When cells reproduce, their DNA is copied – and mistakes are made. These mistakes, or mutations, range from changes in a single letter of the DNA sequence to drastic deletions, duplications or rearrangements of genetic code. The result is genomic variation, which is responsible for major distinctions between species – think flippers, legs and wings – as well as subtle differences within a species, such as eye color or blood type.
Scientists at the University of California–San Diego (UCSD) and Brown University have devised a new method for detecting one source of genomic variation, the “microinversion.” These mutations occur when short DNA sequences – anywhere from a few dozen to a few thousand base pairs of genetic code – break away from the chromosome and then reattach in the reverse direction. The result: A string of code that ought to read “ATTAGCCG” reads “GCCGATTA” instead. Microinversions have been linked to infertility and a rare form of muscular dystrophy.
Distinguishing microinversions from other types of mutations can be tricky, particularly when comparing DNA sequences of distantly related species. This task is now more reliable due to a new software program called InvChecker. Created by computer scientists at UCSD and Brown, and detailed online in the Proceedings of the National Academy of Sciences, the system allows scientists to compare the DNA sequences of different species and identify regions that include the same microinversions.
The software draws on the idea that microinversions are generally preserved during evolution and are much easier to spot when comparing three or more species. For example, if scientists see a microinversion when comparing the human and chimpanzee genomes, this similarity could be the result of chance. But if they see the same reversed sequence of DNA in the rat and rabbit genomes, it is more likely that the mutation is, indeed, shared.
“What we’ve created is a more accurate tool for detecting microinversions,” said Benjamin Raphael, an assistant professor of computer science at Brown and a member of the University’s Center for Computational Molecular Biology. “This software will be very useful for comparative genomics studies and help biologists better understand how genomes evolved over time.”
Work on InvChecker was spearheaded at UCSD. Mark Chaisson, a graduate student in UCSD’s Jacobs School of Engineering, was lead author of the journal article. Pavel Pevzner, a UCSD computer science and engineering professor, served as senior scientist on the project.
Chaisson, Pevzner and Raphael put the software to an ambitious test. They chose a small region of the mammalian genome, called the CFTR region, for study. The scientists chose the CFTR region because it is well studied and widely shared among mammals. They searched for microinversions in this region in the genomes of 15 mammals – from human and chimp to cow and dog to possum and hedgehog – and found that these mutations were found in all species and occur frequently.
The team then used the results to reconstruct an evolutionary tree showing the relationship between these species – a tree strikingly similar to ones created with much more extensive molecular or morphological information.
“What was amazing is that we could accurately trace the evolution of these species simply by studying tiny mutations in a very small region of the genome,” Raphael said. “This really shows that the method works.”
The team also used InvChecker to study the genetic differences between humans and chimpanzees. They discovered 167 new microinversions in humans and chimps, and they found that 80 percent of microinversions previously proposed for these species were actually different types of mutations.
The National Institutes of Health and the Burroughs Wellcome Fund supported the work.
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