Parasites reveal their adaptive genes

Why can malaria parasites get away with so much devastation across the globe and for thousands of years? Part of this answer lies in the parasite's ability to adapt and evolve to overcome the barriers put up by their hosts (e.g. immunity or the sickle gene) , or the difficulties of surviving in an unpredictable environment (e.g. no rain and therefore no mosquitoes to carry them to their next host!)

Scientists at KEMRI-Wellcome Trust in Kenya are trying to identify which of the parasite's genes allow them to change their behaviour to overcome these difficult situations. They have done this using the latest biotechnology - whole genome microarrays - to compare the expression of all the genes from parasite lines that differ in their adaptations. This technology allows the researchers to read off the expression levels of all 5500 of the parasite's genes on a single microscope slide by using fluorescent markers. Very red dots on the slide indicate that the parasite is expressing the gene a lot while blue dots indicate that it is expressing the gene just a little. By comparing the readout from parasites that have adapted to different environments (for example, to different levels of immunity in the host population they come from), they can then describe which genes are important in allowing the parasite to overcome these barriers.

To begin exploring these differences, scientists in Kilifi, Kenya, in collaboration with scientists in Singapore, compared the expression of genes in lines of parasites that had become adapted to the artificial world of the laboratory with expression levels in parasites taken from patients in the field. What they found was that the laboratory-adapted parasites were quite different in their gene expression patterns compared to those adapted to their natural environment in the field.

Parasites from the laboratory are different to parasites from the field.In  what respect did the laboratory parasites differ from field parasites? They differed mostly in genes that help the parasite do what it needs to do in its live host - feed, produce offpsring, and survive its enemy, the immune system.  Laboratory parasites do not need to do these things and so have been free to let these functions go.

But what was responsible for these differences? When the physical location of these adaptive genes on their chromosomes was examined more closely, it was found that their location corresponded broadly with the location of genes that differed in their copy number at the DNA sequence level (known as CNVs - Copy Number Variants) which are common in malaria parasites (as well as humans and many other oganisms). Thus genes showing variation at the expression level broadly coincided on the chromosomes with genes showing variation at the genetic level.

Field parasites have upregulated their genes that export proteins into and out of the host cell to help them surviveNone of this was a surprise because variation at the genetic (DNA) level is usually directly responsible for variation at the expression level. However, the surprise came when a closer look was taken at the exact location of the genes that varied in expression and those that varied in DNA copy number. It was found that genes situated right next to, but outside the CNVs, but which did not themselves vary in copy number at the genetic level, varied in their expression levels along with those genes inside the CNVs. This strongly suggests that the genes adjacent to CNVs were being regulated through mechanisms that somehow depended on the CNV, but were not directly due to genetic variation per se.  Such 'epigenetic' mechanisms  of gene regulation occur in many organisms.  By using this 'soft-wired' mechanism of regulating its gene expression, the parasite allows itself to adapt temporarily to its changing ennvironment  without paying the long-term cost of using a 'hard-wired' mechanism of genetic change such as gene deletion.

Genes just outside CNVs share expression patterns with those inside CNVs even though they do not vary at the genetic level.This principle may be best illustrated by the fact that 27 of the 31 parasite genes known to be up- or down-regulated to suit the pregnant woman, for which the malaria parasite has a particular predilection, are located in very close proximity to CNVs. By being able to alter the expression of such genes through epigenetic mechanisms without altering its genome, the parasite would be provided with just the adaptability it needs in the face of life's great unpredictables - the pregnant woman!

More information can be found by reading the full research paper by Mackinnon and colleagues or at the Mackinnon Group's web page, or by emailing mmackinnonkilifi [dot] kemri-wellcome [dot] org.