May 28

Tsetse Genome Sequenced

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tsetse_picIn another triumph for South African biomedical research, researchers at the South African Medical Research Council’s Bioinformatics Unit, South African Bioinformatics Institute (SANBI), with their international collaborators, have sequenced the tsetse fly genome. The International Glossina Genome Initiative (IGGI), including scientists at SANBI (led by Professor Alan Christoffels) have concluded a ten-year project on the tsetse fly (Glossina morsitans morsitans). Understanding the genomic structure and behavior of the tsetse fly is pivotal to treating sleeping sickness, a disease that affects about 70 million people in sub-Saharan Africa where the tsetse fly is most commonly found. African Sleeping Sickness in humans (Human African Trypanosomiasis-HAT) more often than not, results in death. There is no medically viable course of treatment. Public health efforts to prevent new infections in areas commonly afflicted by HAT have focused on using insect repellants and wearing appropriately protective clothing to avoid being bitten by the tsetse fly. HAT is a dreadful disease to contract. ‘Sleeping sickness’, the colloquial name for HAT, originates from observations of how it affects the human sleep pattern of an infected person. The saliva of the tsetse fly contains a parasite, or trypanosome. When the human host is bitten, the host’s blood is infected with trypanosomes. There is no known vaccine to prevent the spread of infected blood throughout the bloodstream. The early stages of the parasite infection in the host present with fever, headaches, and joint pain. If undetected, the parasite infection attacks the lymphatic system where swelling of the lymph nodes at the back of the neck are prominent. Finally, the central nervous system is assailed by the infection once its crosses the blood-brain barrier. When the host is at this stage of infection, the sleep-cycle is affected. The patient is confused and disoriented and experiences a disrupted sleep pattern with long sleep cycles by day and fragmented periods of wakefulness and delirium at night. Up until recently public health drives were concentrated on preventing new infections in the absence of a vaccine. Ten years ago, scientists formed the International Glossina Genome Initiative (IGGI), with the view that understanding the biology of the fly may be an effective way to prevent the spread of HAT. The aim of the IGGI consortium was clear: unveiling the physiological working of the fly could present the opportunity for biomedical researchers to develop new vector control strategies to limit the spread of sleeping sickness. The tsetse fly has a unique physiognomy, physiology, and, behavioural traits – most notably as a vector for Human African Trypanosomiasis. This is not new to the researchers. But, the primary focus of the IGGI consortium was to sequence the entire tsetse fly: a 366 million base pair genome. The key exercise here was to identify and annotate the genes within the genome sequence. The availability of this genomic data and its concomitant knowledge – including knowledge of the tsetse fly’s vision; olfaction; immune; and, reproductive physiology – provides an unparalleled opportunity to transform tsetse fly research and associated disease control practice. Tsetse flies are known for their unique biology: they feed exclusively on vertebrate blood; they give birth to live young (one at a time); they provide nutrition to their young by lactation; and, they formed complex relationships with no less than three different symbiotic bacteria. And there are no doubt several mysteries lying in wait – the genome holds information for which nobody has yet identified functions. The analysis of the genome assisted in revealing the basic biology of the fly on a fundamental level: for example, identifying genes that produce proteins involved with vision or smell allow researchers to better understand what may attract or repel tsetse flies, and thus trap them or drive them away. An area of interest has been tsetse mechanisms that eliminate parasites in the midgut. This is of both basic and applied research interest, since the ability to engineer greater resistance in flies could solve the problem of disease transmission. The IGGI consortium encompasses and was driven by over one-hundred and forty scientists from a range of research areas at different institutions.* It is truly an inter- and multi-disciplinary research project that includes researchers from inter alia the South African National Bioinformatics Institute in South Africa; the International Centre for Insect Physiology and Entomology (ICIPE) in Kenya; the Yale School of Public Health in the United States; the European Bioinformatics Institute (EBI) and the Wellcome Trust Sanger Centre in England; the Liverpool School of Tropical Medicine in England. A hallmark of this consortium, however, is that African and Africa-based researchers played a decisive leadership role in the research. According to Professor Christoffels: ‘all of the activities were directed at supporting genomics research on the African continent. We have developed partnerships with researchers across the African continent over the course of the project. International genome projects are often directed at the primary goal of sequencing the genome and annotating (describing) the genes. Besides the scientific findings, this programme has demonstrated the value of genomics training in the context of a DNA sequencing project.’ For Professor Christoffels, and his African counterparts, human capacity development was a crucial factor of the success of their scientific endeavour. To this end, SANBI invested heavily in computer-based training pertaining to the analysis of the tsetse fly genomic data. Bioinformatics training at SANBI included: the analysis of the olfactory genes and the iron-metabolism genes; the examination of characteristics that control the ‘on/off’ switch of the genome; the identification of DNA that repeats itself multiple times in the genome; and, the description of the location of particular genes in the genome. Six PhD students conducted their research on this tsetse project. They graduated from the University of the Western Cape of which SANBI is an affiliate. Two PhD students, still conducting research on the tsetse fly, are concurrently supervised at SANBI and ICIPE in Kenya. This collaboration is a fine example of experienced scholars confident of their collaborative relationships and of African institutes of scientific research sharing their distinct expertise. On the continent, the African component of the IGGI consortium comprised over 40 experienced African researchers. They all were involved in multiple group annotations held in South Africa, Kenya, and Uganda. The results of this ten-year collaboration will appear in the journal, Science, on April 25, 2014. A collection of satellite research papers will appear concurrently in the open access journal, PLoS Neglected Tropical Diseases, where various aspects and functions of tsetse fly genes will be further discussed. Trypanosomiasis does not only affect humans. It affects animals, too, particularly cattle. Continued research into various tsetse fly species as they infect cattle via the trypanosome will also be of benefit to the agricultural communities of sub-Saharan countries, and by extension, the broader SADC commercial agricultural economy. Other Members of IGGI

