The single-celled parasite Trypanosoma brucei (appearing in blue), which causes sleeping sickness in humans and trypanosomiasis in livestock, amongst the red blood cells of its mammalian host (photo credit: Parasite Museum website).
Having been domesticated in Africa some 8,000 or more years ago, the N’Dama, the most ancient of African cattle breeds, has had time to evolve resistance to the tsetse-fly-transmitted trypanosome parasites that cause a disease known as African animal trypanosomiasis in animals and sleeping sickness in people.
This makes the N’Dama a valued animal in Africa’s endemic regions. On the other hand, N’Dama cattle tend to be smaller, to produce less milk, and to be less docile than their bigger, humped cousins.
African agriculturalists of all kinds would like to see the N’Dama’s inherent disease resistance transferred to these other more productive breeds, but this is difficult without precise knowledge of the genes responsible for disease resistance in the N’Dama.
An international and inter-institutional team, conducting an African Bovine Trypanosomiasis project, recently made a breakthrough in this gene discovery that was published earlier this month in the Proceedings of the National Academy of Sciences (PNAS) in the USA. The research team made this breakthrough by combining a range of genetic approaches, which until now have largely been used separately.
‘This may be the first example of scientists bringing together different ways of getting to the bottom of the genetics of a very complex trait,’says Steve Kemp a molecular geneticist leading the International Livestock Research Institute (ILRI) team that is part of this collaborative trypanosomiasis project. ‘Combined, the data were like a Venn diagram overlaying different sets of evidence. It was the overlap that interested us.’
They used these genetic approaches to distinguish differences between the ‘trypano-tolerant’ (humpless) N’Dama, which come from West Africa, and ‘trypano-susceptible’ (humped) Boran cattle, which come from Kenya, in East Africa.
The scientists first identified the broad regions of their genomes controlling their different responses to infection with trypanosome parasites, but this was insufficient to identify the specific genes controlling resistance to the disease.
So they began adding layers of information obtained from other approaches. They sequenced genes from these regions to look for differences in those sequences between the two breeds.
A team at Edinburgh conducted gene expression analyses to investigate any differences in genetic activity in the tissues of the two cattle breeds after sets of animals of both breeds were experimentally infected with the parasites.
Then, the ILRI group tested selected genes in the lab. Finally, they looked at the genetics of cattle populations from all over Africa.
Analyzing the vast datasets created in this research presented significant computational challenges.
Andy Brass and his team in the School of Computer Science at the University of Manchester managed to capture, integrate and analyze the highly complex set of biological data by using workflow software called ‘Taverna,’ which was developed as part of a UK e-Science initiative by Manchester computer scientist Carole Goble and her ‘myGrid’ team.
‘The Taverna workflows we developed are capable of analyzing huge amounts of biological data quickly and accurately. Taverna’s infrastructure enabled us to develop the systematic analysis pipelines we required and to rapidly evolve the analysis as new data came into the project,’ Brass said. ‘Many human infections trigger similarly self-destructive immune responses, and our observations may point to ways of reducing such damage in people as well as livestock.’
In celebration of passing this genetic milestone, ILRI conducted short filmed interviews of the key collaborators in this project, who in describing what it took to make this breakthrough, stress the increasing importance of conducting truly international, inter-institutional and inter-disciplinary scientific collaboration in order to make a difference.
The importance of ‘human factors’ in such complex collaborations, where computer science is married to biological science, and informatics specialists must understand geneticists, cannot, they say, be overemphasized. Only by working together, and by doing so so well, did they manage to make this important breakthrough in research on an important, and till now seemingly intractable, livestock disease.
New science is networked science, they (and many others) say. The Bovine Trypanosomiasis Consortium conducting this project, funded by the UK’s Wellcome Trust and BREAD (Basic Research to Enable Agricultural Development), funded by the US National Science Foundation and the Bill and Melinda Gates Foundation, is a case in point.
As a feature in Wired Magazine explored a few years ago (The Petabyte Age, 23 June 2008), ‘Our ability to capture, warehouse, and understand massive amounts of data is changing science, medicine, business, and technology. As our collection of facts and figures grows, so will the opportunity to find answers to fundamental questions. Because in the era of big data, more isn’t just more. More is different.’
Sample Twitter genetic map: Sample data with 1000 friends and 1 year of timeline (graphic credit: Mancel Lemos’ manoellemos’ Flickr photostream).
Watch below the short filmed interviews of the key partners in this project.
Complexities of trypanosmiasis demand formation of unique team: 2:29 minutes (16 May 2011)
To address the problems of trypanosomiasis, a team was formed, new systems were designed and expertise from a range of disciplines were brought together. The results represent a new approach to solving biological problems that has implications way beyond trypanossomiasis itself. ILRI filmed interview of Steve Kemp, a molecular geneticist on joint appointment at the International Livestock Research Institute (ILRI) and the University of Liverpool Institute of Integrative Biology.
Why trypanosomiasis is a problem for farmers and researchers: 3:32 minutes (16 May 2011)
Trypanosomiasis in livestock affects the livelihoods of millions. Researchers have been struggling to overcome the disease for decades, but finding a solution continues to be challenging. ILRI filmed interview of Steve Kemp, a molecular geneticist on joint appointment at the International Livestock Research Institute (ILRI) and the University of Liverpool Institute of Integrative Biology.
Designing computer-based systems that generate testable biological ideas: 4:08 minutes (16 May 2011)
To manage complex, rapidly changing datasets, the Manchester University computer team designed and built analysis systems based on re-useable highly adaptable modules. For the first time, this makes it easy to repeat a complex analysis as well as use the components for different types of data. ILRI filmed interview of Paul Fisher, computer scientist in the University of Manchester’s Computer Science Department.
Implications for farmers of research into cattle resistance to trypanosomiasis: 1:56 minutes (16 May 2011)
By identifying some of the genes involved in resistance to trypanosomiasis, this project is making it possible to conduct faster and cheaper animal breeding schemes. Soon farmers will be able to identify the best animals to breed from to increase their disease resistance. However, both biological and practical challenges remain. ILRI filmed interview of Harry Noyes, a scientist at the University of Liverpool’s Institute of Integrative Biology.
Different responses to trypanosomiasis infections by resistant and susceptible animals: 1:35 minutes (16 May 2011)
Trypanosomiasis infections trigger an immune response in cattle which can be destructive as well as helpful. Understanding how disease-resistant animals are different in their responses to trypanosome infection allows researchers to take lessons for human as well as animal medicine. ILRI filmed interview of Harry Noyes, a scientist at the University of Liverpool’s Institute of Integrative Biology.
Humans, cows and their immune responses: 2:52 minutes (16 May 2011)
Surprisingly, the studies undertaken by the International Livestock Research Institute (ILRI) Collaborative Trypanosomiasis Project have shown that cattle responses to severe trypanosomiasis infections have a lot in common with human responses to severe disease or injury. ILRI filmed interview of Paul Dark, a senior lecturer in medicine at the University of Manchester.
Learning about cattle responses to disease by studying mice: 1:37 minutes (16 May 2011)
The team are conducting studies of mice and cattle in parallel. Exchanging knowledge between these two mammalian systems accelerates understanding by providing different perspectives of the same complex problem. ILRI filmed interview of Morris Agaba, molecular geneticist at the International Livestock Research Institute (ILRI).
New computing approaches allow free information flow among project partners: 2:18 minutes (16 May 2011)
Managing the project’s complex team of experts with different skills and backgrounds presented special challenges. Informatics systems played a vital role in encouraging a free flow of ideas and understanding. ILRI filmed interview of Andy Brass, professor in the University of Manchester’s Computer Science Department.
Data management and the genome revolution: 4:35 minutes runtime (16 May 2011)
The development of the International Livestock Research Institute (ILRI) Collaborative Trypanosomiasis Project that started in 2004 took place at the same time as an explosion in the availability of genomic data, challenging the team to integrate this into their work. ILRI filmed interview of Andy Brass, professor in the University of Manchester’s Computer Science Department.
Studying gene expression helps researchers home in on the genes that matter: 2:17 minutes (16 May 2011)
The International Livestock Research Institute (ILRI) Collaborative Trypanosomiasis Project has been integrating gene mapping data with data showing how genes are used differently by different breeds of livestock in response to infection. As a result it is now possible to identify a short list of genes that might contain the variation which is responsible for the way different animals respond to infection. ILRI filmed interview of Alan Archibald, head of the Genetics and Genomics Department at the Roslin Institute, University of Edinburgh.
NOTE: The writer of this blog post, Susan MacMillan, misspelled ‘petabyte’ as ‘petrabyte’ in the original version of this blog post. That misspelling is now (2 June 2011) corrected above.