‘Memory gene’ discovery could aid in treatment of Alzheimer’s and other diseases
Recent studies have shown that genes play a role in human memory capacity. Some studies have even identified genes that might significantly affect it, but the success of these studies was largely dependent on preexisting knowledge about the genes in question. Researchers have generally lacked the technology needed to screen the large numbers of genes required to identify those associated with memory performance.
Investigators with the Translational Genomics Institute in Phoenix, the University of Zurich in Switzerland, the Mayo Clinic in Scottsdale, Ariz., and the University of Arizona, Phoenix, analyzed 500,000 DNA markers simultaneously, and identified a gene — called Kibra — that is associated with memory. Understanding this gene could go a long way toward explaining how memory works in humans.
Dietrich A. Stephan, director of the neurogenomics division at Translational Genomics and one of the primary authors of the study, noted that, ultimately, this knowledge could contribute to developing therapies for treating memory loss in patients suffering from Alzheimer’s orParkinson’s disease. “If we truly understand the normal process of human memory,” he explained, “then we can tweak it in these disorders to improve memory function.”
The researchers identified the memory gene using the 500K Mendel array set made by Affymetrix Inc. of Santa Clara, Calif. The instrument encompasses two microarrays that genotype more than 500,000 single-nucleotide polymorphisms (SNPs) in a single experiment. Thus, scientists can use it to screen the entire genome for genes associated with specific diseases or drug responses— or with traits such as performance on memory tasks.
The 500K array set is one of the more recent products the company has developed for genetic analysis. To produce the arrays, the company employs a novel photolithographic manufacturing process that combines semiconductor fabrication techniques, solid phase chemistry and robotics. The process begins with coating of a quartz wafer to inhibit coupling with the nucleotides of the DNA probe being created. Lithographic masks are then used to block or allow light onto particular areas on the wafer surface. The latter “deprotects” those areas from coupling when the surface is next flooded with a solution containing adenine, thymine, cytosine or guanine.
The coupled nucleotide is itself protected from the light, so the entire process can be repeated. The microarray is thus created iteratively, by synthesizing the probes through numerous cycles of deprotection and coupling.
“At the time, it was the only platform with sufficient density to do the study,” Stephan said. Since the researchers submitted the paper, in September 2005, to the journal Science, Illumina Inc. of San Diego has introduced a system with similar capabilities. Stephan noted, however, that the two instruments are still the only high-density genotyping platforms available for whole-genome association studies — adding that they are comparable in terms of features and performance.
Using a high-density genotyping platform, with more than 500,000 single nucleotide polymorphisms, investigators have identified a gene associated with memory performance. Understanding this gene could contribute to the development of therapies targeting disorders with a memory loss component.
In the Oct. 20 issue of Science, the researchers reported how the array provided genetic blueprints of study participants by allowing examination of 500,000 DNA markers simultaneously. The investigators compared the blueprints of those who performed well on verbal memory tasks with those who did not, and they noted the genetic variations that were prevalent in one group but not the other. They identified Kibra as a genetic player in human memory in 351 study participants. They found that carriers of Kibra exhibited 24 percent better free recall performance 5 minutes after word presentation than noncarriers, and 19 percent better free recall performance 24 hours after word presentation. Further trials demonstrated similar results, confirming the association of Kibra with human memory performance.
The researchers also explored the relationship between Kibra and human memory-associated neuronal activity using functional MRI with both carriers and noncarriers of the gene. They predicted that the noncarriers would display more activation than carriers in memory-related regions of the brain to achieve the same level of memory performance. The functional MRI experiments bore this out. The noncarriers showed significantly increased activation in those regions during memory retrieval tasks.
Stephan and colleagues have had almost a year and a half to work with the memory gene reported in the Science paper. In that time, they have identified drugs that target the gene and have begun preclinical studies of the drugs in disorders with a memory loss component. They are currently preparing several publications describing their findings.
As for the high-density genotyping platforms, Stephan noted that both Affymetrix and Illumina are planning to launch one-million-SNP instruments in the coming year. “That’s really hitting the sweet spot of where you want to be with these genome scanning tools,” he said. Affymetrix announced its new platform in early January: a single-chip array featuring 500,000 SNPs from the original two-chip 500K array, as well as nearly 500,000 additional probes that researchers can use to measure other genetic differences — including, for example, copy number variation.
The company’s Andrew Noble noted that the new array was developed in collaboration with the Broad Institute of Harvard University and MIT in Cambridge, Mass., as part of an effort to better identify and understand the genetic variations associated with diseases such as autism, autoimmunity, bipolar disorder, cancer, diabetes and heart disease. Currently, investigators with the Autism Consortium and the Broad Institute are using it in a comprehensive study of the genetics of autism.
The new array — the SNP 5.0 — will be available commercially by the end of the first quarter. The company is working with Broad investigators to develop additional data analysis software for the instrument, as well as to incorporate additional SNPs for the next generation of the array, which the company plans to launch later in the year.
Both the 500K array and the SNP 5.0 use data from the International HapMap Project: a collaboration of investigators and funding agencies working to build a public resource to help researchers identify genes associated with specific diseases or drug responses. SNPs from the 500K array are publicly available, Noble said, while researchers can analyze data acquired with either of the instruments in the context of the emerging HapMap.
Contact: Dietrich A. Stephan, Translational Genomics Institute; e-mail: email@example.com; Andrew Noble, Affymetrix Inc.; phone: +1 888-362-2447.
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