Evolutionary relationships between miRNA genes and their activity

BMC Genomics Evolutionary relationships between miRNA genes and their activity Yan Zhu Geir Skogerb 0 Qianqian Ning 1 Zhen Wang 1 Biqing Li 1 Shuang Yang Hong Sun 0 1 Yixue Li 0 1 0 Shanghai Center for Bioinformation Technology , Shanghai 200235 , China 1 Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai 200031 , China Background: The emergence of vertebrates is characterized by a strong increase in miRNA families. MicroRNAs interact broadly with many transcripts, and the evolution of such a system is intriguing. However, evolutionary questions concerning the origin of miRNA genes and their subsequent evolution remain unexplained. Results: In order to systematically understand the evolutionary relationship between miRNAs gene and their function, we classified human known miRNAs into eight groups based on their evolutionary ages estimated by maximum parsimony method. New miRNA genes with new functional sequences accumulated more dynamically in vertebrates than that observed in Drosophila. Different levels of evolutionary selection were observed over miRNA gene sequences with different time of origin. Most genic miRNAs differ from their host genes in time of origin, there is no particular relationship between the age of a miRNA and the age of its host genes, genic miRNAs are mostly younger than the corresponding host genes. MicroRNAs originated over different time-scales are often predicted/verified to target the same or overlapping sets of genes, opening the possibility of substantial functional redundancy among miRNAs of different ages. Higher degree of tissue specificity and lower expression level was found in young miRNAs. Conclusions: Our data showed that compared with protein coding genes, miRNA genes are more dynamic in terms of emergence and decay. Evolution patterns are quite different between miRNAs of different ages. MicroRNAs activity is under tight control with well-regulated expression increased and targeting decreased over time. Our work calls attention to the study of miRNA activity with a consideration of their origin time. - Background MicroRNAs are small endogenously expressed singlestranded RNAs, that regulate gene expression post transcriptionally and shape diverse cellular pathways [1-3]. MicroRNA families have continuously been added to the vertebrate lineage, and when integrated into a genome, a miRNA gene is only rarely lost [4-6]. MicroRNAs date back to the earliest bilaterians, and specific miRNA families operating in specific cells and tissues of both primitive protostomes and primitive deuterostomes have been identified [7], suggesting very early metazoan origin [8]. The emergence of vertebrates is characterized by a strong increase in miRNA families, and correlates with the increase in vertebrate morphological complexity [6,9]. Almost all nodes within Metazoa are characterized by addition of miRNA families that are rarely lost in the descendants [10]. The miRNA family acquisition rate at the emergence of vertebrates have been estimated to 0.9-2.7 families per Myr, and many of these 41 miRNA families show tissue or cell type specific expression, miRNAs may thus lie at the basis of cell and tissue specification in vertebrates [11]. Acquisition of miRNA genes apparently speed up with evolution of organismal complexity. MicroRNAs effects on target gene expression can be roughly classified into two types: tuning and buffering. Tuning relates to effects on the target gene expression level, whereas buffering relates to repression of expressional variation [12]. It is speculated that the dual functions of miRNAs could represent two stages in miRNA evolution, miRNA initially acting by reducing variance in gene expression, and only gradually taking on tuning of the expressional level over time [12]. Apparently, miRNAs of varying age are not equal, as older miRNAs are commonly more highly and broadly expressed than younger miRNAs [13], and knockout of an older miRNA results in a more severe phenotype than knockout of a younger miRNA [14,15]. Liang et. al divided miRNAs into groups based on their expression level, the sequence divergence in the mature regions of miRNAs with higher expression level is significantly lower than that in the remaining regions, and miRNAs with very low expression tend to turn over quickly in evolution [16]. It has been suggested that lowly expressed miRNAs may occasionally be selected and included into the regulatory network [13,17]. If newly emerged miRNAs find targets, their regulation would probably be detrimental [18], however, they may also serve as substrate for natural selection of beneficial target interactions [13,19,20], and newly activated miRNAs may be part of general mechanism by which speciation occurs [18]. Based on the observations that intraspecific variation decrease through evolutionary time, that miRNA decrease stochastic expressional variation, and that miRNA numbers increase through evolutionary time and with morphological complexity, it has been suggested that miRNA are at the basis of the canalization development required for increased organismal complexity [21]. Simulation of selection in presence or absence of miRNA regulation suggested that evolution of population did not take place in absence of miRNA genes [21]. By constraining the gene expression, miRNAs renders phenotypic traits governed by (spatiotemporal) gene expression more heritable, and thereby evolvable [22]. The evolution of miRNA system is intriguing, however, evolutionary questions concerning the origin of miRNA genes and their subsequent evolution remain unexplained. In order to systematically understand the evolutionary relationship between miRNAs gene and their function, in this work, we focused specifically on human miRNAs for their diversified activities during evolution. Results MicroRNA emergence and evolution To further study the evolution of human miRNAs, we divided the human known miRNA genes (miRBase v.15) into eight age groups according to their time of origin as estimated by the maximum parsimony method [23] (Additional file 1: Figure S1). During the first 150 Myrs of vertebrate evolution, the lineage leading to human accumulated less new miRNA genes, compared to ~250 miRNA genes during the last 50 Myrs of evolution along the same lineage (Additional file 1: Figure S2A). In order to estimate the evolutionary turnover rates for human miRNA genes, we applied a method from Lu et al. [24]. This showed that the miRNA birth rate in vertebrates is more than 40 new miRNA genes per Myr, which is about three times higher than that observed in Drosophila (12/Myr; [24]). A large proportion of acquired miRNA genes degenerate rapidly (Additional file 1: Figure S2B), and only around five percent of new vertebrate miRNAs survived in the long run of evolution (100 Myrs). This is nonetheless twice the net increase in miRNA genes found in Drosophila, in which (...truncated)