Germline mutations are the cause of genetic disease, while somatic mutations can lead to cancer. Mutation rates are not uniform across the genome but instead vary by up to 6-fold from one region to another. One of the main factors underlying these regional differences in mutation rates is the time of replication of the underlying DNA. Strikingly, the replication timing program itself varies from one person to another at hundreds of genomic loci (Koren et al., Cell 2014). This project will demonstrate that due to genetic variation in DNA replication timing, every person carries an individual mutational landscape, which is encoded in the genome. We will use innovative experimental and computational methodologies to create a database of DNA replication timing in thousands of people and in three cell types. We will then use this database to identify precise genetic determinants of human DNA replication timing. This, in turn, will link replication timing variation, via shared genetic influences, to other molecular phenotypes such as chromatin structure and gene expression variation, and to human phenotypic variation, including disease susceptibility and cancer risk. Perhaps most excitingly, it will open the way to a new concept in human genetics and in eukaryotic biology in general: that mutation rates at hundreds of genomic regions are genetically encoded and vary in an individual manner. Moreover, linking DNA replication timing to both mutations and gene expression regulation would imply that mutation rates can vary among people in a functionally significant way, altering the risks of genetic diseases and cancer, and changing the evolutionary trajectories of families and populations. The methodologies developed and knowledge obtained through this project will add a new dimension to precision medicine and will transform the field of DNA replication timing, turning it into a mainstream discipline in human molecular, medical, and population genetics.
This project will describe a new form of human genetic variation and reveal genetic determinants and individuality of human mutation rates. These discoveries will influence the understanding, diagnosis, and personalized treatment of mutation-driven diseases, namely genetic diseases and cancer.
