Sequence relationships among C. elegans, D. melanogaster and human microRNAs highlight the extensive conservation of microRNAs in biology

Abstract

microRNAs act in a prevalent and conserved post-transcriptional gene regulatory mechanism that impacts development, homeostasis and disease, yet biological functions for the vast majority of miRNAs remain unknown. Given the power of invertebrate genetics to promote rapid evaluation of miRNA function, recently expanded miRNA identifications (miRBase 10.1), and the importance of assessing potential functional redundancies within and between species, we evaluated miRNA sequence relationships by 5' end match and overall homology criteria to compile a snapshot overview of miRNA families within the C. elegans and D. melanogaster genomes that includes their identified human counterparts. This compilation expands literature documentation of both the number of families and the number of family members, within and between nematode and fly models, and highlights sequences conserved between species pairs or among nematodes, flies and humans. Themes that emerge include the substantial potential for functional redundancy of miRNA sequences within species (84/139 C. elegans miRNAs and 70/152 D. melanogaster miRNAs share significant homology with other miRNAs encoded by their respective genomes), and the striking extent to which miRNAs are conserved across species--over half (73/139) C. elegans miRNAs share sequence homology with miRNAs encoded also in both fly and human genomes. This summary analysis of mature miRNA sequence relationships provides a quickly accessible resource that should facilitate functional and evolutionary analyses of miRNAs and miRNA families.

Figure 1. Clusters of mir genes in the C. elegans and D. melanogaster genomes.

35 of the 137 C. elegans mir genes (the 137 genes produce 139 miRNA forms) (A) and 60 of the 152 D. melanogaster mir genes (B) are situated within 2 Kb of each other on one of their chromosomes (6 chromosomes in C. elegans: Chr. I–V, Chr. X; 4 pairs of chromosomes in D. melanogaster: Chr. 2–4, X/Y). ∼63% clustered mir genes in the C. elegans genome and ∼38% in the D. melanogaster genome are related in sequence. Bounding boxes highlight clustered mir genes of conserved sequences at the 5′ end (ˆ) and/or over full length (#70 indicates ≥70% similarity) (see Tables 1, 2 and Datasets S1, S2, S4 and S5 for details). mir genes on the left or above chromosomes are found in the Watson strand whereas those on the right or below are located in the Crick strand. The physical centers of C. elegans chromosomes are indicated by “0”.

Figure 2. miRNAs of nematode and fly model organisms conserved across species (5′ and/or overall ≥70%).

73/139 C. elegans miRNAs share 5′ end identities and/or ≥70% homology over sequence with miRNAs both in fly and humans. 13 C. elegans miRNAs currently appear to have sequence-related miRNAs limited to C. elegans, 14 miRNAs are shared by nematodes and flies, and 3 miRNAs are shared by nematodes and humans. For Drosophila, 54/152 miRNAs have 5′ and/or ≥70% overall homology to nematode and human miRNAs. 15 D. melanogaster miRNAs have sequence-related sequences restricted to fly, 11 miRNAs appear present both in fly and nematodes and 29 in fly and humans. Names of family members cross species can be found in Tables 1– 6 and sequence alignments in supporting datasets and Figure S1. Human miRNAs that have family members only in human are not included. It should be noted that the Venn diagram is inclusive showing miRNAs that have 5′ and ≥70% overall conserved sequences as well as miRNAs with either 5′ or ≥70% overall conserved sequences. Thus, miRNA totals in the diagram sections do not necessarily match those stated in the main text referring only to 5′ sequence identity or only to ≥70% overall homology. Moreover, dme-miR-3, dme-miR-12 and dme-miR-318 are listed in both fly_nematode and fly_human groups but not in the fly_nematode_human group because their corresponding C. elegans and H. sapiens homologs are not cross related in sequence under our criteria. Similarly, dme-miR-3, dme-miR-12, dme-miR-263a and dme-miR-318 are included in both fly_nematode and fly_human groups but not in the fly_nematode_human group when only 5′ homology is considered (main text).