Figure 4. Replication timing quantitative trait loci (rtQTLs).
Genetic variants underlie differences in DNA replication timing among individuals. Shown are three examples of replication variants with significant genetic association (additional examples are in Figure 5 and Figure S5).
A. Variation in replication timing of a specific locus is strongly associated with SNPs that map within the locus itself. Shown are Manhattan plots of genome-wide association of genetic variants with replication timing. Red arrow: genomic location of the tested replication variant region. Black dashed line: genome-wide association significance threshold.
B. Detailed genetic associations in replication variant regions (dots; right axis) along with replication (read depth) profiles (left axis) for individuals with each of the three genotypes of the most strongly associated SNPs. Yellow dots denote rtQTL SNPs that were also eQTLs for a nearby gene.
C. Left panels: distribution of read depth for individuals with each of the genotypes of the SNP most strongly associated with each variant. Right panels: droplet digital PCR (ddPCR) analysis confirms that the allele associated with early replication is also over-represented in genomic DNA from heterozygous individuals, consistent with a cis-acting, allele-specific effect on DNA replication timing.