Gene Conversion Between The Lcr22s

The LCR22s are more than 98% identical in sequence. Of all LCR22s, LCR22-2 and LCR22-4 are the most similar, and they are more than 99% identical over large regions. The high level of identity between the two may be the reason why unequal homologous recombination events cause 22q11.2 rearrangements. Another type of recombination that is possible in regions of high sequence similarity is gene conversion, where one sequence invades and replaces another.

Paralogs are defined as sequence elements, which are present more than once per genome, arising by duplication processes during evolution. The different LCR22s are examples of paralogs. A nucleotide variation in one vs another LCR is termed a paralogous sequence variant (PSV; such as an A in LCR22-2 and a T in LCR22-4). A series of contiguous PSVs would represent a signature for a particular LCR22. A single nucleotide alteration in LCR22-2 (A/T) and in LCR22-4 (A/T), suggests that gene conversion could have been taking place. This is especially significant if there is a consecutive series of such nucleotide variants in cis. DNA

Fig. 7. Model of gene conversion. An original locus duplicated to copies 1, 2, and 3 during primate evolution. The colored shapes represent individual SNPs, which developed over time. The gene conversion events between copies 1, 2, and 3 result in a homogenization process whereby variation occurs in different individuals. (Modified from ref. 59.)

Fig. 7. Model of gene conversion. An original locus duplicated to copies 1, 2, and 3 during primate evolution. The colored shapes represent individual SNPs, which developed over time. The gene conversion events between copies 1, 2, and 3 result in a homogenization process whereby variation occurs in different individuals. (Modified from ref. 59.)

sequence analyses support the occurrence of gene conversion events in LCR22-2 and LCR22-4 based on our analysis of overlapping BAC clones from different genomic libraries spanning the interval (Morrow et al., unpublished data). The evidence is quite similar to that for the large olfactory receptor gene family segmental duplication and for telomere associated repeats (58,73). A model has been proposed to explain how segmental duplications can become homogenized during evolution (Fig. 7) (59,73,74). This process was hypothesized from data generated in studies of the HERV sequences involved in the AZFa microdeletion on chromosome Y and the CMT1A rearrangement on chromosome 17p12 (75,76). Recently, it has been suggested that regions harboring higher rates of gene conversion might be hotspots for common rearrangements in LCRs (72).

A gene conversion event, detected as a simultaneous loss and gain of a single nucleotide variation, would confirm that the LCR22-2 and LCR22-4 are more dynamic than originally believed. Gene conversion could cause stretches of homology to become larger in length and could more strongly stimulate unequal crossover events, thus leading to a deletion or duplication. It is therefore important to define the rate of gene conversion and identify subregions within LCR22s that have altered rates of gene conversion. Long stretches of sequence identity, perhaps created by gene conversion events, between the two LCR22s might serve as a point for unequal crossover. Based on recent studies of the SMS deletion and reciprocal duplication, there is a potential association between the positions of the unequal crossover and an increased rate of gene conversion (72).

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