Review Article | Published:

Gene conversion: mechanisms, evolution and human disease

Nature Reviews Genetics volume 8, pages 762775 (2007) | Download Citation

Subjects

Abstract

Gene conversion, one of the two mechanisms of homologous recombination, involves the unidirectional transfer of genetic material from a 'donor' sequence to a highly homologous 'acceptor'. Considerable progress has been made in understanding the molecular mechanisms that underlie gene conversion, its formative role in human genome evolution and its implications for human inherited disease. Here we assess current thinking about how gene conversion occurs, explore the key part it has played in fashioning extant human genes, and carry out a meta-analysis of gene-conversion events that are known to have caused human genetic disease.

Key points

  • Gene conversion involves the unidirectional transfer of genetic material from a 'donor' to an 'acceptor' sequence. It mediates the transfer of genetic information from intact homologous sequences to regions containing double-strand breaks (DSBs), and can occur between sister chromatids, homologous chromosomes, and even between homologous sequences on the same chromatid or on different chromosomes.

  • Gene conversion occurs predominantly in meiosis, but also in mitosis.

  • Gene conversion seems to result from either synthesis-dependent strand-annealing (SDSA) or double Holliday junction (HJ) dissolution, rather than from the random resolution of double HJs by an HJ resolvase, as predicted by the seminal double-strand break repair (DSBR) model.

  • Although the helicases Srs2, BLM and Rad54 have been reported to promote SDSA individually, the coordinated action of BLM, topoisomerase IIIα and BLAP75 (also known as RMI1) is needed to promote double-HJ dissolution.

  • The rate of gene conversion depends on multiple factors such as sequence homology and distance between the interacting sequences, but might also be affected by the presence of certain specific sequence motifs.

  • In mammalian cells, gene-conversion tracts are usually short and rarely exceed the order of 1 kb in length.

  • Gene-conversion events constitute an important driving force in genome evolution. Although interlocus gene conversion has been implicated in the concerted evolution of many human gene families, interallelic gene conversion has also been found to occur frequently at certain loci, generating a high level of allelic diversity.

  • The impact of gene conversion on the evolution of multigene families has been mediated by several factors, most notably selection.

  • There is growing evidence from both human population genetic studies and sperm typing to show that gene conversion has had an important role in shaping fine-scale patterns of linkage disequilibrium (LD) in the human genome.

  • Given the widespread presence of gene conversion and the short tract length that is usually involved in gene conversion, gene-conversion-generated SNPs often constitute 'holes' in the haplotype blocks that serve to reduce the efficacy of LD-based association studies.

  • High gene-conversion activity is a common feature of both allelic and non-allelic recombination hotspots; at least 25,000 recombination hotspots have been identified across the human genome.

  • An improved understanding of the role of gene conversion in generating or eliminating recombination hotspots in the human genome promises to improve our ability to predict the locations of unstable genomic regions.

  • Gene conversion has been implicated as the cause of various human genetic diseases.

  • Nearly 50% of the donor genes involved in interlocus gene-conversion events that cause human inherited disease are functional or partially functional.

  • Nearly all the disease-causing gene-conversion events resulted in the functional loss of the respective acceptor gene, the sole exception being a 'gain-of-function' mutation that occurred in the serine protease gene PRSS1.

  • Nearly all known cases of disease-causing interlocus gene conversion occurred between highly homologous sequences located on the same chromosome. There is only one example of the acceptor and donor genes involved residing on different chromosomes: the von Willebrand factor gene (VWF) gene (12p13.3) and its pseudogene (22q11.22–q11.23).

  • Our meta-analysis of pathogenic gene-conversion events revealed that, with one exception (88% between the folate receptor 1 gene (FOLR1) and its pseudogene), the homology between the linked donor and the acceptor gene sequences is always >92% and usually >95%.

  • In stark contrast to the frequent detection of pathogenic interlocus gene-conversion events (44 events in 17 genes), the occurrence of interallelic gene-conversion events causing human inherited disease is quite rare, with probably only one bona fide case identified: the SRY (sex determining region Y)-box 9 (SOX9).

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

  • The occurrence of de novo gene-conversion events is indicative of the dynamic nature of this genetic process.

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

  • In the future, gene conversion might provide a possible means to bring about 'natural gene therapy' by offering an important alternative to the introduction of an entire functional gene.

