genes are redundant and do not interact, so mutation in one copy causes no change in the function (F) and evolve neutrally. B) In the DDC model, duplicate genes, which have two or more modular subfunctions (F1 and F2, blue and yellow), are redundant and do not interact. Degenerative mutations in subfunctions cause no change in function if the subfunction is retained in the other copy and evolve neutrally. C) If a gene depends upon molecular interactions for its function, degenerative mutations in one copy can affect the function of the other and therefore be selected for or against. i) In the case shown, a gene product must dimerize and interact with DNA (white bar) and an accessory factor (orange triangle) for its function (transcriptional activation). ii) After duplication, degenerative mutations that impair the interactions of one copy with the accessory factor yield a nonfunctional product that competes for DNA binding sites, reducing the activity of the other copy. iii) Degenerative mutations that impair DNA binding in one copy yield nonfunctional products that compete for accessory factors and reduce the activity of the other copy. Inhibition also occurs if the duplicate genes do not dimerize but compete for other binding partners.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2527136&req=5

pgen-1000191-g001: Effect of degenerative mutations on the function of a duplicate gene that depends on molecular interactions.A) In the classic model, duplicate genes are redundant and do not interact, so mutation in one copy causes no change in the function (F) and evolve neutrally. B) In the DDC model, duplicate genes, which have two or more modular subfunctions (F1 and F2, blue and yellow), are redundant and do not interact. Degenerative mutations in subfunctions cause no change in function if the subfunction is retained in the other copy and evolve neutrally. C) If a gene depends upon molecular interactions for its function, degenerative mutations in one copy can affect the function of the other and therefore be selected for or against. i) In the case shown, a gene product must dimerize and interact with DNA (white bar) and an accessory factor (orange triangle) for its function (transcriptional activation). ii) After duplication, degenerative mutations that impair the interactions of one copy with the accessory factor yield a nonfunctional product that competes for DNA binding sites, reducing the activity of the other copy. iii) Degenerative mutations that impair DNA binding in one copy yield nonfunctional products that compete for accessory factors and reduce the activity of the other copy. Inhibition also occurs if the duplicate genes do not dimerize but compete for other binding partners.

Mentions: In the classic model [7],[11], having two copies of a gene is phenotypically equivalent to having only one. After duplication, one copy drifts neutrally, free to amass mutations without the constraints of purifying selection (Figure 1A). In the vast majority of cases, degenerative mutations cause one copy to irreversibly lose its function and ultimately disappear from the genome, a process called nonfunctionalization. Rarely, however, mutations that yield a novel, beneficial function occur by chance; selection fixes these mutations and subsequently maintains both the original and “neofunctionalized” copies in the genome. The ultimate fate of a duplicate gene therefore depends on the outcome of a race between neo- and nonfunctionalization. Because gain-of-function mutations are very rare compared to those that compromise function [12]–[15], the vast majority of drifting duplicate genes will be lost, typically within a few million years, long before new functions are expected to evolve [10]. The plausibility of the classic model as a general explanation for the evolution of new functions has therefore been called into question[16],[17].


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)

Effect of degenerative mutations on the function of a duplicate gene that depends on molecular interactions.A) In the classic model, duplicate genes are redundant and do not interact, so mutation in one copy causes no change in the function (F) and evolve neutrally. B) In the DDC model, duplicate genes, which have two or more modular subfunctions (F1 and F2, blue and yellow), are redundant and do not interact. Degenerative mutations in subfunctions cause no change in function if the subfunction is retained in the other copy and evolve neutrally. C) If a gene depends upon molecular interactions for its function, degenerative mutations in one copy can affect the function of the other and therefore be selected for or against. i) In the case shown, a gene product must dimerize and interact with DNA (white bar) and an accessory factor (orange triangle) for its function (transcriptional activation). ii) After duplication, degenerative mutations that impair the interactions of one copy with the accessory factor yield a nonfunctional product that competes for DNA binding sites, reducing the activity of the other copy. iii) Degenerative mutations that impair DNA binding in one copy yield nonfunctional products that compete for accessory factors and reduce the activity of the other copy. Inhibition also occurs if the duplicate genes do not dimerize but compete for other binding partners.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2527136&req=5

pgen-1000191-g001: Effect of degenerative mutations on the function of a duplicate gene that depends on molecular interactions.A) In the classic model, duplicate genes are redundant and do not interact, so mutation in one copy causes no change in the function (F) and evolve neutrally. B) In the DDC model, duplicate genes, which have two or more modular subfunctions (F1 and F2, blue and yellow), are redundant and do not interact. Degenerative mutations in subfunctions cause no change in function if the subfunction is retained in the other copy and evolve neutrally. C) If a gene depends upon molecular interactions for its function, degenerative mutations in one copy can affect the function of the other and therefore be selected for or against. i) In the case shown, a gene product must dimerize and interact with DNA (white bar) and an accessory factor (orange triangle) for its function (transcriptional activation). ii) After duplication, degenerative mutations that impair the interactions of one copy with the accessory factor yield a nonfunctional product that competes for DNA binding sites, reducing the activity of the other copy. iii) Degenerative mutations that impair DNA binding in one copy yield nonfunctional products that compete for accessory factors and reduce the activity of the other copy. Inhibition also occurs if the duplicate genes do not dimerize but compete for other binding partners.
Mentions: In the classic model [7],[11], having two copies of a gene is phenotypically equivalent to having only one. After duplication, one copy drifts neutrally, free to amass mutations without the constraints of purifying selection (Figure 1A). In the vast majority of cases, degenerative mutations cause one copy to irreversibly lose its function and ultimately disappear from the genome, a process called nonfunctionalization. Rarely, however, mutations that yield a novel, beneficial function occur by chance; selection fixes these mutations and subsequently maintains both the original and “neofunctionalized” copies in the genome. The ultimate fate of a duplicate gene therefore depends on the outcome of a race between neo- and nonfunctionalization. Because gain-of-function mutations are very rare compared to those that compromise function [12]–[15], the vast majority of drifting duplicate genes will be lost, typically within a few million years, long before new functions are expected to evolve [10]. The plausibility of the classic model as a general explanation for the evolution of new functions has therefore been called into question[16],[17].

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