Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Technique plucks rapidly evolving genes from a pathogen’s genome

30.04.2004


A quick new technique able to identify genes that evolve rapidly as well as those that change slowly already has pinpointed new targets for researchers developing drugs against tuberculosis and malaria, and it could do the same for other infectious diseases, according to a paper in this week’s Nature.



The technique, reported in the April 29 issue of the journal, was developed by researchers from the University of California, Berkeley, Harvard and Princeton universities, and the National Institutes of Health.

Genes that change slowly or not at all in an organism, or from one organism to another, usually turn out to be critical pieces of molecular machinery and, in an infectious organism, attractive targets for researchers hoping to kill it


Alternatively, genes that change rapidly are presumed to be under selective evolutionary pressure, such as the need for a microbe to continually switch its outer coat to escape detection by the human immune system. Such genes can tell researchers how organisms outwit the immune system or develop drug resistance.

This new technique is a total departure from current methods of finding rapidly evolving genes, and has already pinpointed previously unknown genes in the tuberculosis and malaria parasites that could be potential drug targets.

"In the typical comparative method, researchers take equivalent genes from several organisms, like humans and chimps and mice, line them up and count the differences," explained coauthor Hunter B. Fraser, a graduate student in molecular and cell biology at UC Berkeley. "That gives you an idea of what kinds of changes a gene has undergone over evolution, and from the kinds of changes you see, you can infer something about the way it is evolving - whether it has been pressured to change or pressured to stay the same.

"We’re coming out with a similar end result - knowing what kinds of evolutionary pressures are on different genes - but we can do it with just a single genome sequence, instead of lining up genes from different genomes and comparing sequences."

Fraser works in the laboratory of Michael Eisen, a UC Berkeley adjunct assistant professor of molecular and cell biology and a member of the QB3 consortium (California Institute for Quantitative Biomedical Research).

"This technique can be used to quickly identify pathogenic genes that interact closely with the human immune system, since these genes are under tremendous pressure to evolve quickly," said coauthor Joshua B. Plotkin, a junior fellow in the Faculty of Arts and Sciences at Harvard. "Such genes are prime targets for new drugs and vaccines to counter deadly pathogens."

The technique involves a statistical analysis of an entire genome, comparing the rate of change of a specific gene to the average rate of change within the genome. An organism’s genome is a sequence of DNA nucleotides - either A, G, T or C (for adenine, guanine, thymine and cytosine) - grouped into triplets, called codons. Each codon codes for a specific amino acid to be strung together to create a protein. The series thymine, cytosine and adenine - a TCA codon - always yields a serine amino acid, for example.

Because 64 DNA triplets can be made from the four available DNA nucleotides but there are only 20 different amino acids, some amino acids are coded by more than one codon. Arginine, for example, is coded by six different codons: CGA, CGC, CGG, CGT, AGA and AGG.

Based on an idea by Plotkin, the team zeroed in on the susceptibility of codons to point mutations - alteration of a single DNA nucleotide - and the fact that not all point mutations have the same effect. A random point mutation in some codons is less likely to create a codon that codes for a different amino acid. For example, the conversion of CGA to CGC would still result in an arginine, leaving the protein’s amino acid sequence unchanged. Based on the structure of the genetic code - that is, the translation table connecting codons to amino acids - the group was able to tell which codons were more likely to have been mutated into a codon for a different amino acid.

By counting, for example, the frequency of the six codons coding for arginine in a single gene, and comparing it to the frequency throughout the full genome, the researchers are able to determine whether the gene has likely evolved faster or slower than the genome as a whole.

"We add up over an entire gene which triplets it’s using, and then we ask, ’Would we expect to see this kind of usage of triplets just by chance or not?’" Fraser said. "If not, it’s unusual and gives us a clue to how the gene has been evolving."

"We need the whole genome sequence because we have to learn, for each genome, what its background distribution of triplets is," he added. "If we didn’t know that, we wouldn’t be able to find a gene with a significant departure from that."

The technique only works with some amino acids. The new results come from an analysis of arginine, leucine and serine, each of which is coded for by six different codons, and glycine, which coded for by four different codons.

The team, which included Jonathan Dushoff, a postdoctoral researcher at Princeton and the NIH, used its technique to analyze the 4,000 genes in the genome of the tuberculosis bacterium (Mycobacterium tuberculosis) and the 5,000 genes in the genome of the malaria parasite (Plasmodium falciparum).

The genes in these organisms that turned out to be rapidly evolving were largely those genes coding for antigens, that is, proteins that coat the surface of the pathogen and incite an immune response. By constantly changing its antigen coat, a pathogen can elude the immune system, evolving eventually into a new strain to challenge the human immune system again.

"The fact that we found most antigens were quickly evolving under our metric confirmed that our technique works," Fraser said.

The researchers also discovered previously unrecognized genes that are evolving rapidly. These genes are attractive candidates for further research into which genes may be interacting with the human immune system.

"We also found that within classes of antigens, some are under much stronger selection than others, which people hadn’t found before," he said. "We are able to make hypotheses about which ones are actually interacting with the immune system and which ones are not, based on this new finding."

Fraser emphasized that the technique, referred to as codon volatility, complements comparative gene methods common now. Codon volatility can tell about recent evolutionary pressure on genes, while comparative methods can tell about evolutionary pressure over millions of years.

The codon volatility method has limitations, however, he said. It relies on the fact that the proportion of each of the four DNA nucleotides is fairly uniform across the entire genome of an organism. In humans, however, the proportion is different at different places in the genome. Nevertheless, Fraser said the group is at work modifying the method to analyze codon volatility in the human genome.

The work was supported by the Harvard Society of Fellows and the NIH.

Robert Sanders | EurekAlert!
Further information:
http://www.berkeley.edu/

More articles from Life Sciences:

nachricht Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View
22.06.2018 | University of Sussex

nachricht New cellular pathway helps explain how inflammation leads to artery disease
22.06.2018 | Cedars-Sinai Medical Center

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Temperature-controlled fiber-optic light source with liquid core

In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.

Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...

Im Focus: Overdosing on Calcium

Nano crystals impact stem cell fate during bone formation

Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

Graphene assembled film shows higher thermal conductivity than graphite film

22.06.2018 | Materials Sciences

Fast rising bedrock below West Antarctica reveals an extremely fluid Earth mantle

22.06.2018 | Earth Sciences

Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View

22.06.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>