  • Hokkaido University Research Center for Zoonosis Control (Hokkaido, Japan);
  • Institute of Tropical Medicine (Antwerp, Belgium)
  • Kenya Agricultural Research Institute Trypanosomiasis Research Centre (Kikuyu, Kenya);
  • London School of Hygiene and Tropical Medicine (London, UK);
  • National Livestock Resources Research Institute (Totoro, Uganda);
  • RIKEN (Japan);
  • TIGR (Rockville, USA);
  • Tsetse and Trypanosomiasis Research Institute (Tanga, Tanzania);
  • VectorBase (Notre Dame, USA);
  • WHO Regional Office for Africa (Brazzaville, Congo);

WHO-TDR (Geneva, Switzerland); About SANBI: The South African National Bioinformatics Institute within the University of the Western Cape (not to be confused with the similarly named South African Biodiversity Institute) is a Medical Research Council Unit for bioinformatics capacity development with the mission to conduct cutting edge bioinformatics and computational biology research relevant to South African, African and global populations. For more information about SANBI’s involvement in the project mentioned above, please contact Professor Alan Christoffels at alan@sanbi.ac.za or via telephone at 021 959 2969. For more general information about SANBI, you can visit the SANBI website at www.sanbi.ac.za or contact the SANBI offices at (021) 959 3645 or via email at info@sanbi.ac.za.

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Nov 13

SANBI receives MRC Flagship award

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From left-to-right: Prof Ramesh Baruthram (Deputy Vice Chancellor, UWC), Prof Alan Christoffels (Director, SANBI) and Prof Yusuf Osman (Dean of Dentistry, UWC)

From left-to-right: Prof Ramesh Baruthram (Deputy Vice Chancellor, UWC), Prof Alan Christoffels (Director, SANBI) and Prof Yusuf Osman (Dean of Dentistry, UWC)

