New level of genetic diversity in human RNA sequences uncoveredMay 19, 2011
A detailed comparison of DNA and RNA in human cells has uncovered a surprising number of cases where the corresponding sequences are not, as has long been assumed, identical. The RNA-DNA differences generate proteins that do not precisely match the genes that encode them.
The finding, published May 19, 2011, in Science Express, suggests that unknown cellular processes are acting on RNA to generate a sequence that is not an exact replica of the DNA from which it is copied. Vivian Cheung, the Howard Hughes Medical Institute investigator who led the study, says the RNA-DNA differences, which were found in the 27 individuals whose genetic sequences were analyzed, are a previously unrecognized source of genetic diversity that should be taken into account in future studies.
Genes have long been considered the genetic blueprints for all of the proteins in a cell. To produce a protein, a gene's DNA sequence is copied, or transcribed, into RNA. That RNA copy specifies which amino acids will be strung together to build the corresponding protein. "The idea that RNA and protein sequences are nearly identical to the corresponding DNA sequences is strongly held and has not been questioned in the past," says Cheung, whose lab is at the University of Pennsylvania School of Medicine.
With recent advances in sequencing technology, however, it has become possible to perform the kind of analysis necessary to test that assumption. In their study, Cheung and her colleagues compared the sequences of DNA and RNA in B cells (a type of white blood cell) from 27 individuals. The DNA sequences they analyzed came from large, ongoing genomics projects, the International HapMap Project and the 1000 Genomes Project. They used high-throughput sequencing technology to sequence the RNA of B cells from the same individuals.
Within the sequences' protein-coding segments, they found 10,210 sites where RNA sequences were not the same as the corresponding DNA. They call these sites RNA-DNA differences, or RDDs. They found at least one RDD site in about 40 percent of genes, and many of these RDDs cause the cell to produce different protein sequences than would be expected based on the DNA. In the cells they studied, the sequences of thousands of proteins may be different from their corresponding DNA, the scientists say. "It is important to note that since these RDDs were found with just 27 individuals, they are common," Cheung points out.
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"Our study provides support for why large-scale data are important. Previously the focus was on DNA, now our results suggest that RNA sequences also need to be examined. Exploration of these data, when founded on fundamental biology, will lead to fruitful scientific discoveries."
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Read more here/Leia mais aqui: PhysOrg
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Published Online 19 May 2011
Science DOI: 10.1126/science.1207018
RESEARCH ARTICLE
Widespread RNA and DNA Sequence Differences in the Human Transcriptome
Mingyao Li1,*, Isabel X. Wang8,*, Yun Li6,7, Alan Bruzel8, Allison L. Richards4, Jonathan M. Toung5, and Vivian G. Cheung2,3,8,†
Author Affiliations
1Departments of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
2Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
3Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
4Cell and Molecular Biology Graduate Program, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
5Genomics and Computational Biology Graduate Program, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
6Departments of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
7Department of Biostatistics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
8Howard Hughes Medical Institute.
To whom correspondence should be addressed. E-mail: vcheung@mail.med.upenn.edu
* These authors contributed equally to this work.
ABSTRACT
The transmission of information from DNA to RNA is a critical process. We compared RNA sequences from human B cells of 27 individuals to the corresponding DNA sequences from the same individuals and uncovered more than 10,000 exonic sites where the RNA sequences do not match that of the DNA. All 12 possible categories of discordances were observed. These differences were nonrandom, as many sites were found in multiple individuals and in different cell types, including primary skin cells and brain tissues. Using mass spectrometry, we detected peptides that are translated from the discordant RNA sequences and thus do not correspond exactly to the DNA sequences. These widespread RNA-DNA differences in the human transcriptome provide a yet-unexplored aspect of genome variation.
Received for publication 3 March 2011.
Accepted for publication 10 May 2011.
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