Extended Data Fig. 4: Mosaicism analysis.

a, For each of the three rare variants at positions n.4 and n.35 of RNU2-2 called in the discovery collection, truncated bar charts showing the distribution of the proportions of reads supporting the alternate allele over participants, partitioned into 0% and all left-open intervals of size 4% up to 100%. In contrast to n.4 G > A and n.35 A > G, the reads in the eight participants with the n.35 A > T heterozygous call exhibit a strong skew in favor of the reference allele. Furthermore, seven participants with a homozygous reference call at n.35 have at least 8% of aligned reads at that position supporting the ‘T’ allele, suggesting that n.35 A > T is not a germline variant, but rather a low-frequency somatic mosaic variant. b, Histogram of age at enrollment of participants in the discovery collection. The purple points show the age at enrollment of study participants with at least 8% of aligned reads supporting the ‘T’ allele at n.35. These participants are significantly older than expected by chance (P = 1.3 × 10⁻³, Kolmogorov-Smirnoff test). To comply with Genomics England’s rules on identifiability, all ages of at least 95 years are included in the same x = 95 bin. c, Sanger sequencing traces from an NDA case (in pedigree N1) with the n.4 G > A call, an unaffected participant with the n.35 A > T call, and a control with neither call, showing that n.4 G > A is a germline variant while n.35 A > T is a likely somatic mosaic variant.