Ecological adaptation can be defined as the entirety of molecular and cellular changes that allow an organism to survive and reproduce better in his environment. For example the ability of some yeast species to grow rapidly when the nutrients are scarce or when the temperature is low represent part of their ecological adaptation to those environments, and can be caused by a group of specific alleles, which are more dominant in those conditions.

The purpose of this project is to determine which alleles, belonging to different natural yeast species, carry more weight in the adaptive response towards cold temperatures.

The haploid Yeast Deletion Collection, including ca. 4,500 barcoded laboratory yeast strains each lacking of a specific “domesticated” allele, can be crossed with a cold-resistant natural yeast species (i.e. S. kudriazvevii), so that the mutated genes are compensated by the “natural” alleles. Competition experiments coupled with Barcode Analysis by Sequencing on the Illumina/Solexa platform will be carried out to detect which natural allele is responsible for the adaptation to cold temperature.

This is a large-scale project set to understand how organisms adapt to fluctuation in temperature: a very important question especially in the light of climate change and global warming which poses a serious threat to many species.
 

1. Delneri D., Hoyle D.C., Gkargkas K., Cross E.J.M., Rash B., Zeef L., Leong H.-S., Davey H., Hayes A., Kell D.B., Griffith G.W., and Oliver S.G. (2008). Identification and characterisation of high flux control (HFC) genes of Saccharomyces cerevisiae through competition analyses in continuous cultures. Nature Genetics, 40: 113-117.
2. Holland S., Lodwig L., Sideri T., Reader T., Gkargkas K., Clarke I., Hoyle D. C., Delneri D., Oliver S.G., and Avery S. (2007) Application of the heterozygous yeast strain collection to elucidate the basis of chromium toxicity, Genome Biology, 8 (12): R268.
3. Harrison R., Papp B., Pal C., Oliver S.G. and Delneri D. (2007) Plasticity of genetic interactions in metabolic networks of yeast, Proc Natl Acad Sci U S A. 104: 2307-2312.
 

• Biochemistry
• Biomolecular Sciences
• Biotechnology
• Environmental Biology
• Evolutionary Biology
• Gene Expression
• Genetics
• Microbiology
• Plant Sciences

This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Our research uses DNA sequence analysis to answer archaeological questions. The projects involve analysis of both modern and preserved specimens, the latter studied by ancient DNA techniques, many of which have been developed at Manchester. Ancient DNA has considerable potential as a source of genetic data relating to the kinship affiliations of human skeletal remains, information that would enable archaeologists to make more accurate interpretations of social organisation at individual sites and across communities. We are currently using these techniques with archaeological skeletons from Bronze Age sites in Greece such as Mycenae and Kouphovouno. Ancient DNA also offers new possibilities in the study of palaeodisease by enabling the prevalence of diseases in past populations to be determined by analysis of skeletons for the presence of pathogen DNA. We have worked on malaria and syphilis but current projects focus on tuberculosis and leprosy. We are also studying the origins and spread of agriculture by phylogeographical analysis of large genetic datasets derived from variable loci in landraces of wheat, barley and maize, along with analysis of ancient DNA in preserved specimens. We have shown that crops have more complex genetic origins than previously thought, forcing archaeologists to reassess their interpretations of the processes involved in the transition from hunting-gathering to farming. Much of our current work uses next-generation sequencing methods to obtain large amounts of ancient DNA data from archaeological material, as well as computer modelling of past population structure.

Isaac AD, Muldoon M, Brown KA, Brown TA. (2010). Genetic analysis of wheat landraces enables the location of the first agricultural sites in Italy to be identified. Journal of Archaeological Science, 37, 950-956.

Brown TA. (2010). Stranger from Siberia. Nature, 464, 838-839.

Wilbur AK, Bouwman AS, Stone AC, Roberts CA, Pfister LA, Buikstra JE, Brown TA. (2009). Deficiencies and challenges in the study of ancient tuberculosis. Journal of Archaeological Science, 36, 1990-1997.

Allaby RG, Fuller DQ, Brown TA. (2008). The genetic expectations of a protracted model for the origins of domesticated crops. Proceedings of the National Academy of Sciences, USA, 105, 13982–13986.

Bouwman AS, Brown KA, Prag AJNW, Brown TA. (2008). Kinship between burials from Grave Circle B at Mycenae revealed by ancient DNA typing. Journal of Archaeological Science, 35, 2580–2584.
 

• Bioinformatics
• Biomolecular Sciences
• Evolutionary Biology
• Genetics
• Microbiology
• Molecular Biology
• Plant Sciences

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Background and aims
Aluminium is ubiquitous in the environment, is bioavailable at neutral pH (Desouky et al., 2002) and is highly neurotoxic to freshwater invertebrates (Campbell et al., 2000). Aqueous Al is toxic to the crayfish via damage to the gills resulting in behavioural toxicity within 10 days of exposure (Alexopoulos et al., 2003). Recent unpublished work has shown that Al in the food is also bioavailable and is accumulated in certain tissues. The hypotheses are that Al is toxic to the crayfish, specifically the nervous system, and that this is due to accumulation in the tissues. The aims are to:
1. Examine partitioning of Al in the tissues (including haemolymph) with time.
2. Monitor potential sublethal toxicity of Al to the crayfish by examination of changes in behaviour (using standard behaviour measures plus additional methods to be developed during the course of the study)
3. Examination of electrophysiological properties of central neurones following in vivo exposure to Al, and in vitro.
Methods
• Metal analysis of tissues and water using inductively-coupled plasma optical emission spectroscopy (ICPOES).
• Behavioural monitoring
• Intracellular electrophysiological techniques to examine membrane conductances underlying electrical activity patterns (action potentials)
 

• Desouky, M, Jugdaohsingh, R, McCrohan, C R, White, K N & Powell, J J (2002) Aluminium-dependent regulation of intracellular silicon in the aquatic invertebrate Lymnaea stagnalis. Proc. Nat Acad. Sci. US, 99, 3394-3399.

• Campbell, M M, Jugdaohsingh, R, White, K N, Powell, J J & McCrohan, C R (2000) Aluminium toxicity in a molluscan neuron: effects of counterions. J. Toxicol. Environ. Health, Part A 59, 253-270.

• Alexopoulos, E, McCrohan, C.R., Powell, J.J. Jugdaohsingh, R. & White, K.N. (2003) Bioavailability and toxicity of freshly neutralised aluminium to the freshwater crayfish Pacifastacus leniusculus. Arch. Environ. Contam. Toxicol., 45, 509-514.

• Adaptive Organismal Biology
• Animal Biology
• Environmental Biology
• Integrative Neurobiology & Behaviour
• Physiology
• Toxicology

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

The aim of this project is to determine the function of non-coding RNAs (ncRNAs) in the Hox complex, in particular how they affect gene expression and function during differentiation of the anterior-posterior axis. The Hox complex is clustered set of related transcription factors that establish positional identity on the anterior-posterior axis in all animals. We have used a combination of deep-sequencing and tiling microarray expression analysis to identify more than 20 ncRNAs in the Hox complexes of the fly, beetle, and honeybee. We are interested in understanding how these ncRNAs function and how they evolve. Many of these transcripts have unique, Hox-like expression patterns and some correlate with classically described homeotic mutations or genetically identified regions controlling the temporal and/or spatial regulation of Hox gene expression. We are using a combination of genetic and bioinformatic approaches to study both potential cis and trans functions of these ncRNAs. We are taking advantage of a comparative approach to identify the analogues and homologues of these ncRNAs to determine if there is a pattern of conservation in the sequence or structure that may hint at the function. The results of this work will begin to answer questions regarding how the evolution of these ncRNAs may have contributed to diversification of metazoan bodyplans.

Shippy TD, Ronshaugen M, Cande J, He J, Beeman RW, Levine M, Brown SJ, Denell RE. (2008). Analysis of the Tribolium homeotic complex: insights into mechanisms constraining insect Hox clusters. Development genes and evolution, 218, 127-39.

Ronshaugen M, Biemar F, Piel J, Levine M, Lai EC. (2005). The Drosophila microRNA iab-4 causes a dominant homeotic transformation of halteres to wings. Genes & development, 19, 2947-52.

Ronshaugen M, Levine M. (2004). Visualization of trans-homolog enhancer-promoter interactions at the Abd-B Hox locus in the Drosophila embryo. Developmental cell, 7, 925-32.
 

• Animal Biology
• Bioinformatics
• Developmental Biology
• Evolutionary Biology
• Gene Expression
• Genetics
• Molecular Biology

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Amongst the millions of protein sequences now known from genome projects, many contain intriguing repetitive regions. The repeats confer on their host proteins various properties, including stretchiness, springiness, mechanical strength, adhesion, etc. Structural properties aside, these proteins elicit interest because of their known and suspected roles in mediating certain diseases: e.g., elastins have been implicated in diseases like cutis laxa, where the elasticity of the skin is lost; glutenins have been implicated in food intolerance syndromes like coeliac disease; huntingtin and prion proteins are associated with Huntington’s disease and various human dementias. The repeats vary in complexity, and many of their structures are unknown: some are thought to be disordered, while others are likely to be highly structured (e.g., for binding particular metals, or to form rigid scaffolds or flexible rope-like structures). This project offers interesting opportunities to explore structure-function relationships in repeat-containing proteins using systematic sequence-structure and comparative genome analyses. The results will help to discover whether: 1) the nature of repeats varies across the different kingdoms of life; 2) specific recurrent motifs are indicative of particular types of function or local structure; and 3) there are underlying patterns associated with the onset of different types of disease.

• 1. Coletta A, Pinney JW, Weiss Solis DY, Marsh J, Pettifer SR & Attwood TK (2010) ?Low-complexity regions within protein sequences have position-dependent roles. ?BMC Syst. Biol., 4(1), 43.
• 2. Park H, Huxley-Jones J, Boot-Handford RP, Bishop PN, Attwood TK & Bella J (2008) LRRCE: a leucine-rich repeat cysteine capping motif unique to the chordate lineage. BMC Genomics, 9, 599. doi:10.1186/1471-2164-9-599.
• 3. Nordle AKL, Rios P, Gaulton A, Pulido R, Attwood TK & Tabernero L (2007) ?Functional assignment of MAPK phosphatase domains. ?PROTEINS: Structure, Function & Bioinformatics, 69(1), 19-31.
• 4. Flower DR & Attwood TK (2004) Integrative bioinformatics for functional genome annotation: trawling for G protein-coupled receptors. Semin.Cell Dev.Biol., 15(6), 693-701.
• 5. Attwood TK (2001) A compendium of specific motifs for diagnosing GPCR subtypes. Trends in Pharmacological Sciences, 22(4), 162-165.
   

• Bioinformatics
• Biomolecular Science
• Structural Biology

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

How and why different morphological forms and shapes are generated in nature is one of the fundamental questions in biology. The capitulum (flower head) is an excellent system to address this question. The capitulum is the characteristic trait that defines the Asteraceae family taxonomically and the evolutionary success of Asteraceae, the largest family of flowering plants, is mainly due to the characteristic capitulum. Although superficially a capitulum resembles a solitary flower, it is in fact a compressed inflorescence composed of many small flowers with different floral symmetries. The forms of capitula are also tremendously diverse because each Asteraceae species has invented a highly adapted form of capitulum to maximize pollinator attraction.
The aim of the project is to determine the role of key genetic regulators in controlling different forms of capitula and to understand the evolution of diverse capitulum forms. Experimental approaches such as molecular biology, genetics, plant histology and phylogenetic analysis will be used for the study. This includes techniques such as molecular cloning and expression analysis, in situ hybridization, immunolocalization, plant transformation and tissue culture, Scanning Electron Micrography (SEM) and sequence analysis
 

• Kim, M., Cui, M., Cubas, P., Gilles, .A., Lee, K., Chapman, M., Abbott, R. & Coen, E. (2008) Regulatory genes control a key morphological and ecological trait transferred between species. Science 322(5904): 1116-1119.

• Adaptive Organismal Biology
• Bioinformatics
• Cell Biology
• Developmental Biology
• Evolutionary Biology
• Gene Expression
• Genetics
• Molecular Biology
• Plant Sciences

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

A PhD studentship is available to work on methods to analyse the function and evolution of non-protein-coding DNA sequences in genome sequences, with a special emphasis on the cis-regulatory elements that control transcription in eukaryotes. It is now well appreciated that the vast majority of DNA in the genome sequences of higher eukaryotes is non-protein-coding, yet the function of this noncoding DNA remains largely unknown. The objective of this PhD studentship will be to use comparative genomic data in model organisms (yeast, flies, worms, and/or mammals) to identify signatures of noncoding sequence evolution that are characteristic of cis-regulatory elements such as promoters and enhancers, capitalizing on experience and resources developed in Drosophila. Applicants should have a background in either biology or computer science (ideally with some experience with large-scale data analysis or programming experience). The successful applicant will be given complementary training in genome informatics, comparative genomics, evolutionary biology and data-mining and have ample opportunity to interact with bioinformatics and wet-lab groups in the Faculty working in field of gene expression.

• Halfon MS, Gallo SM, Bergman CM. (2008) REDfly 2.0: an integrated database of cis-regulatory modules and transcription factor binding sites in Drosophila.
  Nucleic Acids Res. 36:D594-8.
• Casillas S, Barbadilla A, Bergman CM. (2007) Purifying selection maintains highly conserved noncoding sequences in Drosophila. Mol Biol Evol. 24:2222-34.
• Pierstorff N, Bergman CM, Wiehe T. Identifying cis-regulatory modules by combining comparative and compositional analysis of DNA. (2006) Bioinformatics.
  22:2858-64.
   

• Bioinformatics
• Gene Expression
• Genetics
• Molecular Biology

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

G protein-coupled receptors (GPCRs) are a large, functionally diverse group of membrane proteins that regulate vital cellular processes. As targets for >50% of prescription drugs, they are of pivotal interest, particularly to pharmaceutical companies who constantly seek to design new, safer and more efficacious drugs. Despite their importance, much remains unknown about how they function: many are 'orphans' with unknown ligand- and G protein-coupling specificities; many function as oligomers or in association with other protein partners, but the sites of interaction are unknown. In the absence of experimental data, we use patterns of conserved motifs (‘fingerprints’) to help functionally characterise GPCRs - to date, we have created >250 fingerprints to diagnose members of this important class of receptors. Using state-of-the-art bioinformatics analysis and computer visualisation techniques (especially the Utopia suite), this project will investigate such GPCR fingerprints in order to understand their roles in ligand binding, G protein coupling, oligomerisation &/or other protein-protein interactions. In the short term, the results will help us both to discover whether there are specific motifs responsible for receptor-ligand binding, and to identify possible allosteric sites that modulate receptor function; in the longer term, the results may feed into pharmaceutical in silico target- and drug-discovery programmes.

• 1. Pettifer S, Thorne D, McDermott P, Marsh J, Villeger A, Kell DB & Attwood TK (2009)?Visualising biological data: a semantic approach to tool and database integration. BMC Bioinformatics, 10, S18.
• 2. Flower DR & Attwood TK (2004) Integrative bioinformatics for functional genome annotation: trawling for G protein-coupled receptors. Semin.Cell Dev.Biol., 15(6), 693-701.
• 3. Gaulton A & Attwood TK (2003) Bioinformatic approaches for analysing GPCRs. Current opinions in pharmacology, 3(2), 114-120.
• 4. Attwood TK (2001) A compendium of specific motifs for diagnosing GPCR subtypes. Trends in Pharmacological Sciences, 22(4), 162-165.
• 5. Pettifer SR, Sinnott JR & Attwood TK (2004) UTOPIA - User-friendly tools for operating informatics applications. Comp.Funct.Genomics, 5(1), 56-60: http://utopia.cs.man.ac.uk/

• Bioinformatics
• Biomolecular Sciences
• Structural Biology

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

A PhD project is available to investigate genome evolution by characterising and comparing how organisms’ gene sequences change over time. This approach could provide a great deal of new information about the organisms’ fundamental biological processes, such as how a cell’s functional components change over time, as well as provide much broader insight into influential events that have shaped the various organisms’ shared histories.

