New gene-editing system enables large-scale studies of gene function.
An international collaboration led by researchers in the US and South Africa announced Nov. 20 the first genome sequence of an extensively drug resistant (XDR) strain of the bacterium Mycobacterium tuberculosis, one linked to more than 50 deaths in a recent tuberculosis (TB) outbreak in KwaZulu-Natal, South Africa.
As part of this work, genomes of multi-drug resistant (MDR) and drug sensitive isolates were also decoded. Initial comparisons of the genome sequences reveal that the drug-resistant and drug-sensitive microbes differ at only a few dozen locations along the four-million-letter DNA code, revealing some known drug resistance genes as well as some additional genes that may also be important to the spread of TB.
The researchers have taken an unusual step of immediately sharing both the genome sequence and their initial analysis far in advance of submitting a scientific paper, in order to accelerate work on drug-resistant TB by researchers around the world.
"Tuberculosis is a major threat to global public health that demands new approaches to disease diagnosis and treatment," said Megan Murray, one of the project's principal investigators, an associate member of the Broad Institute of MIT and Harvard and an associate professor at the Harvard School of Public Health. "By looking at the genomes of different strains, we can learn how the tuberculosis microbe outwits current drugs and how new drugs might be designed."
"Genome information is a powerful tool for understanding the biology of infectious disease, such as tuberculosis," said Eric Lander, founding director of the Broad Institute. "It is important that genomic data be made immediately available, particularly to researchers in areas most heavily burdened by disease."
Globally, tuberculosis is a major cause of infectious disease deaths. Nearly two billion people, comprising roughly one third of the world's population, are thought to carry M. tuberculosis, the culprit bacterium. Major obstacles to controlling the disease stem from the microbe's ability to evade current treatments, which typically require prolonged use by patients and are often not curative. Adding to the problem, inefficient diagnostic methods for TB make it difficult for doctors to determine whether an individual harbors a drug-resistant strain, often delaying proper therapy.
To shed light on the genetic changes that mediate drug resistance, the international team of scientists undertook a large-scale effort to sequence the genomes of drug sensitive, MDR and XDR TB isolates of a strain responsible for the current XDR TB epidemic in KwaZulu-Natal, South Africa.
The draft genome sequences of the various TB strains each cover roughly 95 percent of the M. tuberculosis genome. Comparing the DNA sequences in these regions allows the researchers to pinpoint the key differences among them, shedding light on the genetic factors that contribute to TB drug resistance. Strikingly, comparisons of the draft sequences reveal surprisingly few genetic differences among the drug sensitive, MDR and XDR strains: there are only a few dozen small DNA changes.
"These results also lay the groundwork for the development of a rapid diagnostic test for TB," said Murray. "Such a test would enable more rapid and accurate diagnoses, and help to prevent the spread of TB--especially the most virulent strains."