The evolution of animal microRNA function

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The evolution of animal microRNA functionRyusuke Niwa and Frank J Slack

MicroRNAs (miRNAs) are a large class of small RNAs that

function as negative gene regulators in eukaryotes. Theyregulate diverse biological processes, and bioinformatics data

indicate that each miRNA cancontrol hundreds of gene targets,

underscoringthe potentialinfluence of miRNAs on almostevery

genetic pathway. In addition to the roles in ontogeny, recent

evidence has suggested the possibility that miRNAs have huge

impacts on animal phylogeny. The dramatically expanding

repertoire of miRNAs and their targets appears to be

associated with major body-plan innovations as well as the

emergence of phenotypic variation in closely related species.

Research in the area of miRNA phylogenetic conservation and

diversity suggests that miRNAs play important roles in animal

evolution, by driving phenotypic variation during development.

Addresses

Department of Molecular, Cellular and Developmental Biology,

KBT 936, Yale University, PO Box 208103, 266 Whitney Avenue,

New Haven, CT 06520, USA

Corresponding author: Slack, Frank J ( [email protected] )

Current Opinion in Genetics & Development 2007, 17:145–150

This review comes from a themed issue onChromosomes and expression mechanisms

Edited by Tom Misteli and Abby Demburg

Available online 20th February 2007

0959-437X/$ – see front matter# 2007 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.gde.2007.02.004

IntroductionA fundamental principle in molecular biology, the so-called ‘central dogma’, is that genes are generally protein-

coding and genetic output is almost entirely transacted by

proteins. With this view in mind, biologists have worked

on the premise that evolution should be characterized by

changes in genetic complexity that generate functionally

novel proteins. However, an implication from studies inthe past two decades is paradoxical: even though morpho-

logically complex animals such as vertebrates possess

tissues and organs that are lacking in phylogenetically

basal animals, both lower and higher organisms encode a

majority of the protein-coding gene families, such as

transcription factors and signal transduction molecules

[1,2,3]. Thus, the taxonomic distributions of protein-

coding genes do not correspond to the dramatic increase

in morphological complexity during animal evolution.

Therefore, an idea arose that gene expression in thecomplex metazoan genomes required an additional

level of regulation, such as by alternative splicing and

non-coding RNAs [1

,4].

Over the past few years, a new and surprisingly abundant

class of RNA regulatory genes known as microRNAs

(miRNAs) hasbeen foundto confer a novel layer of genetic

regulation in cells [5–10]. miRNAs comprise a large family

of 22-nucleotide single-stranded RNAs that silence gene

expression by binding to target mRNAs. miRNA–mRNA

binding usually involves strong base-pairing between the

50 endof a miRNA and its target complementary sequence

in the 30-untranslated region (30UTR) of an mRNA, while

additional base pairings can also contribute to the binding.

miRNA binding appears to result in translational repres-

sion and, in some cases, degradation of cognate mRNAs,causing partial or full silencing of the respective protein-

coding genes. We now know that hundreds of distinct

miRNA genes control a range of physiological processes in

almost all eukaryotes, including development, growth,

differentiation and metabolism [5–10]. miRNAs are cur-

rently estimated to comprise 1–5% of animal genes, mak-

ing them one of the most abundant classes of generegulators [5]. Thus, this discovery introduces a new set

of evolutionary mechanisms that has the potential to have

profoundly influenced phenotypic complexity and diver-

sity during animal phylogeny. In this brief review, we

summarize recent advance of our knowledge about how

the conservation and variety of miRNAs and miRNAtargets have evolved, and the potential roles of miRNAs

during animal evolution.

Evolution of miRNA families and theirexpression let-7 : a founder member of evolutionally conserved

miRNAs

The first example of an evolutionally conserved miRNA is

let-7, which was originally identified as an essential reg-

ulator of developmental timing in the nematode Caenor-

habditis elegans [11]. Expression of let-7 miRNA is

undetectable until the late larval stages in C. elegans, when

let-7 directs larval to adult cell fate transitions in manytissues. Soon after the discovery of C. elegans let-7, it was

demonstrated that let-7 belongs to a largergene family that

has been amazingly conserved across almost all groups of

bilaterally symmetrical animals (bilaterians; Figure 1)

[12,13]. Moreover, the temporal expression pattern of

let-7 also appears to be highly conserved in all organisms

examined. For example, let-7 in the fruit fly Drosophila

melanogaster is absentfrom embryonicand larvalstages and

first appears at the entry of metamorphosis [12]. In mollusc

and a polychaete annelids, let-7 miRNAs are detected inadults but not in larvae. Furthermore, in zebrafish and

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mouse, let-7 miRNAs are undetectable in embryos until a

time when adult body plans are conspicuous [12,14,15].

