Mutation rates and fitness consequences of mosaic chromosomal alterations in blood

Mosaic chromosomal alterations (mCAs) are commonly detected in many cancers and have been found to arise decades before diagnosis. A quantitative understanding of the rate at which these events occur and their functional consequences could improve cancer risk prediction and yet they remain poorly characterised. Here we use clone size estimates of mCAs from the blood of 500,000 participants in the UK Biobank to estimate the mutation rates and fitness consequences of acquired gain, loss and copy-neutral loss of heterozygosity (CN-LOH) events at the chromosomal arm level. Most mCAs have moderate to high fitness effects, but occur at a low rate, being over 10-fold less common than equivalently fit SNVs. While the majority of mCAs increase in prevalence with age in a way that is consistent with a constant growth rate, we find specific examples of mCAs whose behaviour deviates from this suggesting fitness effects for these mCAs may depend on inherited variants or be influenced by extrinsic factors. We find an association between mCA fitness effect and future blood cancer risk, highlighting the important role mCAs may play in risk stratification.