Gene Fusion

Abstract

Gene fusion is a process by which the complete or partial sequences of two or more distinct genes are fused into a single chimeric gene or transcript, as a result of deoxyribonucleic acid‐ or ribonucleic acid‐derived rearrangements. This phenomenon is widespread and has been observed across all domains of life. Comparative genomics studies reveal high and persistent incidence of gene fusions and identify lineage‐specific factors that promote or hinder the formation of chimeric genes. Studies of recent gene fusions expose the mechanisms of their origin and the diversity of functional changes that accompany their formation. Gene fusions prominently contribute to evolutionary change by providing a continuous source of new genes. Gene duplications often precede gene fusions, permitting the evolution of chimeric genes, but at the same time preserving the original functions. Despite the reputation of gene fusions as drivers of adaptive evolution, gene fusions can have devastating consequences, often leading to genomic disorders or cancer.

Key Concepts:

  • Gene fusions form through DNA‐derived rearrangements or through transcription‐mediated mechanisms (novel cis‐ or trans‐splicing).

  • Gene or domain duplications often precede gene fusions preserving the original functions of parental genes and therefore facilitating the evolution of new functions by chimeric gene products.

  • Young gene fusions (polymorphic or recently fixed) retain molecular signatures of their formations revealing the mechanisms of origin.

  • The formation of chimeric genes generally involves two steps: juxtaposition of the sequences involved in fusion and subsequent mutations that generate a single chimeric transcriptional unit under the control of a single regulatory system.

  • Various replicative (i.e. replication related) and nonreplicative mechanisms of DNA break repair can result in gene duplication and gene movement.

  • Transposable elements greatly facilitate gene fusions by (1) mediating gene duplication and gene movements, (2) providing the source of reverse transcriptase required for retropositions and (3) directly participating in gene fusions.

  • Gene fusion often generates a novel product with functional capabilities distinct from those of its parental genes, ensuring frequent contribution of chimeric genes to adaptive evolution.

  • Gene fusions in the germline can lead to genomic disorders, whereas gene fusions in somatic cells are associated with many different cancers, frequently as mutations that initiate tumourigenesis.

Keywords: gene fusion; chimeric transcript; gene duplication; DNA repair; recombination; retroposition; adaptive evolution; new genes; novel function; genomic disorders; cancer

Figure 1.

Sdic is an example of a gene fusion that occurred through deletion and was preceded by the duplication of two genes (Cdic and Annx; a and b) involved in the fusion. The duplicated region (a‐b‐a‐b) has been inferred to undergo three deletions that led to the chimeric structure of the new gene Sdic. Sdic was, in turn, duplicated several times, possibly up to ten times, but only four Sdic copies are annotated in FlyBase. The genes Cdic (also known as short wing; sw) and Annx remained in the genome and maintained their functions.

Figure 2.

KUA–UEV transcription‐mediated fusion generates a chimeric protein in the human genome. Exon K6 of KUA and exon U1 of UEV, all intron sequences and an intergenic region, are spliced out in a read‐through transcript.

Figure 3.

Origin of jingwei, a chimeric Drosophila gene. The retrosequence of Adh was inserted into the third intron of a duplicated copy of the ymp gene, yande (ynd). The downstream exons of ynd became pseudoexons as a result of transcription termination signal encoded by the Adh‐derived exon.

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Williford, Anna, and Betrán, Esther(May 2013) Gene Fusion. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005099.pub3]