Research Notes

Elusive "Pingelapese Blindness" Gene Identified Before there was Survivor, the hit summer TV show, there was Pingelapese blindness, a classic example of a population bottleneck. In 1775, a typhoon devastated Pengelap, a coral atoll in the Eastern Caroline Islands in Micronesia. Of the 20 survivors, one male passed along a recessive gene for achromatopsia, and four generations later, the condition began to appear, thanks to two centuries of isolation and inevitable inbreeding. In the condition, impaired signal transduction in cone cells leads to total colorblindness, decreased visual acuity, and intense sensitivity to sunlight. Today, frequency among the 3,000 islanders is 5 percent, compared to one in 50,000 to 100,000 individuals here. Researchers from the Johns Hopkins University School of Medicine have identified the causative gene as a cyclic GMP-gated cation channel that normally enables a cone cell to electrically respond to light (O.H. Sundin et al., "Genetic basis of total colourblindness among the Pingelapese islanders," Nature Genetics, 25:289-93, July 2000). The channel consists of two alpha subunits encoded by genes on chromosome 2 and two beta subunits thought to derive from counterparts in the cell membranes of rod cells, which provide black and white vision. Not so, the researchers found. Instead, the gene encoding a cone-specific beta subunit resides on chromosome 16. "After eight years of investigators looking for a cone homologue for the rod beta gene, it was generally believed that a separate gene did not exist, and that one of the many splice forms served this function. We scoured the databases for weak matches, then used radiation hybrids to map them. One testis cDNA mapped to the right place and turned out to be a splice variant of the gene," explains Hopkins geneticist Olof Sundin. An amino acid switch seems to be behind Pingelapese blindness. "A serine or an alanine is found at this position in all known alpha and beta subunit genes. Phenylalanine substitution places a much larger, hydrophobic amino acid at this position. It may interfere with packing of membrane helices next to the critical central pore," says Sundin. --Ricki Lewis Drosophila as Surrogate Mosquito The best disease treatments are usually those that cut off pathogenesis at the source. In the case of malaria, which annually kills one million and afflicts half a billion people worldwide, that means somehow targeting the disease-causing protozoan Plasmodium falciparum even as it grows inside its carrier, the disease-spreading mosquito. Unfortunately, because the mosquito is an intractable animal model, studying the mosquito-protozoan interaction isn't easy. Geneticists from the Whitehead Institute and from the National Institute of Allergy and Infectious Diseases (NIAID) reasoned that their best bet was to find a surrogate protozoan carrier. The well-characterized, easily manipulated fruit fly seemed the perfect choice. Drosophila, as they show in a recent paper, fulfills two major mosquito model criteria: the fly's immune system recognizes the parasite--they actually used a related protozoan called Plasmodium gallinaceum--and the parasite gets the nutrients that it needs from the fly (D. Schneider, M. Shahabuddin, "Malaria parasite development in a Drosophila model," Science, 288:2376-9, June 30, 2000). Investigators, therefore, may be able to gain insight both into the parasite's nutritional requirements (which could hint at weaknesses) and into how an insect immune system fights the pathogen. "People often use the fly as a model human," says lead author David Schneider, a Whitehead fellow. "So we thought using the fly as a model insect wasn't a big jump." He adds that there are some significant physiological differences between the two; most notably, the fly expresses a different set of genes in response to infection. If Drosophila tools and techniques can be aptly applied to studying Plasmodium, scientists might be able to develop a transmission-blocking vaccine, new drugs based on knowledge of the protozoa's nutritional needs, or even Plasmodium-resistant transgenic mosquitoes that, if proven ecologically safe, could be released into problem areas. --Eugene Russo DNA Caught Mid-Jump Researchers have a stake in understanding DNA transposition or "gene jumping" because it has the potential to remodel genomes. This phenomenon occurs with the help of enzymes called transposases, which cut a sequence of DNA out of a donor and incorporate the sequence into another piece of DNA, the target. For the first time, researchers have glimpsed the structure of a transposase-DNA complex at the stage after the DNA sequence has been excised from its donor (D.R. Davies et al., "Three-dimensional structure of the Tn5 synaptic complex transposition intermediate," Science, 289:77-85, July 7, 2000). William Reznikoff, professor of biochemistry at the University of Wisconsin, Madison, and Igor Goryshin, senior scientist in his lab, laid the groundwork for this research through several years of biochemical and genetic studies. Normally DNA transposition is rare, so they created hyperactive transposase mutants, which produced enough Tn5 transposase-DNA complex to do crystallography. Ivan Rayment, also a professor of biochemistry at the university, headed the crystallography effort, and then both groups participated in the structural analysis. Next, the groups aim to determine some of the structures that make up the other steps of the reaction. "One of the most important structures will be the free protein [Tn5], which is inactive. This may help us understand the conformational changes that activate the enzyme, allowing it to bind to the donor DNA," says Reznikoff. Because the architecture and active site of transposases and integrases, such as the HIV enzyme, are quite similar, Tn5 might act as a structural surrogate in the development of HIV integrase inhibitors, he adds. HIV uses an integrase to incorporate its genetic material into a host's genome. --Nadia S. Halim Neanderthals Aren't Us A multinational research team has strengthened the case against Neanderthals' having contributed to the modern human gene pool. They used whole-genome DNA hybridization experiments that complement as well as confirm earlier comparisons between Neanderthal and modern human mitochondrial (mt) DNA (M. Scholz et al., "Genomic differentiation of Neanderthals and anatomically modern man allows a fossil-DNA-based classification of morphologically indistinguishable hominid bones," American Journal of Human Genetics, 66:1927-32, June 2000). The researchers adapted Southern blotting to compare modern human genomic DNA to DNA from two Neanderthal bone samples, an approach faster and cheaper than mtDNA analysis. The samples were compared to probes made from chimp DNA, and as expected, both the Neanderthal and modern human samples differed from this control to about the same degree. The key differences arose between the two types of human DNA. "The hybridization experiments showed that Neanderthal and modern human DNA differs by a factor of more than two in hybridization intensity. This finding indicates that the composition of the genome as a whole may be different," says Lutz Bachmann, manager of the Pritzker Laboratory for Molecular Systematics and Evolution at Chicago's Field Museum and soon-to-be professor of molecular systematics at the University of Oslo. The genomic difference may lie in repeats, a hypothesis that emerged by a process of elimination. "We didn't expect mtDNA to account for differences in hybridization," he says. And Neanderthals and modern humans are too alike in coding sequences for single-copy genes to account for the difference in hybridization. "We have no idea how the Neanderthal genome was composed, but basically, we expect the differentiation (from modern humans) to be in the repetitive genome components. If so, one assumption is that Neanderthals and modern humans had different gene pools, and so they did not interbreed to an extent. This doesn't mean that it was impossible for them to have done so, but it is likely that they did not do it very much," Bachmann adds. The work may yield practical value in identifying whether a find is of Neanderthal or modern human origin. "Neanderthal skulls have been pretty well described, and we know the differences from modern skulls. But for postcranial skeletons and most bone fragments, we don't have any idea how to tell them apart, how to tell a Neanderthal from a modern human femur, for example. DNA hybridization can provide a diagnostic tool to figure out what type of bone you have, which can be quite useful in anthropology," says Lutz (M. Krings et al., "Neandertal DNA sequence and the origin of modern humans," Cell, 90:19-30, 1997; I.V. Ovchinnikov et al., "Molecular analysis of Neanderthal DNA from the northern Caucasus," Nature, 404:490-3, March 30, 2000). --Ricki Lewis

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Ricki Lewis

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July 2000

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