Gene Conversion in Evolution and Disease

Abstract

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 double‐strand break repair (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 double‐strand break (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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References

Adams JG III, Marrison WT and Steinberg MH (1982) Hemoglobin Parchman: double crossover within a single human gene. Science 218: 291–293.

Allen LA, Achermann JC, Pakarinen P et al. (2003) A novel loss of function mutation in exon 10 of the FSH receptor gene causing hypergonadotrophic hypogonadism: clinical and molecular characteristics. Human Reproduction 18: 251–256.

Ardlie K, Liu‐Cordero SN, Eberle MA et al. (2001) Lower‐than‐expected linkage disequilibrium between tightly linked markers in humans suggests a role for gene conversion. American Journal of Human Genetics 69: 582–589.

Auclair J, Leroux D, Desseigne F et al. (2007) Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Human Mutation 28: 1084–1090.

Blanco P, Shlumukova M, Sargent CA et al. (2000) Divergent outcomes of intrachromosomal recombination on the human Y chromosome: male infertility and recurrent polymorphism. Journal of Medical Genetics 37: 752–758.

Boocock GR, Morrison JA, Popovic M et al. (2003) Mutations in SBDS are associated with Shwachman‐Diamond syndrome. Nature Genetics 33: 97–101.

Bosch E, Hurles ME, Navarro A and Jobling MA (2004) Dynamics of a human interparalogue gene conversion hotspot. Genome Research 14: 835–844.

Bussaglia E, Clermont O, Tizzano E et al. (1995) A frame‐shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients. Nature Genetics 11: 335–337.

Chen JM, Cooper DN, Chuzhanova N, Férec C and Patrinos GP (2007) Gene conversion: mechanisms, evolution and human disease. Nature Reviews. Genetics 8: 762–775.

Cheng Z, Ventura M, She X et al. (2005) A genome‐wide comparison of recent chimpanzee and human segmental duplications. Nature 437: 88–93.

Chuzhanova N, Chen JM, Bacolla A et al. (2009) Gene conversion causing human inherited disease: evidence for involvement of non‐B DNA‐forming sequences and recombination‐promoting motifs in DNA breakage and repair. Human Mutation, in press.

De Marco P, Moroni A, Merello E et al. (2000) Folate pathway gene alterations in patients with neural tube defects. American Journal of Medical Genetics 95: 216–223.

Eickbush TH and Eickbush DG (2007) Finely orchestrated movements: evolution of the ribosomal RNA genes. Genetics 175: 477–485.

Eyal N, Wilder S and Horowitz M (1990) Prevalent and rare mutations among Gaucher patients. Gene 96: 277–283.

Fardella CE, Hum DW, Rodriguez H et al. (1996) Gene conversion in the CYP11B2 gene encoding P450c11AS is associated with, but does not cause, the syndrome of corticosterone methyloxidase II deficiency. Journal of Clinical Endocrinology and Metabolism 81: 321–326.

Friaes A, Rêgo AT, Aragüés JM et al. (2006) CYP21A2 mutations in Portuguese patients with congenital adrenal hyperplasia: identification of two novel mutations and characterization of four different partial gene conversions. Molecular Genetics and Metabolism 88: 58–65.

Gupta PK, Adamtziki E, Budde U et al. (2005) Gene conversions are a common cause of von Willebrand disease. British Journal of Haematology 130: 752–758.

Haber JE, Ira G, Malkova A and Sugawara N (2004) Repairing a double‐strand chromosome break by homologous recombination: revisiting Robin Holliday's model. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 359: 79–86.

Hallast P, Nagirnaja L, Margus T and Laan M (2005) Segmental duplications and gene conversion: human luteinizing hormone/chorionic gonadotropin beta‐gene cluster. Genome Research 15: 1535–1546.

Hatton CE, Cooper A, Whitehouse C and Wraith JE (1997) Mutation analysis in 46 British and Irish patients with Gaucher's disease. Archives of Diseases in Childhood 77: 17–22.

Hauptschein RS, Gaidano G, Rao PH et al. (2000) An apparent interlocus gene conversion‐like event at a putative tumor suppressor gene locus on human chromosome 6q27 in a Burkitt's lymphoma cell line. DNA Research 7: 261–272.

Hayakawa T, Angata T, Lewis AL et al. (2005) A human‐specific gene in microglia. Science 309: 1693.

Heinen S, Sanchez‐Corral P, Jackson MS et al. (2006) De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor H associated with atypical hemolytic uremic syndrome. Human Mutation 27: 292–293.

Hurles ME (2003) Gene conversion. In: Encyclopedia of Life Sciences, http://www.els.net/ [DOI: 10.1038/npg.els.0000816]. Chichester: Wiley.

