Study of The Mechanism of Translocation in Chromosomes

Abstract

Transfer of a segment of chromosome to a non-homologous chromosome is called translocation. It could alter the gene functioning or lead to formation of a fusion gene. Many chromosomal translocations have been associated with a number of human cancers, mainly lymphomas and leukemias. Two examples of leukemia resulting due to formation of fusion genes are Chronic Myeloid Leukemia (CML) and Acute Promyelocytic Leukemia (APL). Various approaches have been undertaken in order to understand the exact mechanism underlying chromosomal translocation. The knowledge regarding the chromosomal breakpoint regions could provide useful insights on how and why the chromosomal breakage and rearrangement occurs. The in silico analysis of these breakpoint regions at the sequence level was done based on physico-chemical properties such as, AT%, flexibility, melting temperature, enthalpy, entropy, stacking energy and free energy of the sequences taking part in formation of fusion gene. Changes in these properties may lead to instability of DNA which could affect gene expression in particular and genome organization in general. The genomic organization of the chromosomes during interphase could allow the arrangement of gene loci in definite regions enhancing the chance of translocation amongst neighboring chromosomes. The gene pairs taking part in translocations were analyzed to check their relative proximities. In order to do this Fluorescence in-situ hybridization (FISH) signals for BCR-ABL and PML-RARA were measured. Our study indicates that the fusion sequences are evidently more unstable and hence, more prone to breakage. The genomic organization of interphase cells showed preferential positioning of the gene pairs. Thus, close distance between the genes could be a possible mechanism facilitating translocation.