Mail Address: Comparative Genomics
Molecular Sciences Bldg 21, James Cook University,
Townsville, 4811, Queensland, Australia
Telephone: 61-7-4781 6220 Fax: 61-7-4781 6078
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.
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
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.
A number of collaborative projects are also currently underway in the Drosophila Genetics Laboratory. These include:
Postdoctoral Research Staff
Graduate Students ·
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.Follow this link for details.
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
The successful applicants receive instruction in the latest recombinant
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 CGC Vacation Studentships are
announced in September each year and close in late October. Contact Bill Warren for further