Current themes of research in the lab include the development of novel substitution models for detecting ancient adaptive evolution, understanding the evolutionary signature of co-evolution (e.g. protein-protein interactions and RNA stems), and modelling the evolution of bacterial systems. Possible research topics for a project include studying the origins of genes and their functions, linking environmental changes and functional adaptive evolution of systems to genomic sequence data, and improving methods for modelling evolution and estimating evolutionary trees. Practically, a research project may involve developing and applying cutting-edge methodology in order to (e.g.) examine the selective pressures acting upon gene sequences, and assessing the relative performance of the different methodologies in drawing biological conclusions.

The project is entirely computer based, and will typically involve tasks such as extracting sequences from databases, aligning them, and modelling their evolutionary history. You will write computer programs to automate many of these tasks and to implement new methodological ideas. During the project, there will be plenty of opportunity to develop advanced skills in bioinformatics, computer programming, and statistics. Applications are encouraged from students with experience in the biological, computer, and mathematical sciences. Experience in computer programming (e.g. PERL, JAVA, C/C++), statistical modelling, evolutionary genetics, or any combination thereof is desirable.
 

a  S. Whelan (2008) Spatial and Temporal Heterogeneity in Nucleotide Sequence Evolution. Mol. Biol. Evol. 25: 1683-1694.
b  Delsuc F., Brinkmann H. & Philippe H. (2005). Phylogenomics and the reconstruction of the tree of life. Nature Reviews Genetics 6: 361-375.
c  Whelan S, Lio P, Goldman N (2001) Molecular phylogenetics: state-of-the-art methods for looking into the past. Trends in Genetics 17: 262-272.
 

• Bioinformatics
• Evolutionary Biology
• Genetics

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

At Manchester we have access to large volumes of mass spectrometry derived data relating to peptide identifications of proteins in the proteome. Although the existing computational tools are good at matching peptide mass spectra to theoretical spectra derived from candidate peptide sequences, few take advantage of the patterns in signal intensity related to the amino acids content. In this project we will exploit our data, building on recent results characterising the distributions of ion intensities, to build better peptide identification pipelines. Similarly, we will exploit machine learning algorithms and multiple search engines to improve peptide identification strategies, testing out our results against annotated genomes. This will include application areas taken from local proteomics projects characterising the proteome of organisms such as E.coli, yeast, chicken and human.

• Lau K, Lynch J, Hart, S, Hubbard SJ, Gaskell. SJ (2009) Observations on the Detection of b- and y-Type Ions in the Collisionally Activated Decomposition Spectra of Protonated Peptides. Rapid Comm Mass Spec. 20, 1508-14.
• Jones A, Siepen JA, Hubbard SJ, Paton NW (2009) A strategy for improving sensitivity in proteome studies, using multiple search engines. Proteomics. 9, 1220-9
• McLaughlin T, Selley J, Lynch J, Siepen JA, Lau KW, Yin H, Gaskell SJ, Hubbard SJ (2006) PepSeeker – a database of proteome peptide identifications. Nucleic Acids Res, 34, D549-D564

• Biochemistry
• Bioinformatics
• Biomolecular Sciences
• Biotechnology

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Protein-protein interactions underpin most biological functions and are an essential building block of a systems wide understanding of cellular function. Proteins work by interacting with one another in molecular machines and in metabolic and regulatory pathways. In this project we will apply computational analyses to study structural and evolutionary properties of protein interfaces in order to predict them from sequence information alone. This will build on existing work looking at domain-domain interactions observed in known structures and expected from sequenced genomes (Littler & Hubbard, 2005) and studies on the molecular co-evolution observed generally between interacting protein families (Lee et al.,submitted). We will also look at novel conserved features of oligomeric protein interfaces, based on preliminary data that shows promise in distinguishing different states. We aim to use molecular modelling, sequence and structural conservation, co-evolution and information theory to study candidate protein-protein interactions in order to detect true interactions from false ones and build an accurate predictive system to help build/validate interaction networks.

 Littler SJ and Hubbard SJ (2005) Conservation of orientation and sequence in protein domain-domain interactions J. Mol. Biol. 345: 1265-1279.

• Biochemistry
• Bioinformatics
• Biomolecular Sciences
• Biotechnology

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Food security is among the most serious challenges facing humanity in the coming decades. Not only do we need to increase agricultural production because of population growth, but also climate change is predicted to have an adverse impact on crops. Periods of drought and heat waves are expected to become more frequent, but crucially it is environmental variability (in terms of light, temperature, water) that imposes the biggest stress on plants. Even periods of moderate stress can, at crucial stages in the growth cycle, have a significant impact on crop yields. Hence, there is an urgent need to develop crops with better tolerance of environmental stress.

Systems biology and computer modelling are becoming major tools to predict properties of living organisms. We are now able to construct genome-scale models that encompass all known metabolic reactions of a species, and we can use these models to make quantitative predictions about the growth of an organism. These methods open novel perspectives to predict the response of plants to environmental variations and to discover new biotechnological solutions to improve crop yields.

We have so far developed genome-scale metabolic models of the plant Arabidopsis thaliana (Radrich et al., 2010) and identified processes that are crucial to the dynamic acclimation of photosynthesis (Athanasiou et al., 2010). Photosynthesis is particularly sensitive to variations in environmental conditions, and changes in photosynthetic activity impact carbon fixation and the whole plant metabolism. The aim of this project will be to investigate how photosynthesis responds to variable environmental conditions and to construct in silico models of the associated metabolic response. Models will be tested experimentally by carrying out selected measurements of metabolite pools in fluctuating conditions. This project offers an exciting opportunity to work in a highly interdisciplinary environment and acquire training in both wet-lab and computer modelling techniques. The project also addresses a fundamental research priority, food security, with the potential of biotechnological applications.
 

Radrich K, Tsuruoka Y, Dobson P, Gevorgyan A, Swainston N, Baart G, Schwartz JM (2010) Integration of metabolic databases for the reconstruction of genome-scale metabolic networks. BMC Systems Biology 4: 114.

Athanasiou K, Dyson BC, Webster RE, Johnson GN (2010) Dynamic acclimation of photosynthesis increases plant fitness in changing environments. Plant Physiology 152: 366-373.
 

• Biochemistry
• Bioinformatics
• Biotechnology
• Environmental Biology
• Plant Sciences

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Most of the world’s biodiversity is found in tropical forests which are under severe threat as they are being lost, fragmented and degraded. The long-term survival of forest species and ecosystems depends on several factors. For example, species need to continue to evolve and adapt to their environment. However, retaining evolutionary potential requires sufficiently high levels of genetic diversity, which will be lost in small and fragmented populations. It is also important that forest species do not become isolated in forest fragments and unable to disperse and exchange genes between populations. The aims of this project would be to: gain an understanding of the processes that have generated tropical forest biodiversity; determine the current levels and distribution of genetic diversity; and to apply this information to long-term conservation management strategies.

Our current studies focus predominantly on amphibians in Central America but similar projects in Southeast Asia may be available. All projects are likely to involve a combination of fieldwork, molecular genetics and computational anlaysis. Projects would use the latest genetic and genomic methods such as high throughput RAD sequencing, DNA barcoding and microsatellites, combined with the latest analytical approaches such as landscape genomics, phylogenetics and the inference of population history parameters. It is important that, in addition to an interest in conservation and biodiversity, the student has an interest in evolutionary genetics and is willing to learn the relevant theoretical background and statistical and analytical skills.
 