A team led by Professor Alan Christoffels recently received a MRC flagship award to undertake research on tuberculosis with a focus on developing methods to accelerate the identification of new tuberculosis drug targets.
Over the past 4 years, the team has been predicting new drug targets for tuberculosis and predicting the effect of DNA modifications on the ability of a patient to metabolize TB drugs. This work has now culminated in the funding of a multi-disciplinary research team comprising researchers at the Universities of Benin, KwaZulu Natal, Stellenbosch, Cape Town and Western Cape (Drs Gamieldien and Tiffin). The project will develop computing workflow systems and a query language to interrogate the myriad of tuberculosis clinical and genetic data. In parallel, this funding allows us to experimentally validate the predicted drug targets and will drive experiments to glean insights into genes that respond to
tuberculosis infection. The latter experiment data will refine our current computational predictive models. According to Professor Christoffels, “… besides the inter-institutional collaborations, we have cemented a collaborative partnership among SANBI, School of Pharmacy and Mathematics at UWC. Our colleagues at the University of Benin are funded by the NIH to look at tuberculosis drug metabolism and their work will enrich the development of a query language that can harness drug metabolism data. We are confident that the R&D on workflow systems will attract the attention of industry partners because of the applications across a range of disciplines”.

Apr 18

Coelacanth genome surfaces

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Drawing of coelacanth

drawing by Elaine Heemstra, used with permission of SAIAB.

An international team of researchers from institutions such as Broad Institute at MIT/Harvard, the South African National Bioinformatics Institute (SANBI) at the University of the Western Cape (UWC) and Rhodes University (RU) has decoded the genome of a creature whose evolutionary history is both enigmatic and illuminating: the African coelacanth. A sea-cave dwelling, five-foot long fish with limb-like fins, the coelacanth was once thought to be extinct. A living coelacanth was discovered off the African coast in 1938, and since then, questions about these ancient-looking fish – popularly known as “living fossils” – have loomed large. Coelacanths today closely resemble the fossilised skeletons of their more than 300-million-year-old ancestors. Its genome confirms what many researchers had long suspected: genes in coelacanths are evolving more slowly than in other organisms.

“We found that the genes overall are evolving significantly slower than in every other fish and land vertebrate that we looked at,” said Jessica Alföldi, a research scientist at the Broad Institute and co-first author of a paper on the coelacanth genome, which appears in Nature this week. “This is the first time that we’ve had a big enough gene set to really see that.”

Researchers hypothesise that this slow rate of change may be because coelacanths simply have not needed to change: they live primarily off of the Eastern African coast (a second coelacanth species lives off the coast of Indonesia), at ocean depths where relatively little has changed over the millennia.

Because of their resemblance to fossils dating back millions of years, coelacanths today are often referred to as “living fossils” – a term coined by Charles Darwin. But the coelacanth is not a relic of the past brought back to life: it is a species that has survived, reproduced, but changed very little in appearance for millions of years. “It’s not a living fossil; it’s a living organism,” said Alföldi. “It doesn’t live in a time bubble; it lives in our world, which is why it’s so fascinating to find out that its genes are evolving more slowly than ours.”

The coelacanth genome has also allowed scientists to test other long-debated questions. For example, coelacanths possess some features that look oddly similar to those seen only in animals that dwell on land, including “lobed” fins, which resemble the limbs of four-legged land animals (known as tetrapods). Another odd-looking group of fish known as lungfish possesses lobed fins too. It is likely that one of the ancestral lobed-finned fish species gave rise to the first four-legged amphibious creatures to climb out of the water and up on to land, but until now, researchers could not determine which of the two is the more likely candidate.

In addition to sequencing the full genome – nearly 3 billion “letters” of DNA – from the coelacanth, the researchers also looked at RNA content from coelacanth (both the African and Indonesian species) and from the lungfish. This information allowed them to compare genes in use in the brain, kidneys, liver, spleen and gut of lungfish with gene sets from coelacanth and 20 other vertebrate species. Their results suggested that tetrapods are more closely related to lungfish than to the coelacanth.

However, the coelacanth is still a critical organism to study in order to understand what is often called the water-to-land transition. Lungfish may be more closely related to land animals, but at 100 billion letters in length, the lungfish genome is simply too unwieldy for scientists to sequence, assemble, and analyze. The coelacanth’s more modest-sized genome (comparable in length to our own) is yielding valuable clues about the genetic changes that may have allowed tetrapods to flourish on land.

By looking at what genes were lost when vertebrates came on land as well as what regulatory elements – parts of the genome that govern where, when, and to what degree genes are active – were gained, the researchers made several unusual discoveries:

  • Sense of smell. The team found that many regulatory changes influenced genes involved in smell perception and detecting airborne odors. They hypothesise that as creatures moved from sea to land, they needed new means of detecting chemicals in the environment around them.
  • Immunity. The researchers found a significant number of immune-related regulatory changes when they compared the coelacanth genome to the genomes of animals on land. They hypothesised that these changes may be part of a response to new pathogens encountered on land.
  • Evolutionary development. Researchers found several key genetic regions that may have been “evolutionarily recruited” to form tetrapod innovations such as limbs, fingers and toes, and the mammalian placenta. One of these regions, known as HoxD, harbors a particular sequence that is shared across coelacanths and tetrapods. It is likely that this sequence from the coelacanth was co-opted by tetrapods to help form hands and feet.
  • Urea cycle. Fish get rid of nitrogen by excreting ammonia into the water, but humans and other land animals quickly convert ammonia into less toxic urea using the urea cycle. Researchers found that the most important gene involved in this cycle has been modified in tetrapods.

Sequencing the full coelacanth genome was uniquely challenging for many reasons. Coelacanths are endangered animals, meaning that samples available for research are almost nonexistent. This meant that each sample obtained was precious: researchers would have one shot at sequencing the collected genetic material, according to Alföldi. But the difficulties in obtaining a sample and the challenges of sequencing it also knit the community together.

South African lead researcher Professor Alan Christoffels started working on a coelacanth project 10 years ago in Singapore when he was part of a team that analysed the developmental genes (HOX genes) of the coelacanth. At that time there was no completely sequenced genome sequence. About a year ago, Christoffels was invited to participate in the genomic analysis of the Coelacanth genome together with his team from UWC’s South African Bioinformatics Institute (SANBI). The team included three postdocs – namely Drs Hesse, Panji and Picone – as well as software programmer Peter van Heusden, and SANBI staff members Dr Junaid Gamieldien and Mario Jonas.

Each of the international teams focused on one aspect of the evolution of this species. We identified what is called “gene expansions” in this ancient organism and found that some of these multiple copies of the same gene are peculiar to coelacanth. This phenomenon usually indicates new adaptations in the context of an organism’s functions. More specifically we identified a class of olfactory genes whose function fits a model for vertebrate adaptation,” says Christoffels

Researchers from 40 institutions across 12 countries contributed to this work. Many funding agencies around the world provided support, from South Africa these  included the South African Institute for Aquatic Biodiversity (SAIAB) African Coelacanth Ecosystem Programme (ACEP) funded by the South African National Department of Science and Technology, which supported the collection of samples from coelacanths found off Sodwana Bay on the East coast of South Africa, Rhodes University (RU), and the National Human Genome Research Institute, which supported the Broad Institute’s contributions including genome sequencing.

About the Coelacanth:

In 1938, a South African museum curator discovered an unusual fish among the catch of a local trawler. This fish was curiously similar to fossils from the Cretaceous period and was soon identified as a modern coelacanth – named by Prof JLB Smith, who identified it, as Latimeria chalumnae after the curator, Marjori Courtnay-Latimer who had discovered it. A second species, the Indonesian coelacanth (Latimeria menadoensis), was discovered in 1998. The coelacanth is a member of the ancient group of lobe-finned fishes, all of which were thought to have been extinct since the Late Cretaceous period, seventy million years ago. Both known species of coelacanth are threatened (the West Indian Ocean/Indonesian coelacanth is critically endangered), making this the most endangered order of animals in the world.

About SANBI:

The South African National Bioinformatics Institute within the University of the Western Cape (not to be confused with the similarly named South African Biodiversity Institute) is a Medical Research Council Unit for bioinformatics capacity development with the mission to conduct cutting edge bioinformatics and computational biology research relevant to South African, African and global populations.

For more information about SANBI’s involvement in the project mentioned above, please contact Professor Alan Christoffels at alan@sanbi.ac.za or via telephone at 021 959 2969. For more general information about SANBI, you can visit the SANBI website at www.sanbi.ac.za or contact the SANBI offices at (021) 959 3645 or via email at info@sanbi.ac.za.

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