Chromosome chaos in serial killer

October 28, 2011

ANTWERP - Scientists found a deadly parasite with some of its chromosomes in duplicate, others in triplicate, while still others are present four or even five times. Moreover, the copy number varies between individuals. Such a bizarre occurrence has never before been found in nature, in any organism. As a rule, chromosomes should come in couples. The scientists, from the Institute of Tropical Medicine (ITG) and the Wellcome Trust Sanger Institute, made the striking discovery while deciphering the genetic code of a series of Leishmania-parasites. Their findings are reported in the respected journal Genome Research.

Leishmania, a unicellular parasite of humans and animals, is reputed amongst biomedical scientists as a bit of a character, being an expert in adaptation to its environment and manipulation of its host cell, the macrophage. The micro-organism causes leishmaniasis, one of the most important parasitic diseases after malaria: transmitted by a mosquito bite, it affects about 2 millions of persons in 88 countries (including Southern European countries) and annually kills more than 50,000 people worldwide. The chromosome juggling should be weird enough for one organism, but ITG and Sanger scientists also discovered that individual parasites of Leishmania donovani (the species causing the deadly disease, visceral leishmaniasis) that are genetically very close, still react completely differently to the same medicine. The researchers studied parasites from Nepal and Bihar (India), all descending from a few survivors of the DDT-campaigns in the sixties and therefore having little genetic variation.

Taking advantage of the most recent developments in DNA sequencing technologies (also known as next generation sequencing), they deciphered the complete genome of 17 L. donovani strains that differed in their response to drugs. The investigators compared the 17 genomes, looking for mutations (termed single nucleotide polymorphisms, or SNPs, in biomedicine) that could explain why some strains were resistant to drugs, and others weren't. They found only a few.

But they did find two other things. They discovered circular pieces of DNA that had extricated themselves from the chromosomes and could correspond to 'first aid kits' allowing the parasite to adapt to the drug pressure. But most important: the chromosomes of the parasites did not occur as pairs, as is customary in nature. In laboratory strains under experimental conditions it was already demonstrated that Leishmania parasites can survive with 'unnatural' numbers of a few chromosomes, but the ITG and Sanger scientists now showed that the parasites do the same in real life - and to an unexpected extent.

Up to now, it was assumed that the cellular machinery of a cell could not function correctly with chromosomes that are present in a different number of copies. Chromosomes ought to occur in pairs, the sex chromosomes X and Y also forming a pair. Some plants have them in fours, but then all chromosomes appear in fourfold. In exceptional cases an organism survives with a single or a triplicate chromosome. As reminded by Dr Jean-Claude Dujardin, senior author from ITM, "most of the time abnormalities in chromosome number are problematic for the organism. For instance, people with Down's syndrome have three specimens of chromosome 21. More radical deviations are not viable.

Or at least this was the rule until now. Leishmania can live perfectly well with several chromosomes in triplicate, others in quadruplicate and even a few in fivefold. And with each of the 17 examined strains the numbers were different!"

It is not completely clear why this parasite behaves so differently from other living organisms, but investigators believe that juggling with the copy number of chromosomes could be a weapon in the unremittingly harsh battle of the parasite against the huge stresses imposed by drugs and the minefield of the human immune system.

"Our work highlights how genomic research changes our perspectives about these parasites," says Dr Matt Berriman, the senior author from the Sanger Institute. "We show that the evolution of these organisms is driven not only by single-letter changes in their genetic codes, but also by larger mutations in the copy numbers of genes and entire chromosomes. The findings have enabled us to discover more about its natural variation and genetic structure which is vital for the further development of effective treatments."

At the moment, clinicians in Nepal and India are isolating hundreds of new strains of the parasite which will ultimately be all sequenced for analysis of their chromosome content among others. This long-term multidisciplinary work is of uppermost importance for health professionals worldwide.

As highlighted by Dr Shyam Sundar (Banaras Hindu University, Varanasi, India), co-author of the study and authority in clinical research on visceral leishmaniasis in the Indian sub-continent: "genome sequence will lead to better understanding of drug targets and designing of new approaches to chemotherapy, it will help in identification of parasite genetic variations leading to drug resistance, ultimately leading to better control of the visceral leishmaniasis epidemic."

Institute of Tropical Medicine Antwerp

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