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KAUST PhD Studentship

The Department of Genetics has a 4-year PhD studentship supported by the KAUST Fund for Biological Sciences that is being offered for the projects outlined below. The studentship will cover the fees (at Home/EU rate) and an annual stipend at RCUK rates.

Potential applicants are strongly advised to make an informal approach to the relevant Supervisor before applying via the University Graduate application system https://www.graduate.study.cam.ac.uk

The deadline for applications is Monday 6th January 2020.

 

Christine Farr

Topoisomerase II alpha - role at the mitotic centrosome?

Type II topoisomerases are essential enzymes that modulate the topology of DNA and their function is necessary for replication, transcription, recombination and the disentanglement of sister chromatids prior to, and during, anaphase segregation. In mitosis itself, topo II is a major chromosomal component, playing a key role in compaction. Depletion of topo II, as well as leading to problems in chromosome compaction, has also been shown to disrupt normal chromosome congression at the metaphase plate. Both human and drosophila cells depleted of topo II display a “trapped arm” phenotype, with chromosome arms stretched from the metaphase plate to the vicinity of the spindle pole. Others have reported the presence of topo II at the centrosome. These observations suggest that topo 2 has functions at the centrosome that remain to be uncovered.

 

Michael Imbeault

Functional overview of the KRAB zinc finger protein family by high resolution ChIP-seq and rapid depletion of TRIM28 in multiple cellular contexts

KRAB zinc finger proteins are the largest family of DNA binding factors in both human and mouse (~350 members each) - most of their binding sites are found on transposable elements, where they recruit TRIM28 to induce heterochromatin. In many cases, these transposable elements are very old, yet conserved, and we have evidence showing that they are still epigenetically active. We hypothesize that the KRAB zinc finger proteins binding them induce epigenetic silencing in a cell-specific fashion, leading to differential accessibility of the underlying regulatory sequences. This project aims to get a global overview of KRAB zinc finger proteins activity between cell types through single basepair resolution ChIP of TRIM28, coupled with rapid TRIM28 depletion with the dTAG system followed by RNA-sequencing. By combining these two approaches together and genome occupancy data of 250 individual KRAB zinc finger proteins, we will better understand where and when they participate in gene regulation, leading to a better functional understanding of the non-coding genome

 

Frank Jiggins

The long-term dynamics of immune genes within rabbit populations.

 Major histocompatibility complex genes encode cell-surface molecules that play a critical role in immune recognition. They are the most polymorphic region of most mammalian genomes, and genetic variants in this region are strongly associated with susceptibility to both autoimmune and infectious disease. By sequencing the MHC region from rabbits from archaeological sites, museums and modern populations, you will reconstruct the long-term dynamics of MHC allele frequencies through time. We have access to a unique collection of rabbit DNA from three independent populations from the neolithic to the present day. This is a unique opportunity to track the frequencies of MHC alleles though time and reconstruct how their fitness has increased or decreased. This will provide insights into the evolutionary forces that are maintaining the extraordinary levels of genetic variation in these genes.  All three of the populations have experienced devastating pandemics of myxomatosis pandemic over the last 70 years, allowing us to link the emergence of a new infectious disease to changes in allele frequency. Finally, for a student interested in a larger component of experimental work, you could express modern and ancient MHC alleles in rabbit cells to examine how natural selection has altered their molecular function.

 

Hansong Ma

Identifying nuclear modifiers that alleviate mitochondrial mutant defects

The animal mitochondrial genome, although small, can have a great impact on health and disease. In humans, mtDNA mutations have been reported to cause a spectrum of mitochondrial diseases that affect 1 in 5,000 individuals in the UK. Interestingly, the type and severity of mtDNA disease symptoms often vary immensely among individuals harbouring the same mutation. It has been proposed that many unexplained variations in penetrance and expression of mtDNA-related diseases are caused by complex mito-nuclear interactions. However, little is known about how that works. Previously, we have developed genetic tools in Drosophila, which allows us to isolate mtDNA mutants in animals. Using these mutants, we found that defects of mitochondrial mutants can be alleviated by suppressors presented in some nuclear backgrounds we screened. For one mutant with a compromised complex IV activity, we have mapped the nuclear suppressor(s) to a small region on 2nd chromosome. This project is designed to map nuclear suppressors and reveal how they mitigate detrimental phenotypes of mitochondrial mutants by cellular and biochemical studies. Besides understanding the co-evolution of two genomes, understanding how a nuclear-encoded protein can modulate mitochondrial mutant defects could lead to new therapeutic options.

 

Aylwyn Scally

Investigating human germline mutation using population-scale genomic data

Germline mutations are copying errors that arise during the transmission of parental DNA to offspring. They occur at an extremely low rate, but when passed on to subsequent generations they are the source of all genetic differences between individuals and groups and the raw material on which natural selection works. Most have negligible effect, but some mutations may cause minor changes in how the individual develops, and on very rare occasions some are responsible for serious genetic disease. Despite the importance of germline mutation however, we have only recently been able to collect datasets of sufficient size to study it in detail. This project will compare the genomes of parents and children in many thousands of UK families, investigating the patterns and possible causes of germline mutation within fathers and mothers, and developing enhanced methods to detect rare pathogenic mutations. The project will build a deeper understanding and statistical analysis of human genetic inheritance based on these data, and will develop computational models of early embryonic stem cell and mutation processes.

 

Marisa Segal

Ras inhibition by a novel class of Ras-interacting proteins - a synthetic approach

Ras small GTPases are highly conserved signal transducers in cellular proliferation, survival and differentiation. Mutations rendering Ras hyperactive are among the most common events in human tumourigenesis. Ras switches between GDP (inactive) and GTP (active) bound states. Activation is promoted by a guanyl nucleotide exchange factor (GEF) and counteracted by GTP hydrolysis stimulated by a GAP. This cycle was first elucidated in S. cerevisiae and is essentially conserved in humans. A new player identified in yeast offers insight into a novel mode of Ras control. Briefly, Lte1 may define a new class of inhibitory Ras-interacting proteins exploiting conserved signatures of GEF domains. Unlike canonical GEFs, Lte1 binds and inhibits specifically RasGTP in a phospho-dependent manner. At the same time, binding to Ras triggers functional interactions with two additional GTPases, Tem1 and Rsr1. We wish to dissect this unique network using cell biological readouts connected to Lte1 and Ras function and establish the molecular basis for Ras inhibition and phospho-dependence. Moreover, human H-Ras can replace yeast Ras genes, enabling us to directly explore functional conservation using a synthetic yeast setup expressing the human Ras module. These studies may expose a novel class of tumour suppressor proteins and the corresponding protein kinases acting as proliferation gatekeepers.