Mechanisms and Impact of Chromosome Abnormalities
Complex
chromosome abnormalities occur in many malignancies, but underlying mechanisms
remain largely unknown.
Chromosomal
instability can occur when the DNA damage response and repair process fail,
resulting in syndromes characterised by growth abnormalities, haematopoietic
defects, immunodeficiency, mutagen sensitivity, and cancer predisposition.
It is important to gain better understanding of the full genetic and
molecular effects of chromosome rearrangements.
Study
of chromosome rearrangements is important for many reasons: (1) Chromosome
abnormalities account for the majority of cases in infertility and foetal loss
in early pregnancy. (2) There exist a significant number of clinical syndromes
with specific chromosome abnormalities. (3) Identification and understanding the
nature of chromosome rearrangements are very important in the diagnosis,
prognosis and therapy of human tumours.
Our laboratory has diverse research interests centring on elucidating the mechanisms and implications of genome instability (functional genomics). We are also interested in studying the effect of chromosome rearrangements on nuclear structures and gene expression. Chromosome analysis of malignant cells provides us with a wealth of information about the genetic and molecular basis of cancer. Chromosome deletions are particularly important as they are frequently accompanied by translocation or other complex chromosome abnormalities. It is important to identify the genes that are lost in chromosome deletions. We will be using the state-of -the art technology such as multicolour fluorescence in situ hybridisation (mFISH) to identify chromosome aberrations in human cells.
Metaphase chromosomes from normal human fibroblasts after multicolour FISH (mFISH): True or merged colour profile from different fluorochromes used. Computer generated pseudo colour image of the same metaphase spread. Note each chromosome is painted in a different colour (Metasystems, Germany)
Metaphase chromosomes from human breast cancer cells after multicolour FISH (mFISH): True or merged colour profile from different fluorochromes used. Computer generated pseudo colour image of the same metaphase spread. Note complex chromosome translocations observed as the juxtaposition of two more colours within one chromosome. As a result of mFISH karyotype analysis, the precise identity of each aberration can be assigned with greater confidence.
Recently developed mBAND FISH (multicolour banding) will be employed to detect changes within a chromosome such as peri- and para-centric inversions. Chromosome inversions can be very important as they may influence the gene expression pattern on a particular chromosome. mBAND FISH will greatly increase the ease and resolution of inversion analysis. In parallel, techniques such as comparative genomic hybridisation (CGH) and cDNA microarray analysis will also be employed.
Human chromosome showing true or merged colour or pseudo colour bands following high-resolution multicolour banding fluorescence in situ hybridisation (mBAND FISH). Any change in the location of the bands termed as intra-chromosomal changes within the chromosome can be detected (peri and para-centric inversions) (Metasystems, Germany).
Research
areas:
Study
of distribution and significance of particular chromosomal rearrangements in
populations and species and predicting gene map positions by mBAND analysis
Relationship
between chromosome abnormalities and the process of gene amplification and
gene loss
Chromosome
inversions and cancer
Chromatin
structure and telomeres
Our multi-parametric approach will allow us to address mechanisms and implication of genome/chromosome instability in human diseases.
Team Members: