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

Abstract

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.

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“…Recently, we found empirical support for this hypothesis, including its applicability to both germline and somatic genes (Bolotin et al, 2021).…”

“…However, genes that are used together are more likely to be transcribed at the same time and place in the nucleus-for example in co-expression domains (Soler-Oliva et al, 2017), topologically associated domains (Dixon et al, 2012) and transcription factories (Jackson et al, 1993;Edelman and Fraser, 2012;Papantonis and Cook, 2013) where DNA loops bring also remote coactive genes together. Therefore, to explain gene fusion, we argued that this presence of the two co-active genes at the same time and place, with the chromatin open at both loci due to transcription, enables various downstream mechanisms, such as reverse transcription of the RNA (perhaps aided by trans-splicing), transposable-element mediated translocation, recombinationbased mechanisms, DNA breaks induced by the spatial chromosomal organization and active gene transcription, and other mechanisms to generate a gene fusion (Livnat, 2017;Bolotin et al, 2021). We furthermore hypothesized that because the genetic information that indicates that the two genes work together, such as shared cis elements and transcription factors that bind to them, is present in the DNA and accessible in the germline, this fusion effect applies not only to pairs of genes that serve germline functions but also to pairs that serve somatic functions (Livnat, 2017;Bolotin et al, 2021).…”

“…Therefore, to explain gene fusion, we argued that this presence of the two co-active genes at the same time and place, with the chromatin open at both loci due to transcription, enables various downstream mechanisms, such as reverse transcription of the RNA (perhaps aided by trans-splicing), transposable-element mediated translocation, recombinationbased mechanisms, DNA breaks induced by the spatial chromosomal organization and active gene transcription, and other mechanisms to generate a gene fusion (Livnat, 2017;Bolotin et al, 2021). We furthermore hypothesized that because the genetic information that indicates that the two genes work together, such as shared cis elements and transcription factors that bind to them, is present in the DNA and accessible in the germline, this fusion effect applies not only to pairs of genes that serve germline functions but also to pairs that serve somatic functions (Livnat, 2017;Bolotin et al, 2021). Indeed, the germline-specific phenomenon of transcriptional promiscuity allows many somatic genes to be regularly transcribed in the germline (Kleene, 2005;Melé et al, 2015;Xia et al, 2020) and thus to participate in mutational mechanisms involving interactions between genes (Livnat, 2013(Livnat, , 2017.…”

“…Indeed, the germline-specific phenomenon of transcriptional promiscuity allows many somatic genes to be regularly transcribed in the germline (Kleene, 2005;Melé et al, 2015;Xia et al, 2020) and thus to participate in mutational mechanisms involving interactions between genes (Livnat, 2013(Livnat, , 2017. Thus, we hypothesized that, in the course of evolution, genes that are used together repeatedly and persistently in a certain context are incomparably more likely than other genes to be fused together by a mutational mechanism (Livnat, 2017;Bolotin et al, 2021): it is genes that are used together that can be fused together-henceforth the "used-fused" effect. This hypothesis offered the first explanation for why there are recurrent gene fusions, and why they are common, both in evolution (Carvalho et al, 2010;Livnat, 2013) and in genetic disease and cancer (Li et al, 2008;Osborne, 2014).…”

“…Second, before the fusion, the two genes had to be activated separately and their products had to meet, whereas the fusion has chunked them together into a single unit that can be activated as one. Therefore, the outcome of the fusion can be seen as a local mutational simplification of gene regulation (Livnat, 2017;Bolotin et al, 2021).…”