A new tool to trace genetic susceptibility.Just like individual people, various mouse strains come in different sizes and colors, and with different predispositions to disease. Since more than 99% of human genes can be matched to analogous mouse genes that have similar functions, scientists often study mouse models to better understand human disease. It's already well known which strains of mice are genetically at greater risk for certain diseases. But what isn't so clear is which small genetic variations, or single-nucleotide polymorphisms (SNPs), lead to these differences.
SNPs aren't large mutations but normal variations of one letter of the genetic code. For example, a sequence that reads AATTCCG in one strain of mouse may show up as AATACCG in another. Now Scientists who study mice as models for human disease have a new tool to help them more quickly home in on the SNPs that matter when it comes to disease susceptibility. With the completion of the NIEHS-funded Resequencing and SNP SNP Scottish National Party
Noun 1. SNP - (genetics) genetic variation in a DNA sequence that occurs when a single nucleotide in a genome is altered; SNPs are usually considered to be point mutations that have been evolutionarily Discovery Project, announced in October 2006, researchers now have free access to a data set of 8.3. million SNPs housed on the National Center for Biotechnology Information The National Center for Biotechnology Information (NCBI) is part of the United States National Library of Medicine (NLM), a branch of the National Institutes of Health. The NCBI is located in Bethesda, Maryland and was founded in 1988. website at http://www.ncbi.nlm.nih.gov/SNP/.
Researchers at Perlegen Sciences, under contract to the National Toxicology Program National Toxicology Program Environment A program that conducts toxicologic tests on substances frequently found at the EPA's National Priorities List sites, which have the greatest potential for human exposure , resequenced the genomic DNA genomic DNA
The full complement of DNA contained in the genome of a cell or organism. of 15 genetically diverse research mouse strains by comparing the sequences to a reference mouse strain (the first mouse strain to have its DNA DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. completely sequenced to very high accuracy). Kelly Frazer, principal investigator Noun 1. principal investigator - the scientist in charge of an experiment or research project
scientist - a person with advanced knowledge of one or more sciences of the project and vice president of genomics at Perlegen Sciences, says, "We take these pieces of DNA and align them to that reference sequence, and we look for differences." To do that, the scientists used the same high-density oligonucleotide array technology that was used to discover common DNA variations in the human genome.
The completion of the project provides a powerful tool; many discoveries should come when scientists use it. "We're looking forward to researchers using these ... SNPs in comparative studies of the different mice strains that are physiologically and physically well characterized," Frazer says.
David Threadgill, an associate professor of genetics at the University of North Carolina at Chapel Hill The University of North Carolina at Chapel Hill is a public, coeducational, research university located in Chapel Hill, North Carolina, United States. Also known as The University of North Carolina, Carolina, North Carolina, or simply UNC , says the data set was critical in recent studies that revealed genes that may contribute to human susceptibility to liver damage from acetaminophen acetaminophen (əsēt'əmĭn`əfĭn), an analgesic and fever-reducing medicine similar in effect to aspirin. It is an active ingredient in many over-the-counter medicines, including Tylenol and Midol. . His work, currently under review for publication, was inspired by a paper published 5 July 2006 in JAMA JAMA
Journal of the American Medical Association showing that a subset of the study participants showed greater susceptibility to liver damage from taking recommended doses of acetaminophen. "However, clearly it's unethical to go in and treat thousands of individuals to try to find the underlying genetic causes of that," Threadgill says.
Instead, Threadgill and colleagues used the SNP maps of the 15 mouse strains to identify genetic variance between strains of mice that differed in liver toxicity due to acetaminophen. They then tested two candidate genes in a small human study. They found that variance in the two candidate genes correctly predicted the patients who showed high levels of serum markers of liver toxicity after taking the maximum recommended dose maximum recommended dose (MRD),
n the highest amount of an anesthetic agent that can be given safely and without complication to a patient while maintaining its efficacy. of acetaminophen for several days. "Without these detailed SNP maps, we would not have been able to have very quickly done that translational test, which we were able to do just in a matter of months," Threadgill says.
NIEHS NIEHS National Institute of Environmental Health Sciences (NIH, DHHS) director David Schwartz says the conclusion of the Resequencing and SNP Discovery Project represents a milestone that builds on fundamental accomplishments such as the 2003 completion of the human genome sequence. "This accomplishment provides the tools to discover genes in mice that play critical roles in the response to environmental toxicants and the development of disease," Schwartz says. "The environmentally responsive genes and the disease-related genes in mice are very likely to be important in human disease. This development can be used to identify those at risk, prevent the development of disease, and also identify promising new forms of treatment.