Genomic differences between individuals can change the physical organization of RNA transcripts

July 2, 2014, Agency for Science, Technology and Research (A*STAR), Singapore
Genomic differences between individuals can change the physical organization of RNA transcripts
Single-nucleotide differences in genomic sequence between two individuals, such as the substitution of guanine (G) with adenine (A), can considerably alter the structure of the resulting mRNA transcript. Credit: Genome Institute of Singapore

The information contained within a messenger RNA (mRNA) transcript goes beyond the protein recipe embedded in its sequence. mRNAs consist of single strands of nucleotides that can pair with each other in the same way as double-stranded DNA molecules. The resulting 'secondary structures' help determine when and how the encoded protein gets produced.

Researchers led by Yue Wan of the A*STAR Genome Institute of Singapore and Howard Chang of Stanford University in the United States have applied a powerful experimental technique to build a detailed map of secondary structures for the entire human mRNA 'transcriptome'.

Their Parallel Analysis of RNA Structure (PARS) method entails isolating the total mRNA content of a biological sample, then treating it with two different enzymes that selectively cut single- or double-stranded RNA segments. By using sequencing technology to map these cut sites, the researchers could chart the secondary structure of each mRNA transcript.

The analysis uncovered some interesting general features of mRNA structure. For example, protein-coding regions had less structure than noncoding regulatory sequences, particularly in segments involved in splicing—an enzymatic process that expands the number of proteins encoded by a single transcript. Additionally, nearly 10 per cent of the mRNAs the team examined assumed multiple secondary structure arrangements, suggesting that 'switching' between conformations plays an important regulatory role.

The researchers also investigated instances where mRNA structure is affected by differences in the genomic DNA sequence from which it was transcribed. "There is extensive genetic variation between individuals," explains Wan. "To understand the extent to which this causes structural alterations in humans, we performed a genome-wide analysis in a family of three individuals." This showed that seemingly minor differences can have a considerable impact: roughly 15 per cent of the single-nucleotide sequence variations between individuals caused structural changes in an mRNA (see image).

Although other researchers predicted that genome sequence differences would have such an effect, Wan's findings represent the first direct demonstration of the extent of this phenomenon. "We identified over 1,900 nucleotide variants that cause structural changes in the human transcriptome—far more than anybody else has discovered previously," he says.

In several instances, the researchers found evidence that these variant-associated changes may impact gene regulation, including protein production, and therefore contribute to certain disease states. "This work was done on healthy individuals, but our findings suggest that some mutations may cause disease by altering gene regulation," says Wan. "Future work could compare diseased with normal tissues to identify and characterize -changing mutations."

Explore further: New mechanism in the regulation of human genes

More information: Wan, Y., Qu, K., Zhang, Q. C., Flynn, R. A., Manor, O. et al. "Landscape and variation of RNA secondary structure across the human transcriptome." Nature 505, 706–709 (2014). dx.doi.org/10.1038/nature12946

Related Stories

New mechanism in the regulation of human genes

July 14, 2011
Scientists at the Technical University of Munich and the Helmholtz Zentrum Muenchen and along with their colleagues from the European Molecular Biology Laboratory (EMBL) in Heidelberg and the Centre for Genomic Regulation ...

A protein complex for the long haul

November 18, 2013
A multiprotein complex called TREX plays a key role in expression of the genetic information. Moreover, as a new study demonstrates – the longer the gene, the greater the need for TREX function.

Recommended for you

Peers' genes may help friends stay in school, new study finds

January 18, 2018
While there's scientific evidence to suggest that your genes have something to do with how far you'll go in school, new research by a team from Stanford and elsewhere says the DNA of your classmates also plays a role.

A centuries-old math equation used to solve a modern-day genetics challenge

January 18, 2018
Researchers developed a new mathematical tool to validate and improve methods used by medical professionals to interpret results from clinical genetic tests. The work was published this month in Genetics in Medicine.

Can mice really mirror humans when it comes to cancer?

January 18, 2018
A new Michigan State University study is helping to answer a pressing question among scientists of just how close mice are to people when it comes to researching cancer.

Group recreates DNA of man who died in 1827 despite having no body to work with

January 16, 2018
An international team of researchers led by a group with deCODE Genetics, a biopharmaceutical company in Iceland, has partly recreated the DNA of a man who died in 1827, despite having no body to take tissue samples from. ...

Epigenetics study helps focus search for autism risk factors

January 16, 2018
Scientists have long tried to pin down the causes of autism spectrum disorder. Recent studies have expanded the search for genetic links from identifying genes toward epigenetics, the study of factors that control gene expression ...

The surprising role of gene architecture in cell fate decisions

January 16, 2018
Scientists read the code of life—the genome—as a sequence of letters, but now researchers have also started exploring its three-dimensional organisation. In a paper published in Nature Genetics, an interdisciplinary research ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.