Leprosy genome shows massive gene decay

Leprosy - the enigmatic scourge

Leprosy genome shows massive gene decay

There are nearly 700,000 new cases of leprosy each year. However, doctors don't fully understand how leprosy spreads and cannot grow it in the laboratory. New research published today in Nature magazine reveals that the organism that causes leprosy may have manoeuvred itself into an evolutionary cul-de-sac.

To understand and, ultimately, to attack this disease, researchers at the Wellcome Trust Sanger Centre near Cambridge and the Institut Pasteur in Paris have sequenced and analysed the genome of the leprosy-causing bacterium, Mycobacterium leprae. They also compared the sequence with that of the closely related organism that causes TB (M. tuberculosis). The sequence of M. leprae and the comparison produce some startling findings:

  • The leprosy genome has only 1600 genes - TB has about 4000
  • Remarkably, 90% of leprosy's reduced gene set is shared with TB
  • Only 50% of the genome of leprosy codes for proteins - in TB, as in most bacteria, it is over 90%
  • More than one quarter of the leprosy genome is pseudogenes - genes that have decayed and become inactive: one-fifth of the genome is probably remnants of genes
  • A family of 170 genes in TB thought to interact with host defences is reduced to only 9 genes in leprosy
  • Leprosy has preserved many of the core functions necessary for bacterial life, but has lost most of the diverse mechanisms found in TB for energy production and nutrient uptake, which probably explains the exceptionally slow growth.

The outcome is that a drastically streamlined genome may mean that M. leprae has discarded so many genes that it can survive only by infecting humans. The reduced gene set may also account for its very slow growth in humans and its inability to grow in culture.

Leprosy is most prevalent in Asia, Africa and Latin America: there are about 1.2 million cases. Often the disease will regress, but only after a prolonged period of infection and damage.

The leprosy bacterium attacks the insulation (the myelin sheath, which is analogous to plastic coating of cables) around nerves. The affected regions become insensitive and easily damaged or disfigured.

"This is an exciting new path to tackling this disease. Diagnosis and treatment of leprosy are currently very difficult: with this new genome information we will be able to develop new and specific diagnostic tests and have already identified new potential targets to attack the leprosy bacterium."

Project Director, Professor Stewart Cole of the Institut Pasteur

"The leprosy genome is a fascinating snapshot of evolution in action. We can see how it has lost so many genes, those it has preserved - most often the core activities - and those that distinguish it from its cousin, the TB bacterium. The analysis shows the power of comparative genomics (looking at DNA from two organisms), one of the strengths of the programmes at the Sanger Centre."

Dr Julian Parkhill, Project Manager at the Sanger Centre

As with all projects at the Sanger Centre, the DNA sequence information is released onto the internet without restriction or charge to users. The project was funded by the Heiser Trust (Heiser Program for Research in Leprosy and Tuberculosis of The New York Community Trust), L'Association Francaise Raoul Follereau, ILEP (which includes LEPRA in the UK), The Institut Pasteur and The Wellcome Trust.

Notes to Editors
  1. The Sanger Centre, which receives the majority of its funding from the Wellcome Trust, is one of the world's leading genome sequencing centres. Both the Sanger Centre and the Wellcome Trust have been at the forefront of efforts to keep sequence data in the public domain. The Sanger Centre employs about 570 people in the purpose-built campus at Hinxton. The Centre is a leading partner in the Human Genome Project, and is responsible for sequencing one-third of the human genome sequence and also contributes to international projects to sequence the genomes of disease-causing organisms. http://www.sanger.ac.uk Details of the Sanger Centre release policy can be found at: http://www.sanger.ac.uk:80/Projects/release-policy.shtml
  2. The Institut Pastuer is a private, non-profit organization, founded in 1887 after Louis Pasteur had successfully developed his vaccine against rabies. Since its founding, the Institut Pasteur has always had three major vocations:
    • Biological research, mainly focused on infectious diseases
    • Public health applications
    • Teaching More than a thousand scientists are working in 110 research units and laboratories on the campus of the Institut Pasteur. Research on infectious diseases represents about half of the scientific work carried out at the Institut Pasteur : in this domain, it is the most important research centrein France and among the most prestigious in the world. The objective in different fields (molecular biology, genomics, physiopathology, immunology, etc.), is to elucidate the invasive and virulence mechanisms of pathogens, or immune mechanisms used by the infected host, in order to find vaccines, and to diagnose and treat diseases.
  3. The Wellcome Trust is the world's largest medical research charity with an annual spend of some £600 million in financial year 1999/2000. The Wellcome Trust supports more than 5000 researchers at 300 locations in 42 different countries, laying the foundations for the healthcare advances of the 21st century and helping to maintain the UK's reputation as one of the worlds leading scientific nations. As well as funding major initiatives in the public understanding of science, the Wellcome Trust is the country's leading supporter of research into the history of medicine.
  4. Funding for the sequencing project was provided by the Heiser Trust (Heiser Program for Research in Leprosy and Tuberculosis of The New York Community Trust), L'Association Raoul Follereau, International Federation of Anti-Leprosy Associations and The Wellcome Trust.
  5. DNA of every living organism is made up of four chemical 'bases' represented by the letters A, C, G and T. The bases are paired together, A with T and C with G to produce double-stranded DNA in the familiar helix. DNA is a digital code and it is the order of base-pairs that contains the information. Thus, the sequence of DNA bases contains all the instructions to make an organism: decoding that set of instructions is the heart of a sequencing project. The number of base-pairs varies from a few thousand for the smallest viruses to several billions for complex organisms. Comparing sequences from different organisms is a valuable method to identify genes and the genetic switches that control them. Regions that are important for gene function are often similar (conserved) between dissimilar species: regions that are not important tend to differ (diverge).
  6. Internet resources
The Sanger Centre M. leprae pageshttp://www.sanger.ac.uk/Projects/M_leprae/
Institut Pasteur Mycobacterial pageshttp://www.pasteur.fr/recherche/unites/Lgmb/
Institut Pasteur M.leprae pageshttp://genolist.pasteur.fr/Leproma/
The Wellcome Trusthttp://www.wellcome.ac.uk/
The Wellcome Trust Beowulf Programmehttp://www.beowulf.org.uk/
World Health Organization leprosy pageshttp://www.who.int/lep/
L'Association Raoul Follereauhttp://www.raoul-follereau.org/
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