Not only is the let-7 miRNA sequence and temporal

regulation maintained across animal phyla but several

of the genes controlled by let-7 are also evolutionally

conserved [16,17]. Moreover, putative binding sites

for let-7 have been identified in the 3 0UTRs of the

let-7 gene target homologs across animal phyla. For

example, the murine and chick orthologs of C. elegans

lin-41 are also controlled by let-7-mediated downregula-

tion [14,18–20]. Another prominent example of an evo-

lutionarily conserved target of the let-7 family is the RAS

family of genes, which are well-known players in cancer

[21]. Lung tumor tissues concurrently display signifi-cantly reduced levels of let-7 and increased levels of

RAS protein relative to normal lung tissue, suggesting

a mechanism for let-7–mediated RAS regulation during

lung oncogenesis [22].

Curiously, let-7 RNA is not found in more basal metazo-

ans, including nonbilaterians such as ctenophores, cnidar-

ians and poriferans (sponges), and lower bilaterians such

as acoels (Figure 1) [12,13]. This implies that acquisition

of the let-7 gene was an essential step of evolution from

lower metazoan to a higher bilaterian. It is noteworthy

that these lower metazoans do not bear true organs, such

as gonads [13]. This observation supports an evolutionary

role for let-7 in higher bilaterians to repress hundreds of

target genes that are required for juvenile ontology and to

subsequently play a role in activating the terminal differ-

entiation of organs, tissues and specific cell types of

adults. Further elucidation of let-7 targets throughout

the coelmate groups will be crucial for understanding

the role of let-7 during animal evolution.

The expansion of the metazoan miRNA repertoireIn addition to let-7, some of the other identified miRNAs

are highly conserved during animal evolution in terms of

both primary sequences and their function [6,7,9]. For

example, mir-1 exhibits muscle-specific expression from

C. elegans to human, indicating that it operates during

muscle development throughout the animal kingdom

[23,24]. Consistent with this proposed function, mir-1 is

essential for maintaining muscle fiber integrity during

Drosophila development [25].

Recent studies using computational approaches have also

revealed several episodes of miRNA innovation that

correspond to major introductions of developmental com-

plexity during evolution. A large number of miRNA

families, including let-7 and mir-1, are acquired at a branch

from the basal metazoans to a common ancestor of ecdy-sozoans, lophotrochozoans and deuterostomes (Figure 1)

[3,26]. In addition, major miRNA innovations are

observed at the branches leading to the vertebrates and

to the placental mammals [26]. Consistent with this,

many vertebrate-specific miRNAs are expressed in

vertebrate-specific organs, including miR-126 in the bloodvessels and miR-206 in the somites [27,28]. Furthermore,

multiple unique miRNAs have emerged only in primates

as compared with other mammals such as rodents and

dogs (Figure 1). Among the 800 total primate miRNAs, at

least 336 are primate-specific miRNAs and are not found

in other mammals [29] (see also Update).

These observations support the hypothesis that lying

behind the origin of complexity of higher organisms, such

as vertebrates, is the dramatic expansion of the noncodingRNA inventory, including the absolute number of miR-

146 Chromosomes and expression mechanisms

Figure 1

Acquisitions of miRNAs in metazoan phylogeny. An abbreviated

phylogeny is modified from earlier studies [13,26,40]. Green lines

represent animal phyla that do not have let-7 miRNAs [13]. Majorinnovations of miRNA repertoires are represented by magenta

arrowheads, which are based on previous data [26,29]. A class of

approximately 20 miRNAs, including let-7 , is common to all bilateriansexcept acoels (a). The next innovation (b) is the addition of about 56 new

families of miRNAs at the branch leading to the vertebrates. A thirdmiRNA innovation (c) occurred at the branch leading to the placental

(eutherian) mammals, at which time about 40 new miRNA families were

acquired. Furthermore, a large number of primate-specific miRNAs are

also identified (d). Each of the nematode and arthropod lineages mightalso have evolved unique miRNA families.