.

• Animal Biology
• Bioinformatics
• Environmental Biology
• Evolutionary Biology
• Genetics

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Vegetation can have an important role in improving the environmental performance of cities, providing cooling, reduction in surface runoff of rain, and absorption of air pollution. The effectiveness of trees, grass, and green roofs is being extensively researched, but far less is known about the possible benefits of living walls: coverings of climbing plants such as ivy. This project will investigate how well living walls can reduce energy exchanges of the buildings they are covering, both by insulating them against cold, and insulating them against the heat and shading them from the sun in summer. The amount of transpirational cooling they provide will also be investigated. This project will provide the knowledge we need to include living walls in climate models and test their effectiveness at helping cites adapt to climate change.

• Ennos, A.R. (2010) Urban cool. Physics World 23 (8), 22-25.
• Gill, S., Handley, J.F., Ennos, A.R. and Pauleit, S. (2007). Adapting cities for climate change: the role of the green infrastructure. Built Environment 33, 97-115.
   

• Evolutionary Biology
• Plant Sciences

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Current conservation plans for amphibians include a large increase in the number of species maintained in ex situ conservation populations. However, there is limited evidence based husbandry and conservation knowledge for most species. Further, maintenance of species in captivity will result in selection that may render the population not viable for reintroduction purposes. This project will seek to establish improvements in husbandry methods for ex situ populations of amphibians and to quantify the selection acting on these populations as a result of husbandry methods. This project would include both lab and field work. Scope exists for this project to be run in collaboration with conservation organizations.

• Environmental Biology
• Evolutionary Biology

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Understanding the varied effects of microbes on animals is one of biology’s most critical research challenges. Traditional approaches to this issue are typically limited to the role of microbes as pathogens or mutualists, and neglect their ecologically significant role as classical competitors with animals. Here we propose to use a multidisciplinary approach to study the coevolutionary interactions between microbes and animal scavengers while they compete for carrion. We will identify chemical, behavioural, and physiological mechanisms, as well as interactions between them, in order to develop a framework for understanding the processes mediating the outcome of inter-kingdom competition.

• Evolutionary Biology
• Genetics
• Microbiology

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Barley was domesticated in the Fertile Crescent of southwest Asia some 10,000 years ago. It is now cultivated in many parts of the world including regions of northern Europe where the climate is much colder and wetter than in the Fertile Crescent. Barley has therefore undergone an enforced climate change as the early farmers moved it to these new environments. How did the plant respond to this climate change? One response was a change in flowering time so plants in northern Europe flower later in the season than ones growing in the Fertile Crescent. This is advantageous in a cool, wet climate as it enables the plants to continue their vegetative growth throughout the summer, and so produce more seeds, compared with plants in hot environments where the seeds must be produced early the year, before the plant is killed by the summer heat. In previous work we have shown that the flowering time adaptation results from a single nucleotide polymorphism (SNP) in the photoperiod response gene, which codes for a protein that enables the plant to respond to daylength. Now we wish to look more generally at the barley genome and identify other genes and/or noncoding regions that are involved in the plant’s response to its environment. We already have a great deal of data on sequence variations in barley varieties from many different parts of Europe and the Near East, and in this project we will add to this information by typing variations in a number of additional genes. The genetic data will then be compared with detailed climatic and environmental data for the regions from which the plants were originally collected. By searching for correlations between the two sets of the data, the project will enable us to identify other genes that have undergone adaptive evolution in response to climate change.

• H.Jones, P.Civan, J.Cockram, F.J.Leigh, L.M.J.Smith, M.K.Jones, M.P.Charles, J.-L. Molina Cano, W.Powell, G.Jones & T.A.Brown (2012) Evolutionary history of barley cultivation in Europe revealed by genetic analysis of modern landraces. BMC Evolutionary Biology in press
• D.L.Lister, S.Thaw, M.A.Bower, H.Jones, M.P.Charles, G.Jones, L.M.J.Smith, C.J.Howe, T.A.Brown & M.K.Jones (2009) Latitudinal variation in a photoperiod response gene in European barley: insight into the dynamics of agricultural spread from ‘historic’ specimens. Journal of Archaeological Science 36: 1092–1096.
• H.Jones, F.J.Leigh, I.Mackay, M.A.Bower, L.M.J.Smith, M.P.Charles, G.Jones, M.K.Jones, T.A.Brown & W.Powell (2008) Population based resequencing reveals that the flowering time adaptation of cultivated barley originated east of the Fertile Crescent. Molecular Biology and Evolution 25: 2211–2219.
• T.A.Brown, H.Jones, L.Smith & W.Powell (2008) Adapting to a new climate. NERC Planet Earth Winter 2008: 28–29. http://www.nerc.ac.uk/publications/planetearth/2008/winter/win08-newclimate.pdf

• Bioinformatics
• Evolutionary Biology
• Genetics
• Plant Sciences

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Protein-protein interactions underpin almost all biological functions, with the majority of proteins making at least one interaction with another. If we are to understand how function arises in the cell, an important prerequisite is to understand how protein-protein interactions arise and evolve.

When we analyse sets of related proteins we find that they vary substantially in the sets of interactions that they make. In other words, the network of interactions “rewires” itself through evolutionary time. This rewiring can give rise to enormous complexity and emergent biological function. We propose to study this process of evolutionary rewiring using computational methods. This will involve the use of protein structure, knowledge of how proteins bind through specific interfaces, and evolutionary models. This approach differs from other techniques that attempt to define specificity and binding surfaces in that it is “function-led” (based on the interaction network and the functional annotation), rather than being “sequence-led” (based one the partitioning of the sequences using a phylogenetic tree).

The majority of the data used will be derived from the yeast Saccharomyces cerevisiae. Since Manchester is a centre for yeast research there is may be a possibility to test computational predictions in collaboration with experimental labs.
 

Bioinformatics

Biomolecular Sciences

Evolutionary Biology

Molecular Biology

Structural Biology

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Climate changes caused by global warming are threatening species worldwide. Accordingly, it is important to develop a mechanistic understanding of how organisms respond to changes in temperature. The brewer's yeast, Saccharomyces cerevisiae, inhabits a broad range of climates and habitats, where it is exposed to significant daily and seasonal natural variation in temperature. This yeast is also the best-understood eukaryote at the molecular and cellular level, and is often used as a model for experimental biology. The aims of this PhD studentship are to answer the following broad questions: Are yeasts from different climates pre-adapted to different ranges of temperatures, and how do they respond to temperature changes in the laboratory? What molecular mechanisms underlie adaptations to different temperatures, and do these changes differ between strains with distinct ecological histories? These questions will be addressed by making use of laboratory screens using collections of wild yeasts, experimental evolution where yeasts are allowed to evolve in the lab for 1000’s of generations, and next generation sequencing. Answers to these questions will provide key insights into mechanisms influencing species range and viability in the face of global climate change. The University of Manchester benefits from state-of-the-art equipment and expertise in the study of yeast biology, genomics and bioinformatics. This project will provide training in evolutionary biology and population genetics using a combination of statistical and experimental evolution approaches.

Dunham, M. J. 2010 Experimental evolution in yeast: a practical guide. Methods Enzymol 470:487-507.
Greig, D., R. H. Borts, and E. J. Louis. 1998. The effect of sex on adaptation to high temperature in heterozygous and homozygous yeast. Proc Biol Sci 265:1017-1023.

