Fig. 2: Early mosaic mutations and their transmission patterns to offspring in a cohort of 1934 quartet families.

A A candidate early mutation with T allele (in red) is within 100 bps of a heterozygous inherited SNP with G allele (in cyan). For inherited germline variant, there should be only two haplotypes at a VAF of ~50% for each. The presence of three haplotypes indicates a post-zygotic mutation¹¹. High VAF from 35% to 45% implies that the mutation occurred during the first zygotic division and marks the dominant cell lineage⁵. B A pedigree structure of 1,934 familial quads in the Simons Simplex Collection¹⁶. C A scatter plot of quantitative characteristics for variants (i.e., dots) with evidance for 3 haplotypes in children. True post-zygotic mutations are in cyan and false positives (i.e., inherited variants observed in parents) are in red. Dashed line defines an approximate border demarcating the two distributions. Trapezoid by solid black lines defines the area to select early mutations in parents for the transmission analysis. The estimated false positives rate in this area is ~17%. D A scatter plot of characteristics for variants with evidance for 3 haplotypes in parents. Same as for children, the trapezoid delimited by solid blue lines defines the area to select early mutations for the transmission analysis. E Comparisons of expected and observed transmission rates of early post-zygotic mutations to offspring for two scenarios: (top) the mutation frequency is 50% in gonads (in green), i.e., dominant and recessive lineage contribute equally to gonads; (bottom) the mutations frequencies in gonads are the same as in the blood, i.e., VAFs are as in trapezoid in (D) Three possible outcomes for mutation transmission are: no transmission (denoted as “None”), transmission to only one child (denoted as “One”), and transmission to two children (denoted as “Both”). The expected distributions are calculated assuming 17% false positive rate from inherited variants. ײ test (two-sided) with 2 degrees of freedom is used to assess the significance of the difference between expected (in green or orange) and observed (in blue) transmission distributions. Source data are provided in Supplementary Data 3.