Biology subjects

Morrison, A. J.

Publications and source records attributed to Morrison, A. J..

3 recordsLinked to original sources

bioRxiv2018

Process-specific somatic mutation distributions vary with three-dimensional genome structure

Somatic mutations arise during the life history of a cell. Mutations occurring in cancer driver genes may ultimately lead to the development of clinically detectable disease. Nascent cancer lineages continue to acquire somatic mutations throughout the neoplastic process and during cancer evolution (Martincorena and Campbell, 2015). Extrinsic and endogenous mutagenic factors contribute to the accumulation of these somatic mutations (Zhang and Pellman, 2015). Understanding the underlying factors generating somatic mutations is crucial for developing potential preventive, therapeutic and clinical decisions. Earlier studies have revealed that DNA replication timing (Stamatoyannopoulos et al., 2009) and chromatin modifications (Schuster-Bockler and Lehner, 2012) are associated with variations in mutational density. What is unclear from these early studies, however, is whether all extrinsic and exogenous factors that drive somatic mutational processes share a similar relationship with chromatin state and structure. In order to understand the interplay between spatial genome organization and specific individual mutational processes, we report here a study of 3000 tumor-normal pair whole genome datasets from more than 40 different human cancer types. Our analyses revealed that different mutational processes lead to distinct somatic mutation distributions between chromatin folding domains. APOBEC- or MSI-related mutations are enriched in transcriptionally-active domains while mutations occurring due to tobacco-smoke, ultraviolet (UV) light exposure or a signature of unknown aetiology (signature 17) enrich predominantly in transcriptionally-inactive domains. Active mutational processes dictate the mutation distributions in cancer genomes, and we show that mutational distributions shift during cancer evolution upon mutational processes switch. Moreover, a dramatic instance of extreme chromatin structure in humans, that of the unique folding pattern of the inactive X-chromosome leads to distinct somatic mutation distribution on X chromosome in females compared to males in various cancer types. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation rate variations observed in human cancer.

genomics↗

bioRxiv2017

Conservation of specificity in two low-specificity proteins

S100 proteins bind linear peptide regions of target proteins and modulate their activity. The peptide binding interface, however, has remarkably low specificity and can interact with many target peptides. It is not clear if the interface discriminates targets in a biological context, or whether biological specificity is achieved exclusively through external factors such as subcellular localization. To discriminate these possibilities, we used an evolutionary biochemical approach to trace the evolution of paralogs S100A5 and S100A6. We first used isothermal titration calorimetry to study the binding of a collection of peptides with diverse sequence, hydrophobicity, and charge to human S100A5 and S100A6. These proteins bound distinct, but overlapping, sets of peptide targets. We then studied the peptide binding properties of S100A5 and S100A6 orthologs sampled from across five representative amniote species. We found that the pattern of binding specificity was conserved along all lineages, for the last 320 million years, despite the low specificity of each protein. We next used Ancestral Sequence Reconstruction to determine the binding specificity of the last common ancestor of the paralogs. We found the ancestor bound the whole set of peptides bound by modern S100A5 and S100A6 proteins, suggesting that paralog specificity evolved by subfunctionalization. To rule out the possibility that specificity is conserved because it is difficult to modify, we identified a single historical mutation that, when reverted in human S100A5, gave it the ability to bind an S100A6-specific peptide. These results indicate that there are strong evolutionary constraints on peptide binding specificity, and that, despite being able to bind a large number of targets, the specificity of S100 peptide interfaces is indeed important for the biology of these proteins.

biochemistry↗

bioRxiv2017

INO80 Chromatin Remodelling Coordinates Metabolic Homeostasis with Cell Division

Adaptive survival requires the coordination of nutrient availability with expenditure of cellular resources. For example, in nutrient-limited environments, 50% of all S. cerevisiae genes synchronize and exhibit periodic bursts of expression in coordination with respiration and cell division in the Yeast Metabolic Cycle (YMC). Despite the importance of metabolic and proliferative synchrony, the majority of YMC regulators are currently unknown. Here we demonstrate that the INO80 chromatin-remodelling complex is required to coordinate respiration and cell division with periodic gene expression. Specifically, INO80 mutants have severe defects in oxygen consumption and promiscuous cell division that is no longer coupled with metabolic status. In mutant cells, chromatin accessibility of periodic genes, including TORC-responsive genes, is relatively static, concomitant with severely attenuated gene expression. Collectively, these results reveal that the INO80 complex mediates metabolic signaling to chromatin in order to restrict proliferation to metabolically optimal states.

molecular biology↗