The evolutionary dynamics and fitness landscape of clonal hematopoiesis
Menée à partir de données de séquençage de l'ADN de cellules sanguines issues d'environ 50 000 personnes et en appliquant la théorie génétique des populations, cette étude analyse l'évolution au cours du vieillissement des mutations génétiques de différentes populations de cellules sanguines et examine la façon dont certaines mutations peuvent conduire à l'expansion de certaines lignées clonales, à la diversité génétique des cellules normales ou au développement de cancers hématologiques
Cells accumulate mutations as we age, and these mutations can be a source of diseases such as cancer. How cells containing mutations evolve, are maintained, and proliferate within the body has not been well characterized. Using a quantitative framework, Watson et al. applied population genetic theory to estimate mutation accumulation in cells in blood from sequencing data derived from nearly 50,000 healthy individuals (see the Perspective by Curtis). By evaluating how mutations differ between blood cell populations, a phenomenon known as clonal hematopoiesis, the researchers could observe how recurrent mutations can drive certain clonal lineages to high frequencies within an individual. The risk of specific mutations, some of which are associated with leukemias, rising to high frequencies may therefore be a function of cellular selection and the age at which the mutation originated.Science, this issue p. 1449; see also p. 1426Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by chance remains largely unknown. Blood sequencing data from ~50,000 individuals reveal how mutation, genetic drift, and fitness shape the genetic diversity of healthy blood (clonal hematopoiesis). We show that positive selection, not drift, is the major force shaping clonal hematopoiesis, provide bounds on the number of hematopoietic stem cells, and quantify the fitness advantages of key pathogenic variants, at single-nucleotide resolution, as well as the distribution of fitness effects (fitness landscape) within commonly mutated driver genes. These data are consistent with clonal hematopoiesis being driven by a continuing risk of mutations and clonal expansions that become increasingly detectable with age.
Science , résumé, 2019