Adaptive Organismal Biology
Bioinformatics
Environmental Biology
Evolutionary Biology
Genetics
Microbiology

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Transposable elements (TEs) are mobile, repetitive DNA sequences that are among the most dynamic, yet least understood, components of eukaryotic genomes. Advances in genome sequencing among closely related strains and species now provides an unparalleled opportunity to study the impact of TEs on eukaryotic genome organisation and evolution. The aim of this project will be to use comparative and population genomic data to identify and analyze the distribution of TE insertions within populations in order to test classical molecular population genetic models of the evolutionary forces that control TE abundance and distribution in eukaryotic genomes. The project will take advantage of the growing number of complete and draft genome sequences generated by classical and next-generation genome sequencing and will primarily use computational biology techniques. Training in molecular population genetics, large-scale data analysis and programming will be provided during the project. A background in genetics, bioinformatics or computer programming is beneficial but not required.

• Bergman, C.M. & D. Bensasson. (2007) Recent LTR insertion contrasts with waves of non-LTR insertion since speciation in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA 104:11340-11345.
• Kim JM, Vanguri S, Boeke JD, Gabriel A, Voytas DF. (1998) Transposable elements and genome organization: a comprehensive survey of retrotransposons revealed by the complete Saccharomyces cerevisiae genome sequence. Genome Research 8:464-78.
• Charlesworth, B. and Langley, C.H. (1989) The population genetics of Drosophila transposable elements. Annu Rev Genet 23:251-287.

• Bioinformatics
• Environmental Biology
• Evolutionary Biology
• Genetics
• Molecular Biology

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Yeast has become over the last decade an excellent model system for environmental genomics research and studies of the molecular mechanisms underpinning speciation. This project aims to understand the impact that chromosomal rearrangements have on fitness and reproductive isolation in different yeast isolates. In particular, Saccharomyces cariocanus and Saccharomyces paradoxus are two species that are reproductively isolated. However, the genome of these two yeasts is almost identical (no sequence divergence), except for the presence of four chromosomal translocations.

Experiments will be designed to show that these yeasts are not two diverged species and that the degree of reproductive isolation present is largely due to the translocations. Molecular tools will be used to undo the rearrangements present in S. cariocanus to render its genome collinear to that of S. paradoxus. The engineered species will then be crossed with S. paradoxus and tested for viable offspring (yeast spores). If the translocations are the main cause of the meiotic defect, than we expect that most of the spores will be viable.
Transcriptome studies, using RNAseq technology on SOLiD platform, will be carried out in different nutritional media in the parental S. cariocanus strain and in the engineered strain (carrying the genome collinear with S. paradoxus) to identify potential fitness advantages inferred by the translocations.

This study will have wide implications since it may lead to a redefinition of the “species concept” currently used for such fungi (biological species concept).
 

Liti et al, Nature, 2009
Delneri et al., Nature Genetics, 2008
Harrison et al., PNAS, 2007
Delneri et al., Nature, 2003
Colson et al., EMBO rep., 2004
 

• Biochemistry
• Bioinformatics
• Biomolecular Sciences
• Biotechnology
• Environmental Biology
• Evolutionary Biology
• Gene Expression
• Genetics
• Microbiology
• Molecular Biology
• Plant Sciences

This project has a Band 3 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Vertebrate haematopoiesis is a highly sophisticated system; it comprises various specialised cell types functioning in gas transport, blood clotting and immune response, while the varieties of these cells are differentiated from only one type of haematopoietic stem cells (HSC). Although the progress of molecular and developmental biology in the last decade has revealed the molecular mechanism of this process, little is known about its evolutionary origin. This is mainly because most data have come from experiments using model vertebrates such as mouse, chicken or zebrafish. Although recent studies of Drosophila haematopoiesis show that some fundamental mechanisms are conserved between Drosophila and vertebrates, we still do not know how the multiple lineages of vertebrate blood cells and HSC system were established in evolution.
In this project, we will analyse the haematopoiesis and its ontogeny in the basal vertebrates, namely lampreys and hagfish. These jawless-fishes are known as the extant representatives of the oldest lineage of vertebrates and are in the best phylogenetic positions to address the evolutionary origin of vertebrate haematopoiesis. As these animals have not been studied in detail like other model vertebrates, we will first describe the developmental and the differentiation process of blood cells and then analyse their underlying molecular mechanisms and compare them with the data from model vertebrate animals or Drosophila in order to study how this elaborate system has been established during the early evolutionary history of the vertebrate.
This project will use molecular, developmental and haematological techniques including isolation of genomic and cDNA sequences, developmental analyses, in situ hybridisation, cytochemistry, flowcytometry as well as comparative genomics.
 

• Adaptive Organismal Biology
• Animal Biology
• Cell Biology
• Developmental Biology
• Evolutionary Biology
• Genetics
• Immunology
• Molecular Biology
• Physiology
• Stem Cell Research

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Metagenomics – the analysis of genomic material from complex environmental samples – is a powerful cross-disciplinary approach that can be applied to many questions in environmental sciences ranging from bioremediation to microbial ecology to host-parasite co-evolution. Next-generation sequencing technologies have allowed metagenomics datasets to be generated for large numbers of samples, allowing the microbial communities of different environments to be analysed in evolutionary and ecological contexts. The aim of this project will be to use next-generation sequencing data to study the co-evolution of microbial communities with their host for two insect model systems – fruitflies and burying beetles. Both species harbour symbiotic gut bacterial communities that are transmitted by distinct modes to offspring. In addition, because both species develop on decomposing matter—fruits and carrion, respectively—they are exposed to high densities of potentially harmful bacteria as larvae and pupae. Thus these insects are well suited to understanding host-symbiont interactions in a natural context. Both publically available data and experimental data generated during the project will be used to answer questions relating to host-symbiont co-evolution. Training in genomics, bioinformatics, microbiology, evolution, large-scale data analysis and programming will be provided during the project. No previous computer programming or bioinformatics background is required.

1) Chandler JA, Morgan Lang J, Bhatnagar S, Eisen JA, Kopp A (2011) Bacterial communities of diverse Drosophila species: ecological context of a host–microbe model system. PLoS Genet 7(9): e1002272.

• Bioinformatics
• Biotechnology
• Environmental Biology
• Evolutionary Biology
• Genetics
• Immunology
• Microbiology
• Molecular Biology

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Non-protein-coding RNA genes produce a functional RNA product, rather than a translated protein. An unexpectedly large number of non-coding RNAs are found in the animal genome – over 5000 functional RNAs can be easily annotated in human, including around 1000 microRNAs, 400 small nucleolar RNAs (snoRNAs), 500 transfer RNAs, and 60 spliceosomal RNAs – and computational prediction hints at as many as 30000 structured RNAs. Many RNA transcripts appear to make multiple functional products; for example microRNAs and snoRNAs are often located in introns of protein-coding genes, and many primary microRNA transcripts are processed to produce multiple mature microRNAs. These genomic relationships highlight fundamental questions regarding RNA function:

1. Are functional intronic RNAs co-transcribed with host genes?
2. Do linked RNA and protein products function in common pathways?
3. Are patterns of co-transcription and common function conserved between related species?

This project will make use of a wide range of computational biology and comparative genomics techniques, resources and algorithms to approach the above questions. The work will involve generation and analysis of RNA deep sequencing data as well as mining existing publicly available datasets. Fundamental insights will be gained into the genomic context, transcriptional regulation and function of non-protein-coding RNAs in the animal genome.
 

[1] Griffiths-Jones S. (2007). Annotating noncoding RNA genes. Annu Rev Genomics Hum Genet. 8:279-298.
[2] Bartel D.P. (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281-97.
[3] Saini H.K., Enright A.J. and Griffiths-Jones S. (2008) Annotation of mammalian primary microRNAs. BMC Genomics 9:564.
 

