ScienceDaily (June 1, 2010) — Genetic abnormalities are most often discussed in terms of differences so minuscule they are actually called "snips" -- changes in a single unit along the 3 billion that make up the entire string of human DNA.
Genetic variation on the order of thousands to hundreds of thousands of DNA's smallest pieces -- large swaths varying in length or location or even showing up in reverse order -- appeared 4,205 times in a comparison of DNA from just four people, according to a new study.
(Credit: iStockphoto/Andrey Prokhorov)
Variation on the order of thousands to hundreds of thousands of DNA's smallest pieces -- large swaths varying in length or location or even showing up in reverse order -- appeared 4,205 times in a comparison of DNA from just four people, according to a study published May 31 in the Proceedings of the National Academy of Sciences.
Those structural differences popped into clear view through computer analysis of more than 500 linear feet of DNA molecules analyzed by the powerful genome mapping system developed over nearly two decades by David C. Schwartz, professor of chemistry and genetics at UW-Madison.
"We probably have the most comprehensive view of the human genome ever," Schwartz says. "And the variation we're seeing in the human genome is something we've known was there and important for many years, but we haven't been able to fully study it."
To get a better picture of those structural variations, Schwartz and his team developed the Optical Mapping System, a wholly new type of genome analysis that directly examines millions of individual DNA molecules.
Common systems for analyzing genomes typically chop long DNA molecules into fragments less than a couple thousand base pairs long and multiply them en masse, like a copy machine, to develop a chemical profile of each piece.
Reading such small sections without seeing their place in the larger picture of DNA leaves out critical understanding. To make matters worse, interesting parts of the human genome are often found within DNA's trickiest stretches.
"Short pieces could really come from so many different locations," Teague says. "An enormous part of the genome is composed of repeating DNA, and important differences are often associated with areas that have a lot of repeated sections."
It's a problem inherent to the method that has irked Schwartz for a long time.
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High-resolution human genome structure by single-molecule analysis
Brian Teague a, Michael S. Waterman b, Steven Goldstein a, Konstantinos Potamousis a, Shiguo Zhou a,
Susan Reslewic a, Deepayan Sarkar c, Anton Valouev b, Christopher Churas a,Jeffrey M. Kidd d, Scott Kohn a, Rodney Runnheim a, Casey Lamers a, Dan Forrest a, Michael A. Newton c,e, Evan E. Eichler d,
Marijo Kent-First f, Urvashi Surti g, Miron Livny h, and David C. Schwartz a,1
-Author Affiliations
aThe Laboratory for Molecular and Computational Genomics, Department of Chemistry, Laboratory of Genetics and Biotechnology Center, University of Wisconsin, 425 Henry Mall, Madison, WI 53706-1580;
bDepartment of Biological Sciences, University of Southern California, 1050 Childs Way, Los Angeles, CA 90089-2910;
cDepartment of Statistics, University of Wisconsin, 1300 University Avenue, Madison, WI 53706-1510;
dDepartment of Genome Sciences, University of Washington, 1705 NE Pacific Street, Seattle, WA 98195-5065;
eDepartment of Biostatistics and Medical Informatics, University of Wisconsin, 1300 University Avenue, Madison, WI 53706-1510;
fDepartment of Animal Science, Department of Biological Sciences, Mississippi State University, 130 Harned Hall, Lee Boulevard, Mississippi State, MS 39762-9698;
gDepartment of Pathology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213-2536; and
hDepartment of Computer Sciences, University of Wisconsin, 1210 West Dayton Street, Madison, WI 53706-1685
Edited* by David E. Housman, Massachusetts Institute of Technology, Cambridge, MA, and approved May 6, 2010 (received for review December 17, 2009)
Abstract
Variation in genome structure is an important source of human genetic polymorphism: It affects a large proportion of the genome and has a variety of phenotypic consequences relevant to health and disease. In spite of this, human genome structure variation is incompletely characterized due to a lack of approaches for discovering a broad range of structural variants in a global, comprehensive fashion. We addressed this gap with Optical Mapping, a high-throughput, high-resolution single-molecule system for studying genome structure. We used Optical Mapping to create genome-wide restriction maps of a complete hydatidiform mole and three lymphoblast-derived cell lines, and we validated the approach by demonstrating a strong concordance with existing methods. We also describe thousands of new variants with sizes ranging from kb to Mb.
structural variation copy number variation optical mapping single-molecule genomics genome assembly
Footnotes
1To whom correspondence should be addressed. E-mail:dcschwartz@wisc.edu.
Author contributions: B.T., M.S.W., S.G., S.R., D.S., A.V., and D.C.S. designed research; B.T., K.P., S.R., C.L., and M.K.-F. performed research; B.T., M.S.W., S.G., K.P., D.S., A.V., C.C., J.M.K., S.K., R.R., D.F., M.A.N., E.E.E., M.K.-F., U.S., and M.L. contributed new reagents/analytic tools; B.T., M.S.W., S.G., K.P., S.Z., S.R., D.S., A.V., C.C., J.M.K., M.A.N., E.E.E., and D.C.S. analyzed data; and B.T., S.G., S.R., and D.C.S. wrote the paper.
The authors declare no conflict of interest.
*This Direct Submission article had a prearranged editor.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.0914638107/-/DCSupplemental.
Freely available online through the PNAS open access option.
Freely available online through the PNAS open access option.
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