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Acknowledgements

We regret that, owing to space limitations, much of the relevant work could not be cited. We are indebted to R. Kanaar for critically reading the manuscript and for his valuable and detailed comments. We also thank the three anonymous reviewers for their constructive criticism of the manuscript. This work was partially supported by the INSERM (Institut National de la Santé et de la Recherche Médicale), France, and the Erasmus University Medical Center, Rotterdam, The Netherlands.

Author information

Affiliations

  1. INSERM, U613, 29220 Brest, France.

    • Jian-Min Chen
    •  & Claude Férec
  2. Etablissement Français du Sang — Bretagne, 46 rue Félix Le Dantec, 29220 Brest, France.

    • Jian-Min Chen
    •  & Claude Férec
  3. Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.

    • David N. Cooper
  4. Department of Biological Sciences, University of Central Lancashire, Preston PR1 2HE, UK.

    • Nadia Chuzhanova
  5. Faculté de Médecine de Brest et des Sciences de la Santé, Université de Bretagne Occidentale, 29238 Brest, France.

    • Claude Férec
  6. Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Centre Hospitalier Universitaire de Brest, Hôpital Morvan, 29220 Brest, France.

    • Claude Férec
  7. Erasmus University Medical Center, Faculty of Medicine and Health Sciences, MGC-Department of Cell Biology and Genetics, PO BOX 2040, 3000 CA, Rotterdam, The Netherlands.

    • George P. Patrinos

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jian-Min Chen or George P. Patrinos.

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    Supplementary information S1

    Collation of human pathogenic gene–conversion events

Glossary

Unequal crossover

A recombination event between non-allelic sequences on non-sister chromatids of a pair of homologous chromosomes.

Homologous recombination

The process by which segments of DNA are exchanged between two DNA duplexes that share high sequence similarity.

Double-strand break

Breaks in opposite DNA strands that lie within 10–20 bp of each other.

Holliday junction

A point at which the strands of two dsDNA molecules exchange partners, an event that occurs as an intermediate in crossing over or gene conversion.

Mismatch repair

A natural enzymatic process that replaces a mispaired nucleotide within a DNA duplex to yield perfect Watson–Crick base pairing.

Orthologue

A homologous gene that is derived from a speciation event or by vertical descent.

Gene-conversion tract

In theory, this is the portion of the 'acceptor' sequence that is copied from the 'donor'. Because in practice the length of the tract cannot be precisely known, it must be expressed in terms of the lengths of the minimal and maximal converted tracts: the former refers to the entire region spanned by converted discriminant nucleotides and the latter refers to the region that is delimited by the two nearest unconverted discriminant nucleotides between the donor and acceptor sequences.

Double crossover

Two crossovers that occur in a chromosomal region between highly homologous genes, resulting in reciprocal sequence exchange between them.

Chi (χ) sequence

An 8-bp sequence (5′-GCTGGTGG-3′) that acts as a recombination hotspot in Escherichia coli.

Z-DNA

One of several possible double-helical structures of DNA. Z-DNA is a left-handed double-helical structure in which the double helix winds to the left in a zig-zag pattern, rather than to the right, as occurs in the more common B-DNA form.

Concerted evolution

The process by which repetitive DNA sequences are homogenized such that the individual members of a given DNA repeat or multigene family in one species come to show a higher degree of sequence identity with each other than they do with members of the same DNA repeat or multigene family in another species.

Paralogue

One of a set of homologous genes in the same species that have evolved from a gene duplication, and that can be associated with a subsequent divergence of function.

Segmental duplication

A segment of DNA of larger than 1 kb that occurs in two or more copies per haploid genome, with the different copies sharing >90% sequence identity.

Linkage disequilibrium

A statistical association between particular alleles at two or more neighbouring loci on the same chromosome that results from a specific ancestral haplotype being common in the population under study.

Tag SNPs

SNPs that are correlated with, and can therefore serve as a proxy for, much of the known remaining common variation in a region.

Somatic hypermutation

A process that occurs after immunoglobulin gene rearrangement, whereby the base sequences of part of the immunoglobulin variable regions are mutated more frequently than the rest of the genome. This sequence variation is subject to a selection process in the immune system that favours those cells that express immunoglobulins with the highest affinity for an antigen.

Class switch recombination

The somatic recombination process by which immunoglobulin isotypes are switched to IgG, IgA or IgE, without altering antigen specificity.

Multiplex ligation-dependent probe amplification analysis

A semi-quantitative PCR-based method that allows multiple targets to be amplified with only a single primer pair, and that is widely used for detecting copy-number variations.

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DOI

https://doi.org/10.1038/nrg2193

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