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DNA-RNA mismatch

There may be widespread, nonrandom differences between DNA sequences and their corresponding RNA transcripts in human cells

By | May 19, 2011

The central dogma in molecular biology states that DNA is copied into RNA, one nucleotide at a time. But it turns out that copy may be a lot less exact than scientists previously thought.
linkurl:iStockphoto.com;iStockphoto.com
A new paper, published today in linkurl:Science,;http://www.sciencexpress.org identifies widespread differences between DNA sequences and their corresponding RNA transcripts in human cells, and demonstrates that these differences result in proteins that do not precisely match the genes that encode them. The finding challenges the assumption that RNA is a perfect one-to-one match to its corresponding DNA sequence and may open the door to an unexplored area of variation in the human genome. "Most people assume the information in DNA is faithfully transferred to RNA and then the RNA is translated into proteins," said linkurl:Jin Billy Li,;http://lilab.stanford.edu/index.html a geneticist at Stanford University who was not involved in the research. If additional research confirms the results, "the central dogma will have to be revised. You can't assume the DNA [code] is transferred to RNA without any changes." linkurl:Vivian Cheung;http://genomics.med.upenn.edu/vcheung/index.html and colleagues at the University of Pennsylvania School of Medicine used next generation sequencing tools to sequence RNA from B cells of 27 individuals who were part of the International HapMap and 1000 Genomes Projects. They then compared those RNA sequences to their corresponding genes in the DNA. Cheung was surprised to find more than 10,000 sites where RNA bases did not match the corresponding DNA sequence. "We didn't really expect anything, and then we saw a lot of differences," says Cheung. Her initial reaction was to blame the differences on technical errors or artifacts, so the team performed numerous experiments to rule out a technical fluke. In the process, they noticed that many of the differences were not random. Time and again, a single RNA base was always changed in the exact same way from cell to cell. A site that should be AA might be edited to AC, for example, and every individual would either have the original AA or the edited AC, but no other possible modifications, such as AG or AT. Then the team looked at the resulting proteins and found that they reflected the edited RNA sequences, meaning the DNA did not directly encode its protein products. In some cases, the changes were minor, but not all. In one, a RNA variant led to the loss of a stop codon, and the protein was 55 amino acids longer than would have been encoded by the DNA. Past research has identified several post-transcriptional mechanisms that result in RNA editing, but these mechanisms account for less than half of the differences uncovered in the new study, the authors write. Cheung and the team do not yet know the mechanisms that might be causing the systematic RNA modifications, nor how the resulting protein changes might affect protein function. Still, "this is one source of genomic variation we didn't know about," says Cheung. "We always think of DNA sequences as the causes or reasons why some of us are more or less prone to certain diseases, but we certainly didn?t think RNA sequences as being the possible cause. And now we have all these forms of proteins we didn?t know existed." But additional research needs to be done to confirm the findings, said Li, who is performing similar studies in his lab. "Mapping these differences is not a trivial thing," he cautioned. Many genes exist two or more times in the human genome, and researchers could mistakenly map an RNA sequence to the wrong region. "If that happens, you may miscall that as RNA editing," he said. Li, M., et al., "Widespread RNA and DNA sequence differences in the human transcriptome," Science, doi: 10.1126/science.1207018, 2011.
**__Related stories:__***linkurl:RNA repeats protect DNA;http://www.the-scientist.com/blog/display/57135/
[4th February 2010] *linkurl:DNA repeats hold RNA starts;http://www.the-scientist.com/blog/display/55625/
[20th April 2009] *linkurl:The Human Genome: RNA Machine;http://www.the-scientist.com/2007/10/1/61/1/
[1st October 2007]

Comments

Avatar of: anonymous poster

anonymous poster

Posts: 1

May 20, 2011

It has been known for a while that there are other forms of epimutations besides aberrant DNA methylation changes, such as posttranscriptional mutations. The news is therefore not surprising in itself. The interesting aspect is the scale. \nThe findings do not invalidate the central dogma in any way and saying so rests on erroneous assumptions. The dogma was always a stipulation about the direction of the information flow, and a negative one at that (saying that the information in the protein sequence could not be used for de novo synthesis of DNA, RNA or Proteins with equivalent information content). The existence of large scale posttranscriptional mutations/variation does not invalidate this directional flow. Prions are therefore not challenging the letter of the central dogma as such (configurational rather than sequential self-replication), but rather its spirit.
Avatar of: anonymous poster

anonymous poster

Posts: 3

May 20, 2011

My biggest question is as to how widespread this effect will be. B cells in particular undergo a number of unique DNA rearrangements that are not seen in other cells, presumably to increase the number of unique antibodies that our immune system can produce. What if extensive RNA editing is merely another strategy to increase heterogeneity? Most cells do not require, and likely actively avoid, such levels of variation, making it possible that this is not a generalized phenomenon outside of the immune system.
Avatar of: DENNIS HOLLENBERG

DENNIS HOLLENBERG

Posts: 26

May 24, 2011

We do not know the exact set of mechanisms causing this, or any other transcription-phase modification (or post-transcription mods, for that matter). I say the mechanism likely involves operations performed by trans or _preexisting_ ribosomal-protein complexes. Regardless, Cheung and colleagues performed masterfully.\n\nThe central dogma states that cellular genetic information flows exclusively from DNA to RNA to proteins. Cheung et al. show that RNA modification information can come from some place else.\n\nKeep in mind that DNA isn't "smart." DNA is but a substrate of molecular information harvested and transformed by the cell's molecular networks in often custom ways suited to the local part of the cell's microenvironment.\n\nThe problem with the glib central dogma is that it answers a question that is wrong headed. That is, the central dogma assumes that the cell is a centrally controlled machine. It is not. In fact, modifications occur generally, universally. Therefore, the central dogma is irrelevant and has always been so. Get real, folks.
Avatar of: anonymous poster

anonymous poster

Posts: 2

May 26, 2011

Dogma states that information flows from DNA to RNA to protein. It does not exclude that this flow can be context dependent, or even subject to feedback. Transcriptional, post-Transcriptional, Translational, and post-Translational modifications to not change the fact that the core information is in the DNA. Even the information to create the modification systems are typically of genomic origin. It will be interesting to learn the mechanism behind the differences found in these new experiments, and where it is employed besides lymphocytes.\n\nBaxter Zappa

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