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.
Highlights
Genomic copy number changes are inherited, de novo and somatically acquired deviations from a diploid state within a particular chromosomal segment
As an initial validation of this methodology we analyzed the 133 samples (127 low coverage and 6 high coverage) sequenced as part of the 1000 Genomes Project that had been analyzed for FCGR locus copy number using an integrated approach involving five molecular assays [14]
The wide use of tag SNPs to genotype copy-number variation at the FCGR locus is unlikely to be universally useful; we were unable to identify tags for duplication in any Caucasian, South Asian or African populations, consistent with previous reports [2,14], suggesting that the duplication events happened at multiple times in the respective population histories, in contrast to the major duplication event we discovered in South East Asian (CHB, CHS, JPT, CDX, KHV) and American (MXL, PEL) populations
Summary
Genomic copy number changes are inherited, de novo and somatically acquired deviations from a diploid state within a particular chromosomal segment. At a single locus level, candidate gene studies based on single-probe quantitative polymerase chain reaction analysis with an internal diploid standard have implicated common CN variation (CNV) at a limited number of genes in auto-inflammatory diseases [3,4,5,6,7,8,9,10,11,12] Even these single gene studies are beset by technical challenges [6,13,14,15], meaning that there is not widespread confidence in these data [16,17]. Metaanalysis using studies employing more robust methodologies provides strong evidence supporting a role for FCGR3B deletion in systemic autoimmunity [6]
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