COMPARATIVE GENOMICS CENTRE
Mail Address: Comparative Genomics Centre,
Molecular Sciences Bldg 21, James Cook
University,
Townsville, 4811, Queensland, Australia
Telephone: 61-7-4781 6220 Fax:
61-7-4781 6078
Mail Address: Comparative Genomics Centre,
Molecular Sciences Bldg 21, James Cook
University,
Townsville, 4811, Queensland, Australia
Telephone: 61-7-4781 6220 Fax:
61-7-4781 6078
CONTENTS:
Drosophila Genetics Group's main focus is to investigate human disease using the model organism Drosophila melanogaster. Drosophila melanogaster (also known as the vinegar fly, pumice fly or fruit fly), is a cosmopolitan insect species found in all corners of the globe. It is not an agricultural pest or a vector for human disease.
Drosophila have been studied extensively for over
90 years and have been the subject of over 130,000 research reports. Today
there are approximately 2000 research laboratories around the world that
use Drosophila for their research and about 20 laboratories operate in Australia
and New Zealand that are actively conducting Drosophila research. Researchers
use Drosophila to study an enormous range of biological phenomenon, including
fundamental cell biology, learning and memory, embryonic development, the
genetics of populations, drug sensitivity and longevity. Our main interests
are studying Chromosome Segregation and DNA Repair mechanisms.
Chromosome Segregation
and Birth Defects
Sister-chromatid cohesion is one of several carefully
regulated cellular mechanisms critical for ensuring a single copy of each
chromo-some gets partitioned into each daughter cell. Normally, newly replicated
chromosomes, (called sister chromatids) become co-joined immediately following
DNA synthesis in S phase. This linkage is normally maintained until a cell
has entered the M phase of the cell cycle. Only then, after chromosomes
have become highly condensed, a spindle has been assembled and each pair
of co-joined chromatids is attached via their kinetochores to opposite poles
of the spindle, is sister-chromatid cohesion dissolved. This robust mechanism,
which is common to all eukaryotic species, ensures each daughter cell receives
an identical copy of each and every chromosome. However, errors in either
the establishment or release of chromatid cohesion can cause chromosomes
to be unequally distributed between the daughter cells - a condition known
as aneuploidy.
Aneuploidy - an increase or decrease in the number or
composition of one or more chromosomes - is a common cause of birth defects
in humans. Some babies with aneuploid cells, such as those suffering from
Down's Syndrome (trisomy 21) or Turner's Syndrome (XO karyotype), mature
into adults with only mild to moderate handicaps. The majority, however,
are afflicted by such severe developmental abnormalities in utero that they
die before or shortly after birth. Aneuploidy-associated genetic imbalances
lead to abnormal cellular functions through the production of either excess
levels protein (as occurs in Down's Syndrome), or insufficient levels (as
occurs in Turner's Syndrome). The end result of these imbalances is perturbation
of normal development. Most foetuses with genetic imbalances involving
chromosomes other than the X or 21 abort spontaneously, as they typically
alter the expression of a larger number of genes and perturb an increased
number of cellular and biochemical processes. The majority of aneuploidy-associated
birth defects are thought to result from errors in chromosome segregation
during gametogenesis (production of eggs and sperm) or in the early cell
divisions following fertilization. In recent years, prenatal screening has
had a major impact on reducing the number of affected children born with
such overt karyotypic abnormalities. Nevertheless, we still know relatively
little of how these errors in chromosome segregation arise in the first
place. A greater understanding of the molecular details of how chromosome
segregation is regulated is likely to improve our chances of developing
more sophisticated screening 
and prevention techniques for birth defects caused by chromosome abnormalities.
Our lab is using Drosophila to study the molecular mechanisms that ensure
chromosome segregation occurs correctly. Our main focus is the function
and regulation of a protein complex, called Cohesin. This protein complex
has many similarities protein complexes involved in DNA repair (see below)
Our studies of sister-chromatid cohesion are kindly supported by grants
from the Australian Research Council
and the March of Dimes Foundation
Cellular DNA Repair and
Cancer
DNA double strand breaks (DSBs) present one of the
most serious forms of damage our genome faces, and as a consequence, human
cells exhibit multiple layers of intricately regulated DSB sensing and repair
mechanisms. Two evolutionarily conserved repair pathways operate to repair
DSBs in eukarytotic cells; homologous recombination (HR), where accurate
repair is effected using a homologous sequence, and non-homologous end joining
(NHEJ), a error-prone process where DSBs are resected and then simply rejoined.
That tumour cells routinely display a marked reduction in DNA repair
efficiency and/or fidelity, and DSB-producing ionizing radiation is commonly
employed as a powerful therapeutic to treat cancer, underscores the importance
of achieving a comprehensive understanding DSB repair for human health.
Nibrin (the protein encoded by NBS1), functions
in both the HR and NHEJ DSB repair pathways. Protein truncating mutations
in NBS1 result in the chromosome instability syndrome Nijmegan Breakage Syndrome
(NBS), a rare disease associated with developmental abnormalities, mental
retardation, and an elevated incidence of cancer. Two mouse models for NBS
have been recently developed. Characterization of these models show that
the maintenance of genetic stability, through the proper response to DNA
damage, is not only crucial for cell survival and suppression of oncogenesis
but is also critical for the correct functioning of a number of developmental
pathways. However, the precise role of nibrin in regulating development
is at present unknown.
The overall aim of this study is to investigate the functional role of NBS1 in development. To do this we propose to use the Drosophila (vinegar fly) genetic model system, which is well suited to addressing questions relating to the genetic control of development. Our central hypothesis is that NBS1 functions not only in the conserved HR and NHEJ pathways that repair DNA damage, but either directly or indirectly plays a critical role in development in multicellular eukaryotes through a number of as yet unidentified tissue development regulatory pathways.
Collaborative Projects
A number of collaborative projects are also currently underway in the
Drosophila Genetics Laboratory. These include:
Postdoctoral Research Staff
Research Staff
Graduate Students ·
Undergraduate Students
The Australian Postgraduate Award (APA) and James Cook University
Postgraduate Research Scholarship (JCUPRS) are open to applicants with,
or who expect to hold, a first class honours degree or equivalent by the
end of the year and who wish to undertake full-time research Masters or PhD
program. In 2003 the stipends for an APA were $18,006 pa (full time) or
$9620 (part-time). APA applicants must be Australian citizens or have been
granted permanent resident status and lived in Australia continuously for
12 months prior to 31 October 2001; Information and application forms can
be obtained from the Research
Scholarships Officer, or from the following website: http://www.jcu.edu.au/office/grs/scholarships/index.html
Closing Date: 31 October of each year
Honours
Students who have completed their undergraduate training in a BSc, BBiomedSc,
BMedlabSc or equivalent program and are interested in participating in
the Biochemistry and Molecular Biology Honours Program are encouraged to
contact Bill Warren for a description
of currently available projects. Honours studies require a full-time commitment
for one year (two semesters) and can start in either February or August.
Undergraduate
There are two main opportunities for undergraduates to participate in
the ongoing research of the Drosophila Genetics Group.
Students enrolled in BC3203 (Special Topics in Biochemistry and Molecular Biology - second semester) could ask that they undertake their research project in the Drosophila Genetics Laboratory.
Students can apply for a Comparative Genomics Centre Vacation Scholar Award.
The successful applicants receive instruction in the latest recombinant DNA
and genetics techniques, receiving a stipend of $200 per week for a full-time
commitment of between 6 and 10 weeks over the summer break. Applications
for the 2003 CGC Vacation Studentships will be announced later in the year
and will close in late October. Contact Bill Warren for further details
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