Synonymous mutations reveal genome-wide driver mutation rates in healthy tissues

Abstract

Genetic alterations that drive clonal expansions in ostensibly healthy tissues have implications for cancer risk. However, the total rate at which clonal expansions occur in healthy tissues remains unknown. Synonymous passenger mutations that hitchhike to high variant allele frequency due to a linked driver mutation can be used to estimate the total rate of positive selection across the genome. Because these synonymous hitchhikers are influenced by all mutations under selection, regardless of type or location, they can be used to estimate how many driver mutations are missed by narrow gene-focused sequencing panels. Here we analyse the variant allele frequency spectrum of synonymous passenger mutations to estimate the total rate at which mutations driving clonal expansions occur in healthy tissues. By applying our framework to data from physiologically healthy blood, we find that a large fraction of mutations driving clonal expansions occur outside of canonical cancer driver genes. In contrast, analysis of data from healthy oesophagus reveals little evidence for many driver mutations outside of those in NOTCH1 and TP53. Our framework, which generalizes to other tissues, sheds light on the fraction of drivers mutations that remain undiscovered and has implications for cancer risk prediction.

To portray clonal evolution in blood cancer, count your stem cells

“…concluded that there must be hidden driver mutations to explain the allele frequency distribution of synonymous mutations. 63 In conclusion, current evidence points to a role for natural selection in clonal hematopoiesis but more evidence is needed before ruling out a role of neutral evolution.…”

“…10% of myeloproliferative neoplasms, 95,96 although it is always possible that genetic or epigenetic driver alterations have been undetected. 63 In addition, genetic drift could explain growth of clones with mutations providing no clear fitness advantage to stem cells such as JAK2 V617F , 97 or SRSF2 P95H mutations, 98 The final column states the impact of the mutation as predicted by 21 . D indicates that the mutation is predicted to be damaging and N that the mutation is predicted to be neutral.…”

Clonal hematopoiesis is associated with risk of severe Covid-19

“…The mutational events that drive CH overlap with known drivers of hematologic malignancies. However, the majority of mutations in CH appear to occur outside of canonical cancer driver genes 11,12 . The impact of individual mutational events on hematopoietic stem and progenitor cells differs by the nature of the genomic aberration.…”

“…As such, the observed events that are highly enriched in CH could be 'passenger' mutations that co-occur with a positively selected, undetected 'driver' mutation such as recurrent CNVs. 12,13 Alternatively, driver mutations may have been incompletely classified as "non-driver" events using our methodology. However, cancer driver genes tend to recur in multiple patients, and the majority of witnessed non-driver mutated genes in our cohort were non-recurrent suggesting that clonal expansion, and not the specific event driving clonal expansion, may be associated with Covid-19 disease severity.…”

“…A substantial body of evidence now links somatic alterations in hematopoietic stem and progenitor cells to a variety of health outcomes, with inflammation emerging as a key mediator. [2][3][4][5][10][11][12][13] Our data, along with results in the accompanying manuscript by annotated with VEP(version 86) and OncoKb. We applied a series of post-processing filters to further remove false positive variants caused by sequencing artifacts and putative germline polymorphisms as previously described 24 .…”