DNA variation uncovered; may control gene activity

PULLMAN – Researchers at Washington State University have identified a new class of DNA sequence variation in gene promoter regions that could help control the activity of genes.

The novel variations, dubbed “multiple nucleotide length polymorphisms,” or MNLPs, altered transcription of the genes they were associated with as much as 11-fold. The presence of such sequences could provide organisms with a way to modify their gene expression without altering the actual coding sequence of genes.

“It’s a new feature in genome study,” said lead author Zhihua Jiang, assistant professor in the Department of Animal Sciences. “Obviously it makes our genome more complicated in terms of function, and also in terms of evolution. We need to figure out what process led to the formation of this type of mutation.”

The report is published in the May issue of the scientific journal Genetics.

The MNLPs were discovered within the promoter regions of two genes that belong to the CRH, or corticotropin-releasing hormone family of peptides.
CRH modulates cardiovascular and gastrointestinal function and is involved in control of motor activity, among other roles.

The genes examined in the current study, which code for the hormone urocortin 3 and its receptor, CRHR2, came from cattle. The researchers found two MNLPs associated with each of the two genes; each copy of a gene had a single MNLP in its promoter region. MNLPs with the urocortin 3 gene were either five or 10 bases long, and MNLPs with the CRHR2 gene were 12 or
18 bases long. All the MNLPs were nonrepetitive and did not resemble each other. DNA sequences flanking the MNLPs were identical in each case.

In the current study, each MNLP reduced transcription by at least 1.7-fold and as much as 11-fold. Nancy Magnuson, professor in the School of Molecular Biosciences and study co-author, said that as more MNLPs are identified, some might be found to boost transcription. The mechanism by which MNLPs modify gene activity is not yet known; a leading hypothesis is that the short sequences change a promoter’s ability to bind proteins that regulate transcription.

MNLPs join the list of sequence variations that have been discovered in recent years, including SNPs (single nucleotide polymorphisms), INDELs (insertions or deletions of various lengths), and STRs (short tandem repeats). Medical researchers have explored the possibility of using these genetic polymorphisms in tests to screen individuals for susceptibility to various diseases including cancer.

This study is the first report of MNLP sequences from any organism. Jiang said currently-understood mutational mechanisms do not explain how they arose. He said he plans to look for MNLPs in other ruminant species, such as sheep and deer, to try to determine whether the sequences he’s found so far are related via a common ancestor sequence.

Financial support for the work was provided by the National Institutes of Health and the Merial Ltd. Animal Genomics Research Fund.

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