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CSHL Study Finds Gene Splicing Marks Genomic Landscape

NEW YORK (GenomeWeb News) – Genetic signals that govern gene splicing are under selective evolutionary pressure and are not the product of neutral evolution, new research suggests.
Researchers from the Cold Spring Harbor Laboratory and elsewhere used statistical analysis to investigate genetic patterns related to gene splicing. They found that these sequence asymmetries are not distributed randomly through the genome. Instead, exons, which code for mature RNA, and introns, which code for regions that are spliced out of RNA before translation, contain specific nucleotides at different frequencies — a disparity that seems to have arisen evolutionarily.
The research, which appeared online this week in the Proceedings of the National Academy of Sciences, underscores the functional importance of splicing regulators. It also demonstrates a method by which exons and introns are differentiated in the genome.
“Our results suggest that human genes have been optimized for exon and intron discrimination through an RNA landscape shaped during evolution,” senior author Michael Zhang, a computational genomics researcher at Cold Spring Harbor Laboratory, and his colleagues wrote in the paper.
“The systematic bias and the pattern of [splicing-regulatory element] distribution cannot be explained by a neutral evolution model, suggesting that human genes have been optimized during evolution for discrimination between exons and introns, among other potential functional constraints.”
Only a fraction of the human genome encodes proteins. The rest of the genome remains largely mysterious, though its function is slowly being unraveled. One way to find regions of functional importance is to look for regions that are under specific selective pressure.
In this paper, Zhang and his team did just that, looking for mutations related to gene splicing that were selected for in the genome. Specifically, they focused on strand asymmetries — unexpected differences between nucleotides in the two DNA strands.
First, the researchers looked for individual nucleotide strand asymmetry in five regions of human and mouse exon and intron sequences. Indeed, some nucleotides were favored in coding regions, while others were favored in non-coding regions. For instance, there were more T’s than A’s and more G’s than C’s in introns. Exons, on the other hand, had more A’s than T’s and only slightly more G’s than C’s.
Similarly, the researchers reported that the distribution of several established exonic splicing enhancers and exonic splicing silencers is different than the distribution of random genetic elements. The exonic splicing silencers were enriched in introns but relatively depleted in exons. Exonic splicing enhancers had the opposite pattern: these were enriched in exons and present at lower levels in introns.
The researchers argue that certain sequences may highlight regions that need to be removed. Without these, they speculated, genes may be improperly spliced.
“Taken together, the analyses of both ESSs and ESEs provide strong evidence that the distribution of [splicing regulatory elements] is selected to maximize splicing fidelity in both exons and introns, even for deep intronic sequences, which were assumed to be neutral,” the authors wrote.
Zhang and his team also demonstrated that they can apply their knowledge of strand-asymmetry patterns to predict new regions with roles in regulating gene splicing. They predicted thousands of previously unidentified regions that fit their splicing regulatory element profile and classified these as either exon-identity elements or intron-identity elements.
Though they noted that these need to be verified experimentally, the researchers emphasized the significance of their finding that multiple-exon genes — representing a third of the genome — are under selective pressure.
“Detecting non-coding sequences under functional selection is an important step to decode the genetic information in the genome,” the authors wrote. “The widespread selection is consistent with and provides further insight into the current understanding of mechanisms that confer splicing fidelity.”

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