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The Hox cluster microRNA miR-615: a case study of intronic microRNA evolution.

Quah S, Holland PW - Evodevo (2015)

Bottom Line: The miR-615 gene evolved within the intron of Hoxc5 in the ancestor of placental mammals.Using miR-615 as a case study, we propose a model by which a functional miRNA can emerge within an intron gradually, by selection on secondary structure followed by evolution of an independent miRNA promoter.The location within a Hox gene intron is of particular interest as the miRNA is specific to placental mammals, is co-expressed with its host gene and may share complementary functions.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS UK.

ABSTRACT

Background: Introns represent a potentially rich source of existing transcription for the evolution of novel microRNAs (miRNAs). Within the Hox gene clusters, a miRNA gene, miR-615, is located within the intron of the Hoxc5 gene. This miRNA has a restricted phylogenetic distribution, providing an opportunity to examine the origin and evolution of a new miRNA within the intron of a developmentally-important homeobox gene.

Results: Alignment and structural analyses show that the sequence is highly conserved across eutherian mammals and absent in non-mammalian tetrapods. Marsupials possess a similar sequence which we predict will not be efficiently processed as a miRNA. Our analyses suggest that transcription of HOXC5 in humans is accompanied by expression of miR-615 in all cases, but that the miRNA can also be transcribed independently of its host gene through the use of an intragenic promoter. We present scenarios for the evolution of miR-615 through intronic exaptation, and speculate on the acquisition of independent transcriptional regulation. Target prediction and transcriptomic analyses suggest that the dominant product of miR-615 is involved in the regulation of growth and a range of developmental processes.

Conclusions: The miR-615 gene evolved within the intron of Hoxc5 in the ancestor of placental mammals. Using miR-615 as a case study, we propose a model by which a functional miRNA can emerge within an intron gradually, by selection on secondary structure followed by evolution of an independent miRNA promoter. The location within a Hox gene intron is of particular interest as the miRNA is specific to placental mammals, is co-expressed with its host gene and may share complementary functions.

No MeSH data available.


Related in: MedlinePlus

Predicted secondary structures for example miR-615 precursors in marsupials and the four major eutherian clades. Minimum free energies for all species tested are listed in Additional file 4
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Fig3: Predicted secondary structures for example miR-615 precursors in marsupials and the four major eutherian clades. Minimum free energies for all species tested are listed in Additional file 4

Mentions: Having established that all therian mammals (eutherians and marsupials) studied possess a sequence similar to the annotated mir-615 genes of human and mouse (Figs. 1, 2), we analysed these sequences for fulfilment of published structural and energetic criteria used in miRNA annotation. This analysis reveals that all the eutherian mir-615 orthologues are likely to produce functional pre-miR-615. Analysis of aligned eutherian pre-miR-615 structures using RNAz is strongly supportive of the existence of a conserved fold (Additional file 3: Supplement S3B). However, in the two marsupials analysed minimum folding energy (MFE) for the putative pre-miR-615 homologues (−39.40 kcal/mol in M. eugenii and −42.60 kcal/mol in S. harrisii) are higher than those observed for all eutherian miR-615 precursors (mean MFE −59.40 kcal/mol). Both marsupial sequences also have large internal loops, bulges and mismatches which are likely to preclude efficient entry into the miRNA pathway (Fig. 3). These predicted structures also differ between M. eugenii and S. harrisii, suggesting a lack of selection on the secondary structure of this region in marsupials. It is therefore likely that marsupials lack the ability to generate mature miR-615.Fig. 3


The Hox cluster microRNA miR-615: a case study of intronic microRNA evolution.

Quah S, Holland PW - Evodevo (2015)

Predicted secondary structures for example miR-615 precursors in marsupials and the four major eutherian clades. Minimum free energies for all species tested are listed in Additional file 4
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4597612&req=5

Fig3: Predicted secondary structures for example miR-615 precursors in marsupials and the four major eutherian clades. Minimum free energies for all species tested are listed in Additional file 4
Mentions: Having established that all therian mammals (eutherians and marsupials) studied possess a sequence similar to the annotated mir-615 genes of human and mouse (Figs. 1, 2), we analysed these sequences for fulfilment of published structural and energetic criteria used in miRNA annotation. This analysis reveals that all the eutherian mir-615 orthologues are likely to produce functional pre-miR-615. Analysis of aligned eutherian pre-miR-615 structures using RNAz is strongly supportive of the existence of a conserved fold (Additional file 3: Supplement S3B). However, in the two marsupials analysed minimum folding energy (MFE) for the putative pre-miR-615 homologues (−39.40 kcal/mol in M. eugenii and −42.60 kcal/mol in S. harrisii) are higher than those observed for all eutherian miR-615 precursors (mean MFE −59.40 kcal/mol). Both marsupial sequences also have large internal loops, bulges and mismatches which are likely to preclude efficient entry into the miRNA pathway (Fig. 3). These predicted structures also differ between M. eugenii and S. harrisii, suggesting a lack of selection on the secondary structure of this region in marsupials. It is therefore likely that marsupials lack the ability to generate mature miR-615.Fig. 3

Bottom Line: The miR-615 gene evolved within the intron of Hoxc5 in the ancestor of placental mammals.Using miR-615 as a case study, we propose a model by which a functional miRNA can emerge within an intron gradually, by selection on secondary structure followed by evolution of an independent miRNA promoter.The location within a Hox gene intron is of particular interest as the miRNA is specific to placental mammals, is co-expressed with its host gene and may share complementary functions.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Oxford, South Parks Road, Oxford, OX1 3PS UK.

ABSTRACT

Background: Introns represent a potentially rich source of existing transcription for the evolution of novel microRNAs (miRNAs). Within the Hox gene clusters, a miRNA gene, miR-615, is located within the intron of the Hoxc5 gene. This miRNA has a restricted phylogenetic distribution, providing an opportunity to examine the origin and evolution of a new miRNA within the intron of a developmentally-important homeobox gene.

Results: Alignment and structural analyses show that the sequence is highly conserved across eutherian mammals and absent in non-mammalian tetrapods. Marsupials possess a similar sequence which we predict will not be efficiently processed as a miRNA. Our analyses suggest that transcription of HOXC5 in humans is accompanied by expression of miR-615 in all cases, but that the miRNA can also be transcribed independently of its host gene through the use of an intragenic promoter. We present scenarios for the evolution of miR-615 through intronic exaptation, and speculate on the acquisition of independent transcriptional regulation. Target prediction and transcriptomic analyses suggest that the dominant product of miR-615 is involved in the regulation of growth and a range of developmental processes.

Conclusions: The miR-615 gene evolved within the intron of Hoxc5 in the ancestor of placental mammals. Using miR-615 as a case study, we propose a model by which a functional miRNA can emerge within an intron gradually, by selection on secondary structure followed by evolution of an independent miRNA promoter. The location within a Hox gene intron is of particular interest as the miRNA is specific to placental mammals, is co-expressed with its host gene and may share complementary functions.

No MeSH data available.


Related in: MedlinePlus