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Patterns of mutation in the human genome

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posted on 2023-06-07, 16:10 authored by Alan James Hodgkinson
The processes that underlie point mutations in the human genome are largely unknown. However, the cumulative effect of these processes have a large impact on how mutation rates vary across a number of different scales and contexts, and consequently guide our understanding of human disease and evolution. Although variation in the mutation rate has been characterized on many different levels, it is not fully understood the extent to which the rate of mutation can vary outside of the general patterns already observed. Beginning with the human genome project, many studies have produced large unbiased sequence datasets within a number of human populations. To that end, we analysed a number of sequence datasets in an attempt to better understand the patterns and causes of variation in the rate of mutation that exists across the genome. Firstly, we find that the mutation rates of single sites vary by more than is currently understood, and that this variation is not associated with any specific process or feature on either a local or genomic scale. Although we have been unable to uncover the source of such variation, understanding the range of mutability at sites in the human genome is important since it may point to functional regions, disease phenotypes and prompt further ideas on the underlying mechanisms associated with such a result. Furthermore, we find evidence that a mutational process that can generate the simultaneous production of two new alleles within the same individual during a single, or tightly linked series of mutation events increases the number of tri-allelic sites in the human genome. There are a number of potential mechanisms that may drive this process, and the consequences of such an event may be far reaching, as the generation of two new alleles at a single site in functional regions may allow a more rapid exploration of evolutionary space. Furthermore, this process appears to make a reasonable contribution to variation in the human genome, thus providing a substrate for evolutionary change. Finally, we observe significant variation in the mutation rate over all scales in cancer genomes. Part of this result can be explained by the actions of specific carcinogens, however it is striking that patterns of mutation can be both consistent across different cancer types, but also very different between individuals with the same type of cancer over different scales. This result points to the idea that the patterns of mutation may vary widely between different genomes under different conditions, and the identification of general patterns in a small number of samples may not fully describe the extent to which mutation rates can vary. Taken together, these conclusions suggest that the patterns and processes underlying mutation are highly complex, and require further analysis if they are to be fully understood.


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