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RESEARCH BRIEFSStudy Writes 'Guidebook' to Chromosome 7An international team of 90 scientists, with 13 members from HMS, has published a comprehensive description of human chromosome 7, including hundreds of known and suspected disease genes. Led by Stephen Scherer and colleagues at the Hospital for Sick Children in Toronto, the Chromosome 7 Annotation Project gathered and meshed mountains of data, including the draft genome sequence released in 2001, additional sequence data, and every chromosome 7-related paper published in the scientific literature. The authors compiled a database that links the sequence and annotation (data on exons and introns, breakpoints, polymorphisms, and other points of interest) to a wealth of information on disease associations and comparative genomics. An appendix lists 367 known disease genes on chromosome 7, and the work suggests new candidate genes for autism and other developmental disorders.
The annotation project "is sort of like writing the guidebook" to the chromosome's raw DNA sequence, said Cynthia Morton, the William Lambert Richardson professor of obstetrics, gynecology, and reproductive biology and professor of pathology at HMS and Brigham and Women's Hospital. "We need to know where the genes are and what human diseases could be due to rearrangements, deletions, or mutations of those genes." Morton is director, and the other 12 HMS authors are members, of the Developmental Genome Anatomy Project (DGAP), a multi-institutional effort including researchers from BWH, Children's Hospital, and Massachusetts General Hospital. "Using patients who have chromosomal rearrangements and major congenital anomalies, we strive to use those breakpoints to find the genes that cause that developmental disorder," she said. DGAP studies abnormalities throughout the genome, and the leaders of the chromosome 7 project incorporated DGAP's findings for that chromosome. Among the chromosome 7 project's discoveries are 1,455 potential protein-coding genes and 20 "putative gene deserts," 500-plus-kilobase stretches of DNA lacking any known or predicted genes. Since these are conserved through evolution, they must have some yet unknown role. The publication is a landmark, but far from the end of the road for chromosome 7 research, the authors said. "A major challenge ahead will be to represent chromosome alterations, variants, and polymorphisms and their related phenotypes (or lack thereof) in an accessible way," the researchers write on the project's new website. "This is our first attempt to accomplish this and ... improvements will occur incrementally. The project will be considered a success when an equal number of molecular biologists, medical geneticists, and physicians utilize the information."
Alzheimer's Marker Revealed in EyeThe amyloid-beta protein that forms plaques in the brains of Alzheimer's disease patients also shows telltale patterns in the lenses of their eyes, a discovery that could lead to tests for diagnosing and monitoring the disease. The study, published in the April 12 Lancet, was led by investigators at Massachusetts General Hospital and the Medical School. "The formation of A-beta plaques in the brain and the development of cataracts in the lens are both examples of accumulated protein associated with age-related degenerative damage," said lead author Lee Goldstein, HMS assistant professor of psychiatry at MGH. "In addition, people with Down's syndrome, who develop Alzheimer's at an early age, are also prone to early-onset cataracts. But as far as we know, no one had investigated whether there might be any association between the pathology of Alzheimer's disease and age-related changes in the lens." The researchers used immunologic assays and mass spectrometry to look for evidence of A-beta in lens tissue from nine autopsied Alzheimer's patients and eight controls. In specimens from both groups, they found the protein in concentrations similar to those found in aged brain tissue samples. They also found A-beta in samples of aqueous humor taken from three non-Alzheimer's patients who were having cataracts removed. Most importantly, they found in Alzheimer's patients--but not controls--both cataracts and a distinctive pattern of cytoplasmic A-beta deposits in the outer, peripheral portion of the lenses. The lens does not clear protein deposits the way brain tissue does, and the researchers believe the protein deposits are the cause of the cataracts. "One of the most exciting aspects of this finding is the fact that these deposits are associated with a type of cataract seen rarely in the general population," known as equatorial supranuclear cataracts, said Leo Chylack Jr., HMS professor of ophthalmology at Brigham and Women's Hospital. "These cataracts do not block vision and can only be seen when the pupil is dilated widely, so they previously would not have been detected in Alzheimer's patients. If the association of these deposits with Alzheimer's holds up in future studies, it would be very simple to develop a noninvasive test of disease progression." Chylack and Ashley Bush, HMS associate professor of psychiatry at MGH, are co-senior authors of the Lancet report. An intensive project to develop such a test is under way.
Informatics System Simplifies Complex Image AnalysisIn the past, researchers interested in obtaining quantitative data from microscopic images had to enter data from images into spreadsheets by hand or grapple with image file formats unrecognizable to their analysis programs. The Open Microscopy Environment (OME), an image informatics system described in the April 4 Science, is designed to remedy much of that inconvenience. Authors of the report include HMS's Erik Brauner, head of Chemical and Biological Computing at the Institute for Chemistry and Cell Biology, and MIT's Peter Sorger. "The primary goal of OME is to provide open source tools that make it easy to automatically analyze microscopic images," said Brauner. OME does this by providing both a storage center for image data from virtually any microscope as well as a framework for its analysis. OME translates files from optical microscopes into an OME file type, which is capable of preserving the optical settings of the microscope when the image was taken, the experimental setup, sample number, fluorophore type, and even information related to the image that has been derived by analysis. OME also makes complex quantitative image analyses possible, which allows for hypothesis testing from what began as a raw image. It does this by feeding OME files into currently existing and popular analysis tools like Matlab, but also by linking several analysis programs together, allowing the results of one to be fed into another. "The goal is not to compete with [existing] programs for image manipulation, but to manage the data generated by them in a scientific setting and draw statistics from them, compare results, et cetera. The idea is to make outside modules as seamless as possible," Brauner said. "Although there are a lot of programs out there to detect boundaries or edges or backgrounds, there aren't many programs out there that will do something simple like count the number of cells or give the average nuclear area in a couple hundred cells in a picture," he added. "It turns out there is a way to chain together programs that will do this, but it's tough to do that on your own, and this is one of the problems OME is designed to address." --Jennifer Frazer |
