Detection of de novo copy number deletions from targeted sequencing of trios

Motivation: De novo copy number deletions have been implicated in many diseases, but there is no formal method to date that identifies de novo deletions in parent‐offspring trios from capture‐based sequencing platforms. Results: We developed Minimum Distance for Targeted Sequencing (MDTS) to fill this void. MDTS has similar sensitivity (recall), but a much lower false positive rate compared to less specific CNV callers, resulting in a much higher positive predictive value (precision). MDTS also exhibited much better scalability. Availability and implementation: MDTS is freely available as open source software from the Bioconductor repository. Supplementary information: Supplementary data are available at Bioinformatics online.

[1]  Peter Holmans,et al.  De novo CNVs in bipolar affective disorder and schizophrenia , 2014, Human molecular genetics.

[2]  Bin Alwi Zilfalil,et al.  Mutation screening of IRF6 among families with non-syndromic oral clefts and identification of two novel variants: review of the literature. , 2012, European journal of medical genetics.

[3]  Yufeng Shen,et al.  CANOES: detecting rare copy number variants from whole exome sequencing data , 2014, Nucleic acids research.

[4]  S. Gabriel,et al.  Advances in understanding cancer genomes through second-generation sequencing , 2010, Nature Reviews Genetics.

[5]  Bradley P. Coe,et al.  Genome structural variation discovery and genotyping , 2011, Nature Reviews Genetics.

[6]  M. Metzker.  Sequencing technologies — the next generation , 2010, Nature Reviews Genetics.

[7]  Holger Schwender,et al.  A genome-wide study of de novo deletions identifies a candidate locus for non-syndromic isolated cleft lip/palate risk , 2014, BMC Genetics.

[8]  Jason Li,et al.  CONTRA: copy number analysis for targeted resequencing , 2012, Bioinform..

[9]  A. Magi,et al.  Detection of Genomic Structural Variants from Next-Generation Sequencing Data , 2015, Front. Bioeng. Biotechnol..

[10]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[11]  Alexander Hoischen,et al.  New insights into the generation and role of de novo mutations in health and disease , 2016, Genome Biology.

[12]  Vikas Bansal,et al.  Outlier-Based Identification of Copy Number Variations Using Targeted Resequencing in a Small Cohort of Patients with Tetralogy of Fallot , 2014, PloS one.

[13]  P. Buckley.  Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia , 2009 .

[14]  Holger Schwender,et al.  Fast detection of de novo copy number variants from SNP arrays for case-parent trios , 2012, BMC Bioinformatics.

[15]  J. Veltman,et al.  De novo mutations in human genetic disease , 2012, Nature Reviews Genetics.

[16]  Tom Walsh,et al.  Accurate and exact CNV identification from targeted high-throughput sequence data , 2011, BMC Genomics.

[17]  L. Vissers,et al.  Genome sequencing identifies major causes of severe intellectual disability , 2014, Nature.

[18]  Bradley P. Coe,et al.  Copy number variation detection and genotyping from exome sequence data , 2012, Genome research.

[19]  Seng-Teik Lee,et al.  De novo 2.3 Mb microdeletion of 1q32.2 involving the Van der Woude Syndrome locus , 2013, Molecular Cytogenetics.

[20]  A. Singleton,et al.  Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia , 2008, Science.

[21]  Hanlee P. Ji,et al.  Next-generation DNA sequencing , 2008, Nature Biotechnology.

[22]  Ingo Ruczinski,et al.  Identification of functional variants for cleft lip with or without cleft palate in or near PAX7, FGFR2, and NOG by targeted sequencing of GWAS loci. , 2015, American journal of human genetics.

[23]  Kali T. Witherspoon,et al.  Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID , 2016, Molecular Psychiatry.

[24]  Mahlet G. Tadesse,et al.  Modeling genetic inheritance of copy number variations , 2008, Nucleic acids research.

[25]  Yufeng Shen,et al.  Increased Frequency of De Novo Copy Number Variants in Congenital Heart Disease by Integrative Analysis of Single Nucleotide Polymorphism Array and Exome Sequence Data , 2014, Circulation research.

[26]  Yadong Wang,et al.  Joint detection of copy number variations in parent-offspring trios , 2016, Bioinform..

[27]  Gary D Bader,et al.  Functional impact of global rare copy number variation in autism spectrum disorders , 2010, Nature.

[28]  Eric Talevich,et al.  CNVkit: Genome-Wide Copy Number Detection and Visualization from Targeted DNA Sequencing , 2016, PLoS Comput. Biol..

[29]  Jason C. Ting,et al.  Analysis and visualization of chromosomal abnormalities in SNP data with SNPscan , 2006, BMC Bioinformatics.

[30]  Jake K. Byrnes,et al.  Genome-wide association study of copy number variation in 16,000 cases of eight common diseases and 3,000 shared controls , 2010 .

[31]  Hannes P. Eggertsson,et al.  Parental influence on human germline de novo mutations in 1,548 trios from Iceland , 2017, Nature.

[32]  M. Wigler,et al.  Circular binary segmentation for the analysis of array-based DNA copy number data. , 2004, Biostatistics.

[33]  Ingo Ruczinski,et al.  Visualization of uniparental inheritance, Mendelian inconsistencies, deletions, and parent of origin effects in single nucleotide polymorphism trio data with SNPtrio , 2007, Human mutation.

[34]  E. S. Venkatraman,et al.  A faster circular binary segmentation algorithm for the analysis of array CGH data , 2007, Bioinform..

[35]  Jake K. Byrnes,et al.  Genome-wide association study of copy number variation in 16,000 cases of eight common diseases and 3,000 shared controls , 2010, Nature.

[36]  Frederick E. Dewey,et al.  CLAMMS: a scalable algorithm for calling common and rare copy number variants from exome sequencing data , 2015, Bioinform..

[37]  Lachlan James M. Coin,et al.  cnvOffSeq: detecting intergenic copy number variation using off-target exome sequencing data , 2014, Bioinform..

[38]  Menachem Fromer,et al.  Using XHMM Software to Detect Copy Number Variation in Whole‐Exome Sequencing Data , 2014, Current protocols in human genetics.

[39]  Tien Yin Wong,et al.  cnvCapSeq: detecting copy number variation in long-range targeted resequencing data , 2014, Nucleic acids research.

[40]  J. Lupski,et al.  Non-coding genetic variants in human disease. , 2015, Human molecular genetics.

[41]  Qingguo Wang,et al.  Computational tools for copy number variation (CNV) detection using next-generation sequencing data: features and perspectives , 2013, BMC Bioinformatics.

[42]  Jos Jonkers,et al.  CopywriteR: DNA copy number detection from off-target sequence data , 2015, Genome Biology.

[43]  Ryan M. Layer,et al.  LUMPY: a probabilistic framework for structural variant discovery , 2012, Genome Biology.

[44]  J. R. MacDonald,et al.  A copy number variation map of the human genome , 2015, Nature Reviews Genetics.