Organization and evolution of low copy repeats (LCR) on chromosome 22q11

Abstract

Chromosome 22q11 harbors low copy repeat sequences that can mediate deletions, duplications, and translocations. The eight low copy repeats on chromosome 22q11, LCR22s, contain genes and pseudogenes. There are four main genes, USP18, BCR, GGTLA, and GGT, that have portions that were duplicated and transposed to the other LCR22s. Besides the complex nature of the genes/pseudogenes LCR22s also harbor other sequence elements, like AT-rich repeats, which have the potential to form cruciform structures.;In order to better understand the complex nature of these LCR22s, I wanted to determine how the LCR22s evolved and what role did the AT-rich repeats have within the LCR22s. I hypothesized that since AT-rich repeats can mediate translocations in meiosis, they might also play a role in shaping the organization of the LCR22s.;The complexity of the LCR22s was shown through their evolution. By performing array comparative hybridization, fluorescent in-situ hybridization, real time PCR, and mapping of BAC clones, I determined that there were gene duplications and LCR22 formations in the non-human hominoids. Interestingly, the lineage specific amplification of the LCR22s found in gorilla appeared to be located at the sub-telomere ends of the chromosomes, which suggests that these regions are prone to rearrangements.;Besides the evolution of the genes shedding some light onto the complex nature of the LCR22s, the AT-repeat also showed to be a complex element not only mediating recombination events in LCR22s but also being involved in heterochromatic regions of the acrocentric chromosomes, especially on chromosome Yq12. The AT-rich repeat is clustered with other sequence elements, an Alu element and a satellite DNA, HSAT I. This HSAT I/Alu/AT-rich repeat was also present on the acrocentric chromosomes and on Yq12. The HSAT I/Alu/AT-rich repeat was also found within the main LCR22s and that breakage within the AT-rich repeats have shaped the LCR22 organization. Overall, the organization of the genes within the LCR22s and the AT-rich repeats provides evidence of the complex nature of the LCR22s playing an important role in mediating chromosomal rearrangements.