Research
Life requires mistakes.
If our DNA replication machinery operated with perfect fidelity and every damaged nucleotide were faithfully repaired, the forces of selection, drift, and gene flow would be powerless. Germline mutations provide the raw material for adaptive evolution, and somatic mutations transform every tissue into a unique mosaic of genetic variation. Although eukaryotes share much of their DNA repair and replication machinery, mutation rates vary by orders of magnitude across the tree of life. Even within the same organism, one cell type might accumulate mutations a hundred times more quickly than another. Mutation rate variation has a profound impact on evolution and disease, but we know surprisingly little about the genetic and environmental factors that affect germline and somatic mutagenesis.
In our lab, we want to understand when, where, and how mutations occur.
Future research projects
We are pursuing a number of exciting new research directions. Using model systems, we will measure the transgenerational inheritance of DNA damage and use recombinant inbred lines to discover natural, segregating mutator alleles. In parallel, we are developing new machine learning methods to uncover hidden mutation signatures in large sequencing datasets. Using sequencing data from non-human species, we will also measure the mutagenic potential of the early mammalian embryo.
Past research projects
Mapping mutator alleles
Variants in DNA repair or replication genes — often called “mutator alleles” — can dramatically increase the mutation rate. Using a panel of recombinant inbred mouse lines, we found a large-effect germline mutator allele in the DNA repair gene Mutyh. Later, we developed a new statistical method to find another mutator allele in a DNA repair gene called Ogg1.
Variability in human germline de novo mutation rates
In 2019, we sequenced 33 large, multi-generational human families and identified de novo germline mutations in hundreds of children. Some families accumulated mutations at much higher rates than others, and almost 10% of “apparent” germline mutations occurred in the early embryo.
Read the paper here
Hyper-mutable tandem repeat loci
Tandem repeats are repetitive nucleotide motifs that comprise almost 10% of our genomes. TRs mutate up to 10,000 times more often than single-nucleotide sites, making them potent engines of mutagenesis. We recently used long-read sequencing technologies to find hyper-mutable TR loci, which mutate up to 10 times in a single generation.