Genes that are Used Together are More Likely to be Fused Together in Evolution by Mutational Mechanisms: A Bioinformatic Test of the Used-Fused Hypothesis

Evgeni Bolotin, Daniel Melamed, Adi Livnat

Research output: Contribution to journalArticlepeer-review


Cases of parallel or recurrent gene fusions in evolution as well as in genetic disease and cancer are difficult to explain, because unlike point mutations, they can require the repetition of a similar configuration of multiple breakpoints rather than the repetition of a single point mutation. The used-together-fused-together hypothesis holds that genes that are used together repeatedly and persistently in a specific context are more likely to undergo fusion mutation in the course of evolution for mechanistic reasons. This hypothesis offers to explain gene fusion in both evolution and disease under one umbrella. Using bioinformatic data, we tested this hypothesis against alternatives, including that all gene pairs can fuse by random mutation, but among pairs thus fused, those that had interacted previously are more likely to be favored by selection. Results show that across multiple measures of gene interaction, human genes whose orthologs are fused in one or more species are more likely to interact with each other than random pairs of genes of the same genomic distance between pair members; that an overlap exists between genes that fused in the course of evolution in non-human species and genes that undergo fusion in human cancers; and that across six primate species studied, fusions predominate over fissions and exhibit substantial evolutionary parallelism. Together, these results support the used-together-fused-together hypothesis over its alternatives. Multiple implications are discussed, including the relevance of mutational mechanisms to the evolution of genome organization, to the distribution of fitness effects of mutation, to evolutionary parallelism and more.

Original languageEnglish
Number of pages26
JournalEvolutionary Biology
Issue number1
StatePublished - 2023

Bibliographical note

Funding Information:
This publication was made possible through the support of a grant from the John Templeton Foundation. The opinions expressed in this publication are those of the authors and do not necessarily reflect the views of the John Templeton Foundation.

Publisher Copyright:
© 2022, The Author(s).


  • Exon shuffling
  • Fusion mutation
  • Genome organization
  • Nonrandom mutation
  • Parallelism
  • Translocation mutation

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics


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