Predominance of constitutional chromosomal rearrangements in human chromosomal fragile sites

Inês J Sequeira,João T Mexia,Aldina Brás,Elisa Silva,Rita Mamede,José Rueff,Jorge Santos,Daniel Faria,João Santiago

doi:10.4236/ojgen.2013.32a3002

Abstract

Chromosomal fragile sites (CFSs) are loci or regions susceptible to spontaneous or induced occurrence of gaps, breaks and rearrangements. In this work, we studied the data of 4535 patients stored at DECIPHER (Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources). We mapped fragile sites to chromosomal bands and divided the 23 chromosomes into fragile and non-fragile sites. The frequency of rearrangements at the chromosomal location of clones found to be deleted or duplicated in the array/CGH analysis, provided by DECIPHER, was compared in Chromosomal Fragile Sites vs. non-Fragile Sites of the human genome. The POSSUM Web was used to complement this study. The results indicated 1) a predominance of rearrangements in CFSs, 2) the absence of statistically significant difference between the frequency of rearrangements in common CFSs vs. rare CFSs, 3) a predominance of deletions over duplications in CFSs. These results on constitutional chromosomal rearrangements are evocative of the findings previously reported by others relatively to cancer supporting the current line of evidence and suggesting that a common mechanism can underlie the generation of constitutional and somatic rearrangements. The combination of insights obtained from our results and their interrelationships can indicate strategies by which the mechanisms can be targeted with preventive medical interventions.

Highlights

From a mere cytogenetic observation of 40 years ago [1], fragile sites of human chromosomes became the subject of important studies in human genetics.Based on their inheritance patterns and population frequency, chromosomal fragile sites (CFSs) were classified in two main categories: rare and common
We studied the data of 4535 patients stored at DECIPHER (Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources)
We take into account that 1) the fragile sites’ set was recently extended [3], 2) common and rare chromosomal fragile sites share some characteristics [4], 3) some rare fragile sites span the same genomic regions as common fragile sites [13], and 4) the CFS do not break at defined sequences but in breakage-prone regions [5,6]

Summary

INTRODUCTION

From a mere cytogenetic observation of 40 years ago [1], fragile sites of human chromosomes became the subject of important studies in human genetics. Based on their inheritance patterns and population frequency, chromosomal fragile sites (CFSs) were classified in two main categories: rare and common. The traditional classification of fragile sites has recently been questioned [3] and the extension of the definition of CFSs to chromosomal fragile regions has been proposed, since molecular genetic mapping data indicated that breaks do not occur in a defined sequence of CFSs, but most likely in regions prone to breakage as large as 10 Mb [5,6]. Comparison of the frequencies of chromosomal aberrations in these sites will help clarify the molecular events that might lead to disease

METHODS

Study Strategy

Statistical Analysis

Predominance of Constitutional Chromosomal Rearrangements in CFSs

The Most Frequent Chromosomal Rearrangements That Occur in CFSs Are Deletions