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2017 ; 18
(1
): 672
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Ancient human miRNAs are more likely to have broad functions and disease
associations than young miRNAs
#MMPMID28859623
Patel VD
; Capra JA
BMC Genomics
2017[Aug]; 18
(1
): 672
PMID28859623
show ga
BACKGROUND: microRNAs (miRNAs) are essential to the regulation of gene expression
in eukaryotes, and improper expression of miRNAs contributes to hundreds of
diseases. Despite the essential functions of miRNAs, the evolutionary dynamics of
how they are integrated into existing gene regulatory and functional networks is
not well understood. Knowledge of the origin and evolutionary history a gene has
proven informative about its functions and disease associations; we hypothesize
that incorporating the evolutionary origins of miRNAs into analyses will help
resolve differences in their functional dynamics and how they influence disease.
RESULTS: We computed the phylogenetic age of miRNAs across 146 species and
quantified the relationship between human miRNA age and several functional
attributes. Older miRNAs are significantly more likely to be associated with
disease than younger miRNAs, and the number of associated diseases increases with
age. As has been observed for genes, the miRNAs associated with different
diseases have different age profiles. For example, human miRNAs implicated in
cancer are enriched for origins near the dawn of animal multicellularity.
Consistent with the increasing contribution of miRNAs to disease with age, older
miRNAs target more genes than younger miRNAs, and older miRNAs are expressed in
significantly more tissues. Furthermore, miRNAs of all ages exhibit a strong
preference to target older genes; 93% of validated miRNA gene targets were in
existence at the origin of the targeting miRNA. Finally, we find that human
miRNAs in evolutionarily related families are more similar in their targets and
expression profiles than unrelated miRNAs. CONCLUSIONS: Considering the
evolutionary origin and history of a miRNA provides useful context for the
analysis of its function. Consistent with recent work in Drosophila, our results
support a model in which miRNAs increase their expression and functional
regulatory interactions over evolutionary time, and thus older miRNAs have
increased potential to cause disease. We anticipate that these patterns hold
across mammalian species; however, comprehensively evaluating them will require
refining miRNA annotations across species and collecting functional data in
non-human systems.