Limits...
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 de novo copy-number variants in offspring.(A) De novo arisen 67 kb-long deletion on chromosome 6:80596173–80663256 in family T39. Children 1–3 (C010135, C010136 and C010137) have inherited one normal haplotype from both parents. One child (Child 4, C010138) has inherited one normal haplotype from his mother (C010134) and a paternal haplotype with a de novo deletion event in the corresponding region. (B) De novo arisen 167 kb-long duplication on chromosome 2:110175122–110331912 in family T07. The only child (C010026) has inherited one normal haplotype from her mother (C010025) and a paternal haplotype with a de novo intra-chromosomal duplication event in the corresponding region. 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.g004: Examples of de novo copy-number variants in offspring.(A) De novo arisen 67 kb-long deletion on chromosome 6:80596173–80663256 in family T39. Children 1–3 (C010135, C010136 and C010137) have inherited one normal haplotype from both parents. One child (Child 4, C010138) has inherited one normal haplotype from his mother (C010134) and a paternal haplotype with a de novo deletion event in the corresponding region. (B) De novo arisen 167 kb-long duplication on chromosome 2:110175122–110331912 in family T07. The only child (C010026) has inherited one normal haplotype from her mother (C010025) and a paternal haplotype with a de novo intra-chromosomal duplication event in the corresponding region. 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: The subsequent three groups of CNV regions were subjected to haplotype phasing using the PiCNV program in both HapMap YRI and EGCUT datasets combined. The PiCNV was able to unambiguously phase 93.6% (1414 out of 1510) of all CNV regions and automatically determine the distribution of normal and deletion or duplication-carrying haplotypes in parents and their offspring (Table 2; Figs 3 and 4). The unambiguous phasing efficiency was the highest in group A of CNV regions, reaching 96.3% (1366 out of 1418; Table 2). All remaining CNV regions (3.7%; 52 out of 1418) in group A were duplication CNV regions (CN≥3) containing only uninformative monomorphic genotypes (e.g. ‘AA’ or ‘AAA’, etc.) or CNV probes that do not interrogate any SNP variants. Subsequently, PiCNV was not able to unambiguously distinguish between exact maternal and paternal haplotypes and/or follow their transmission in offspring, resulting in several equally possible Mendelian transmissions in the corresponding families (S2a Fig). Similar limitations were also observed in several CNV regions in groups B and C resulting in unambiguous phasing in 60% and 33.3% of CNV regions in those groups, respectively (Table 2). In groups B and C, higher phasing efficiency was observed for deletion CNV loci and in larger families (data not shown). In the remaining CNV regions of groups B and C, it was not possible to unambiguously determine the underlying haplotypes and/or follow their transmission due to the combination of complex CNVs (multi-copy parental CNVs) and/or presence of only uninformative SNP and CNV genotypes, resulting in several equally possible Mendelian or non-Mendelian transmissions (e.g. de novo duplication or uniparental heterodisomy) in the corresponding loci and families (S2b and S2d Fig).


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 de novo copy-number variants in offspring.(A) De novo arisen 67 kb-long deletion on chromosome 6:80596173–80663256 in family T39. Children 1–3 (C010135, C010136 and C010137) have inherited one normal haplotype from both parents. One child (Child 4, C010138) has inherited one normal haplotype from his mother (C010134) and a paternal haplotype with a de novo deletion event in the corresponding region. (B) De novo arisen 167 kb-long duplication on chromosome 2:110175122–110331912 in family T07. The only child (C010026) has inherited one normal haplotype from her mother (C010025) and a paternal haplotype with a de novo intra-chromosomal duplication event in the corresponding region. 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.g004: Examples of de novo copy-number variants in offspring.(A) De novo arisen 67 kb-long deletion on chromosome 6:80596173–80663256 in family T39. Children 1–3 (C010135, C010136 and C010137) have inherited one normal haplotype from both parents. One child (Child 4, C010138) has inherited one normal haplotype from his mother (C010134) and a paternal haplotype with a de novo deletion event in the corresponding region. (B) De novo arisen 167 kb-long duplication on chromosome 2:110175122–110331912 in family T07. The only child (C010026) has inherited one normal haplotype from her mother (C010025) and a paternal haplotype with a de novo intra-chromosomal duplication event in the corresponding region. 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: The subsequent three groups of CNV regions were subjected to haplotype phasing using the PiCNV program in both HapMap YRI and EGCUT datasets combined. The PiCNV was able to unambiguously phase 93.6% (1414 out of 1510) of all CNV regions and automatically determine the distribution of normal and deletion or duplication-carrying haplotypes in parents and their offspring (Table 2; Figs 3 and 4). The unambiguous phasing efficiency was the highest in group A of CNV regions, reaching 96.3% (1366 out of 1418; Table 2). All remaining CNV regions (3.7%; 52 out of 1418) in group A were duplication CNV regions (CN≥3) containing only uninformative monomorphic genotypes (e.g. ‘AA’ or ‘AAA’, etc.) or CNV probes that do not interrogate any SNP variants. Subsequently, PiCNV was not able to unambiguously distinguish between exact maternal and paternal haplotypes and/or follow their transmission in offspring, resulting in several equally possible Mendelian transmissions in the corresponding families (S2a Fig). Similar limitations were also observed in several CNV regions in groups B and C resulting in unambiguous phasing in 60% and 33.3% of CNV regions in those groups, respectively (Table 2). In groups B and C, higher phasing efficiency was observed for deletion CNV loci and in larger families (data not shown). In the remaining CNV regions of groups B and C, it was not possible to unambiguously determine the underlying haplotypes and/or follow their transmission due to the combination of complex CNVs (multi-copy parental CNVs) and/or presence of only uninformative SNP and CNV genotypes, resulting in several equally possible Mendelian or non-Mendelian transmissions (e.g. de novo duplication or uniparental heterodisomy) in the corresponding loci and families (S2b and S2d Fig).

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