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Melanism in peromyscus is caused by independent mutations in agouti.

Kingsley EP, Manceau M, Wiley CD, Hoekstra HE - PLoS ONE (2009)

Bottom Line: Identifying the molecular basis of phenotypes that have evolved independently can provide insight into the ways genetic and developmental constraints influence the maintenance of phenotypic diversity.While variation in the Mc1r coding region does not correlate with melanism in any population, in a New Hampshire population, we find that a 125-kb deletion, which includes the upstream regulatory region and exons 1 and 2 of Agouti, results in a loss of Agouti expression and is perfectly associated with melanic color.In a second population from Alaska, we find that a premature stop codon in exon 3 of Agouti is associated with a similar melanic phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Organismic and Evolutionary Biology and the Museum of Comparative Zoology, Harvard University, Cambridge, Massachusetts, United States of America. ekingsley@oeb.harvard.edu

ABSTRACT
Identifying the molecular basis of phenotypes that have evolved independently can provide insight into the ways genetic and developmental constraints influence the maintenance of phenotypic diversity. Melanic (darkly pigmented) phenotypes in mammals provide a potent system in which to study the genetic basis of naturally occurring mutant phenotypes because melanism occurs in many mammals, and the mammalian pigmentation pathway is well understood. Spontaneous alleles of a few key pigmentation loci are known to cause melanism in domestic or laboratory populations of mammals, but in natural populations, mutations at one gene, the melanocortin-1 receptor (Mc1r), have been implicated in the vast majority of cases, possibly due to its minimal pleiotropic effects. To investigate whether mutations in this or other genes cause melanism in the wild, we investigated the genetic basis of melanism in the rodent genus Peromyscus, in which melanic mice have been reported in several populations. We focused on two genes known to cause melanism in other taxa, Mc1r and its antagonist, the agouti signaling protein (Agouti). While variation in the Mc1r coding region does not correlate with melanism in any population, in a New Hampshire population, we find that a 125-kb deletion, which includes the upstream regulatory region and exons 1 and 2 of Agouti, results in a loss of Agouti expression and is perfectly associated with melanic color. In a second population from Alaska, we find that a premature stop codon in exon 3 of Agouti is associated with a similar melanic phenotype. These results show that melanism has evolved independently in these populations through mutations in the same gene, and suggest that melanism produced by mutations in genes other than Mc1r may be more common than previously thought.

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Schematic and VISTA alignment of the Mc1r and Agouti loci in Mus, Rattus, and Peromyscus.Dark blocks represent coding sequences; light blocks represent untranslated exons. Mc1r consists of a single exon that spans approximately 1.5 kb similar to its Mus ortholog. The Agouti locus spans over 100 kb. Grey arrows indicate a duplication present in all three taxa; brackets indicate the inversion of the duplicated region in Peromyscus. Asterisks mark the location of a conserved region that is necessary for Agouti expression (Y. Chen and G. S. Barsh, pers. comm.). The red line and red arrowhead mark the locations of the aΔ125kb deletion and the aQ65term premature stop codon, respectively. The conservation plot was generated by aligning Peromyscus BAC sequence and sequence from the Rattus genome using LAGAN [75] and plotting conservation with mVISTA [76].
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pone-0006435-g002: Schematic and VISTA alignment of the Mc1r and Agouti loci in Mus, Rattus, and Peromyscus.Dark blocks represent coding sequences; light blocks represent untranslated exons. Mc1r consists of a single exon that spans approximately 1.5 kb similar to its Mus ortholog. The Agouti locus spans over 100 kb. Grey arrows indicate a duplication present in all three taxa; brackets indicate the inversion of the duplicated region in Peromyscus. Asterisks mark the location of a conserved region that is necessary for Agouti expression (Y. Chen and G. S. Barsh, pers. comm.). The red line and red arrowhead mark the locations of the aΔ125kb deletion and the aQ65term premature stop codon, respectively. The conservation plot was generated by aligning Peromyscus BAC sequence and sequence from the Rattus genome using LAGAN [75] and plotting conservation with mVISTA [76].

Mentions: The phenotypic similarity between melanic Peromyscus and mouse (Mus) Agouti mutants and the recessive nature of the melanic allele in P. maniculatus suggested that Agouti is a strong candidate gene. We sequenced a 180 kb BAC clone containing Agouti from P. maniculatus rufinus and compared it to the corresponding sequence from the Mus genome. In Mus, the Agouti gene consists of four non-coding exons (1A, 1A′, 1B, and 1C) and three protein-coding exons (2, 3, and 4); this arrangement appears to be conserved in other mammals, including rat (Rattus). Sequences orthologous to the exons in Mus and Rattus are conserved in the P. maniculatus sequence (Figure 2). However, when compared to the published genome sequences of Mus and Rattus, an inversion of the region containing exons 1A and 1A' is present in P. maniculatus. Inversions in this region are sometimes associated with differences in ventral pigmentation in different strains of Mus [19].