• Bioinformatics
• Developmental Biology
• Evolutionary Biology
• Gene Expression

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Redox systems are crucial in metabolic and control processes throughout biology. Intracellular compartmentalisation in eukaryotic cells allows the creation of separate redox environments, with the constituent sets of macro- and small molecules evolved to provide specific functionality [1]. A key component of reduction/oxidation networks is the thiol group of cysteine residues, for which the surrounding protein environment modulates activity. This computational project will predict the redox activity of thiol groups in model organisms, and use these predictions to (i) compare with redox networks in disparate organisms, and (ii) investigate the role of altered redox properties in disease. A hierarchical framework will be employed, in which molecular models for thiol activity [2], refined against experimental data, are coupled with genome-wide modelling and 3D structure in normal and disease-associated proteins. Comparative studies will be made between organelles and between organisms (i.e. comparative genomics). Recent work from our group using a similar comparative approach, in the context of organelle proteomics, uncovered evidence for adaptation of pH-dependence to subcellular pH [3]. A final layer of the hierarchy will place the work in the context of systems biology models for cellular function, so that the project will also provide methods and computer code to parameterise the redox inputs to systems models.

1. Redox compartmentalization in eukaryotic cells. Go YM and Jones DP (2008) Biochim Biophys Acta 1780:1273-1290.
2. Prediction of pKa and redox properties in the thioredoxin superfamily. Moutevelis F and Warwicker J (2004) Protein Sci 13:2744-2752.
3. Evidence for the adaptation of protein pH-dependence to subcellular pH. Chan P and Warwicker J (2009) BMC Biol 7:69.
 

• Biochemistry
• Bioinformatics
• Biomolecular Sciences
• Biotechnology
• Cell Biology
• Organelle Function
• Structural Biology

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Because of their shared evolutionary history all tetrapods face the constraint of simultaneous breathing and locomotion. Among the tetrapods birds are unique is their capabilities for multiple forms of locomotion; there are birds that can fly, swim, dive and run for example. Birds also have a unique respiratory system with a rigidly fixed lung, air sacs and uncinate processes. Our recent work has demonstrated that adaptations to different forms of locomotion functionally contrains respiration in birds. This project will examine the activity of respiratory and locomotor muscles in birds adapted to different forms of locomotion and ultimately aims to better understand the evolution of avian body form.

• Codd JR, Boggs DF, Perry SF & Carrier DR (2005) Activity of three muscles associated with the uncinate processes of the giant Canada goose Branta canadensis maximus. J. Exp. Biol. 208(5): 849-857
• Tickle PG, & Codd JR (2009) Ontogenetic development of the uncinate processes in the domestic turkey (Meleagris gallopavo) Poultry Sci. 88: 179-184.
• Tickle PG, Nudds RL & Codd JR (2009) Uncinate process length in birds scales with resting metabolic rate PLoS ONE 4(5): e5667.
• Codd JR. (2010) Uncinate processes in birds: morphology, physiology, & function. Comp. Biochem. Physiol. A. 156A(3): 303-308
 

Adaptive Organismal Biology
Animal Biology
Evolutionary Biology
Physiology

 

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

From genome sequences, the total number of genes in several organisms can now be predicted. However, the functions of many of these genes remain unknown. The number and percentage of genes that are required for development and classified as essential varies among organisms. The percentage of genes required for human survival is unknown. However, studies in the mouse allow mammalian essential genes to be identified from experimental data. From these data a subset of essential and non-essential genes have been discovered. The task that remains is to identify all the genes that are likely to be required for mammalian development using the mouse as a model, and comparative genomics to then characterise essential human genes. Incorporating a machine learning approach, we seek to identify characteristics that are over-represented in genes known to be required for development. This will allow us to develop criteria for essential genes. By applying these criteria to the mouse genome, we can then identify regions of the genome that contain high numbers of essential genes, as well as identify the individual genes that are likely to be required for mammalian development.

Hentges KE, Pollock DD, Liu B, Justice MJ. Regional variation in the density of essential genes in mice. PLoS Genet. 2007 May 4;3(5):e72.

Lovell SC, Li X, Weerasinghe NR, Hentges KE. Correlation of microsynteny conservation and disease gene distribution in mammalian genomes. BMC Genomics. 2009 Nov 12;10:521.
 

• Bioinformatics
• Developmental Biology

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Work at Manchester and elsewhere has shown that metal colloids such as aluminium is bio-available and toxic to invertebrates at neutral pH. Aqueous Al acts endogenously following accumulation from the food (e.g. Desouky et al., 2002) and exogenously following binding to the gills (e.g. Alexopoulos et al., 2003). Nanoparticles have experienced a huge expansion in recent years and the most common nano-material used in consumer products are nono-metals such as silver which also in a colloidal form.
Invertebrates have the ability to overcome infection through a non-specific but highly efficient immune system involving recognition and elimination of non-self material by circulating haemocytes Trace metals such as copper and zinc adversely affect immunocompetence in invertebrates and we have shown that Al colloids also impairs the ability of crayfish haemocytes to remove bacteria from the circulation in vivo (Ward et al., 2006).
The project will examine the effects of silver nanoparticles (silverNP) on the immune system of selected invertebrates, specifically to test the following hypotheses:
• Invertebrates exposed to silverNPs have an impaired immune response due to a reduction in the ability of circulating haemocytes to recognise, phagocytose and kill potentially infective agents.
• The response to exogenous silverNPs on the immune system of invertebrates possessing gills is a non-specific stress response resulting from respiratory dysfunction.
• The response to endogenous silverNPs is a metal-specific effect resulting from the toxic effects of the accumulated metal on haemocyte function.
The student will receive training in animal husbandry, metal analytical techniques, haemocyte culture, in vitro and in vivo measures of phagocytosis, recognition and killing of bacteria, electron microscopy.
 

• Alexopoulos, E, McCrohan, C.R., Powell, J.J. Jugdaohsingh, R. & White, K.N. (2003) Bioavailability and toxicity of freshly neutralised aluminium to the freshwater crayfish Pacifastacus leniusculus. Arch. Environ. Contam. Toxicol. 45, 509-514.
• Desouky, M, Jugdaohsingh, R, McCrohan, C R, White, K N & Powell, J J (2002) Aluminium-dependent regulation of intracellular silicon in the aquatic invertebrate Lymnaea stagnalis. Proc. Nat Acad. Sci. US, 99, 3394-3399.
• Ward, R.J, McCrohan, C R, & White, K N (2006) Influence of aqueous aluminium on the immune system of the freshwater crayfish Pacifasticus leniusculus. Aquatic Toxicol. 77, 222-228

• Adaptive Organismal Biology
• Animal Biology
• Environmental Biology
• Immunology
• Physiology

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

New millennium biology is in crisis, overwhelmed both by data and publications describing those data: with 1.5 billion bases pouring monthly into DNA databases, and a new article appearing in Medline every 30 seconds, it is impossible to keep abreast of developments. As we systematically bury our knowledge in data and literature silos, we no longer know what we know, nor know how to find it!
To address these issues, new approaches are needed to manage, merge, interrogate and exploit 'big data' from modern, high-throughput genomic and proteomic experiments. Next-generation software (including new 'social’ software) is required to turn the rapidly accumulating information into biochemical, biophysical and biomedical knowledge; new approaches are also needed to interface with the research hubs that build the databases on which modern biology now depends.
This project is an opportunity to work at this interface, building on collaborations with the curators of important protein databases (InterPro, UniProt, Gene3D, etc.) and with publishers. The broad aim is to integrate data in articles with information stored in databases, to be able to visualise and seamlessly interact with them in real time. The initial focus is on proteins, their families, their structures and interactions; in time, this will broaden to genes and genomic data.
We have built Utopia [1,2], software that semantically integrates visualisation and data-analysis tools with document-reading/management utilities. Utopia uses Web-services to marshal functionality from the Internet [3,4], gathering new tools within a single, user-friendly interface. Extending this work to focus explicitly on protein families [5] and protein-protein interactions, and taking advantage both of the results of the FEBS Letters experiment with the MINT protein interaction database and our semantic Biochemical Journal Experiment with Portland Press [2], this project will begin by exploring exciting new ways for visualising, analysing and understanding proteins and their interactions.
 

