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Genomic correlates of relationship QTL involved in fore- versus hind limb divergence in mice.

Pavlicev M, Wagner GP, Noonan JP, Hallgrímsson B, Cheverud JM - Genome Biol Evol (2013)

Bottom Line: Using the known polymorphisms (single nucleotide polymorphisms [SNPs]) between the parental strains, we characterized and compared the genomic regions in which the rQTL, as well as their interaction partners (intQTL), reside.This result is consistent with the widely accepted view that protein-coding mutations have broader pleiotropic effects than cis-regulatory polymorphisms.This is the first study to systematically document the population-level molecular variation underlying the evolution of character individuation.

View Article: PubMed Central - PubMed

Affiliation: Konrad Lorenz Institute for Evolution and Cognition Research, Altenberg, Austria.

ABSTRACT
Divergence of serially homologous elements of organisms is a common evolutionary pattern contributing to increased phenotypic complexity. Here, we study the genomic intervals affecting the variational independence of fore- and hind limb traits within an experimental mouse population. We use an advanced intercross of inbred mouse strains to map the loci associated with the degree of autonomy between fore- and hind limb long bone lengths (loci affecting the relationship between traits, relationship quantitative trait loci [rQTL]). These loci have been proposed to interact locally with the products of pleiotropic genes, thereby freeing the local trait from the variational constraint due to pleiotropic mutations. Using the known polymorphisms (single nucleotide polymorphisms [SNPs]) between the parental strains, we characterized and compared the genomic regions in which the rQTL, as well as their interaction partners (intQTL), reside. We find that these two classes of QTL intervals harbor different kinds of molecular variation. SNPs in rQTL intervals more frequently reside in limb-specific cis-regulatory regions than SNPs in intQTL intervals. The intQTL loci modified by the rQTL, in contrast, show the signature of protein-coding variation. This result is consistent with the widely accepted view that protein-coding mutations have broader pleiotropic effects than cis-regulatory polymorphisms. For both types of QTL intervals, the underlying candidate genes are enriched for genes involved in protein binding. This finding suggests that rQTL effects are caused by local interactions among the products of the causal genes harbored in rQTL and intQTL intervals. This is the first study to systematically document the population-level molecular variation underlying the evolution of character individuation.

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The suggested genetic architecture of divergent traits affects trait covariance. (A) Undifferentiated limbs with fully shared genetic basis (left) and coordinated change in the mean values of both traits (right) as the genetic basis changes (I→I′). (B) Local interaction with shared genetic basis (left) generates the potential in forelimb (FL) to individualize the variation as interacting locus varies (R→R′→R″).
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evt144-F6: The suggested genetic architecture of divergent traits affects trait covariance. (A) Undifferentiated limbs with fully shared genetic basis (left) and coordinated change in the mean values of both traits (right) as the genetic basis changes (I→I′). (B) Local interaction with shared genetic basis (left) generates the potential in forelimb (FL) to individualize the variation as interacting locus varies (R→R′→R″).

Mentions: In this study, our goal was to discover the molecular nature of the mutations involved in character individuation, specifically the individuation of fore- and hind limbs in mice. We hypothesized that character individuation results from the character-specific modification of the effects of pleiotropic genes (fig. 6). In our QTL mapping approach, the modifying genes are identified as rQTL and the pleiotropic genes as genes interacting with rQTL, called intQTL. For genes in intQTL intervals, we find sequences with a high density of nonsynonymous SNPs but no enrichment of SNPs in putative cis-regulatory regions. In contrast, rQTL intervals have a genomic signature that suggests cis-regulatory variation. We thus conclude that, in our system, pleiotropic mutations tend to affect protein coding sequences, whereas mutations causing rQTL effects are more likely cis-regulatory. The specific molecular nature of the modification of pleiotropic effects by rQTL genes cannot be inferred from the current data, except that it likely occurs downstream of both types of genes.Fig. 6.—


Genomic correlates of relationship QTL involved in fore- versus hind limb divergence in mice.

