Gene Conversion in Evolution and Disease


Gene conversion involves the unidirectional transfer of genetic material from a ‘donor’ sequence to a highly homologous ‘acceptor’. Gene conversion is initiated by double‐strand breaks and can arise from mutually exclusive pathways. Over evolutionary time, gene conversion has homogenized the paralogous sequences within each species whereas diversifying the orthologous sequences between closely related species; interallelic gene conversion has generated a high level of allelic diversity at certain loci. Not only has gene conversion played a key role in fashioning extant human genes but it has also been implicated as the molecular cause of an increasing number of human genetic diseases.

Key concepts

  • Gene conversion involves the unidirectional transfer of genetic material from a ‘donor’ sequence to a highly homologous ‘acceptor’ and occurs in both meiosis and mitosis.

  • Gene conversion is initiated by DNA double‐strand breaks and appears to arise from different mutually exclusive pathways.

  • The rate of gene conversion is mainly determined by sequence homology and by the distance between the interacting sequences, but it may also be affected by specific sequence motifs or/and sequences capable of forming non‐B DNA structures.

  • Interallelic gene conversion events occur between alleles on homologous chromosomes whereas nonallelic or interlocus events can occur between paralogues on the same chromatid, sister chromatids or homologous chromosomes.

  • Interlocus gene conversion events have driven the concerted evolution of many human gene families whereas interallelic events have generated a high level of allelic diversity at certain loci.

  • Gene conversion has also been implicated as the cause of a variety of different human inherited diseases.

  • In stark contrast to the frequent detection of pathogenic interlocus gene conversion events, the occurrence of interallelic gene conversion events causing human inherited disease is quite rare.

  • Only a few well‐documented examples of gene conversion events in cancer have been reported in the literature.

  • Gene conversion can account for the occurrence of some recurrent mutations on different chromosomal backgrounds in different ethnic groups.

  • Gene conversion may provide a possible future means to bring about ‘natural gene therapy’ by offering an important alternative to the introduction of an entire functional gene.

Keywords: gene conversion; cancer; concerted evolution; homologous recombination; human genetic disease

Figure 1.

Mechanisms of gene conversion. The (DSBR; a–b–d), synthesis‐dependent strand annealing (SDSA; a–c) and double Holliday junction (HJ) dissolution (a–b–e) models are illustrated. All models share a common initiating step: the 5′ ends of the (DSB) are resected to form 3′ ssDNA tails; the tails actively ‘scan’ the genome for homologous sequences, and one tail invades the homologous DNA duplex forming a displacement (D)‐loop, which is then extended by DNA synthesis. SDSA diverges from the other two pathways after D‐loop extension: the invading strand and the newly synthesized DNA are displaced from the template and annealed to the other 3′ end of the DSB, leading to the formation of only gene‐conversion events. Otherwise, the other 3′ end of the DSB is captured, and DNA synthesis and ligation of nicks lead to the formation of double HJs. According to the dissolution model, BLM, topoisomerase IIIα (Topo IIIα) and the BLM‐associated protein BLAP75 (also known as RMI1) act together to remove the double HJs via convergent branch migration (indicated by green arrows at both HJs) leading exclusively to gene conversion. In DSBR, the resolution of the double HJs by an HJ resolvase, GEN1 in humans and Yen1 in yeast (Ip et al., ), is predicted to generate an equal number of noncrossover (indicated by red arrows at both HJs) and crossover (indicated by green arrows at one HJ and red arrows at the other HJ) events. Adapted from Chen et al. .

Figure 2.

Definition of gene conversion event and converted tracts. Although, the length of the minimal converted tract (MinCT) is usually shorter than the true tract; that of the maximal converted tract (MaxCT) is usually longer than the true tract. Initiating/terminating points of gene conversion may occur anywhere within the two regions that are marked in black. Adapted from Chen et al. .

Figure 3.

Types of gene conversion. (a) Nonallelic or interlocus gene conversion events in trans [between nonallelic gene copies (shown as blue and orange boxes) residing on sister chromatids or homologous chromosomes]. (b) Interlocus gene conversion events in cis (between nonallelic gene copies residing on the same chromatid). Gene conversion events, depicted in (a) and (b), are virtually indistinguishable from each other. (c) Interallelic gene conversion events between alleles residing on homologous chromosomes. Adapted from Chen et al. .



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Further Reading

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Chen, Jian‐Min, Cooper, David N, Chuzhanova, Nadia, Férec, Claude, and Patrinos, George P(Sep 2009) Gene Conversion in Evolution and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005100.pub2]