Melanism in peromyscus is caused by independent mutations in agouti.

Kingsley EP, Manceau M, Wiley CD, Hoekstra HE - PLoS ONE (2009)

Schematic and VISTA alignment of the Mc1r and Agouti loci in Mus, Rattus, and Peromyscus.Dark blocks represent coding sequences; light blocks represent untranslated exons. Mc1r consists of a single exon that spans approximately 1.5 kb similar to its Mus ortholog. The Agouti locus spans over 100 kb. Grey arrows indicate a duplication present in all three taxa; brackets indicate the inversion of the duplicated region in Peromyscus. Asterisks mark the location of a conserved region that is necessary for Agouti expression (Y. Chen and G. S. Barsh, pers. comm.). The red line and red arrowhead mark the locations of the aΔ125kb deletion and the aQ65term premature stop codon, respectively. The conservation plot was generated by aligning Peromyscus BAC sequence and sequence from the Rattus genome using LAGAN [75] and plotting conservation with mVISTA [76].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2713407&req=5

pone-0006435-g002: Schematic and VISTA alignment of the Mc1r and Agouti loci in Mus, Rattus, and Peromyscus.Dark blocks represent coding sequences; light blocks represent untranslated exons. Mc1r consists of a single exon that spans approximately 1.5 kb similar to its Mus ortholog. The Agouti locus spans over 100 kb. Grey arrows indicate a duplication present in all three taxa; brackets indicate the inversion of the duplicated region in Peromyscus. Asterisks mark the location of a conserved region that is necessary for Agouti expression (Y. Chen and G. S. Barsh, pers. comm.). The red line and red arrowhead mark the locations of the aΔ125kb deletion and the aQ65term premature stop codon, respectively. The conservation plot was generated by aligning Peromyscus BAC sequence and sequence from the Rattus genome using LAGAN [75] and plotting conservation with mVISTA [76].
Mentions: The phenotypic similarity between melanic Peromyscus and mouse (Mus) Agouti mutants and the recessive nature of the melanic allele in P. maniculatus suggested that Agouti is a strong candidate gene. We sequenced a 180 kb BAC clone containing Agouti from P. maniculatus rufinus and compared it to the corresponding sequence from the Mus genome. In Mus, the Agouti gene consists of four non-coding exons (1A, 1A′, 1B, and 1C) and three protein-coding exons (2, 3, and 4); this arrangement appears to be conserved in other mammals, including rat (Rattus). Sequences orthologous to the exons in Mus and Rattus are conserved in the P. maniculatus sequence (Figure 2). However, when compared to the published genome sequences of Mus and Rattus, an inversion of the region containing exons 1A and 1A' is present in P. maniculatus. Inversions in this region are sometimes associated with differences in ventral pigmentation in different strains of Mus [19].

Bottom Line: Identifying the molecular basis of phenotypes that have evolved independently can provide insight into the ways genetic and developmental constraints influence the maintenance of phenotypic diversity.While variation in the Mc1r coding region does not correlate with melanism in any population, in a New Hampshire population, we find that a 125-kb deletion, which includes the upstream regulatory region and exons 1 and 2 of Agouti, results in a loss of Agouti expression and is perfectly associated with melanic color.In a second population from Alaska, we find that a premature stop codon in exon 3 of Agouti is associated with a similar melanic phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Organismic and Evolutionary Biology and the Museum of Comparative Zoology, Harvard University, Cambridge, Massachusetts, United States of America. ekingsley@oeb.harvard.edu

ABSTRACT
Identifying the molecular basis of phenotypes that have evolved independently can provide insight into the ways genetic and developmental constraints influence the maintenance of phenotypic diversity. Melanic (darkly pigmented) phenotypes in mammals provide a potent system in which to study the genetic basis of naturally occurring mutant phenotypes because melanism occurs in many mammals, and the mammalian pigmentation pathway is well understood. Spontaneous alleles of a few key pigmentation loci are known to cause melanism in domestic or laboratory populations of mammals, but in natural populations, mutations at one gene, the melanocortin-1 receptor (Mc1r), have been implicated in the vast majority of cases, possibly due to its minimal pleiotropic effects. To investigate whether mutations in this or other genes cause melanism in the wild, we investigated the genetic basis of melanism in the rodent genus Peromyscus, in which melanic mice have been reported in several populations. We focused on two genes known to cause melanism in other taxa, Mc1r and its antagonist, the agouti signaling protein (Agouti). While variation in the Mc1r coding region does not correlate with melanism in any population, in a New Hampshire population, we find that a 125-kb deletion, which includes the upstream regulatory region and exons 1 and 2 of Agouti, results in a loss of Agouti expression and is perfectly associated with melanic color. In a second population from Alaska, we find that a premature stop codon in exon 3 of Agouti is associated with a similar melanic phenotype. These results show that melanism has evolved independently in these populations through mutations in the same gene, and suggest that melanism produced by mutations in genes other than Mc1r may be more common than previously thought.

Show MeSH
Related in: MedlinePlus