Dataset Information

Intraspecific evolution of human RCCX copy number variation traced by haplotypes of the CYP21A2 gene.

ABSTRACT: The RCCX region is a complex, multiallelic, tandem copy number variation (CNV). Two complete genes, complement component 4 (C4) and steroid 21-hydroxylase (CYP21A2, formerly CYP21B), reside in its variable region. RCCX is prone to nonallelic homologous recombination (NAHR) such as unequal crossover, generating duplications and deletions of RCCX modules, and gene conversion. A series of allele-specific long-range polymerase chain reaction coupled to the whole-gene sequencing of CYP21A2 was developed for molecular haplotyping. By means of the developed techniques, 35 different kinds of CYP21A2 haplotype variant were experimentally determined from 112 unrelated European subjects. The number of the resolved CYP21A2 haplotype variants was increased to 61 by bioinformatic haplotype reconstruction. The CYP21A2 haplotype variants could be assigned to the haplotypic RCCX CNV structures (the copy number of RCCX modules) in most cases. The genealogy network constructed from the CYP21A2 haplotype variants delineated the origin of RCCX structures. The different RCCX structures were located in tight groups. The minority of groups with identical RCCX structure occurred once in the network, implying monophyletic origin, but the majority of groups occurred several times and in different locations, indicating polyphyletic origin. The monophyletic groups were often created by single unequal crossover, whereas recurrent unequal crossover events generated some of the polyphyletic groups. As a result of recurrent NAHR events, more CYP21A2 haplotype variants with different allele patterns belonged to the same RCCX structure. The intraspecific evolution of RCCX CNV described here has provided a reasonable expectation for that of complex, multiallelic, tandem CNVs in humans.

SUBMITTER: Banlaki Z

PROVIDER: S-EPMC3595039 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Intraspecific evolution of human RCCX copy number variation traced by haplotypes of the CYP21A2 gene.

Bánlaki Zsófia Z Szabó Julianna Anna JA Szilágyi Ágnes Á Patócs Attila A Prohászka Zoltán Z Füst George G Doleschall Márton M

Genome biology and evolution 20130101 1

The RCCX region is a complex, multiallelic, tandem copy number variation (CNV). Two complete genes, complement component 4 (C4) and steroid 21-hydroxylase (CYP21A2, formerly CYP21B), reside in its variable region. RCCX is prone to nonallelic homologous recombination (NAHR) such as unequal crossover, generating duplications and deletions of RCCX modules, and gene conversion. A series of allele-specific long-range polymerase chain reaction coupled to the whole-gene sequencing of CYP21A2 was develo ...[more]

PMID: 23241443

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Project description:Many nematodes form dauer larvae when exposed to unfavorable conditions, representing an example of phenotypic plasticity and a major survival and dispersal strategy. In Caenorhabditis elegans, the regulation of dauer induction is a model for pheromone, insulin, and steroid-hormone signaling. Recent studies in Pristionchus pacificus revealed substantial natural variation in various aspects of dauer development, i.e. pheromone production and sensing and dauer longevity and fitness. One intriguing example is a strain from Ohio, having extremely long-lived dauers associated with very high fitness and often forming the most dauers in response to other strains' pheromones, including the reference strain from California. While such examples have been suggested to represent intraspecific competition among strains, the molecular mechanisms underlying these dauer-associated patterns are currently unknown. We generated recombinant-inbred-lines between the Californian and Ohioan strains and used quantitative-trait-loci analysis to investigate the molecular mechanism determining natural variation in dauer development. Surprisingly, we discovered that the orphan gene dauerless controls dauer formation by copy number variation. The Ohioan strain has one dauerless copy causing high dauer formation, whereas the Californian strain has two copies, resulting in strongly reduced dauer formation. Transgenic animals expressing multiple copies do not form dauers. dauerless is exclusively expressed in CAN neurons, and both CAN ablation and dauerless mutations increase dauer formation. Strikingly, dauerless underwent several duplications and acts in parallel or downstream of steroid-hormone signaling but upstream of the nuclear-hormone-receptor daf-12. We identified the novel or fast-evolving gene dauerless as inhibitor of dauer development. Our findings reveal the importance of gene duplications and copy number variations for orphan gene function and suggest daf-12 as major target for dauer regulation. We discuss the consequences of the novel vs. fast-evolving nature of orphans for the evolution of developmental networks and their role in natural variation and intraspecific competition.

Dataset Information

Intraspecific evolution of human RCCX copy number variation traced by haplotypes of the CYP21A2 gene.

Publications

Intraspecific evolution of human RCCX copy number variation traced by haplotypes of the CYP21A2 gene.

Similar Datasets

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