title: Systematic inference of copy-number genotypes from personal genome sequencing data reveals extensive olfactory receptor gene content diversity.
abstract: Copy-number variations (CNVs) are widespread in the human genome, but comprehensive assignments of integer locus copy-numbers (i.e., copy-number genotypes) that, for example, enable discrimination of homozygous from heterozygous CNVs, have remained challenging. Here we present CopySeq, a novel computational approach with an underlying statistical framework that analyzes the depth-of-coverage of high-throughput DNA sequencing reads, and can incorporate paired-end and breakpoint junction analysis based CNV-analysis approaches, to infer locus copy-number genotypes. We benchmarked CopySeq by genotyping 500 chromosome 1 CNV regions in 150 personal genomes sequenced at low-coverage. The assessed copy-number genotypes were highly concordant with our performed qPCR experiments (Pearson correlation coefficient 0.94), and with the published results of two microarray platforms (95-99% concordance). We further demonstrated the utility of CopySeq for analyzing gene regions enriched for segmental duplications by comprehensively inferring copy-number genotypes in the CNV-enriched >800 olfactory receptor (OR) human gene and pseudogene loci. CopySeq revealed that OR loci display an extensive range of locus copy-numbers across individuals, with zero to two copies in some OR loci, and two to nine copies in others. Among genetic variants affecting OR loci we identified deleterious variants including CNVs and SNPs affecting ~15% and ~20% of the human OR gene repertoire, respectively, implying that genetic variants with a possible impact on smell perception are widespread. Finally, we found that for several OR loci the reference genome appears to represent a minor-frequency variant, implying a necessary revision of the OR repertoire for future functional studies. CopySeq can ascertain genomic structural variation in specific gene families as well as at a genome-wide scale, where it may enable the quantitative evaluation of CNVs in genome-wide association studies involving high-throughput sequencing.
authors.affiliation: Department of Molecular Genetics, Crown Human Genome Center, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Sebastian M
authors.initials: SM
authors.lastname: Waszak
authors.forename: Yehudit
authors.initials: Y
authors.lastname: Hasin
authors.forename: Thomas
authors.initials: T
authors.lastname: Zichner
authors.forename: Tsviya
authors.initials: T
authors.lastname: Olender
authors.forename: Ifat
authors.initials: I
authors.lastname: Keydar
authors.forename: Miriam
authors.initials: M
authors.lastname: Khen
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Stütz
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlattl
authors.forename: Doron
authors.initials: D
authors.lastname: Lancet
authors.forename: Jan O
authors.initials: JO
authors.lastname: Korbel
mesh_terms: D002874:Chromosome Mapping; D056915:DNA Copy Number Variations; D030541:Databases, Genetic; D014644:Genetic Variation; D005828:Genetics, Population; D016678:Genome; D023281:Genomics / Q000379:methods*; D005838:Genotype; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D018035:Receptors, Odorant / Q000235:genetics*; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D012984:Software; D044465:White People
chemical_list: D018035:Receptors, Odorant