Geographical differences in transmission revealed by cryptic population structure

Two papers that I co-authored with colleagues at Lancaster and Massey Universities appear this month in the October 2010 issue of Epidemiology & Infection. The common theme is that cryptic differences in the population structure of the enteric pathogen Campylobacter jejuni, revealed by my method for attributing cases to source populations, suggest subtle differences in transmission between rural and urban districts.

The method, implemented in the software iSource (available on my website), allows strains of campylobacter to be characterized as poultry- or cattle-associated based on their genetic profiles. Interestingly, when the relative incidence of poultry- and cattle-associated strains is plotted on a map, there is a significantly higher occurrence of poultry-related disease in urban areas and cattle-related disease in rural areas. Both studies – one in Lancashire led by Edith Gabriel and one in New Zealand led by Petra Mullner – draw the same conclusion. These findings imply that there are subtle differences in transmission in rural and urban areas. Whether they represent geographical differences in the profile of food pathogens, environmental exposure, resistance to infection or other risk factors is not understood.

Evolutionary Genetics for Translational Research

This month saw the 2010 Infectious Disease Genomics & Global Health meeting at Hinxton, which attracted a good number of people involved in the Modernising Medical Microbiology consortium, of which I am a participant. Rory Bowden and Rosalind Harding presented our group's progress on piecing together intra-host evolution of Staphylococcus aureus and reconstructing transmission chains in Clostridium difficile. My role in the projects has so far been one of assisting in ongoing evolutionary analyses and collaborating in the design of bioinformatics pipelines to make sense of the raw Illumina short-read sequencing data. At the same time I have been devising research plans for my own group, and spending time in the lab preparing sequencing experiments with Bernadette Young. In the poster I presented at Hinxton (available here), and at an internal talk I gave earlier in the year (slides here) I set out what I see as the strengths of Evolutionary Genetics for addressing translational medical problems including

• Tracking the transmission of hospital-acquired pathogens
• Understanding transmission dynamics at the population level
• Identifying the mechanistic and adaptive basis of disease
• Explaining how pathogens emerge, persist and spread globally

Of the many stimulating talks at the Hinxton conference, those by Dominic Kwiatkowski on the population genomics of Plasmodium falciparum, Christophe Fraser on "hyper-recombination" in Streptococcus pneumoniae and Paul Keim on the challenges for understanding the population genetics of non-clonal bacterial pathogens particularly interested me. Prof Keim gave an equally captivating talk the following day at the Health Protection 2010 meeting in Warwick on his microbial forensics work tracing the origin of Bacillus anthracis spores used in bioterrorism attacks. What I especially admired about his presentations was the dogged pursuit of new methods and ways of thinking in order to better address the biological questions at hand.

What are the conditions for multiple foci of adaptation?

Selection on standing variation, soft sweeps, parallel adaptation: these alternatives to the population genetics paradigm of the S-shaped selective sweep have in common the idea that the response of a species to a change in selection pressure may frequently involve multiple mutations, which may arise in multiple locales, and which may appear at different sites in the genome. Consequently, the footprint of selection in the genome is different to that expected under a single selective sweep and therefore likely to be missed by scans of the genome looking for selection.

Many examples of parallel adaptation have been put forward, for instance multiple drug resistance in the malaria parasite Plasmodium vivax. But how plausible is parallel adaptation as an evolutionary mechanism, and what are the conditions that make it likely? These questions were addressed by Graham Coop presenting joint work with his postdoc Peter Ralph in one of the stand-out talks of the SMBE conference in Lyon.

Their key finding is that the multifarious parameters that go into building a spatial model of adaptation (strength of selection, the mutation rate, population density, average dispersal distance of offspring) can be distilled down to a single key quantity: the characteristic length given by the equation

When the geographical extent of the species range exceeds this characteristic length, the conditions are right for parallel adaptation. Graham's talk made accessible the complex mathematics behind this result. He has kindly made the slides available (click here) and the paper is now available at the Genetics website (click here).

Discovering the distribution of fitness effects

At this year's Society for Molecular Biology and Evolution meeting in Lyon I presented ongoing work estimating the distribution of fitness effects, which is a collaborative venture with Molly Przeworski and Peter Andolfatto. Earlier versions of this research appeared in talks I presented at Chicago in December (Ecology and Evolution Departmental seminar) and Liverpool in January (UK Population Genetics Group meeting), and it follows on from last year's SMBE presentation in which I discussed methods to tease out sub-genic variation in selection pressure.

