Transmission rate of deletion- and duplication-carrying haplotypes in HapMap YRI and EGCUT datasets combined.

<p>*Statistically significant (multiple-testing corrected p-value<0.05) deviations from the expected Mendelian transmission rate of 50%.</p><p>Transmission rate together with the number of transmitted variant-carrying haplotypes and the number of all transmission events (1 event/per locus/per child) for each of the non-overlapping CNV length intervals.</p><p>Transmission rate of deletion- and duplication-carrying haplotypes in HapMap YRI and EGCUT datasets combined.</p

Phasing and allelic composition of normal and CNV-carrying haplotypes on parental homologous chromosomes.

<p>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 <i>between</i> 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 <i>within</i> the duplication-carrying haplotype), indicated with dotted rectangle.</p

Computational phasing of normal and CNV-carrying haplotypes.

<p>(<b>A</b>) First, CNV and regular two-letter genotypes are collected from the QuantiSNP output for each family member at a locus of interest. (<b>B</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. (<b>C</b>) Informative high-confidence genotypes are then phased considering all family members simultaneously and the resulting haplotypes are presented as the result. (<b>D</b>) The family tree of these phased haplotypes can be further visualised for the corresponding CNV region.</p

Unambiguously phased CNV regions in families.

<p>Percentage of CNV regions in HapMap YRI and EGCUT families where <i>PiCNV</i> was automatically able to unambiguously determine the underlying normal and CNV-carrying haplotypes in parents and follow their transmission in offspring. Group A—CNV regions where only one parent had a CNV; group B—CNV regions where both parents had a CNV in the same locus; group C—putative <i>de novo</i> CNV regions.</p><p>Unambiguously phased CNV regions in families.</p

Examples of <i>de novo</i> copy-number variants in offspring.

<p>(<b>A</b>) <i>De novo</i> 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 <i>de novo</i> deletion event in the corresponding region. (<b>B</b>) <i>De novo</i> 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 <i>de novo</i> 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.</p

Examples of unambiguously phased CNV regions involving deletion- and duplication-carrying haplotypes in families.

<p>(<b>A</b>) 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>B</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.</p

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.

<p>In case informative polymorphic genotypes are present <i>between</i> haplotypes in an individual, copy number gain-carrying haplotypes (cn>1) can be deterministically distinguished from the normal single copy haplotypes (cn = 1). Furthermore, these informative genotypes can be used to establish the allelic composition and different allelic copies <i>within</i> copy number gain-carrying haplotypes.</p><p>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.</p

Detailed description of analysed family-based SNP microarray datasets.

<p>Detailed description of analysed family-based SNP microarray datasets.</p

Association of rs1426654 genotypes with melanin index.

<p>(A) Distribution of melanin index (MI) in 1228 individuals of Cohort A. The two dotted black lines represent approximately 10% thresholds for the low (MI<38) and high (MI>50) MI groups, which were used to assess genotype-phenotype association using a logistic regression model. (B) Distribution of mean melanin index for the genotypes of rs1426654. The mean melanin indices for each genotype, as obtained separetely for males and females are shown together with their 95% confidence intervals, as estimated by multiple imputation model (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003912#pgen.1003912.s008" target="_blank">Table S3A</a>).</p

Heat map showing the intra- and inter-population variation measured by average pairwise sequence differences of the <i>SLC24A5</i> gene.

<p>The upper triangle of the matrix (green) shows average pairwise differences between populations (PiXY). The average number of pairwise differences (PiX) within each population is shown along the diagonal (orange). The lower triangle of the matrix (blue) shows differences between populations based on Nei's distance, i.e., corrected average pairwise differences (PiXY−(PiX+PiY)/2).</p