• 1. Pettifer S, Thorne D, McDermott P, Marsh J, Villeger A, Kell DB & Attwood TK (2009) Vis-ualising biological data: a semantic approach to tool and database integration. BMC Bioinformatics, 10, S18.
• 2. Attwood TK, McDermott P, Marsh J, Pettifer S & Thorne D (2009) Calling International Rescue: knowledge lost in data and literature landslide! Biochemical Journal, 424(3), 317-333.
• 3. Stockinger H, Attwood TK, Chohan SN, Cote R, Cudre-Mauroux P, Falquet L, Fernandes P et al. (2008) Experience using Web services for biological sequence analysis. Briefings in Bioinformatics,
• 9(6), 493-505.
• 4. Pettifer S, Thorne D, McDermott P, Attwood T, Baran J, Bryne JC, Hupponen T, Mowbray D & Vriend G (2009) An active registry for bioinformatics Web services. Bioinformatics, 25, 2090-2091
• 5. Hunter S, Apweiler R, Attwood TK, Bairoch A, Bateman A, Binns D, Bork P et al. (2009) InterPro: the integrative protein signature database. Nucleic Acids Res., 37, D211-5.

• Bioinformatics
• Biomolecular Sciences
• Structural Biology

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

The human immunodeficiency virus type 1 (HIV-1) interacts with 100s of specific proteins of the host
system to use its cellular machinery in order to replicate. A comprehensive database of HIV-1-tohuman
protein interactions was created recently, comprising over 2500 unique HIV-1-to-human
molecular interactions. So far, however, the HIV-1-to-human protein interaction system has been
analysed as a static network only, with no attempt to integrate temporal and spatial aspects. The aim
of this project is to apply a dynamic model to HIV-1 infection. Logical models are powerful tools to
predict the dynamics of complex biological systems when detailed kinetic parameters are unavailable
or prohibitively difficult to determine experimentally. In a logical model, nodes (proteins) are
connected by edges, which describe the nature of the action occurring between two proteins. Typical
examples of actions are activation, inhibition, binding, catalysis, etc. The model will be used to
simulate different scenarios of perturbations of the host system by viral proteins, in order to better
understand the mechanisms used by the virus to hijack the cellular machinery. The project will involve
training in computational, molecular and systems biology.

• Klamt S, Rodriguez JS and Gilles E (2007) Structural and functional analysis of cellular networks with CellNetAnalyzer. BMC Systems Biology, 1:2.
•  MacPherson JI, Dickerson JE, Pinney JW and Robertson DL (2010) Patterns of HIV-1 protein interaction identify perturbed host-cellular subsystems. PLoS Computational Biology, 6:e1000863.
• Pinney JW, Dickerson JE, Fu W, Sanders-Beer BE, Ptak RG and Robertson DL (2009) HIV-host interactions: a map of viral perturbation of the host system. AIDS, 23:549-554.
• Ptak RG, Fu W, Sanders-Beer BE, Dickerson JE, Pinney JW, Robertson DL, Rozanov MN, Katz KS, Maglott DR, Pruitt KD and Dieffenbach CW (2008) Cataloguing the HIV-Human Protein Interaction Network. AIDS Research and Human Retroviruses, 24:1-6.
• •Schwartz JM and Nacher JC (2009) Local and global modes of drug action in biochemical networks. BMC Chem Biol 9:4.

• Bioinformatics
• Biomolecular Sciences
• Cell Biology
• Genetics
• Immunology
• Microbiology
• Molecular Biology

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Research in my group is focussed on bioinformatics and molecular evolution. We study evolution at the molecular level from genes to genomes to systems biology, and use computers to address analytical and theoretical questions/hypotheses. Specific PhD projects available include:

1. Duplication, “rewiring” and redundancy in protein-protein interaction networks.
2. Co-evolution of binding specificity in protein interaction networks.
3. Co-evolution of viruses with their hosts.
4. Quantification of constraints on viral diversity and evolution.

    

• Bioinformatics
• Evolutionary Biology
• Genetics

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

It is known that the use of post-translational modification (PTM) to modulate protein activity is widespread. Improvements in the detection and quantification of PTMs, coupled with genome sequence data, are supplying data in this area faster than can be analysed experimentally on a case by case basis. Taking phosphorylation as a key exemplar PTM, computational approaches are also contributing, helping to give a general picture of kinase specificities and of the properties of target regions. For example, the vast majority of phosphorylation lies outside of (3D) folded regions. This leaves the question: What are the molecular mechanisms by which phosphorylation mediates biological activity? Where a folded region is the target, then a change in conformation and/or binding preferences can often be inferred [1]. This is also the case for linear stretches that bind to specific domains, such as peptides containing phosphorylated tyrosine binding to SH2 domains. However, the accumulated substrate data (e.g. see Phospho.ELM [2]), are much more widespread. An obvious association with phosphorylation is the addition of negative charge, and although modulation of net charge is believed to be a key factor in many cases, there exists no model for predicting such effects. This computational project will address that deficit, through bioinformatics analysis tied to physical chemistry. Bioinformatics will tell us about similarities in the properties of substrates and how they associate with biological and molecular function, whilst physical chemistry provides the tools to develop models based on the delicate charge balances that mediate structure and interactions.

1. Charge environments around phosphorylation sites in proteins. Kitchen J, Saunders RE and Warwicker J (2008) BMC Struct Biol 8:19.
2. Phospho.ELM: a database of phosphorylation sites – update 2008. Diella F, Gould CM, Chica C, Via A and Gibson TJ (2008) Nucl Acids Res36:D240-D244.
 

• Biochemistry
• Bioinformatics
• Biomolecular Sciences
• Biotechnology
• Cell Biology
• Structural Biology

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

The shapes of organisms are integrated so that functionally and developmentally interacting parts vary together. Morphological integration is often clearly structured, so that there are modules that are tightly integrated internally and relatively independent of other modules. Such integration and modularity is thought to be the result of adaptive evolution and, in turn, it also influences the potential for further evolution. My lab uses the methods of geometric morphometrics to address various questions concerning integration and modularity of shapes in diverse study systems including fly wings and mammalian skulls. We also have developed new methods for examining patterns of integration, for testing hypotheses of modularity and for inferring the developmental basis of morphological integration.

Your project will expand on this work. Current challenges in the field concern the evolution of integration and its genetic basis. Accordingly, your project could either use a comparative approach or the methods of quantitative genetics. Depending on these choices, your research could be lab-based or primarily use museum collections. It is also possible to include a component of methods development into the project in addition to the empirical work. The precise topic of your project will be decided after discussion, and so it is possible to take into account your previous background and experience as well as your interests and personal preferences.
 

• Klingenberg, C. P. 2010. Evolution and development of shape: integrating quantitative approaches. Nature Reviews Genetics 11:623–635. doi:10.1038/nrg2829
• Klingenberg, C. P., and N. A. Gidaszewski. 2010. Testing and quantifying phylogenetic signals and homoplasy in morphometric data. Systematic Biology 59:245–261. doi:10.1093/sysbio/syp106

• Adaptive Organismal Biology
• Animal Biology
• Developmental Biology
• Evolutionary Biology
• Genetics

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

This project will use behavioural, electrophysiological and molecular techniques to study the chemosensory behaviour of adult Drosophila. Responses to both taste (salt, sugar, amino-acids) and pheromonal stimuli will be studied. Electrical response patterns of individual sensory neurons, extracted from multi-unit recordings using spike analysis software, will be characterised. The aim is to develop neurophysiological coding correlates of well-known behavioural responses, using mutant lines affecting peripheral chemosensory coding. Investigating neuronal activity following stimulation with both artificial and extracted cuticular hydrocarbon pheromones will be a central part of the project, testing hypotheses about the role of the components of the fruitfly's pheromone bouquet. Combining the genetic flexibility of Drosophila with the neurobiological challenge of chemoreception, this project is appropriate for a student wishing to obtain unique skills in one of the most fast-moving fields of neuroscience.

