Abstract
BackgroundThe determination of structural haplotypes at copy number variable regions can indicate the mechanisms responsible for changes in copy number, as well as explain the relationship between gene copy number and expression. However, obtaining spatial information at regions displaying extensive copy number variation, such as the DEFA1A3 locus, is complex, because of the difficulty in the phasing and assembly of these regions. The DEFA1A3 locus is intriguing in that it falls within a region of high linkage disequilibrium, despite its high variability in copy number (n = 3–16); hence, the mechanisms responsible for changes in copy number at this locus are unclear.ResultsIn this study, a region flanking the DEFA1A3 locus was sequenced across 120 independent haplotypes with European ancestry, identifying five common classes of DEFA1A3 haplotype. Assigning DEFA1A3 class to haplotypes within the 1000 Genomes project highlights a significant difference in DEFA1A3 class frequencies between populations with different ancestry. The features of each DEFA1A3 class, for example, the associated DEFA1A3 copy numbers, were initially assessed in a European cohort (n = 599) and replicated in the 1000 Genomes samples, showing within-class similarity, but between-class and between-population differences in the features of the DEFA1A3 locus. Emulsion haplotype fusion-PCR was used to generate 61 structural haplotypes at the DEFA1A3 locus, showing a high within-class similarity in structure.ConclusionsStructural haplotypes across the DEFA1A3 locus indicate that intra-allelic rearrangement is the predominant mechanism responsible for changes in DEFA1A3 copy number, explaining the conservation of linkage disequilibrium across the locus. The identification of common structural haplotypes at the DEFA1A3 locus could aid studies into how DEFA1A3 copy number influences expression, which is currently unclear.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-614) contains supplementary material, which is available to authorized users.
Highlights
The determination of structural haplotypes at copy number variable regions can indicate the mechanisms responsible for changes in copy number, as well as explain the relationship between gene copy number and expression
In the case of the association of low FCGR3B copy number with systemic lupus erythematosus (SLE), it is the presence of a zero-copy FCGR3B haplotype, which leads to aberrant expression of a chimeric gene, FCGR2B,’ in natural killer cells, that may be the key factor in an increased SLE risk, and not a reduced dosage of FCGR3B [13,14]
Non-allelic homologous recombination (NAHR) between haplotypes from the same DEFA1A3 haplotype class. This process would allow changes in DEFA1A3 copy number, via NAHR resulting in chromosomal crossover, but would preserve the surrounding linkage disequilibrium (LD), as rearrangements would occur between haplotypes within the same DEFA1A3 class
Summary
The determination of structural haplotypes at copy number variable regions can indicate the mechanisms responsible for changes in copy number, as well as explain the relationship between gene copy number and expression. An increase in copy number does not always result in increased mRNA levels and, in turn, an increased protein production [12]. In these circumstances, the knowledge of the structure of the locus can be essential for understanding the effect of CNV on phenotype. Understanding the effect of copy number variation on phenotype comes from knowing the copy number of a region, but the spatial arrangement of the locus
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