Fig 1.
Phasing and allelic composition of normal and CNV-carrying haplotypes on parental homologous chromosomes.
A chromosomal region involving copy number variation is denoted with ‘R2’. In the given example, father is the carrier of two normal haplotypes of ‘R2’ on chromosomes P1 and P2 (diploid copy number of ‘R2’, CN = 2), whereas mother has a combination of a duplication-carrying (on M1) and normal (M2) haplotypes (diploid copy number of ‘R2’, CN = 3). Haplotype-informative SNP genotypes in ‘R2’ sequence that can be used for phasing and determining the parental origin (in offspring) of given normal and CNV-carrying haplotypes are given in bold letters and genotypes that are polymorphic between normal or duplication-carrying parental haplotypes are indicated with dashed rectangles. The duplication-carrying haplotype on maternal M1 chromosome is composed of two allelic copies of the sequence ‘R2’ distinguished by genotype variability at position SNP7 (polymorphic SNP variant within the duplication-carrying haplotype), indicated with dotted rectangle.
Fig 2.
Computational phasing of normal and CNV-carrying haplotypes.
(A) First, CNV and regular two-letter genotypes are collected from the QuantiSNP output for each family member at a locus of interest. (B) Next, markers that have any low-confidence genotype calls or the call could not have been made (‘NC’ genotypes, e.g. marker rs10801575, marked with the red background) and monomorphic markers that are not informative for haplotype phasing in the studied region (e.g. marker rs7517836; marked with the red background) are filtered out. (C) Informative high-confidence genotypes are then phased considering all family members simultaneously and the resulting haplotypes are presented as the result. (D) The family tree of these phased haplotypes can be further visualised for the corresponding CNV region.
Fig 3.
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.
Table 1.
Detailed description of analysed family-based SNP microarray datasets.
Table 2.
Unambiguously phased CNV regions in families.
Fig 4.
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.
Table 3.
Transmission rate of deletion- and duplication-carrying haplotypes in HapMap YRI and EGCUT datasets combined.
Table 4.
CNV regions in HapMap YRI and EGCUT parents where allelic variability between and within normal and copy number gain-carrying haplotypes can be deterministically differentiated.