Abstract
The extent of contribution from common gene copy number (CN) variants in human disease is currently unresolved. Part of the reason for this is the technical difficulty in directly measuring CN variation (CNV) using molecular methods, and the lack of single nucleotide polymorphisms (SNPs) that can tag complex CNV that has arisen multiple times on different SNP haplotypes. One CNV locus implicated in human disease is FCGR. Here we aimed to use next-generation sequencing (NGS) data from the 1000 Genomes Project to assign CN at FCGR3A and FCGR3B and to comprehensively assess the ability of SNPs to tag specific CN variants. A read-depth algorithm was developed (CNVrd) and validated on a subset of HapMap samples using CN assignments that had previously been determined using molecular and microarray methods. At 7 out of 9 other complex loci there was >90% concordance with microarray data. However, given that some prior knowledge of CN is required, the generalizability of CNVrd is limited and should be applied to other complex CNV loci with caution. Subsequently, CN was assigned et FCGR3B using CNVrd in a total of 952 samples from the 1000 Genomes Project, using three classes and SNPs that correlated with duplication were identified. The best tag SNP was observed in the Mexican-American sample set for duplication at FCGR3B. This SNP (rs117435514, r2 = 0.79) also tagged similar duplication in Chinese and Japanese (r2 = 0.35-0.60), but not in Caucasian or African. No tag SNP for duplication at FCGR3A or deletion at FCGR3B was identified in any population. We conclude that it is possible to tag CNV at the FCGR locus, but CN and SNPs have to be characterized and correlated on a population-specific basis.