X inactivation skew across blood, saliva, buccal swab, and retina in a healthy patient. (A) Collected samples: four quadrants of the retina from one eye (purple discs), blood, saliva, and buccal swab. (B) Cumulative sum of CpG islands overlapped by haplotype blocks. (C) Nonfolded and folded distributions of haplotype blocks’ skews in the seven samples. Blood and saliva show a clear skew, whereas the buccal swab and all four retina samples are not highly skewed. (D) Positive correlation of the nonfolded haplotype blocks’ skews across samples shows that the Xa allelic bias is consistent across tissues (the same X Chromosome in the preferentially active X in all skewed tissues). (E) Skewed X inactivation allows scaffolding haplotype blocks into alleles. Log-likelihood ratio of haplotype 1 being the preferential Xa over Xi for each block. A red line is plotted at y = 1 (haplotype 1 is 10 times more likely than haplotype 2 to be the preferential Xa) and y = −1 (haplotype 2 is 10 times more likely than haplotype 1 to be the preferential Xa). (F) Up to 18% of the X Chromosome for patient H1 can be arranged in a consistent haplotype (higher-order phasing) based on haplotype block skew.
