Mutations observed in somatic evolution reveal underlying gene mechanisms.
Michael W J HallDavid ShorthouseRachel AlcraftPhilip H JonesMichael W J HallPublished in: Communications biology (2023)
Highly sensitive DNA sequencing techniques have allowed the discovery of large numbers of somatic mutations in normal tissues. Some mutations confer a competitive advantage over wild-type cells, generating expanding clones that spread through the tissue. Competition between mutant clones leads to selection. This process can be considered a large scale, in vivo screen for mutations increasing cell fitness. It follows that somatic missense mutations may offer new insights into the relationship between protein structure, function and cell fitness. We present a flexible statistical method for exploring the selection of structural features in data sets of somatic mutants. We show how this approach can evidence selection of specific structural features in key drivers in aged tissues. Finally, we show how drivers may be classified as fitness-enhancing and fitness-suppressing through different patterns of mutation enrichment. This method offers a route to understanding the mechanism of protein function through in vivo mutant selection.
Keyphrases
- wild type
- single cell
- copy number
- physical activity
- body composition
- gene expression
- high throughput
- genome wide
- cell therapy
- induced apoptosis
- dna methylation
- cell death
- autism spectrum disorder
- machine learning
- electronic health record
- mesenchymal stem cells
- cell free
- intellectual disability
- artificial intelligence