• Svetec N, Cobb M, Ferveur JF (2005) Current Biology 15:R790-R792.
• Hoare D, McCrohan CR and Cobb M (2008) Precise and fuzzy coding by olfactory sensory neurons. J.Neurosci. 28, 9710-9722.

• Adaptive Organismal Biology
• Animal Biology
• Genetics
• Integrative Neurobiology & Behaviour
• Molecular & Cellular Neuroscience
• Neuroscience

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

The olfactory system of Drosophila larvae provides a simple model system in a highly manipulable organism. The organisation of the olfactory system is essentially identical to that in higher vertebrates, with the exception of its scale: the larva has only 21 olfactory sensory neurons (OSNs), whereas the mouse has 2 million.
Behavioural studies have shown that olfactory responses are plastic; following prolonged stimulation, some odours cease to elicit a response, whereas other odours change from being attractive to being repulsive. Furthermore, we have demonstrated that there are peripheral changes in the electrophysiological response of the OSNs following prolonged odour stimulation.
We hypothesise that the behavioural effects are due in part to local interactions between the activity of peripheral OSNs, in addition to changes in the action of central pathways. The project will combine electrophysiological recording, molecular genetics and behavioural studies. The power of Drosophila neurogenetics will be applied to create larvae with only one functional OSN, lacking a particular OSN and with altered central structures. This will enable us to address the key problem of plasticity in olfactory responses, which occurs in all organisms.
 

• Hoare D, McCrohan CR and Cobb M (2008) Precise and fuzzy coding by olfactory sensory neurons. J.Neurosci. 28, 9710-9722.

• Adaptive Organismal Biology
• Animal Biology
• Genetics
• Integrative Neurobiology & Behaviour
• Molecular & Cellular Neuroscience
• Neuroscience

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

The greatest impediment to producing effective treatments for HIV is the high rate of viral evolution. HIV’s rapid evolution represents a significant challenge for all types of HIV therapy, including drug therapy and vaccine design.

Although the degree of sequence diversity is extremely high, it is not without limit. In particular mutations have the potential to disrupt the protein structure and so can have a negative effect on the structural integrity, and therefore function, of any of HIV’s constituent molecules. Fortunately, the likely effect of a given substitution can be predicted from the known characteristics of the structure and the particular side chain substituted. We therefore aim to predict whether a given evolutionary trajectory is viable or not, and so predict the likely evolution path of HIV. This will be done using computational models of protein evolution and protein structure.
 

Bioinformatics

Biomolecular Sciences

Evolutionary Biology

Molecular Biology

Structural Biology

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

In recent years there has been much research on the identification of mutations associated with cancer (Stratton at al., 2009). This includes both mutations that are heritable and predispose an individual to cancer, and those that are at the level of a single cell and so contribute to the emergence of a cancerous lineage. The locations of both types of mutations (heritable and somatic) permit the identification of the proteins and functions associated with cancer.

In this project we propose to use an existing database of mutations associated with cancer (http://www.sanger.ac.uk/genetics/CGP/cosmic/) to identify shared properties of cancer-associated proteins. These will include their essentiality, post-translational modifications, length, biophysical properties, number of subunits, position in the human interaction network, number of protein-protein interactions, whether they are duplicated, level of conservation and expression levels. Proteins associated with both heritable and somatic mutations will be compared to each other and to proteins not known to be involved in cancer. The features will be used for input into machine learning methods which will determine an optimal way to separate the protein classes using their properties. This will allow the assignment of any protein as cancer-associated or not. Using these models, we will be able predict novel proteins not identified to-date as having a role in cancer, after running the entire human proteome, with verification by comparing to the recent literature on new cancer proteins. This work will follow our existing methodology for studying drug target proteins (Bakheet & Doig, 2009), but will use an entirely different data set (i.e. cancer proteins).

Ultimately the project will contribute to our understanding of the properties of proteins that are associated with progression to cancer. This will permit the identification of proteins previously not found to be associated with cancer and, thus, new potential drug targets.
 

TM, Doig AJ. (2009) Properties and Identification of Human Protein Drug Targets. Bioinformatics; 25: 451-457.

Stratton MR, Campbell PJ, Futreal PA. (2009) The cancer genome. Nature;458(7239):719-24.
 

Biochemistry
Bioinformatics
Biomolecular Sciences
Biotechnology
Molecular Cancer Studies
 

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Therapeutic proteins are biological drugs, such as antibodies, hormones, enzymes, synthetic peptides, toxins and cytokines. There are currently over 100 therapeutic proteins in use in humans, with most introduced in the last decade. Their main applications are for imaging and diagnosis, blood coagulation, fertility, hormone replacement, enzyme replacement, cancer or immunomodulation. Features which complicate the use of therapeutic proteins include protein aggregation, immunogenicity and cleavage by proteases, which can lead to a decrease in efficacy and/or increased toxicity. Despite this, therapeutic proteins have a better success rate in drug development than small molecule drugs. Most are human, synthetic or human chimeras which helps minimise unwanted immunogenicity.

In this project we will survey known therapeutic proteins to identify their shared properties. These will include essentiality and location in biochemical pathways, post-translational modifications, biophysical properties, protein structure, number of subunits, protein-protein interactions, whether they are duplicated, level of conservation, immunogenicity and expression levels, amongst others. Therapeutic proteins are frequently modified to improve their behaviour. We will therefore compare modified, unmodified and non-therapeutic proteins. This work will give rules for the identification and design of new therapeutic proteins.

The most important features that we discover will be used for input into machine learning methods, such as random forests or support vector machines, which will determine the optimal way to distinguish therapeutic from non-therapeutic proteins. This will allow the prediction of new potential therapeutic proteins, after running the entire human proteome, with verification by comparing to the recent literature on new therapeutic proteins. This entirely computational project will follow our existing methodology for studying drug target proteins (Bakheet & Doig, 2009; Bakheet & Doig, 2010), but will use an entirely different data set.
 

Bakheet TM, Doig AJ. (2009) Properties and Identification of Human Protein Drug Targets. Bioinformatics; 25: 451-457.

Bakheet, TM, Doig, AJ. (2010). Properties and identification of antibiotic drug targets. BMC Bioinformatics, 11, 195-204.
 

• Biochemistry
• Bioinformatics
• Biomolecular Sciences
• Biotechnology
• Immunology

This project has a Band 1 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.

Key to unravelling the origins of bird flight is the ability to bring fossil birds, such as Archaeopteryx, and their feathered ancestors (proto-birds) to life. Although several different approaches have attempted to do this, none so far have provided definitive estimates of the flight capabilities of feathered fossil taxa. This project will use a new approach that integrates the biomechanical properties of flight feathers with the distribution of aerodynamic forces upon a feathered wing to determine maximum flight performance. Wind tunnel experiments will be conducted to measure the aerodynamic force distribution upon the flight feathers of different shaped bird wings and model proto-bird forelimbs. These experiments will be conducted for three broad modes of flight: gliding, using isolated fixed bird wings; simple flapping, using isolated bird wings attached to a mechanical flapper & natural flapping using live birds.

Simultaneously the maximum buckling strength of flight feathers in relation to feather morphology will be determined using universal testing machines. The feather strength data will then be used to estimate the maximum sustainable force of the feathers of early birds and proto-birds. The more manoeuvrable and agile the flight is, the higher the forces that are generated upon the wing and its feathers. Hence, coupling the aerodynamic force data to the feather strength data will allow the flight capabilities of feathered fossil birds and their ancestors (proto-birds). Once the flight capabilities of these fossils are known the likely origin of flight in birds may be identified.

Nudds, R. L. & Dyke, G. J. (2010) Narrow Primary Feather Rachises in Confuciusornis and
Archaeopteryx Suggest Poor Flight Ability. Science 328, 887-889.

• Adaptive Organismal Biology
• Evolutionary Biology

This project has a Band 2 fee. Details of different fee bands are available for UK/EU or International applicants. See: Fees.