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Background  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. 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.    Results  In 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.    Conclusions  Structural 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 material  The online version of this article (doi:10.1186/1471-2164-15-614) contains supplementary material, which is available to authorized users.

Inferring mechanisms of copy number change from haplotype structures at the human DEFA1A3 locus