Genome complexity: the role of miRNA's (Introduction)

by David Turell , Wednesday, December 07, 2016, 19:19 (2689 days ago) @ David Turell

The role of miRNA is vast in modifying gene transcription:

http://phys.org/news/2016-12-atlas-rna-universe.html

In the last few years, small snippets of RNA, which may have played a key role in the planet's earliest flickering of life, have been uncovered and examined in great detail. Their discovery, first in the tiny soil-dwelling nematode worm C. elegans and shortly thereafter, across the web of life, marks a revolution in biology, with broad implications in the fight against nearly every known disease.

These abbreviated RNA fragments, known as microRNA (miRNA) are composed of just 18-22 nucleotides. They are too short to code for proteins, (in the manner of longer messenger RNA or mRNA strands). Instead, they act as a subtle and extremely sophisticated network of gene regulators.

To accomplish this, miRNAs find complementary sections of mRNA targets and bind with a specific location known as the 3'UTR (for UnTranslated Region). After binding to the UTR, the miRNA inactivates mRNA, interfering with its translation to protein.

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Over the course of evolution, higher species have become heavily invaded by miRNA, which have undergone radical expansion in vertebrates, while the number of genes has remained stable. Astonishingly, worms, flies, and humans all have roughly 20,000 protein coding genes, though humans have far more miRNA than simpler species. Mangone insists this intriguing puzzle begs for a convincing explanation.

"What we found is that these miRNAs started parasitizing cells because they needed to target and regulate more gene expression, modulating entire pathways not just single genes," Mangone says.

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These tiny strips of RNA, many with very similar nucleotide sequences, form miRNA families, capable of targeting disparate gene pathways. While these miRNA families were originally thought to provide redundancy and robustness in gene regulation, the new study suggests a different explanation for miRNA abundance and proliferation in higher species.

The research findings show that miRNA not only target specific genes but expand their network of action through minor mutations in specific portions of their sequence, which Mangone named "evolutionary hotspots." This allows particular miRNA family members to extend their range of modulating activity while maintaining a common set of core targets.

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The results of the study are thought-provoking and run counter to previously proposed ideas about the nature and function of miRNAs. The study explores miRNA families, finding that the mutations that give rise to them do not occur randomly, with respect to either sequence location or function. Rather, mutations occur in preferential regions—evolutionary hotspots—indicating the mutations are functional and maintained through evolution. Contrary to the common conception of single miRNAs regulating single genes, the study observed that each miRNA tends to control multiple members in the same regulatory pathways.

Finally, the study explores the specific sequence locations in miRNAs known as the seed regions, often assumed to be essential for binding with the 3'UTRs. "We show in this manuscript that there are a lot of targets that do not have the seed region, yet they are still targeted, suggesting that just the presence of the seed region in the 3' UTR doesn't correlate with the binding on the miRNA. There are other rules, but now we begin to understand the language that these miRNAs speak."

Comment: We don't know how this all works so far, but it is obvious that the layers of the genome are very deep and are the reason that 22,000 gens in humans can create all of our complexities. Not by chance!