Gene Conversion - Mechanistic Basis of Gene Conversion

Mechanistic Basis of Gene Conversion

This conversion of one allele to the other is due to base mismatch repair during recombination: if one of the four strands during meiosis pairs up with one of the four strands of a different chromosome, as can occur if there is sequence homology, mismatch repair can alter the sequence of one of the chromosomes, so that it is identical to the other.

Gene conversion can result from the repair of damaged DNA as described by the Double Strand Break Repair Model. Here a break in both strands of DNA is repaired from an intact homologous region of DNA. Resection (degradation) of the DNA strands near the break site leads to stretches of single stranded DNA that can invade the homologous DNA strand. The intact DNA can then function as a template to copy the lost DNA. During this repair process a structure called a double Holliday structure is formed. Depending on how this structure is resolved (taken apart) either cross-over or gene conversion products result.

From various genome analyses, it was concluded that the double-strand breaks (DSB) can be repaired via homologous recombination by at least two different but related pathways. In case of major pathway, homologous sequences on both sides of the DSB will be employed which seems to be analogous to the conservative DSB repair model (Szostak et al., 1983) that was originally proposed for meiotic recombination in yeast. where as the minor pathway is restricted to only one side of the DSB as postulated by nonconservative one-sided invasion model. However, in both the cases the sequence of the recombination partners will be absolutely conserved. By virtue of their high degree of homology, the new gene copies that came in to existence following the gene duplication naturally tend to either unequal crossover or unidirectional gene conversion events. In the latter process, there exists the acceptor and donor sequences and the acceptor sequence will be replaced by a sequence copied from the donor, while the sequence of the donor remains unchanged (Chen et al., 2007).

The effective homology between the interacting sequences makes the gene conversion event successful. Additionally, the frequency of gene conversion is inversely proportional to the distance between the interacting sequences in cis (Schildkraut et al., 2005), and the rate of gene conversion is usually directly proportional to the length of uninterrupted sequence tract in the assumed converted region. It seems that conversion tracts accompanying crossover are longer (mean length = ∼460 bp) than conversion tracts without crossover (mean length = 55–290 bp). In the studies of human globulin genes, it has long been supported that the gene conversion event or branch migration events can either be promoted or inhibited by the specific motifs that exist in the vicinity of the DNA sequence (Papadakis and Patrinos, 1999). Another basic classification of gene conversion events is the interlocus (also called nonallelic) and interallelic gene conversions. The cis or trans nonallelic or interlocus gene conversion events occur between nonallelic gene copies residing on sister chromatids or homologous chromosomes, and, in case of interallelic, the gene conversion events take place between alleles residing on homologous chromosomes (Adapted from Chen et al., (2007). If the interlocus gene conversion events are compared, it will be frequently revealed that they exhibit biased directionality. Sometimes, such as in case of human globin genes (Papadakis and Patrinos, 1999), the gene conversion direction correlates with the relative expression levels of the genes that participate in the event, with the gene expressed at higher level, called the ‘master’ gene, converting that with lower expression, called the ‘slave’ gene. Originally formulated in an evolutionary context, the ‘master/slave gene’ rule should be explained with caution. In fact, the increase in gene transcription exhibits not only the increase in likelihood of it to be used as a donor but also as an acceptor (Schildkraut et al., 2006).