Current Opinion in Genetics & Development 2007, 17:145–150 www.sciencedirect.com



NAs, rather than an increase in the protein-encodinginventory [1,4]. Moreover, a comparative genomic study

has argued that both flies and vertebrates have increased

their respective number ofcell types over geologic time in a

manner strikingly similar to the acquisition of their respect-

ive number of miRNAs [3

]. The increasing complexity of gene networks established over the course of animal phy-

logeny is probably due to miRNAs that regulate a growing

number of gene targets, thus driving animal evolution.

miRNA sequence conservation does not imply conservation of expressionMost miRNAs identified to date are expressed in a tissue-

specific manner [10]. Based on the high degree of miRNA

sequence conservation, it has been assumed that there is

also a high degree of expression conservation across

animal phyla. However, a recent study has warned against

this simplistic assumption [30]. Comparison of the

expression of 100 miRNAs in fish, chicken and mouse

has revealed that the timing and location of miRNA

expression is not strictly conserved. Even between two

closely related species, medaka and zebrafish, severalconserved miRNAs, such as miR-145 , miR-205 and

miR-454a, exhibit clear spatial expression differences

[30]. It is thus attractive to speculate that variations in

the expression of conserved miRNAs also play a role in

shaping the developmental and physiological differences

produced during animal evolution.

Evolution of miRNA target sites in 30UTRsequencesmiRNAs have a significant impact on the evolution of

30UTRsGiven that miRNA regulatory systems have a significant

influence on gene expression, many genes are probably

under evolutionary pressure to maintain or avoid miRNA

complementary sites in their 30UTRs [10,31]. For

example, genes whose expression patterns exhibit

a high degree of overlap with a particular miRNA tend

to lack target sites for that miRNA. In addition, broadlyand highly expressed housekeeping genes, such as

ribosomal-associated genes, seem to avoid miRNA

targeting by exclusion of target sites and by maintenance

of relatively short 30UTRs [32]. These data support a

concept of ‘antitargets’. These are genes expressed at

high levels in tissues where miRNAs are expressed, butwhich seem to avoid having sequences to which those

miRNAs could bind [32,33].

Target sequences of miRNAs fall into two categories:

conserved and non-conserved. Computer analyses have

shown that only one-tenth of these predicted target sites

are conserved across species [34,35]. This does not mean

that the non-conserved sites are not functional; reporter

gene analysis has shown comparable levels of repression

mediated by conserved or non-conserved sites [33].However, large-scale microarray analysis has revealed that

targets in these two categories are distinguished by theirgeneral tissue-specific expression patterns. Genes with

non-conserved target sites tend to be expressed in tissues

lacking the corresponding miRNA. By contrast, conserved

sites are found preferentially in genes that are co-

expressed with their miRNAs [33

]. It is proposed [10]that the interaction between miRNAs and their conserved

target sites is essential for cell-fate switches and is posi-

tively selected for during evolution. By contrast, non-

conserved miRNA target sequences may have neutral

fitness as long as the miRNAs that could bind to them

are not expressed in the same tissue [10]. Taken together,

the concepts of conserved targeting, non-conserved target-

ing and targeting avoidance are consistent with the idea

that miRNAs influence the evolution of most mRNAs.

miRNAs and phenotypic variations

Significant phenotypic variations may emerge by evolving

miRNA–mRNA 30UTR interactions. In some instances,

polymorphisms that affect miRNA–mRNA binding can

lead to disease states, whereas in other cases this results in

non-deleterious phenotypic changes.

Tourette’s syndrome is a genetic neuropsychiatric dis-

order. In some pedigrees, this disease is caused by a

frameshift loss-of-function mutation in an open reading

frame of SLITRK1 ( Slit- and Trk-like 1), which encodes a

single-pass transmembrane protein [36]. Patients in ot-

her pedigrees have a G-to-A single-base change that maps

to the 30UTR of the SLITRK1 gene. This change replaces

a G:U wobble base pair with an A:U Watson–Crick paring

in a miR-189 binding site (Figure 2). This mutation

stabilizes the interaction between the miR-189 and itsbinding site and, as a consequence, levels of SLITRK1

translation are reduced compared with those in normal

individuals [36].

