Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
A comparison of the Human Genome Project's public and private sequences has turned up a number of duplicated segments that may contain disease-related genes. The study also provides a valuable resource for generating a finished version of the human genome sequence, independently published in the year 2000 by the public international consortium and the private data generated by Celera Genomics, of Rockville, Md.
The analysis confronting both sources appears in Science dated Aug. 9, 2002, titled: "Recent segmental duplications in the human genome." Its senior author is molecular geneticist Evan Eichler, an assistant professor of genetics at Case Western University School of Medicine in Cleveland.
"The main finding," he said, "would be the identification of regions that share a large degree of sequence identity, the finding of sequences that are virtually identical that exist in more than one region of the genome.
"The reason that's important is that these regions of the genome are associated with disease at higher frequencies than most areas. We identified in our study about 170 such regions, and we know that only 24 of these are strongly associated with disease. So we now have the potential to go back and look at these regions, and see if there's association with other complex genetic diseases.
"The other thing that we know about these regions," he continued, "is that they change very rapidly during primate evolution. You've heard people say that the chimp and the human genome are 99 percent identical. In these areas of the genome, the structures of these regions change very, very rapidly. So you have these specific areas, which may be involved in significant changes in the structural organization of our genome, and therefore may have phenotypic consequences that may be important in helping to distinguish the chimp vs. the human.
"The primary potential application of our analysis," Eichler pointed out, "is in terms of diagnosis. We have the ability now to go back to patient material. For example, a relatively large proportion of the population is born with severe to moderate to mild mental retardation. And it's clear that these children from the age of 5 have some type of mental deficit. Most of these kids, once they're identified, go through testing. That means a blood sample is drawn and sent to a clinical laboratory. It looks for obvious aberrations, such as chromosome rearrangement, like trisomy 21 with Down's syndrome. Or they may do a molecular test for the common forms of disease, such as fragile X syndrome.
"In 20 percent of the cases," Eichler continued, "a diagnosis comes back to the family telling them that their child has this mental defect because of this genetic phenomenon. In 80 percent of the cases, no result is sent to the parents, so they are no better off than when they started the long process of diagnosis. What we want to do," Eichler went on, "is go back to these genomic sites that we know are unstable over very short periods of evolutionary time. Knowing there could be a molecular basis for rearrangement in a specific area, we would look at those kids who have been diagnosed as having no explanation for their disorder. We want to see if these specific areas are hot spots' - rearranged, deleted or duplicated.
"Additional diagnoses would try to identify genes associated with autism, perhaps even such neurological disorders as schizophrenia, bipolar depression and so on. So I think there's a significant challenge that this may lead to the identification of new, previously unrecognized syndromes because we didn't understand the architecture of our human genome - making us distinct from other primates, for example.
"If I were a betting man," Eichler concluded, "I would wager that molecular diagnosis will be a very important innovation."
Inner-Ear Hair Cells Turn Over Every 48 Hours, Reports A Previously Unknown Finding
Stereocilia, the minute bundles of hairs in the inner ear that make hearing possible, replace themselves every second day. These mechanosensitive organelles of the inner ear's sensory hair cells are supported by a rigid dense core of actin filaments. Like the needle on a phonograph, the hairs convert vibrations detected by the eardrum into electric nerve signals. A Brief Communication in Nature dated Aug. 22, 2002, is titled: "Rapid renewal of auditory hair bundles: The recovery time after noise-induced hearing loss is in step with a molecular treadmill." Its authors are at NIH's National Institute on Deafness and Other Communication Disorders in Bethesda, Md.
Their paper reports that these microhairs are being continuously regenerated from tip to base, and are totally replaced after about 48 hours - roughly how long it takes to recover from temporary hearing loss. The time-frame coincidence suggests that damaged stereocilia are responsible for the temporary deafness. Alternatively, the authors propose, their findings could help explain how newborns acquire hearing, and how some permanent hearing abnormalities occur.
Inhaled Anthrax Spores Destroy Macrophages In Lungs Before They Can Alert Defenses
During inhalation anthrax - the most lethal form of the infection - Bacillus anthracis spores are engulfed by the immune system's scavenger macrophages, which are resident in the lungs. However, the spores survive phagocytosis, germinate within the macrophages, and the pathogens eventually reach the bloodstream. In this late stage of bacteremia, the infected individual succumbs to fatal systemic shock.
A Science Express report, released Aug. 29, 2002, bears the title: "Macrophage apoptosis by anthrax lethal factor . . ." Its authors describe how the pathogen paralyzes its host's immune defenses by subverting the macrophage, which initially serves as a lying-in chamber that nurses the germinating spores into the instrument of its own destruction.
Typically, the initially activated macrophages secrete chemical signals that alert the rest of the immune system to the pathogen's invasion. But the bacteria evade detection by killing the macrophages before they can sound their alarm. "Lethal factor" in the spores induces the macrophages to commit cell suicide.