There is intrinsic interest in the fitness effects of novel mutations in coding regions of the genome, especially the relative frequency of occurrence of neutral, beneficial and deleterious variants. Yet estimating the distribution of fitness effects (the DFE) is also of practical use when localizing the signal of adaptive evolution. The reason is that in Bayesian analyses, the assumed DFE can influence the strength of evidence for or against adaptation at a particular site. Consequently it is preferably to estimate the DFE at the same time as detecting adaptation at individual sites to avoid prior assumptions unduly influencing the results.

Having estimated the DFE, it is of use in quantifying the relative contribution of adaptation versus drift to genome evolution. The figure, taken from my talk in Lyon (slides here), illustrates the idea when a normal distribution is used to estimate the DFE; the relative area of the green to the yellow shaded regions represents the respective contribution of adaptation versus drift in amino acid substitutions accrued along the Drosophila melanogaster lineage.

Election to St. John's College

I'm pleased to have been elected to membership of the SCR at St. John's College, my alma mater. The college is an important aspect of life at Oxford as it gives an alternative centre of gravity outside the department for participation in social and academic activities. As a member of University staff with solely research responsibilities, it is a welcome opportunity to interact with the community of teaching fellows, students and junior researchers who belong to the college.

The picture is of the Spring crocus lawn taken in the college gardens.

Postdoc and PhD position available

These positions are now closed.

Advertised today in Nature and on Thursday in New Scientist are two positions in my lab. I am looking for a postdoc and a PhD student to work on the genome evolution and epidemiology of four human pathogens as part of the Modernising Medical Microbiology project. Three of the pathogens share the theme of hospital-acquired infections: they are Staphylococcus aureus (of MRSA infamy), Clostridium difficile and norovirus (aka winter vomiting disease). The fourth is Mycobacterium tuberculosis (TB) which is a re-emerging problem in developed countries.

The aim of the project is to use whole genome sequencing of many isolates (100s to 1000s) in order to reconstruct evolutionary relationships and deconstruct transmission routes. We hope to develop the technology to the stage that we can trace the spread of pathogens in real time, and uncover the epidemiological triggers for the spread of disease.

As of January I have relocated to the Nuffield Department of Clinical Medicine at the University of Oxford, and the project is a collaborative affair between people at Oxford (including Rory Bowden, Derrick Crook, Peter Donnelly and Rosalind Harding), the Wellcome Trust Sanger Institute, the NHS and the Health Protection Agency. The project is funded by the UKCRC and further details of the positions are available online for the postdoc and PhD studentship. The closing date for applications is Friday, 2 April 2010.

Holding early human stone tools

Today I had an extraordinary experience, precipitated by my visit to the British Museum on something of a whim. Listening to the Radio 4 series A History of the World in 100 Objects, my imagination had been captured by the descriptions of early stone tools - a chopper and a hand axe - featured in the first couple of programmes in the series. These tools, which were found in the Olduvai Gorge, in modern-day Tanzania, are examples of the oldest known objects made by humans. What is fascinating is that their simple design belies a capacity for mental forethought. They are tangible evidence that the humans living 2 million years ago had the intelligence to conceive of and the dexterity to manufacture tools.
I had been visiting friends in London, and before leaving I decided to pass by the museum to see these relics for myself. I found the stone tools in a dim room in the near corner of the museum, shielded by glass cases. After reading the descriptions and wandering round I noticed a lady showing some children a bunch of similar-looking objects she had in a wooden box. I asked if they were casts and could hardly believe it when she told me it was the real thing. Two stone hand axes, 1 million years old, made from basalt and quartz, and a basalt chopper, 2 million years old - the oldest items in the museum. To hold in the palm of my hand a tool fashioned 2 million years ago by a cognizant proto-human, I could imagine the heavy object fitting just as neatly into the hand of its designer, and in trying to understand the way it might have been used to butcher carcasses, pound meat and scrape flesh off bones I felt I got a brief glimpse into the intentions of its designer. The study of evolution rarely affords such vivid connections with its subject matter, and I felt privileged to stumble across such an encounter today.