Another interesting example of a miRNA involved in

phenotypic variation is the case of Texel sheep. Texel

sheep are renowned for their exceptionally well-developed muscles. A locus with a major effect on the

muscle mass has been mapped to an interval encompass-

ing the myostatin gene GDF8 [37]. Loss of function in

GDF8 causes strong musculature in mice, cattle and

humans [38]. Although no polymorphic differences have

been found in the protein-coding regions of GDF8 between Texel and control sheep, the Texel GDF8 gene

carries a G-to-A substitution in the 30UTR. This mutation

switches the GDF8 mRNA from an antitarget into a target

of miR-1 and miR-206 , which are highly expressed in

muscle (Figure 2), causing decreased GDF8 levels which,

in turn, leads to the musculature phenotype [37].

These studies clearly demonstrate that changes in

miRNA-based regulation can be expected to make

important contributions to phenotypic variation, suchas disease susceptibility in man, and to microevolution

The evolution of animal microRNA function Niwa and Slack 147




among closely related species. Researchers are currently

constructing a new database named Patrocles (http://

www.patrocles.org), which is a compilation of polymorph-isms that might affect the interaction between miRNAs

and their targets in different organisms [37].

Conclusions

Although the importance of miRNAs in animal ontogenyhas been rapidly elucidated, much less is known about the

phylogenetic aspects of miRNA functions. However,

studies in this field to date support the hypothesis that

dramatic expansions of the miRNA repertoire appear to

be associated with major body-plan innovations as well as

the emergence of phenotypic variation in closely related

species during animal evolution. Moreover, it is even

possible that we have underestimated the impact of

the miRNA regulatory system to animal evolution,

because new miRNAs and their targets are discovered

every day. Research in this area will undoubtedly provide

new insight into the underlying mechanisms of animal

phylogeny.

UpdateRecent work has revealed a large number of new miRNAs

in human and chimpanzee brains [41]. This work also

showed several interesting profiles for the newly ident-

ified miRNAs. Even though some miRNAs are not con-

served beyond primates, a subset of these species-specificmiRNAs is expanded in one species through duplication

events. Both this study and the previous one [29]

support the idea that a pool of such miRNAs contributes

to the diversity of developmental and cellular processes

and thus promotes the innovation of new miRNA-con-

taining regulatory pathways during evolution.

AcknowledgementsWe thank Atsuo Nishino, Mona Nolde and Sarah Roush for criticalreading of the manuscript. RN is supported by a fellowship from theInternational Human Frontier Science Program Research Organization.FJS is supported by a grant from the National Science Foundation.


Figure 2

Two examples of miRNA target polymorphisms and the resulting phenotypic variations: Tourette’s syndrome (upper) [ 36] and Texel sheep

(lower) [37]. Each arrowhead indicates a site showing nucleotide polymorphism between normal and mutant. Boxes represent 6-bp seed

pairing regions, in which a perfect match between miRNAs and their target is crucial for the miRNA–mRNA interaction in many cases [34]. In bothcases of Tourette’s syndrome and Texel, the G-to-A substitutions make stronger interactions between the miRNAs and their targets, leading to

increased inhibition of protein synthesis from the targets and causing the relevant phenotypic variations.


http://www.patrocles.org/






References and recommended readingPapers of particular interest, published within the period of review,have been highlighted as:

of special interest of outstanding interest

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The authors have developed new miRNA discovery tools that combinebioinformatic predictions with microarray analysis and sequence-direc-ted cloning. They successfully cloned a large number of new humanmiRNAs that were missed by ordinary methods. They estimated that the

The evolution of animal microRNA function Niwa and Slack 149




total number of human miRNAs is at least 800, larger than initiallybelieved. Furthermore, several of the newlyidentified miRNAs are specificto primates and are not conserved across mammals. These data supportthe idea that miRNAs have a key role in the evolution of complexity of higher mammals, such as humans.

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microRNA expression. Proc Natl Acad Sci USA 2006,103:14385-14389.By comparing the expression of many evolutionally conserved miRNAs inmedaka and chicken with existing data for zebrafish and mouse, theauthors concluded that the spatial and temporal expression patterns of these ‘conserved’ miRNAs are not strictly conserved. They also arguethat differences in expression of some of miRNAs are associated withchanges in miRNA copy number and/or differences in genomic contextbetween species.

