Genes used together are more likely to be fused together in evolution by mutational mechanisms: A bioinformatic test of the used-fused hypothesis

Cases of parallel or recurrent gene fusions, whether in evolution or in cancer and genetic disease, are difficult to explain, as they require multiple of the same or similar breakpoints to repeat. The used-together-fused-together hypothesis holds that genes that are used together repeatedly and persistently in a certain context are more likely than otherwise to undergo a fusion mutation in the course of evolution--reminiscent of the Hebbian learning rule where neurons that fire together wire together. This mutational hypothesis offers to explain both evolutionary parallelism and recurrence in disease of gene fusions under one umbrella. Here, we test this hypothesis using bioinformatic data. Various measures of gene interaction, including co-expression, co-localization, same-TAD presence and semantic similarity of GO terms show that human genes whose homologs are fused in one or more other organisms are significantly more likely to interact together than random genes, controlling for genomic distance between genes. In addition, we find a statistically significant overlap between pairs of genes that fused in the course of evolution in non-human species and pairs that undergo fusion in human cancers. These results provide support for the used-together-fused-together hypothesis over several alternative hypotheses, including that all gene pairs can fuse by random mutation, but among pairs that have thus fused, those that have interacted previously are more likely to be favored by selection. Multiple consequences are discussed, including the relevance of mutational mechanisms to exon shuffling, to the distribution of fitness effects of mutation and to parallelism.