Fig. 1: The Human Genome’s Replication Timing Program is Extensively Encoded in DNA.

a Replication timing (blue line; Z-score) inferred from read depth fluctuations (gray) for the H9 cell line. Orange: Repli-Seq data for H9⁷⁴. b Replication timing profiles are highly reproducible among samples. c, d PC-correction improves replication profile accuracy. e–g Genetic relatedness associated with replication timing similarity. e Sibling vs. unrelated hESCs (two-sided Wilcoxon rank-sum test). n = 5754 (pairs of genetically unrelated samples), n = 24 (pairs of genetic siblings). f Genomic regions stratified by increasing identity-by-descent (ANOVA). n = 14,856 (pairs of genomic regions with IBD 0), n = 7010 (pairs of genomic regions with IBD 1), and n = 262 (pairs of genomic regions with IBD 2). g iPSCs from the same or different donors (two-sided Wilcoxon rank-sum test). n = 44,742 (pairs of iPS cell lines from different donors), n = 108 (pairs of iPS cell lines from the same donor [derived separately]). For panels e, f, and g, top and bottom whiskers denote the maximum and minimum value, respectively. The top and bottom boxes denote the third and first quartile, respectively. Center denotes the median. Outliers removed using R boxplot option “outline=F”. b A genomic region (gray) with inter-individual replication timing variation. i–k Genetic association reveals rtQTLs. i A haplotype strongly associated with the replication timing variant from panel h (panel k genome-wide association). Mean replication timing (left Y axis) for individuals with different genotypes at rs12713840, the top SNP, demonstrates that SNPs in cis (right Y axis) associate with replication initiation. Gray: affected region. j Replication timing at the variant from panel h, stratifying individuals by rs12713840 genotype. Genotype is the main determinant of replication timing variation. l Additional rtQTL examples. m All rtQTLs. Each horizontal line is an rtQTL, oriented from the replication timing locus with maximum difference between genotypes (Δ_RT), showing the averaged replication timing difference on both sides of that locus. Foreground (gray-purple) shades: rtQTL SNPs, color-coded by p values, and placed according to their distance to the locus of maximal Δ_RT. Most rtQTLs influence surrounding genomic region (“local”), while a subset show long-range effects.