Gene Conversion in Evolution and Disease

Abstract

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.