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Haplotype phasing and inheritance of copy number variants in nuclear families.

Palta P, Kaplinski L, Nagirnaja L, Veidenberg A, Möls M, Nelis M, Esko T, Metspalu A, Laan M, Remm M - PLoS ONE (2015)

Bottom Line: 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.We applied our method to study the composition and inheritance of haplotypes in CNV regions of 30 HapMap Yoruban trios and 34 Estonian families.Furthermore, allelic composition analysis identified the co-occurrence of alternative allelic copies within 66.7% of haplotypes carrying copy number gains.

View Article: PubMed Central - PubMed

Affiliation: 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.

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 , 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.

No MeSH data available.


Related in: MedlinePlus

Examples of unambiguously phased CNV regions involving deletion- and duplication-carrying haplotypes in families.(A) Inherited 820 kb-long deletion on chromosome 16:15369798–16190572 in family T3. A deletion-carrying haplotype (cn = 0) is inherited from father (C010008) to son (Child 2, C010010). The daughter (Child 1, C010011) has inherited normal haplotypes (cn = 1) from both parents. (B) Inherited 166 kb-long duplication on chromosome 10:47007374–47173619 in family T14. A duplication-carrying haplotype (cn = 2) is inherited from father (C010046) to one son (Child 1, C010049) and daughter (Child 2, C010052). All other children have inherited normal haplotypes (cn = 1) from both parents. Coloured arrows show the transmission of specific haplotypes from parents to offspring in a given CNV region. Respective B-allele frequency (BAF, upper panel) and total fluorescent signal intensity (Log R Ratio—LRR, lower panel) plots from Illumina Genome Viewer are shown next to the parents and each child.
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pone.0122713.g003: Examples of unambiguously phased CNV regions involving deletion- and duplication-carrying haplotypes in families.(A) Inherited 820 kb-long deletion on chromosome 16:15369798–16190572 in family T3. A deletion-carrying haplotype (cn = 0) is inherited from father (C010008) to son (Child 2, C010010). The daughter (Child 1, C010011) has inherited normal haplotypes (cn = 1) from both parents. (B) Inherited 166 kb-long duplication on chromosome 10:47007374–47173619 in family T14. A duplication-carrying haplotype (cn = 2) is inherited from father (C010046) to one son (Child 1, C010049) and daughter (Child 2, C010052). All other children have inherited normal haplotypes (cn = 1) from both parents. Coloured arrows show the transmission of specific haplotypes from parents to offspring in a given CNV region. Respective B-allele frequency (BAF, upper panel) and total fluorescent signal intensity (Log R Ratio—LRR, lower panel) plots from Illumina Genome Viewer are shown next to the parents and each child.

Mentions: PiCNV works by examining consecutive regular (two-letter) and CNV genotypes in each family member in a CNV region present in any member of the corresponding family. It will test all possible haplotypes and their transmission according to all Mendelian inheritance scenarios in the studied CNV locus in a given family. If the family includes more than one child, all children will be considered simultaneously in this step and conclusively, for each CNV locus, PiCNV will select these normal and deletion- or duplication-carrying haplotypes and transmission scenarios that can explain the allelic composition for every member of the corresponding family (Fig 3). In case it is not possible to explain the allelic composition in an offspring by Mendelian transmission of parental haplotypes, non-Mendelian transmission scenarios—de novo deletion/duplication events and uniparental isodisomy/heterodisomy are automatically considered. Provided informative genotypes are present in parental haplotypes, PiCNV is also able to determine on which parental chromosome the de novo event has occurred. Complete source code and Linux binaries for PiCNV are available from http://bioinfo.ut.ee/picnv.


Haplotype phasing and inheritance of copy number variants in nuclear families.

Palta P, Kaplinski L, Nagirnaja L, Veidenberg A, Möls M, Nelis M, Esko T, Metspalu A, Laan M, Remm M - PLoS ONE (2015)

Examples of unambiguously phased CNV regions involving deletion- and duplication-carrying haplotypes in families.(A) Inherited 820 kb-long deletion on chromosome 16:15369798–16190572 in family T3. A deletion-carrying haplotype (cn = 0) is inherited from father (C010008) to son (Child 2, C010010). The daughter (Child 1, C010011) has inherited normal haplotypes (cn = 1) from both parents. (B) Inherited 166 kb-long duplication on chromosome 10:47007374–47173619 in family T14. A duplication-carrying haplotype (cn = 2) is inherited from father (C010046) to one son (Child 1, C010049) and daughter (Child 2, C010052). All other children have inherited normal haplotypes (cn = 1) from both parents. Coloured arrows show the transmission of specific haplotypes from parents to offspring in a given CNV region. Respective B-allele frequency (BAF, upper panel) and total fluorescent signal intensity (Log R Ratio—LRR, lower panel) plots from Illumina Genome Viewer are shown next to the parents and each child.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390228&req=5

pone.0122713.g003: Examples of unambiguously phased CNV regions involving deletion- and duplication-carrying haplotypes in families.(A) Inherited 820 kb-long deletion on chromosome 16:15369798–16190572 in family T3. A deletion-carrying haplotype (cn = 0) is inherited from father (C010008) to son (Child 2, C010010). The daughter (Child 1, C010011) has inherited normal haplotypes (cn = 1) from both parents. (B) Inherited 166 kb-long duplication on chromosome 10:47007374–47173619 in family T14. A duplication-carrying haplotype (cn = 2) is inherited from father (C010046) to one son (Child 1, C010049) and daughter (Child 2, C010052). All other children have inherited normal haplotypes (cn = 1) from both parents. Coloured arrows show the transmission of specific haplotypes from parents to offspring in a given CNV region. Respective B-allele frequency (BAF, upper panel) and total fluorescent signal intensity (Log R Ratio—LRR, lower panel) plots from Illumina Genome Viewer are shown next to the parents and each child.
Mentions: PiCNV works by examining consecutive regular (two-letter) and CNV genotypes in each family member in a CNV region present in any member of the corresponding family. It will test all possible haplotypes and their transmission according to all Mendelian inheritance scenarios in the studied CNV locus in a given family. If the family includes more than one child, all children will be considered simultaneously in this step and conclusively, for each CNV locus, PiCNV will select these normal and deletion- or duplication-carrying haplotypes and transmission scenarios that can explain the allelic composition for every member of the corresponding family (Fig 3). In case it is not possible to explain the allelic composition in an offspring by Mendelian transmission of parental haplotypes, non-Mendelian transmission scenarios—de novo deletion/duplication events and uniparental isodisomy/heterodisomy are automatically considered. Provided informative genotypes are present in parental haplotypes, PiCNV is also able to determine on which parental chromosome the de novo event has occurred. Complete source code and Linux binaries for PiCNV are available from http://bioinfo.ut.ee/picnv.

Bottom Line: 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.We applied our method to study the composition and inheritance of haplotypes in CNV regions of 30 HapMap Yoruban trios and 34 Estonian families.Furthermore, allelic composition analysis identified the co-occurrence of alternative allelic copies within 66.7% of haplotypes carrying copy number gains.

View Article: PubMed Central - PubMed

Affiliation: 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.

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 , 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.

No MeSH data available.


Related in: MedlinePlus