Hurles ME, Willey D, Matthews L and Hussain SS (2004) Origins of chromosomal rearrangement hotspots in the human genome: evidence from the AZFa deletion hotspots. Genome Biology 5: R55.

Innan H (2003) A two‐locus gene conversion model with selection and its application to the human RHCE and RHD genes. Proceedings of the National Academy of Sciences of the USA 100: 8793–8798.

Inoue S, Inoue K, Utsunomiya M et al. (2002) Mutation analysis in PKD1 of Japanese autosomal dominant polycystic kidney disease patients. Human Mutation 19: 622–628.

Ip SC, Rass U, Blanco MG et al. (2008) Identification of Holliday junction resolvases from humans and yeast. Nature 456: 357–361.

Ira G, Malkova A, Liberi G, Foiani M and Haber JE (2003) Srs2 and Sgs1‐Top3 suppress crossovers during double‐strand break repair in yeast. Cell 115: 401–411.

Ira G, Satory D and Haber JE (2006) Conservative inheritance of newly synthesized DNA in double‐strand break‐induced gene conversion. Molecular Cellular Biology 26: 9424–9429.

Jackson MS, Oliver K, Loveland J et al. (2005) Evidence for widespread reticulate evolution within human duplicons. American Journal of Human Genetics 77: 824–840.

Jeffreys AJ and May CA (2004) Intense and highly localized gene conversion activity in human meiotic crossover hot spots. Nature Genetics 36: 151–156.

Jonkman MF, Scheffer H, Stulp R et al. (1997) Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion. Cell 88: 543–551.

Kalamaras A, Chassanidis C, Samara M et al. (2008) The 5′ regulatory region of the human fetal globin genes is a gene conversion hotspot. Hemoglobin 32: 572–581.

Lee‐Chen GJ and Wang TR (1997) Mucopolysaccharidosis type I: identification of novel mutations that cause Hurler/Scheie syndrome in Chinese families. Journal of Medical Genetics 34: 939–941.

Marais G (2003) Biased gene conversion: implications for genome and sex evolution. Trends in Genetics 19: 330–338.

Millar DS, Lewis MD, Horan M et al. (2003) Novel mutations of the growth hormone 1 (GH1) gene disclosed by modulation of the clinical selection criteria for individuals with short stature. Human Mutation 21: 424–440.

Minegishi Y, Coustan‐Smith E, Wang YH et al. (1998) Mutations in the human lamda5/14.1 gene results in B cell deficiency and agammaglobulinemia. Journal of Experimental Medicine 187: 71–77.

Nakashima E, Mabuchi A, Makita Y et al. (2004) Novel SBDS mutations caused by gene conversion in Japanese patients with Shwachman‐Diamond syndrome. Human Genetics 114: 345–348.

Nicod J, Dick B, Frey FJ and Ferrari P (2004) Mutation analysis of CYP11B1 and CYP11B2 in patients with increased 18‐hydroxycortisol production. Molecular Cellular Endocrinology 214: 167–174.

Nicolis E, Bonizzato A, Assael BM and Cipolli M (2005) Identification of novel mutations in patients with Shwachman–Diamond syndrome. Human Mutation 25: 410.

Ogino S, Gao S, Leonard DG, Paessler M and Wilson RB (2003) Inverse correlation between SMN1 and SMN2 copy numbers: evidence for gene conversion from SMN2 to SMN1. European Journal of Human Genetics 11: 275–277.

Papadakis MN and Patrinos GP (1999) Contribution of gene conversion in the evolution of the human beta‐like globin gene family. Human Genetics 104: 117–125.

Patrinos GP, Kollia P, Loutradi‐Anagnostou A, Loukopoulos DL and Papadakis MN (1998) The Cretan type of non‐deletional hereditary persistence of fetal hemoglobin [Agamma –158 C>T] results from two independent gene conversion events. Human Genetics 102: 629–634.

Plotnikova OV, Kondrashov FA, Vlasov PK et al. (2007) Conversion and compensatory evolution of the gamma‐crystallin genes and identification of a cataractogenic mutation that reverses the sequence of the human CRYGD gene to an ancestral State. American Journal of Human Genetics 81: 32–43.

Pop R, Zaragoza MV, Gaudette M, Dahrmann U and Scherer G (2005) A homozygous nonsense mutation in SOX9 in the dominant disorder campomelic dysplasia: a case of mitotic gene conversion. Human Genetics 117: 43–53.

Reiter LT, Hastings PJ, Nelis E et al. (1998) Human meiotic recombination products revealed by sequencing a hotspot for homologous strand exchange in multiple HNPP deletion patients. American Journal of Human Genetics 62: 1023–1033.

Reyniers E, Van Thienen MN, Meire F et al. (1995) Gene conversion between red and defective green opsin gene in blue cone monochromacy. Genomics 29: 323–328.

Roesler J, Curnutte JT, Rae J et al. (2000) Recombination events between the p47‐phox gene and its highly homologous pseudogenes are the main cause of autosomal recessive chronic granulomatous disease. Blood 95: 2150–2156.

Rozen S, Skaletsky H, Marszalek JD et al. (2003) Abundant gene conversion between arms of palindromes in human and ape Y chromosomes. Nature 423: 873–876.

Schildkraut E, Miller CA and Nickoloff JA (2005) Gene conversion and deletion frequencies during double‐strand break repair in human cells are controlled by the distance between direct repeats. Nucleic Acids Research 33: 1574–1580.

Schildkraut E, Miller CA and Nickoloff JA (2006) Transcription of a donor enhances its use during double‐strand break‐induced gene conversion in human cells. Molecular Cellular Biology 26: 3098–3105.

Sharon D, Glusman G, Pilpel Y et al. (1999) Primate evolution of an olfactory receptor cluster: diversification by gene conversion and recent emergence of pseudogenes. Genomics 61: 24–36.

Slightom JL, Blechi AE and Smithies O (1980) Human fetal Gγ‐ and Aγ‐globin genes: complete nucleotide sequences suggest that DNA can be exchanged between these duplicated genes. Cell 21: 627–638.

Szostak JW, Orr‐Weaver TL, Rothstein RJ and Stahl FW (1983) The double‐strand‐break repair model for recombination. Cell 33: 25–35.

Teich N, Nemoda Z, Köhler H et al. (2005) Gene conversion between functional trypsinogen genes PRSS1 and PRSS2 associated with chronic pancreatitis in a six‐year‐old girl. Human Mutation 25: 343–347.

Vanita, Sarhadi V, Reis A et al. (2001) A unique form of autosomal dominant cataract explained by gene conversion between beta‐crystallin B2 and its pseudogene. Journal of Medical Genetics 38: 392–396.

Vázquez N, Lehrnbecher T, Chen R et al. (2001) Mutational analysis of patients with p47‐phox‐deficient chronic granulomatous disease: the significance of recombination events between the p47‐phox gene (NCF1) and its highly homologous pseudogenes. Experimental Hematology 29: 234–243.

Vazquez‐Salat N, Yuhki N, Beck T, O'brien SJ and Murphy WJ (2007) Gene conversion between mammalian CCR2 and CCR5 chemokine receptor genes: a potential mechanism for receptor dimerization. Genomics 90: 213–224.

Verrelli BC and Tishkoff SA (2004) Signatures of selection and gene conversion associated with human color vision variation. American Journal of Human Genetics 75: 363–375.

Vyletal P, Sokolová J, Cooper DN et al. (2007) Haplotype diversity of cystathionine β‐synthase alleles bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion. Human Mutation 28: 255–264.

Watnick TJ, Gandolph MA, Weber H, Neumann HP and Germino GG (1998) Gene conversion is a likely cause of mutation in PKD1. Human Molecular Genetics 7: 1239–1243.

Woelk CH, Frost SD, Richman DD et al. (2007) Evolution of the interferon alpha gene family in eutherian mammals. Gene 397: 38–50.

Wolf A, Millar DS, Caliebe A et al. (2009) A gene conversion hotspot in the human growth hormone (GH1) gene promoter. Human Mutation 30: 239–247.

Wu L and Hickson ID (2003) The Bloom's syndrome helicase suppresses crossing over during homologous recombination. Nature 426: 870–874.

Zangenberg G, Huang MM, Arnheim N and Erlich H (1995) New HLA‐DPB1 alleles generated by interallelic gene conversion detected by analysis of sperm. Nature Genetics 10: 407–414.

Zhang J, Lindroos A, Ollila S et al. (2006) Gene conversion is a frequent mechanism of inactivation of the wild‐type allele in cancers from MLH1/MSH2 deletion carriers. Cancer Research 66: 659–664.

Further Reading

Galtier N and Duret L (2007) Adaptation or biased gene conversion? Extending the null hypothesis of molecular evolution. Trends in Genetics 23: 273–277.

Krogh BO and Symington LS (2004) Recombination proteins in yeast. Annual Reviews in Genetics 38: 233–271.

Liu Y and West SC (2004) Happy Hollidays: 40th anniversary of the Holliday junction. Nature Reviews. Molecular Cell Biology 5: 937–944.

Pâques F and Haber JE (1999) Multiple pathways of recombination induced by double‐strand breaks in Saccharomyces cerevisiae. Microbiology and Molecular Biology Reviews 63: 349–404.

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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. http://www.els.net [doi: 10.1002/9780470015902.a0005100.pub2]