title: Haplotype phasing and inheritance of copy number variants in nuclear families.
abstract: DNA copy number variants (CNVs) that alter the copy number of a particular DNA segment in the genome play an important role in human phenotypic variability and disease susceptibility. A number of CNVs overlapping with genes have been shown to confer risk to a variety of human diseases thus highlighting the relevance of addressing the variability of CNVs at a higher resolution. So far, it has not been possible to deterministically infer the allelic composition of different haplotypes present within the CNV regions. We have developed a novel computational method, called PiCNV, which enables to resolve the haplotype sequence composition within CNV regions in nuclear families based on SNP genotyping microarray data. The algorithm allows to i) phase normal and CNV-carrying haplotypes in the copy number variable regions, ii) resolve the allelic copies of rearranged DNA sequence within the haplotypes and iii) infer the heritability of identified haplotypes in trios or larger nuclear families. To our knowledge this is the first program available that can deterministically phase null, mono-, di-, tri- and tetraploid genotypes in CNV loci. We applied our method to study the composition and inheritance of haplotypes in CNV regions of 30 HapMap Yoruban trios and 34 Estonian families. For 93.6% of the CNV loci, PiCNV enabled to unambiguously phase normal and CNV-carrying haplotypes and follow their transmission in the corresponding families. Furthermore, allelic composition analysis identified the co-occurrence of alternative allelic copies within 66.7% of haplotypes carrying copy number gains. We also observed less frequent transmission of CNV-carrying haplotypes from parents to children compared to normal haplotypes and identified an emergence of several de novo deletions and duplications in the offspring.
authors: Department of Bioinformatics, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: Priit
authors: P
authors: Palta
authors: Department of Bioinformatics, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; Estonian Biocentre, Tartu, Estonia.
authors: Lauris
authors: L
authors: Kaplinski
authors: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors: Liina
authors: L
authors: Nagirnaja
authors: Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors: Andres
authors: A
authors: Veidenberg
authors: Estonian Biocentre, Tartu, Estonia; Chair of Mathematical Statistics, Institute of Mathematical Statistics, University of Tartu, Tartu, Estonia.
authors: Märt
authors: M
authors: Möls
authors: The Estonian Genome Center of University of Tartu, Tartu, Estonia.
authors: Mari
authors: M
authors: Nelis
authors: The Estonian Genome Center of University of Tartu, Tartu, Estonia; Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, United States of America; Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America; Broad Institute, Cambridge, Massachusetts, United States of America.
authors: Tõnu
authors: T
authors: Esko
authors: Estonian Biocentre, Tartu, Estonia; The Estonian Genome Center of University of Tartu, Tartu, Estonia; Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors: Andres
authors: A
authors: Metspalu
authors: Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
authors: Maris
authors: M
authors: Laan
authors: Department of Bioinformatics, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia; Estonian Biocentre, Tartu, Estonia.
authors: Maido
authors: M
authors: Remm
mesh_terms: D000465:Algorithms; D000483:Alleles; D056915:DNA Copy Number Variations / Q000235:genetics*; D030541:Databases, Genetic; D015894:Genome, Human; D005838:Genotype; D060148:HapMap Project; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D009679:Nuclear Family; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide