The decoding of what the press has dubbed the 'book of life' in the form of the human genome has certainly caught the public imagination, and the Wellcome Trust has played a pivotal role in supporting both the Human Genome Project and sequencing of other organisms. But what of the next step – working out what genes actually do? "It's not quite a needle in a haystack," says Alan Doyle, a Scientific Programme Manager in the Functional Genomics Programme, "but we do need to harness that huge wealth of genetic information to real therapeutic ends. That is where functional genomics come in."

The Trust's Functional Genomics Development Initiative aims to promote the use of genome sequence information to improve human and animal health. "We want to see the Trust's heavy investment in sequencing translated into an understanding of what the genome is doing," says Dr Doyle, "and an understanding of how genes affect physiological actions, or pathogenic actions."

The Initiative provides funding in four main areas of work: large-scale thematic programmes, technology development and sharing, databases and bioinformatics, and resource-based activities. The resource-based activities will help to provide the bedrock of resources that will be of great practical benefit to researchers. Recent awards illustrate how shared resources can accelerate research in human genetics and on human pathogens.

"I ran a biological resource centre myself for nearly 15 years," says Dr Doyle, "so I know what a hand-to-mouth existence it can be. The Trust is very pleased to be able to recognise the huge value of these resources, to ensure that they are consolidated, and to enhance their vital role in functional genomics."

Sleeping sickness

Sara Melville, a Senior Research Fellow at the Department of Pathology, University of Cambridge, together with Michael Turner of the University of Glasgow, is developing a resource of materials related to Trypanosoma brucei. T. brucei is a single-celled tropical parasite that causes sleeping sickness in humans in sub-Saharan Africa (and, together with related species, a wasting disease amongst domestic livestock).

The life cycle of T. brucei depends on a vertebrate host and the tsetse fly vector. When an infected fly bites a suitable host, the parasite enters the bloodstream, where it disseminates throughout the body. In the human brain, the parasite causes tissue damage leading to lethargy and confusion – hence 'sleeping sickness' – and eventually death.

Sleeping sickness is deadly if left untreated, and what treatments exist have severe side-effects and may be fatal in themselves. The disease currently affects hundreds of thousands of people every year. There is an urgent need for new preventive measures and treatments, and the World Health Organization (WHO) has designated sleeping sickness a major priority for research.

With funding initially from the Overseas Development Agency, then the WHO, Dr Melville began exploring the T. brucei genome almost ten years ago. "We started working on the general structure of the genome, the number of chromosomes, and so on. In the course of this work we began to build up both biological resources – cell lines, DNA – and also genetic data. WHO gave us some funds to set up as a resource centre. The aim was to gather the T. brucei research community into a coherent network, to share information and biological resources, and to enable efficient working towards common goals. Our resource centre operated on this basis for the last five years – pretty much on a shoestring."

The Wellcome grant, says Dr Melville "has enabled us to put the resource centre on a sound footing. It will see us through to the end of the sequencing process". Dr Melville and Dr Turner will provide DNA resources for genome sequencing work and for the transition to functional genomic analyses, as well as a single repository for all the experimentally important strains of T. brucei, including genetically manipulated lines. They will also provide a central database of available resources, genetic markers and hybridisation data, and details on how to obtain resources, all accessible to the whole T. brucei research community.

T. brucei is being extensively studied by biologists and geneticists, and the Wellcome Trust Sanger Centre (together with The Institute for Genomic Research in the USA) is currently sequencing its genome. Its interest lies partly in its medical and social importance, but also in its biological value – and its study has led to many discoveries about basic cellular processes.

The sequencing of T. brucei will be complete in about four years' time. At that point, says Dr Melville, there will be a reappraisal of what kind of biological resources are needed. Functional genomic analysis of the sequenced strains will take over fully from the initial sequencing work, although there is likely to be great value in comparative sequencing of related species or other strains. "The field is moving at amazing speed. As each sequencing project is finished we will need to create a permanent archive of both biological resources and data, but as yet we don't know the best context for that, whether it should be part of an academic institution or some more centralised resource. Together we have to find our long-term vision."

Human genetic disorders

The human genome sequence is a rich resource in itself. Yet it is far from clear what many of the newly discovered genes in the human genome actually do. One of the most important ways of understanding how genes function is to study how mutations in these genes cause disease. Professor Richard Trembath of the University of Leicester and Professor Eamonn Maher of the University of Birmingham have been awarded a grant to build up a biological resource and databank on a particular class of mutations, those giving rise to autosomal recessive disorders.

Autosomal recessive disorders occur when both parents pass on a harmful alteration in the same gene to a child. "There are hundreds of autosomal recessive diseases," says Professor Trembath, "the most common being cystic fibrosis and the thalassaemias. Many of these disorders are very rare, but cumulatively they are an important cause of disease and mortality, particularly in certain ethnic groups."

Of particular interest are a unique group of patients in the UK, in families where close relations, often cousins, marry. Affected offspring in these families are likely to have inherited the same mutation from both carrier parents, the mutation having arisen in a common ancestor of both parents. This is known as autozygosity.

"Autozygosity allows an extremely direct and powerful mapping of the location of genes responsible for rare autosomal recessive disorders," says Professor Trembath, "because far fewer families are required to give you the robustness of data you need." However, autozygosity mapping is only possible when appropriate biological material is available for analysis.

Normally, families for mapping studies would be found by research groups interested in a specific disease, on a one-off basis. But this approach can mean that families with a different autosomal disorder can be overlooked because their particular condition is not being studied at the time. "There is a danger of these diseases becoming 'Cinderella' conditions, because they are rare," says Professor Trembath. "But of course to the families that have them, their cause and consequences have terrible importance."

Professors Trembath and Maher are conducting a much broader documentation of consanguineous families, including the collection of DNA, mainly through blood samples. They have already developed a localised DNA bank and clinical and genetic database of over 3000 consanguineous Asian families in Leicester, Birmingham and Leeds, with offspring affected by a range of recessive disorders. Researchers investigating an autosomal disorder will thus be able to access one central resource rather than having to scour the country looking for affected families.

The resource will now be extended on a national basis. Great attention will be paid to the key ethical issues such as data protection, confidentiality and informed consent. Of course, it is not just the researchers who will benefit: the project will lead to the creation of a biological resource and database that will be of direct value to at-risk families, in enabling accurate genetic counselling, prenatal diagnosis and carrier testing. But the resource will also have much wider significance, helping researchers map and isolate recessive disease genes, and providing genetic epidemiological data, stepping stones to better prevention and treatment of these inherited disorders.

See also

• Human Genome Project
• Functional genomics: Further details
• A biological dream team: Article describing the Thematic research programme

External links

• Trypanosoma brucei Genome network
• Department of Pathology: Dr Sara Melville at the University of Cambridge
• Dr Michael Turner at the University of Glasgow
• Wellcome Centre for Molecular Parasitology at the University of Glasgow
• Professor Richard Trembath at the University of Leicester
• Professor Eamonn Maher at the University of Birmingham
• Sanger Centre on the Wellcome Trust Genome Campus
• Institute of Genomic Research USA
• WHO: World Health Organization

Further reading

Dr Sara E Melville
Melville S E, Leech V, Gerrard C S, Tait A, Blackwell J M. (1998). The molecular karyotype of the megabase chromosomes of Trypanosoma brucei and the assignment of chromosome markers. Molecular and Biochemical Parasitology 94:155-173.

Johnston D, Blaxter M, deGrave W, Ivens A, Melville S (1999). Genomics and the biology of parasites. BioEssays, 21:131–147.

Melville S E, Gerrard C S, Blackwell J M (1999). Multiple causes of size polymorphism in African trypanosome chromosomes. Chromosome Research 7(3):191–203.

Hope M, MacLeod A, Leech V, Melville S E, Sasse J, Tait A, Turner C M R (1999). Analysis of ploidy (in megabase chromosomes) of Trypanosoma brucei after genetic exchange. Mol. Biochem. Parasitol. 104(1):1–9.

Melville S E, Leech V, Navarro M, Cross G (2000). The molecular karyotype of T. brucei strain 427-221a. Molecular and Biochemical Parasitology 111:261–273.

El-Sayed N, Hegde P, Quackenbush J, Melville S E, Donelson J E (2000). The African trypanosome genome. International Journal for Parasitology 30:329–345.