Pavlicev M, Wagner GP, Noonan JP, Hallgrímsson B, Cheverud JM - Genome Biol Evol (2013)

The suggested genetic architecture of divergent traits affects trait covariance. (A) Undifferentiated limbs with fully shared genetic basis (left) and coordinated change in the mean values of both traits (right) as the genetic basis changes (I→I′). (B) Local interaction with shared genetic basis (left) generates the potential in forelimb (FL) to individualize the variation as interacting locus varies (R→R′→R″).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814202&req=5

evt144-F6: The suggested genetic architecture of divergent traits affects trait covariance. (A) Undifferentiated limbs with fully shared genetic basis (left) and coordinated change in the mean values of both traits (right) as the genetic basis changes (I→I′). (B) Local interaction with shared genetic basis (left) generates the potential in forelimb (FL) to individualize the variation as interacting locus varies (R→R′→R″).
Mentions: In this study, our goal was to discover the molecular nature of the mutations involved in character individuation, specifically the individuation of fore- and hind limbs in mice. We hypothesized that character individuation results from the character-specific modification of the effects of pleiotropic genes (fig. 6). In our QTL mapping approach, the modifying genes are identified as rQTL and the pleiotropic genes as genes interacting with rQTL, called intQTL. For genes in intQTL intervals, we find sequences with a high density of nonsynonymous SNPs but no enrichment of SNPs in putative cis-regulatory regions. In contrast, rQTL intervals have a genomic signature that suggests cis-regulatory variation. We thus conclude that, in our system, pleiotropic mutations tend to affect protein coding sequences, whereas mutations causing rQTL effects are more likely cis-regulatory. The specific molecular nature of the modification of pleiotropic effects by rQTL genes cannot be inferred from the current data, except that it likely occurs downstream of both types of genes.Fig. 6.—

Bottom Line: Using the known polymorphisms (single nucleotide polymorphisms [SNPs]) between the parental strains, we characterized and compared the genomic regions in which the rQTL, as well as their interaction partners (intQTL), reside.This result is consistent with the widely accepted view that protein-coding mutations have broader pleiotropic effects than cis-regulatory polymorphisms.This is the first study to systematically document the population-level molecular variation underlying the evolution of character individuation.

View Article: PubMed Central - PubMed

Affiliation: Konrad Lorenz Institute for Evolution and Cognition Research, Altenberg, Austria.

ABSTRACT
Divergence of serially homologous elements of organisms is a common evolutionary pattern contributing to increased phenotypic complexity. Here, we study the genomic intervals affecting the variational independence of fore- and hind limb traits within an experimental mouse population. We use an advanced intercross of inbred mouse strains to map the loci associated with the degree of autonomy between fore- and hind limb long bone lengths (loci affecting the relationship between traits, relationship quantitative trait loci [rQTL]). These loci have been proposed to interact locally with the products of pleiotropic genes, thereby freeing the local trait from the variational constraint due to pleiotropic mutations. Using the known polymorphisms (single nucleotide polymorphisms [SNPs]) between the parental strains, we characterized and compared the genomic regions in which the rQTL, as well as their interaction partners (intQTL), reside. We find that these two classes of QTL intervals harbor different kinds of molecular variation. SNPs in rQTL intervals more frequently reside in limb-specific cis-regulatory regions than SNPs in intQTL intervals. The intQTL loci modified by the rQTL, in contrast, show the signature of protein-coding variation. This result is consistent with the widely accepted view that protein-coding mutations have broader pleiotropic effects than cis-regulatory polymorphisms. For both types of QTL intervals, the underlying candidate genes are enriched for genes involved in protein binding. This finding suggests that rQTL effects are caused by local interactions among the products of the causal genes harbored in rQTL and intQTL intervals. This is the first study to systematically document the population-level molecular variation underlying the evolution of character individuation.

Show MeSH
Related in: MedlinePlus