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New Data Point to Population, Gender Differences in isomiR Expression

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NEW YORK (GenomeWeb) – While recent advances in next-generation sequencing have established the existence of multiple mature microRNA species that arise from the same arm of a hairpin miRNA precursor, new data out of Thomas Jefferson University has revealed a new layer of complexity to this system by showing that these so-called isomiRs can vary depending on gender and population within the same cell type.

The findings, which appeared in Oncotarget, are "pointing us to directions we didn't consider before," suggesting that the current concept of the mature miRNA product may be too limited, Isidore Rigoutsos, director of TJU's Computational Medicine Center and senior author of the report, said.

Still, additional analysis in multiple cell types and tissues will be required to show that the study results are more than just a phenomenon limited to the lymphoblastoid cell lines (LCLs) tested in the experiments, he cautioned.

Though studied by many groups, the biological significance of isomiRs remains unclear. Investigations have by and large focused on either isomiRs of a single miRNA or on their expression patterns within a specific tissue, with systemic analysis hampered by the limited number of samples available.

As such, Rigoutsos and his colleagues took advantage of data from a recent deep sequencing study in LCLs of 452 healthy men and women from five different populations: Utah Residents with Northern and Western European ancestry; Finnish from Finland; British from England and Scotland; Toscani Italians; and Yoruban Africans from the city of Ibadan.

They analyzed all of the datasets and identified 194 miRNA precursor arms, each of which gave rise to one or more significantly expressed mature miRNAs for a total of 445 unique isomiRs.

Concerned that the miRNA product variability observed was the result of technical artifacts or random degeneration, the scientists studied isomiR expression in sequenced technical replicates where five samples — one from each population — were sequenced a total of seven times each.

"We used these replicates to determine the extent at which the expression of isomiRs remained consistent across datasets generated by the different sequencing centers," they wrote in Oncotarget. After normalization, they found that the isomiR profiles were "remarkably consistent" across the replicates.

Meanwhile, a review of their datasets showed that the primary sequences of identified isomiRs differed from known miRNAs in miRBase either at their 5' ends, their 3' ends, or both simultaneously. Argonaute PAR-CLIP data confirmed that many of the isomiRs associate with the Ago silencing complex, suggesting they have functional gene-silencing roles.

As the researchers had expected, the numbers and endpoint characteristics of the isomiRs were very similar within and across population groups, and the populations show extensive overlap in the identity of isomiRs present in each group, the TJU group wrote.

However, the expression of statistically significant isomiRs was not so consistent, and in some cases changed by as much as eight-fold between two populations. For example, two isomiRs from the 3p arm of miR-1304 are between 5.6 and 9.5 times more abundant in the Yoruban African group compared to the other four, while two isomiRs from the 3p arm of miR-143 were significantly more abundant in the Northern and Western European population than the other groups.

Even more striking were the differential expression profiles between men and women, even those of the same populations, Rigoutsos noted.

When the investigators focused only on the male members of each population, they found 76 unique isomiRs whose expression levels showed statistically significant population-dependent differences. Among the females of all five groups, 146 isomiR expression profiles were found to be population-dependent.

However, none of the isomiRs from miR-143-3p showed differential expression in any male-only population comparisons. Yet isomiRs from miR-1304-3p were more abundant in Yoruban Africans versus the other four populations in both male- and female-only comparisons.

Other examples of precursor arms that give rise to differentially expressed isomiRs include miR-34a-5p, which yielded less abundant isomiRs in Yoruban Africans versus the other groups in female-only comparisons; and miR-221-3p and miR-222-3p, both of which gave rise to isomiRs that were less abundant in Northern and Western Europeans compared with the other groups in female-versus-female comparisons.

Such data "make it evident that when comparing any two population groups there are many more isomiRs that are differentially expressed — and statistically significant — among females than are among males," the TJU researchers wrote in their paper. "Interestingly, and for all five populations, when we compared males vs. females within a population we did not find any isomiRs whose differential expression reached statistical significance."

To Rigoutsos, these findings are not likely to be limited to the populations or cell type examined in the current study, but in the absence of experimental data, this cannot be known for certain. "In fact, it is conceivable that additional factors define the exact isomiR population from a given precursor arm and it could well be the case that different expression rules govern a given arm across different cell types," he and his team concluded in their report.

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