Dr Peter Ellis joined the school of Biosciences in September 2014. His first degree was in Medical Sciences at Cambridge University (1999). Subsequently he studied for a PhD with Professor Nabeel Affara in the Department of Pathology at Cambridge, where he was among the first people worldwide to apply microarray expression profiling to the study of reproductive functions in mouse and human models of infertility. Peter subsequently continued his training as a post-doctoral researcher in the same group, leading a team investigating genes on the mouse Y chromosome and their roles in spermatogenesis and in genome evolution. Peter is a member of the Centre for Interdisciplinary Studies of Reproduction (CiSOR)
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DNA damage surveillance in germ cells and in cancer
Meiotic germ cells and cancer cells share a number of unusual features including the activation of specific genes (the "cancer-testis antigens"), the ability to tolerate high numbers of DNA strand breaks without undergoing apoptosis, and (in oocytes) a lowered stringency spindle assembly checkpoint that permits cell division even in the presence of unattached kinetochores. Work in Dr Ellis' laboratory seeks to define the mechanisms of the intracellular mechanisms that monitor DNA damage and chromosomal alignment during cell division in order to understand how these are perturbed in disease states.
An epigenetic switch of particular interest involves phosphorylation of histone H2AX at residues Ser139 and Tyr142 in response to DNA damage.
These modifications of H2AX act to "flag" the DNA damage and subsequently direct the cells to either repair the damage or to die. In kidney cells, the form known as mono-gH2AX has been shown to be associated with DNA damage repair, while the form known as di-gH2AX is associated with apoptosis. Despite its importance to the most basic of all cellular processes – the choice between life and death – the mechanics of this cellular switch between the mono- and di-gH2AX forms remain unknown. Dr Ellis has developed new antibodies to study this process in both cancer cells and in germ cells undergoing meiotic recombination.
The role of Yq-linked genes in fertility and offspring sex ratio
Mouse chromosome arm Yq is highly ampliconic, with Yq-linked genes being present in up to ~600 copies. Deletions on Yq (Yqdel) titrate the copy number level of the ampliconic genes on this chromosome arm. Yqdel males show a dose-dependent fertility phenotype, with smaller deletions leading to mild teratozoospermia and larger deletions leading to severe teratozoospermia and infertility. In the fertile males with smaller deletions, there is an offspring sex ratio skew in favour of females. Since X and Yqdel-bearing sperm are produced in equal numbers, the skew must be due to differential fertilising capacity between X-bearing and Yqdel-bearing sperm.
Dr Ellis's transcriptional profiling of testes from Yqdel males identified three novel gene families on Yq (Sly, Asty, Orly) in addition to the one previously known (Ssty1/2), and demonstrated an antagonistic transcriptional regulatory interaction between the sex chromosomes. In Yqdel males, there is a global upregulation of X chromosome transcription in spermatids, and the degree of upregulation varies according to the extent of the Yq deletion. These data suggested a probable reason for the sex ratio skew seen in these mice: that it is a consequence of altering the balance of "selfish" sex ratio distortion genes involved in an evolutionary arms race. This work was also the first study to show global transcriptional regulation of the sex chromosomes in spermatids, and was consequently important in the discovery of post-meiotic sex chromatin (PMSC), a repressive chromatin state which suppresses sex chromosome gene expression in spermatids.
Ongoing work in the Yqdel males an related transgenic models is aimed at:
- clarifying the physiological basis of the sex ratio skew.
- understanding the molecular functions of the Yq-encoded genes that regulate post-meiotic sex chromatin.
Commercial application of research findings relating to fertility
The identification of genes associated with sex ratio skewing in mammals is of key interest to the farming industry, where in many cases one sex of offspring is much more desirable than the other. Improved methods for sex selection would therefore have considerable animal welfare benefits in addition to the economic impact of more efficient animal husbandry practices. Dr Ellis has therefore developed links with relevant industry partners to pursue avenues potentially leading to novel sex selection methods in agriculturally-relevant species.
The role of Zfy-related genes in male and female fertility
In recent years, the Y-linked gene Zfy2 has been implicated in many aspects of male fertility (i.e. the mid-pachytene synapsis checkpoint, the meiosis I spindle checkpoint and spermatid elongation), and also in XY female infertility. In males, transcriptional analysis of developing testes with and without Zfy2 shows that meiotic sex chromosome inactivation is impaired in the absence of Zfy2. In females, meiosis II defects are seen in female carriers of Zfy2 transgenes. These are associated with gross disruption of the oocyte transcriptome, in particular misexpression of genes relating to cell and embryo polarity. Zfx/y genes are a complex gene family with multiple splice variants and alternative promoters: key aims for future projects are to further define the various abnormal phenotypes in males according to which family member / which splice variant is disrupted, and to pin down the precise nature of the meiosis II defects in females bearing Zfy2 transgenes.
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- BI324 Genetics and Evolution
- BI600 Biology Project
- Masters in Reproductive Medicine
Biosciences representative on the Research Ethics Advisory Group for the Faculty of Sciences.