Many developments in modern medicine are based on the enormous progress made over the last 50 years in our understanding of how our genes work. For example, drugs interact with genes to change how biological systems function. Much of the research that has led to this progress is hard or impossible to do in humans. Because all animals share evolutionary origins, study of simple animals helps to understand human biology. Certain key model organisms have been the focus of intensive study, and some of the most important progress has been made with extremely simple animals. One of these is the tiny roundworm, or nematode, Caenorhabditis elegans. C. elegans research has been strategically supported by the MRC for over 40 years, leading to two Nobel prizes in the last five years, and is a key contributor to our understanding of basic processes such as cell death and aging. Genetic research has been revolutionized in the last few years by obtaining the complete DNA sequence (the genome) of the organism being studied, which contains all the gene sequences. C. elegans was the first animal to have its genome sequenced. To use genome sequences and all the new information about genes requires information resources that tie together DNA information with experimental data, and relate corresponding genes across animals. This application will enable continued support and development of WormBase, the reference information resource for all genomic and biological data for C. elegans. Wormbase is essential for research using C. elegans, and for relating the results of that research to human biology and medicine. In addition to its relevance for understanding animal biology, research on C. elegans is particularly important to our understanding of the biology of other nematodes. There are many human nematode parasites, such as those causing river blindness in Africa, which cause an enormous disease burden in the developing world. Major programmes are now collecting genome sequences for these organisms, to enable modern genomic biology to address these diseases. The proposed research also supports the application of the information, experience and technology developed for C. elegans to ensure the most effective exploitation of the new genome data from parasites.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

In genetic terms, there is relatively little variation between humans. The differences between any two individuals, regardless of how diverse their origins, count for only a small fraction of the total genetic content stored in the DNA of either one. But the variation that does exist is important: some of it affects not only physical characteristics like size or shape, but also differences in disease susceptibility or the risk of genetic disorders. Until recently, it has only been feasible to study genetic variation at very short length scales within the DNA sequence. Now a new technology is becoming available for reading DNA much more quickly and at much less cost than before. This has made it possible to begin a comprehensive study of all types of variation amongst hundreds of individuals from all around the world. Analysing the data produced in this study will require powerful and sophisticated computing techniques. Our research will develop and refine these techniques, and will use them to make discoveries about some of the factors that have shaped human evolution. We will investigate how the human DNA sequence has been affected in different ways by the environments we inhabit, the threats we face, and the ancestors we share.

Clostridium difficile caused or contributed to the deaths of 8700 hospitalized patients in the UK during 2007, making it the most significant hospital-acquired pathogen. C. difficile is estimated to cost the US health care system 3 Billion USD/year (no current estimates available for UK) representing a serious economic burden that impacts the overall performance and safety of our hospitals {Dubberke, 2009}. C. difficile persists in hospitals by exploiting an infection cycle that is dependent on humans shedding highly resistant and infectious spores. As a result, C. difficile is endemic in many hospitals and outbreaks are difficult to contain, highlighting the compelling need to understand the spore-mediated infection cycle and the factors that lead to C. difficile transmission between individuals. The proposed research will utilize cutting edge genomic and proteomic technologies in combination with in vitro and murine models to study the biology of C. difficile spores, specifically, the signals and molecular processes that lead to the formation of spores and the molecular interactions between spores and the host during colonization. This work has the potential to lead to novel infection control interventions that interfere with C. difficile spore formation and block host colonization by spores.

Malaria killed nearly 800,000 people in 2009 alone, mostly children in Africa. Targeting the mosquitoes that transmit the disease has proven to be the most effective strategy towards reducing the number of malaria cases. As mosquitoes tend to bite at night and indoors, the increased use of bednets in recent years has contributed to the decrease of malaria cases. However, some mosquitoes are showing evidence of increased biting in the daytime and outdoors where bednets offer no protection, so new methods of control must be developed. Based on the fact that some mosquitoes are better malaria transmitters than others, this project aims to investigate the differences in the genetic make-up of these mosquitoes using a technology that intimately examines the mosquito genome. This comparison and follow-up tests will identify genes that are associated with mosquito capacity to carry the most deadly of the human malarias. Discovering the mosquito genes that have a big impact on malaria transmission is an essential step towards the promising strategy of developing drugs and vaccines that target the parasite while it is in the mosquito.