Individualized Mutational Landscapes Encoded in Our DNA
Gene mutations can lead to genetic disease and cancer, but the rates of mutation are not uniform across the genome. One of the main factors that influence these differences in mutation rates is the time of replication of the underlying DNA, or the order in which sections of the DNA initiate replication. Strikingly, the replication timing program itself varies from one person to another at hundreds of genomic locations.
According to Amnon Koren, Molecular Biology and Genetics, the genetic variation in DNA replication timing and mutation rates means that every person carries an individual mutational landscape, which is encoded in the genome. Understanding this landscape could eventually help researchers uncover how certain characteristics of DNA replication timing predispose some to mutation and disease.
Koren and his team are using innovative experimental and computational methodologies to create a database of DNA replication timing in thousands of people, in three cell types. They will use this database to identify genetic determinants of human DNA replication timing. This, in turn, will link replication timing variation to phenotypes such as chromatin structure and gene expression variation. Researchers will also be able to link DNA replication timing to variations in human phenotypes, including disease susceptibility and cancer risk.
Perhaps most excitingly, this project will open the way to a new concept in human genetics and in eukaryotic biology: that mutation rates at hundreds of genomic regions are genetically encoded and vary in an individual manner. The project will therefore add a new dimension to precision medicine, bringing the field of DNA replication timing into the mainstream in human molecular, medical, and population genetics. NIH Award Number: 1DP2GM123495-01