Not that we’re trying to downplay the magnitude of getting peeps on the moon, but when you consider the amount of gene regulation that can be packed into a confined miRNA-target interaction one small step for man seems kinda 40yr old hat. It’s no wonder that single base changes in miRNAs and/or their targets can really stir things up a bit.
Shortly after the concept that miRNA-target interactions were governed by a 5’ 6-7 nucleotide “seed” was planted in our heads, a dynamic trio of Johns Hopkins researchers showed us that a little variation on the 3’ end of miRNAs can go a long way too. So if a minor change in the seed sequence can tweak miRNA-target interactions, and subtle changes near the 3’ end of miRNAs send them off to different cellular zip codes, why haven’t we seen more work focused on the impact of SNPs in miRNA regulation? We’re not sure either, but we were glad to see some recent investigations make their way into PubMed.
A research team led by John Rossi and Steve Sommer at the City of Hope National Medical Center recently poked around X chromosomes of male patients diagnosed with schizophrenia or autism to track down cool miRNA phenomena (RNA July 17, 2009). When compared with controls, the patients had 24 SNPs in mature miRNA sequences or precursor regions of miRNA genes. Some variants caused defects in miRNA processing. One of these SNPs even changed the Drosha and Dicer cutting sites in miR934, generating a brand-new miRNA with altered strand selection for miRISC loading.
In a related paper, the researchers (plus some colleagues from the U of Washington and MEDomics) found that a subset of those SNPs is statistically unique to schizophrenia patients (PLoS One July 1, 2009). Some of the SNPs had undetermined or only small effects in assays, but Rossi says, “Even a small effect by a single miRNA on its native target, which can be >200 different mRNAs, could have a huge impact on neural development or neural physiology.”
But SNPs in miRNA genes may be just half of the equation. Rossi explains that his group is working on a point mutation in a miRNA target sequence that’s involved in breast cancer. And a recent paper by scientists at Brown University and the Boston U School of Public Health zeroes in on a let-7 miRNA binding-site SNP that is linked to reduced survival time for patients with oral cancers (Carcinogenesis April 20, 2009).
M. Eileen Dolan and colleagues at the U of Chicago put the two together and even added copy number variations (CNVs) to the mix (RNA Biology July 2009). Scanning the human genome for variations in miRNA genes and miRNA targets, they racked up 187 SNPs in pre-miRNAs and 497 SNPs in seed-matching UTRs of target genes. Also popping up in the analysis were CNVs that included pre-miRNA precursors and miRNA processing genes.
One hurdle for these researchers is that products currently on the market for SNP analysis are lacking, to say the least, when it comes to miRNAs. “They’re not geared towards miRNAs; they’re more geared towards coding sequences,” says Rossi. “So for this type of analysis, you almost have to just do massive sequencing.” Hear that tool companies? A whole new market has opened up for you!