Gene fusion, fission, lateral transfer, and loss: Not-so-rare events in the evolution of eukaryotic ATP citrate lyase

• Single and double-subunit ATP citrate lyase are widespread but do not co-occur in eukaryotes.
• Single-subunit ACL arose via an ancient fusion event of the two dsACL-encoding genes.
• Both forms likely existed in the Last Eukaryotic Common Ancestor.
• Multiple gene fusion, fission, and transfer events complicate ACL’s evolutionary history.

ATP citrate lyase (ACL) is an enzyme critical to the generation of cytosolic acetyl-CoA in eukaryotes. In most studied organisms, ACL activity is conferred in combination by two proteins, ACLA and ACLB (dsACL); however, animals encode a single-subunit ACL (ssACL) – the result of a gene fusion event. Through phylogenetic analyses, we investigated the evolution of ACL in a broad range of eukaryotes, including numerous microbes (protists). We show that the fused form is not restricted to animals, and is instead widely distributed among eukaryotes. Furthermore, ssACL and dsACL are patchily distributed and appear to be mutually exclusive; both types arose early in eukaryotic evolution. Finally, we present several compelling hypotheses of lateral gene transfer and gene loss, along with the secondary gene fission of ssACL in Ascomycota. Collectively, our in-depth analyses suggest that a complex suite of evolutionary events, usually considered rare, has shaped the evolution of ACL in eukaryotes.

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