Mutagenesis and its Biomedical Impact

Of the many thousands of DNA differences between individuals, only a minority have important contributions to disease risk or other traits that differ between them. Finding those rare consequential differences is the basis for genetic diagnosis and predicting traits like height and drug response. It is also often the first step in understanding the basis of a disease at a molecular level. As a community we can only efficiently find the consequential differences if they directly alter an encoded protein, the vast majority don’t. We are developing ways to understand the consequences of the majority of DNA changes regardless of whether they alter a protein. Our approaches are often based on studying how large numbers of DNA sequence differences are inherited through generations of the human population. It allows us to tease apart two patterns, the pattern of new mutations and the pattern shaped by the health of people that carried those mutations. The pattern of new mutations tells us about the underlying biology of the DNA, how it is replicated and repaired as well as showing how likely a piece of DNA is likely to be disrupted by a new mutation. The second pattern is what tells us if a type of DNA change is likely to have a consequence for human health. Although described here in the context of inherited DNA differences, we apply similar approaches to interpret the new mutations that arise in and drive the development of cancer.