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With the turn of the millennium, the genome of humans, the
Anopheles mosquito and the P. falciparum parasite have been sequenced. Thus for
the first time, a wealth of information is available for all the three species that
comprise the life cycle of the malaria parasite and this would help in a better
understanding of the interactions among the three species that have long been evolving
together. The genome sequence of P. falciparum was published in Nature (Nature,
Plasmodium genomics special issue, 3rd October 2002 See
http://www.nature.com/nature/malaria/index.html) and of the mosquito Anopheles
gambiae was published in the same week in Science (Science, The Mosquito
Genome: Anopheles gambiae, 298:5591; 4th October, 2002 See
http://nora.embl.de/ivica/publications/12364791.pdf).
The human genome
sequence was published simultaneously in Nature (Initial sequencing and analysis of the human genome. Nature 409, 860-921 (15 February 2001)
Available at
http://www.nature.com/nature/journal/v409/n6822/full/409860a0.html ) and Science (Science Special Issue, February 2001 Vol 291, Issue 5507, Pages 1145-1434. Available at
http://www.sciencemag.org/content/vol291/issue5507/index.dtl16 ) in
February 2001. The sequencing of the genes opens up new approaches
to the development of drugs, vaccines, insecticides and insect
repellents, as well as intervention into malarial transmission.
Genetic tools will also enable sampling of parasite, mosquito, and
human genomes in malaria affected areas to support the malaria
control activities.
The
Malaria genome:
The sequencing of P. falciparum
resulted from an international collaboration established in 1996, comprising of NIAID
(National Institute of Allergy and Infectious Diseases), the Wellcome Trust, the Burroughs
Wellcome Fund and the U.S. Department of Defense. Sequencers worked at The Institute for
Genomic Research (TIGR) in Rockville, MD, the Stanford Genome Center in Palo Alto,
California, and the Wellcome Trust Sanger Institute in the United Kingdom. The lead
investigator, Malcolm Gardner of TIGR, co-authored the Nature paper with 44
researchers working in sites in the United States, the United Kingdom and Australia.
The genome sequence of P. falciparum
covers 22.8 million bases of DNA, split into 14 chromosomes. Within the genome, 5279 genes
have been identified. Only 733 of the 5279 genes have been identified as enzymes.
Most of the biosynthetic pathways appear
to be localized in the apicoplast, a structure within the cell that has its own genome and
is similar to the chloroplasts of plants and algae. Although this genome encodes only 57
proteins, it is calculated that around 10 per cent of the proteins encoded by the nucleus
may be destined for this structure. The genome sequence also identifies the molecules
within the apicoplast that are the targets of several existing drugs, like antibiotics and
may open many potential drug targets.
The parasite appears to lack some key
biosynthetic pathways; for example, making or interconverting amino acids, making purines,
two protein components of ATP synthase (a mitochondrial ATP-producing enzyme) and
components of a conventional NADH dehydrogenase complex. It has also been proposed that
the regulation of protein levels is controlled through mRNA processing and translation,
rather than by gene transcription and this may be another potential drug target.
Regions near the ends of each chromosome
of the P. falciparum genome are interesting. The genes residing here encode
surface proteins or antigens that are sometimes recognized by the human immune system to
stimulate immune response. But exchange of material between chromosome ends gives the
parasite a great capacity for change and thereby immune evasion.
The Anopheles genome:
France was the first country to undertake
a large-scale sequencing program for the Anopheles genome. As early as 1998, Genoscope and
the Unit of Insect Biochemistry and Molecular Biology at the Institut Pasteur sequenced
and analyzed the ends of 12,000 large genome fragments from a "bank" set up by
Frank Collins at the University of Notre-Dame in the United States. Subsequent work of
sequencing the 14,000 genes of the Anopheles was a collective effort of the Anopheles
Gambiae Genome Consortium (AGGC) set up in March 2001 and was performed at Genoscope with
funds from the French government and at the Celera Genomics Group in Rockville, MD. The
strategy selected for the sequencing of the Anopheles' 280 million bases (Megabases - Mb)
was the "whole genome shotgun" method. The institutions contributing to the
effort included NIAID, the Special Program of Research on Tropical Diseases of the World
Health Organization; European Molecular Biology Laboratory of Germany; the Institute of
Molecular Biology and Biotechnology in Crete; the Institut Pasteur in Paris; TIGR; and the
universities of Iowa, Rome, Notre Dame, and Texas A&M. Celera's Robert A. Holt heads a
list of 123 authors on the Science paper, submitted on behalf of the AGGC.
Information from the Anopheles genome is giving researchers new insights into mosquito
physiology and behavior. Identification of the mosquito genes involved in the parasite's
transmission, resistance to insecticides, the mosquito's olfactory system, its immunity,
its ability to digest blood, its choice of humans as a blood source etc should eventually
lead to the development of ways to control the transmission of malaria by this vector.
Some fifty genes are known to be related to the mosquito's resistance to insecticides and
four of these have been identified.
Comparisons between the genome sequence
of Drosophila fruit fly (obtained in year 2000) and that of the mosquito have helped in
the discovery of the mosquito's equivalent gene mechanism capable of blocking development
of the parasite in the mosquito. This could be a potential target for preventing the
development of the parasite.
The mosquito's smell receptors, are
probably implicated in the female Anopheles' attraction to humans and a whole range of
genes associated with smell has been discovered. This will considerably facilitate
research on these receptors, and will probably result in the development of new repellents
or new attractants. Furthermore, the possibility of a better understanding of the
metabolism of the mosquito's resistance to current insecticides could allow a more
ecological use of these products.
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