Haplotype phasing and inheritance of copy number variants in nuclear families

PLoS One. 2015 Apr 8;10(4):e0122713. doi: 10.1371/journal.pone.0122713. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Alleles
  • DNA Copy Number Variations / genetics*
  • Databases, Genetic
  • Genome, Human*
  • Genotype
  • HapMap Project
  • Haplotypes / genetics*
  • Humans
  • Nuclear Family
  • Oligonucleotide Array Sequence Analysis
  • Pedigree
  • Polymorphism, Single Nucleotide

Grants and funding

This work was funded by workgroup grant SF0180026s09 from the Estonian Ministry of Education and Research and by the European Union grant through the European Regional Development Fund through the Estonian Centre of Excellence in Genomics (to MR). PP was also supported by personal research grant from the Finnish Cultural Foundation. Human Molecular Genetics Research Group was supported from the Estonian Ministry of Education and Research Core Grants (SF0180022s12); European Union through the European Regional Development Fund (project HAPPY PREGNANCY, 3.2.0701.12-0047) and Estonian Science Foundation Grant ETF9030 (to ML). The Estonian Genome Center of University of Tartu received financing from FP7 programs (ENGAGE, OPENGENE), targeted financing from Estonian Government (SF0180142s08), and also from Estonian Research Roadmap through Estonian Ministry of Education and Research, Center of Excellence in Genomics (EXCEGEN) and University of Tartu (SP1GVARENG), Estonian Research Council IUT2-2 and European Regional Development Fund (to AM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.