Research Notes

An international group of researchers recently provided a glimpse of how disease shapes evolution in its work on G6PD (glucose-6-phosphate dehydrogenase) deficiency, an X-linked, hemopathologic trait that confers resistance to malaria (www.sciencemag.org/cgi/expresspdf/1061573v1.pdf). The study, involving genetics, evolution, anthropology, and more, offers insight into nature's response to malaria, which kills 2 million annually. As with sickle cell, G6PD deficiency correlates to a reduced risk of contracting malaria, but at the possible price of developing anemias. Andrew Clark, a Pennsylvania State University biology professor, developed a forward-in-time statistical model incorporating linkage disequilibrium, microsatellite data, and the selection rate to estimate the alleles' age. The A-allele, typical throughout sub-Saharan Africa, arose within the past 3,840 to 11,760 years, which correlates to historic and archaeological evidence according to the group, which includes collaborators from Tunisia, Rome, and South Africa. It also bolsters hypotheses that tie the spread of highly endemic malaria to the advent of slash-and-burn agriculture or other climatic changes, which created an increase in sunlit pools and allowed for a population explosion. The group estimates that the Med allele, prevalent around the Mediterranean area, and India, to be between 1,600 and 6,640 years old, which is consistent with Greek and Egyptian texts. These report a surge in more severe types of malaria after 500 B.C. Researchers link the allele's rapid spread to migration or increased trade routes. Further research is needed to understand the mechanisms by which G6DP deficiency protects against malaria, says primary author Sarah Tishkoff, an assistant biology professor at the University of Maryland.

By better understanding the biological effects of drug use, researchers hope to find ways to stymie addiction. A recent study revealing the neurological footprint of just one dose of cocaine suggests one such clue (M.A. Ungless et al., "Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons," Nature, 411:583-7 May 31, 2001). Scientists at the University of California, San Francisco, and Stanford University found that cocaine induces long-term potentiation (LTP) in dopaminergic neurons in mice. University of Chicago researchers had previously shown in vitro that nicotine induces LTP, the protracted enhancement of the electrical charge in the membrane of a postsynaptic neuron (H.D. Mansvelder, D.S. McGehee, "Long-term potentiation of excitatory inputs to brain reward areas by nicotine," Neuron, 27: 349-57, Aug. 2000). But the recent study reports the first demonstrated in vivo link between drug addiction and LTP, a long studied phenomenon related to learning and memory. More importantly, investigators found that cocaine stimulated LTP for about a week. "What we think is that during this week of LTP produced by cocaine, the brain might be vulnerable to relapse and have an increased craving to further cocaine use," says Antonello Bonci, an assistant professor of neurology at UCSF. Bonci and his colleagues are now investigating the LTP duration that results from repeated weekly administrations of cocaine. Such experiments, which mimic "recreational" drug use in people, will suggest whether the collective effect of cocaine doses causes a more permanent LTP effect. "The idea is if we can block that LTP," says Bonci, "we can inhibit this effect and basically close this window of vulnerability."

Researchers are challenging the long-held notion that chromatin regulates transcription by limiting access of transcription factors to DNA. David Gross, biochemistry and molecular biology professor at Louisiana State University Health Sciences Center, and graduate student Edward Sekinger have begun to pick apart the theory that the Silent Information Regulatory (SIR) complex--which has been connected to aging--incorporates a shield-like structure physically limiting access of the activators and general transcription factors to genes (E.A. Sekinger, D.S. Gross, "Silenced Chromatin Is Permissive to Activator Binding and PIC Recruitment," Cell 105:403-14, May 4, 2001). Applying chromatin immunoprecipitation to yeast cells that were engineered to repress the heat-shock protein gene (hsp82), they found that three initiation components--heat shock factor, TATA binding protein, and RNA Polymerase II--bound to the promoter of hsp82, itself tightly bound in SIR-generated heterochromatin. Intriguingly, they found a hyperphosphorylated version of Polymerase II (ready for transcription) also present at the silenced promoter. A second yeast gene, HMRa1, a natural target of SIR repression, showed a similar association with general transcription factors. Gross says this suggests that the specialized chromatin structure silences gene expression, "not by excluding the binding but by permitting [factors] to bind and then gumming up the machinery once everything's in place." Gross and Sekinger also provide evidence for a separate silencing mechanism that works on inducible factors, like heat shock factor, much the way scientists had always believed: by structurally blocking their binding. Gross says that much more research is needed to change the current dogma on chromatin-mediated regulation as this mechanism has only been identified in yeast.