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The authors extensively analyzed expression of predicted miRNAs andtheir cognate targets in several Drosophila species. They report that alarge set of genes involved in basic cellular processes avoid miRNA

regulation by utilizing short 30

UTRs that are specifically depleted of miRNA binding sites. In addition to the study by Farh et al . [33], thisreport finds evidence for ‘antitargets’, which are genes expressed at highlevels in tissues where miRNAs are expressed, and which seem to lackmiRNA binding sites. This mutually exclusive expression argues thatmiRNAs confer robustness to tissue-specific gene expression by block-ing potentially large sets of mRNAs whose presence would be harmful tothe tissue.

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These authors examine global tissue expression profiles of miRNA s andtheir targets in mice. Strikingly similar to the study by Stark et al . [32],they found that mRNAsco-expressed with miRNAshave evolved to avoidtargeting by these miRNAs. A unique point demonstrated by this study isthe functional significance of the difference between conserved and non-conserved miRNA target sites. Both this study and that by Stark et al .[32] essentially come to the same conclusion that miRNAs have had awidespread influence on spatial and temporal gene expression patternsin organisms.

34. Lewis BP, Burge CB, Bartel DP: Conserved seed pairing, oftenflanked by adenosines, indicates that thousands of humangenes are microRNA targets. Cell 2005, 120:15-20.

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Abelson JF, Kwan KY, O’Roak BJ, Baek DY, Stillman AA,Morgan TM, Mathews CA, Pauls DL, Rasin MR, Gunel M et al.:Sequence variants in SLITRK1 are associated with Tourette’ssyndrome. Science 2005, 310:317-320.

This study shows genetic evidence that Tourette’s syndrome, a geneti-cally influenced developmental neuropsychiatric disorder, is associatedwith the loss of function of the Slit- and Trk-like 1 ( SLITRK1 ) gene. Inaddition to a frameshift mutation causing a truncated SLITRK1 protein in

some patients, the authors have found independent occurrences of theidentical variant binding site for miR-189 in another unrelated patient. Thevariation inhibits the translationof the SLITRK1 protein more potently thannormal, potentially resulting in the cause of the disorder. This studyprovides us with the first example that changes in miRNA-based regula-tion could make crucial contributions to human diseases.

37.

Clop A, Marcq F, Takeda H, Pirottin D, Tordoir X, Bibe B,Bouix J, Caiment F, Elsen JM, Eychenne F et al.: A mutationcreating a potential illegitimate microRNA target site in themyostatin gene affects muscularity in sheep. Nat Genet 2006,38:813-818.

The authors performed quantitative trait loci mapping to identify the generesponsible for the hypertrophically muscled sheep strain called Texel.Theauthors nicely reveal that a GDF8 ( myostatin ) allele in the Texel sheepis characterized by a nucleotide transition in the 3 0UTR that creates atarget site forbindingof miR-1 and miR-206. Given that these miRNAsarehighly expressed in skeletal muscle, the substitution causes a reductionof the GDF8 protein levels and presumably contributes to the muscularhypertrophy of the sheep. Furthermore, the group of authors has startedconstructinga newSNP database (Patrocles) to evaluate thefrequency of polymorphic miRN A–target interactions. Their analyses, as well as thoseof Abelson et al. [36], suggest that mutations creating or diminishingmiRNA binding sites in targets are important for generating phenotypicvariations.

38. Dominique JE, Gerard C: Myostatin regulation of muscledevelopment: molecular basis, natural mutations,physiopathological aspects. Exp Cell Res 2006, 312:2401-2414.

39. Johnson SM, Lin SY, Slack FJ: The time of appearance of the C.elegans let-7 microRNA is transcriptionallycontrolled utilizinga temporal regulatory element in its promoter . Dev Biol 2003,259:364-379.

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41.

Berezikov E, Thuemmler F, van Laake LW, Kondova I, Bontrop R,Cuppen E, Plasterk RH: Diversity of microRNAs in human andchimpanzee brain. Nat Genet 2006, 38:1375-1377.

In addition to the previous study by Bentwich et al . [29], this workcompares the miRNA content in the brains of primates such as humanand chimpanzee by massive sequencing. Among all of miRNAs in thisstudy, 75% of known human miRNAs cloned were conserved in verte-brates and mammals, 14% were conserved in invertebrates, 10% wereprimate-specific and 1% were human-specific. These data demonstratethat a certain number of the miRNAs are not evolutionally conserved andmight have species-specific function(s).



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