Signatures of neutral evolution in exponentially growing tumors: A theoretical perspective

PLoS Comput Biol. 2021 Feb 11;17(2):e1008701. doi: 10.1371/journal.pcbi.1008701. eCollection 2021 Feb.

Abstract

Recent work of Sottoriva, Graham, and collaborators have led to the controversial claim that exponentially growing tumors have a site frequency spectrum that follows the 1/f law consistent with neutral evolution. This conclusion has been criticized based on data quality issues, statistical considerations, and simulation results. Here, we use rigorous mathematical arguments to investigate the site frequency spectrum in the two-type model of clonal evolution. If the fitnesses of the two types are λ0 < λ1, then the site frequency spectrum is c/fα where α = λ0/λ1. This is due to the advantageous mutations that produce the founders of the type 1 population. Mutations within the growing type 0 and type 1 populations follow the 1/f law. Our results show that, in contrast to published criticisms, neutral evolution in an exponentially growing tumor can be distinguished from the two-type model using the site frequency spectrum.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Biological Evolution
  • Clonal Evolution*
  • Computer Simulation
  • Gene Frequency
  • Genome, Human
  • Genomics
  • Humans
  • Linear Models
  • Models, Genetic*
  • Mutation
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / physiopathology*
  • Ploidies
  • Probability
  • Selection, Genetic

Grant support

Both authors were partially supported by NSF grant 1614838 (https://www.nsf.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.