Gene conversion



Gene conversion is an event in DNA genetic recombination, which occurs at high frequencies during meiotic division but which also occurs in somatic cells. It is a process by which DNA sequence information is transferred from one DNA helix (which remains unchanged) to another DNA helix, whose sequence is altered. It is one of the ways a gene may be mutated. Gene conversion may lead to non-Mendelian inheritance and has often been recorded in fungal crosses.

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 exits 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 affective 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 also 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 which involves in gene conversion process (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 occurs between nonallelic gene copies residing on sister chromatids or homologous chromosomes and in case of Interallelic the gene conversion events takes 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, like 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 that expressed at higher level, called ‘master’ gene, converting that of the lower expression, called ‘slave’ gene. Since it was 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).

Evolutionary importance of gene conversion
In the discussions of genetic diseases in humans, pseudogene mediated gene conversion that introduce pathogenic mutations into functional genes is a well known mechanism of mutation. In opposite, is there any chance for the pseudogenes to serve as templates from which during the course of evolution multiple changes in their single copy functional source genes which are potentially advantageous have been derived? The pseudogene-templated changes might eventually become fixed as long as they did not possess the deleterious effects. So, in fact, the pseudogenes can act as a source of sequence variants which can be transferred to the functional gene in novel combinations that are not tried so far and can be acted up on by selection. Lectin 11 (SIGLEC11) gene, which is a human immunoglobulin that binds to sialic acid can be considered as an example for such an gene conversion events which play a significant role in evolution. While comparing the homologous genes of human SIGLEC11 and its pseudogene in chimpanzee, bonobo, gorilla and orangutan, it came to know about the event of gene conversion of the sequence of 5’ upstream regions and the exons that encodes the sialic acid recognition domain which counts approximately 2kb by the closely flanking hSIGLECP16 pseudogene (Hayakawa et al., 2005). The three realizing points about this event have together suggested this as an adaptive change which is very evolutionarily important in genus Homo. Those includes that only in human lineage this gene conversion happened, the brain cortex has acquired an important expression of SIGLEC11 specifically in human lineage and the exhibition of a change in substrate binding in human lineage when compared to that of its counterpart in chimpanzees. Of course the frequency of the contribution of this pseudogene-mediated gene conversion mechanism to functional and adaptive changes in evolution of human is still unknown and so far it has been scarcely explored (Chen et al., 2007). In spite of that, the introduction of positively selective genetic changes by such mechanism can be put forward for consideration by the example of SIGLEC11. Sometimes due to interference of transposable elements in to some members of a gene family, it causes a variation among them and finally it may also cease the rate of gene conversion due to lack of sequence similarity which leads to divergent evolution.

Effect
Normally, an organism that has inherited different copies of a gene from each of its parents is called heterozygous. This is generically represented as genotype: Aa (i.e. one copy of variant (allele) 'A', and one copy of allele 'a'). When a heterozygote creates gametes by meiosis, the alleles normally split, and end up in a 1:1 ratio in the resulting cells. However, in gene conversion, a ratio other than the expected 1A:1a is observed, in which A and a are the two alleles. Such examples are 3A:1a, 1A:3a, 5A:3a or 3A:5a. In other words there can, for example, be three times as many A alleles as a alleles expressed in the daughter cells, as is the case in 3A:1a.

Medical relevance
Gene conversion resulting in mutation of the CYP21A2 gene is a common underlying genetic cause of congenital adrenal hyperplasia.

Somatic gene conversion is one of the mechanisms that can result in familial retinoblastoma, a congenital cancer of the retina.

It is theorized that gene conversion may play a role in the development of Huntington's Disease.