Poster #41: Jessica Knapp

Characterizing the mutation spectra of mammalian X chromosomes to identify related mutagenic processes

Jessica Knapp, PhD Student, Cell and Molecular Biology, Biological Graduate Sciences, Perelman School of Medicine, University of Pennsylvania; Ziyue Gao, PhD, Department of Genetics, Perelman School of Medicine, University of Pennsylvania; Iain Mathieson, PhD, Department of Genetics, Perelman School of Medicine, University of Pennsylvania

In humans, the mutation spectrum (i.e., the relative rates of different mutation types such as C>A or T>G) varies between the autosomes and the sex chromosomes. Some of this variation could result from differences in effective population size or inheritance patterns between sex chromosomes and autosomes. Genomic features including replication timing and X inactivation could also drive the variation in mutation spectra. For example, some mutations that are enriched on the human X chromosome have been associated with its late replication timing. Outside of humans, autosomal mutation spectra across species have been characterized, but sex chromosomes’ mutation spectra are unknown. We are characterizing the mutation spectra of X chromosomes across mammals to better understand the mutagenic processes driving this enrichment, and their conservation across species. To assess the conservation of X chromosome mutational enrichments, we characterized the mutation spectra of X chromosomes across ten mammalian species. Then, we contrasted the X chromosomes’ mutation spectra with the autosomes’ within each species. The X mutational enrichments across mammals are weakly correlated, suggesting the existence of both shared and species-specific mutagenic processes. For example, C>A mutations are enriched on the X chromosome across mammals, likely representing a shared underlying mutagenic process. In contrast, NTpG>NApG mutations are the four most enriched trinucleotide mutation types on the canine X chromosome, but are not as highly enriched in other species. The canine X chromosome is also enriched for canine endogenous retroviruses (CERV) compared to the autosomes, which may play a role in gene regulation. We hypothesize that the TpG>ApG mutational enrichment on the canine X chromosome may be driven by transcription factor (TF) binding at CERV sites since NTpG>NApG are enriched at TF binding sites in humans. We will assess by mapping mutations’ loci to annotated CERV sites.