Systematic Inference of Copy-number Genotypes from Personal Genome Sequencing Data Reveals Extensive Olfactory Receptor Gene Content Diversity

Overview

Journal PLoS Comput Biol

Specialty Biology

Date 2010 Nov 19

PMID 21085617

Citations 40

Authors

Sebastian M Waszak

Yehudit Hasin

Thomas Zichner

Tsviya Olender

Ifat Keydar

Miriam Khen

Adrian M Stutz

Andreas Schlattl

Doron Lancet

Jan O Korbel

Affiliations

Soon will be listed here.

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.

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References

Korbel J, Abyzov A, Mu X, Carriero N, Cayting P, Zhang Z . PEMer: a computational framework with simulation-based error models for inferring genomic structural variants from massive paired-end sequencing data. Genome Biol. 2009; 10(2):R23. PMC: 2688268. DOI: 10.1186/gb-2009-10-2-r23. View

Zhang F, Gu W, Hurles M, Lupski J . Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet. 2009; 10:451-81. PMC: 4472309. DOI: 10.1146/annurev.genom.9.081307.164217. View

She X, Jiang Z, Clark R, Liu G, Cheng Z, Tuzun E . Shotgun sequence assembly and recent segmental duplications within the human genome. Nature. 2004; 431(7011):927-30. DOI: 10.1038/nature03062. View

Feuk L, Carson A, Scherer S . Structural variation in the human genome. Nat Rev Genet. 2006; 7(2):85-97. DOI: 10.1038/nrg1767. View

Lam H, Mu X, Stutz A, Tanzer A, Cayting P, Snyder M . Nucleotide-resolution analysis of structural variants using BreakSeq and a breakpoint library. Nat Biotechnol. 2009; 28(1):47-55. PMC: 2951730. DOI: 10.1038/nbt.1600. View

Kidd J, Sampas N, Antonacci F, Graves T, Fulton R, Hayden H . Characterization of missing human genome sequences and copy-number polymorphic insertions. Nat Methods. 2010; 7(5):365-71. PMC: 2875995. DOI: 10.1038/nmeth.1451. View

Li R, Fan W, Tian G, Zhu H, He L, Cai J . The sequence and de novo assembly of the giant panda genome. Nature. 2009; 463(7279):311-7. PMC: 3951497. DOI: 10.1038/nature08696. View

Sharp A, Locke D, McGrath S, Cheng Z, Bailey J, Vallente R . Segmental duplications and copy-number variation in the human genome. Am J Hum Genet. 2005; 77(1):78-88. PMC: 1226196. DOI: 10.1086/431652. View

Bentley D, Balasubramanian S, Swerdlow H, Smith G, Milton J, Brown C . Accurate whole human genome sequencing using reversible terminator chemistry. Nature. 2008; 456(7218):53-9. PMC: 2581791. DOI: 10.1038/nature07517. View

10.

Nozawa M, Kawahara Y, Nei M . Genomic drift and copy number variation of sensory receptor genes in humans. Proc Natl Acad Sci U S A. 2007; 104(51):20421-6. PMC: 2154446. DOI: 10.1073/pnas.0709956104. View

11.

Ye K, Schulz M, Long Q, Apweiler R, Ning Z . Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads. Bioinformatics. 2009; 25(21):2865-71. PMC: 2781750. DOI: 10.1093/bioinformatics/btp394. View

12.

Korbel J, Urban A, Affourtit J, Godwin B, Grubert F, Simons J . Paired-end mapping reveals extensive structural variation in the human genome. Science. 2007; 318(5849):420-6. PMC: 2674581. DOI: 10.1126/science.1149504. View

13.

Craddock N, Hurles M, Cardin N, Pearson R, Plagnol V, Robson S . Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature. 2010; 464(7289):713-20. PMC: 2892339. DOI: 10.1038/nature08979. View

14.

Lee S, Hormozdiari F, Alkan C, Brudno M . MoDIL: detecting small indels from clone-end sequencing with mixtures of distributions. Nat Methods. 2009; 6(7):473-4. DOI: 10.1038/nmeth.f.256. View

15.

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

16.

McCarroll S, Kuruvilla F, Korn J, Cawley S, Nemesh J, Wysoker A . Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet. 2008; 40(10):1166-74. DOI: 10.1038/ng.238. View

17.

Campbell P, Stephens P, Pleasance E, OMeara S, Li H, Santarius T . Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet. 2008; 40(6):722-9. PMC: 2705838. DOI: 10.1038/ng.128. View

18.

Xie C, Tammi M . CNV-seq, a new method to detect copy number variation using high-throughput sequencing. BMC Bioinformatics. 2009; 10:80. PMC: 2667514. DOI: 10.1186/1471-2105-10-80. View

19.

Chen K, Wallis J, McLellan M, Larson D, Kalicki J, Pohl C . BreakDancer: an algorithm for high-resolution mapping of genomic structural variation. Nat Methods. 2009; 6(9):677-81. PMC: 3661775. DOI: 10.1038/nmeth.1363. View

20.

Chiang D, Getz G, Jaffe D, OKelly M, Zhao X, Carter S . High-resolution mapping of copy-number alterations with massively parallel sequencing. Nat Methods. 2008; 6(1):99-103. PMC: 2630795. DOI: 10.1038/nmeth.1276. View