PhD student, University of Cambridge
Most cells within an organisms have two copies of DNA, which is called a diploid genome. Sperm and egg cells, which are specialised cell types that pass on genetic information to the next generation carry only one copy of DNA, which - when combined at fertilisation - make up a diploid genome again. The process that reduces the genetic content of gametes is termed meiosis and consists of two consecutive cell divisions. Proper quality control of this process is of utmost importance for the survival of a species, as errors in DNA content passed on from the gametes can have devastating consequences in developing embryos. In humans, errors in meiosis frequently lead to aneuploidy - an abnormal number of chromosomes within a cell. Aneuploidy is often embryonically lethal and is a major cause of human miscarriages or can cause genetic disorders, the most common one being Down syndrome in humans which is caused by the presence of a third copy of chromosome 21. In our research, we make use of a mouse model for Down syndrome, that carries a copy of human chromosome 21 and mimics many of the phenotypes of the human disease. We are particularly interested in the control mechanisms operating during meiosis and how aneuploidy is sensed and dealt with. In particular, enormous differences in the stringency of these control mechanisms exists between males and females and we are dissecting how the same molecular mechanisms can have a higher error rate in one sex compared to the other.
Abstract: In mammals, fertilization typically involves the ovulation of one or a few eggs at one end of the female reproductive tract and the entry of millions of sperm at the other. Given this disparity in numbers, it might be expected that the more precious commodity-eggs-would be subject to more stringent quality-control mechanisms. However, information from engineered mutations of meiotic genes suggests just the opposite. Specifically, the available mutants demonstrate striking sexual dimorphism in response to meiotic disruption; for example, faced with adversity, male meiosis grinds to a halt, whereas female meiosis soldiers on. This female "robustness" comes with a cost, however, because aneuploidy appears to be increased in the resultant oocytes.
Pub.: 22 Jun '02, Pinned: 01 Jul '17
Abstract: In Neurospora, DNA unpaired in meiosis both is silenced and induces silencing of all DNA homologous to it. This process, called meiotic silencing by unpaired DNA, is thought to protect the host genome from invasion by transposable elements. We now show that silencing of unpaired (unsynapsed) chromosome regions also takes place in the mouse during both male and female meiosis. The tumor suppressor protein BRCA1 is implicated in this silencing, mirroring its role in the meiotic silencing of the X and Y chromosomes in normal male meiosis. These findings impact on the interpretation of the relationship between synaptic errors and sterility in mammals and extend our understanding of the biology of Brca1.
Pub.: 08 Dec '04, Pinned: 01 Jul '17
Abstract: Aneuploidies are common chromosomal defects that result in growth and developmental deficits and high levels of lethality in humans. To gain insight into the biology of aneuploidies, we manipulated mouse embryonic stem cells and generated a trans-species aneuploid mouse line that stably transmits a freely segregating, almost complete human chromosome 21 (Hsa21). This "transchromosomic" mouse line, Tc1, is a model of trisomy 21, which manifests as Down syndrome (DS) in humans, and has phenotypic alterations in behavior, synaptic plasticity, cerebellar neuronal number, heart development, and mandible size that relate to human DS. Transchromosomic mouse lines such as Tc1 may represent useful genetic tools for dissecting other human aneuploidies.
Pub.: 24 Sep '05, Pinned: 01 Jul '17