Figure 3. Inheritance state analysis, error estimation, and phasing.

A, A Hidden Markov Model (HMM) was used to infer one of four Mendelian and two non-Mendelian inheritance states for each allele assortment at variant positions across the quartet. “MIE-rich” refers to Mendelian-inheritance error (MIE) rich regions. “Compression” refers to genotype errors from heterozygous structural variation in the reference or study subjects, manifest as a high proportion of uniformly heterozygous positions across the quartet. B, A combination of quality score calibration using orthogonal genotyping technology and filtering SNVs in error prone regions (MIE-rich and compression regions) identified by the HMM resulted in >90% reduction in the genotype error rate estimated by the MIE rate. C, Consistent with PRDM9 allelic status, approximately half of all recombinations in each parent occurred in hotspots. The mother has two haplotypes in the gene RNF212 associated with low recombination rates, while the father has one haplotype each associated with high and low recombination rates. Notation denotes base at [rs3796619, rs1670533]. D, Variant phasing using pedigree, inheritance state, and population linkage disequilibrium data. Pedigree data were first used to phase informative allele assortments in trios (top). The inheritance state of neighboring regions was used to phase positions in which all members of a mother-father-child trio were heterozygous and the sibling was homozygous for the reference or non-reference allele (middle). For uniformly heterozygous positions, we phased the non-reference allele using a maximum likelihood model to assign the non-reference allele to paternal or maternal chromosomes based on population linkage disequilibrium with phased SNVs within 250 kbp (bottom). In all panels a corresponds to the reference allele and b to the non-reference allele.