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Title: Determining multiallelic complex copy number and sequence variation from high coverage exome sequencing data
Authors: Forni, Diego
Martin, Diana
Abujaber, Razan
Sharp, A. J.
Sironi, M.
Hollox, Edward J.
First Published: 2-Nov-2015
Publisher: BioMed Central
Citation: BMC Genomics, 2015, 16 (1) : 891
Abstract: BACKGROUND: Copy number variation (CNV) is a major component of genomic variation, yet methods to accurately type genomic CNV lag behind methods that type single nucleotide variation. High-throughput sequencing can contribute to these methods by using sequence read depth, which takes the number of reads that map to a given part of the reference genome as a proxy for copy number of that region, and compares across samples. Furthermore, high-throughput sequencing also provides information on the sequence differences between copies within and between individuals. METHODS: In this study we use high-coverage phase 3 exome sequences of the 1000 Genomes project to infer diploid copy number of the beta-defensin genomic region, a well-studied CNV that carries several beta-defensin genes involved in the antimicrobial response, signalling, and fertility. We also use these data to call sequence variants, a particular challenge given the multicopy nature of the region. RESULTS: We confidently call copy number and sequence variation of the beta-defensin genes on 1285 samples from 26 global populations, validate copy number using Nanostring nCounter and triplex paralogue ratio test data. We use the copy number calls to verify the genomic extent of the CNV and validate sequence calls using analysis of cloned PCR products. We identify novel variation, mostly individually rare, predicted to alter amino-acid sequence in the beta-defensin genes. Such novel variants may alter antimicrobial properties or have off-target receptor interactions, and may contribute to individuality in immunological response and fertility. CONCLUSIONS: Given that 81 % of identified sequence variants were not previously in dbSNP, we show that sequence variation in multiallelic CNVs represent an unappreciated source of genomic diversity.
DOI Link: 10.1186/s12864-015-2123-y
eISSN: 1471-2164
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2015 Forni et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.
Appears in Collections:Published Articles, Dept. of Genetics

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