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Mobile DNA. 2019 Apr 13;10(1):15
The Author(s).
Gagnier, Liane
Belancio, Victoria P
Mager, Dixie L
Transposable element (TE) insertions are responsible for a significant fraction of spontaneous germ line mutations reported in inbred mouse strains. This major contribution of TEs to the mutational landscape in mouse contrasts with the situation in human, where their relative contribution as germ line insertional mutagens is much lower. In this focussed review, we provide comprehensive lists of TE-induced mouse mutations, discuss the different TE types involved in these insertional mutations and elaborate on particularly interesting cases. We also discuss differences and similarities between the mutational role of TEs in mice and humans.
REVIEW Open AccessMouse germ line mutations due toretrotransposon insertionsLiane Gagnier1, Victoria P. Belancio2 and Dixie L. Mager1*AbstractTransposable element (TE) insertions are responsible for a significant fraction of spontaneous germ line mutationsreported in inbred mouse strains. This major contribution of TEs to the mutational landscape in mouse contrastswith the situation in human, where their relative contribution as germ line insertional mutagens is much lower. Inthis focussed review, we provide comprehensive lists of TE-induced mouse mutations, discuss the different TE typesinvolved in these insertional mutations and elaborate on particularly interesting cases. We also discuss differencesand similarities between the mutational role of TEs in mice and humans.Keywords: Endogenous retroviruses, Long terminal repeats, Long interspersed elements, Short interspersedelements, Germ line mutation, Inbred mice, Insertional mutagenesis, Transcriptional interferenceBackgroundThe mouse and human genomes harbor similar types ofTEs that have been discussed in many reviews, to whichwe refer the reader for more in depth and general infor-mation [1–9]. In general, both human and mouse con-tain ancient families of DNA transposons, nonecurrently active, which comprise 1–3% of these genomesas well as many families or groups of retrotransposons,which have caused all the TE insertional mutations inthese species. As in humans [4], the mouse genome con-tains active retrotransposon families of long and shortinterspersed repeats (LINEs and SINEs) that can causegerm line mutations via new insertions but, in contrastto humans, the mouse also contains several groups ofretrotranspositionally active endogenous retroviral ele-ments (ERVs) that are responsible for most reported in-sertional mutations.ERVs/LTR retrotransposonsERVs are the result of retroviral infections or retrotran-spositions in the germline. The general structure of anERV is analogous to that of an integrated provirus, withflanking long terminal repeats (LTRs) containing thetranscriptional regulatory signals, specifically enhancer,promoter and polyadenylation motifs and often a splicedonor site [10, 11]. Sequences of full-length ERVs canencode gag, pol and sometimes env, although groups ofLTR retrotransposons with little or no retroviral hom-ology also exist [6–9]. While not the subject of this re-view, ERV LTRs can often act as cellular enhancers orpromoters, creating chimeric transcripts with genes, andhave been implicated in other regulatory functions [11–13]. The mouse genome contains many different groupsof ERVs and related LTR retrotransposons that togethercomprise ~ 10% of the sequenced genome [1] and whichhave been characterized to varying extents [6, 9, 14, 15].ERVs in mouse and other vertebrates are generally catego-rized into three classes. Class I ERVs are most related tothe exogenous gamma-retroviral genus, Class II to beta-and alpha-retroviruses and Class III to spuma-retroviruses[6, 9]. The very large non-autonomous MaLR (mamma-lian apparent LTR retrotransposon) group is also consid-ered Class III but has only very small traces of retroviralhomology. Different mammals have distinct collections ofERVs and the mouse is unusual in having a much higherfraction of Class II elements compared to humans orother mammals [1, 6]. For all but very young groups, themajority of ERV loci exist only as solitary LTRs, the prod-uct of recombination between the 5′ and 3′ LTRs of inte-grated proviral forms [16, 17]. Moreover, for ERVs thathave not undergone this recombination event, most have© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.* Correspondence: dmager@bccrc.ca1Terry Fox Laboratory, BC Cancer and Department of Medical Genetics,University of British Columbia, V5Z1L3, Vancouver, BC, CanadaFull list of author information is available at the end of the articleGagnier et al. Mobile DNA (2019) 10:15 https://doi.org/10.1186/s13100-019-0157-4lost coding competence due to mutational degradationover time.Unlike human ERVs that are likely no longer capable ofautonomous retrotransposition [18, 19], some mouseERVs are retrotranspositionally active and are significantongoing genomic mutagens in inbred strains, causing 10–12% of all published germ line mutations via new integra-tion events [1, 20]. The large Intracisternal A-particle(IAP) ERV group is responsible for close to half the re-ported mutations due to new ERV insertions, with theEarly Transposon (ETn)/MusD ERV group also contribut-ing substantially [20](Fig. 1a). These groups and othermutation-causing ERVs will be discussed in more detail inthe subsequent relevant sections. The majority of muta-genic ERV insertions occur in introns and disrupt normaltranscript processing (e.g. splicing and polyadenylation) tovarying degrees, a mechanism well recognized since the1990s [21–25] and discussed further below.Long interspersed repeats (LINEs)LINE-1s (L1s) are autonomous non-LTR elements thathave accumulated to as many as 500,000 copies in bothmouse and human genomes using a copy-and-pastemechanism of amplification [1–3, 26]. Full length L1sare 6–7 kb and contain two open reading frames (ORFs)encoding ORF1p and ORF2p, with the latter havingendonuclease and reverse transcriptase activity [27–30].The number of potentially active L1s (i.e. full-length ele-ments containing intact ORFs) varies significantly be-tween human and mouse. Bioinformatics analyses of thereference genomes have documented 2811 mouse and146 human L1s that are fully structurally intact [31].Functional studies have estimated numbers of active L1sto be ~ 3000 for mouse [32] and 80–100 for human [33].In contrast to the human genome that has had a singlesubfamily of LINEs active at any given evolutionary time,the mouse genome contains three concurrently active L1subfamilies (T(F), A, and G(F)) [32, 34] that are inser-tionally polymorphic among strains [17, 35]. One of thedistinguishing features of these subfamilies is the differ-ing 5′ monomer tandem repeats which, when combinedwith a downstream non-monomeric sequence, formtheir 5′ UTRs [36]. The 5′ UTR also contains the L1 polII promoter, which occurs downstream of the transcrip-tional start site [37, 38], an arrangement common tonon-LTR retrotransposons [39], allowing the promoterto be retained in the L1 mRNA.Mouse and human L1s contain promoters, splice andpolyadenylation signals in both sense and antisense di-rections that are utilized during L1 and host gene tran-scription, also sometimes leading to the formation ofchimeric mRNAs [40–44]. As with ERVs [20, 45], suchcis-acting sequences are a likely reason for the negativeimpact of some intronic L1 insertions on gene expres-sion [43]. De novo L1 inserts can vary in size from just afew bases to those containing a full-length L1 sequence[26], with the vast majority of such inserts being5′-truncated to varying extents. Although the exactmechanisms underlying this truncation phenomenon re-main unclear, there is a positive correlation between thefrequency of retrotransposition and insert length [46],and cellular DNA repair interference with L1 integrationmay play a role [47, 48].Sporadically, new germ line L1 insertions cause muta-tions when they land in or near a gene in human [4] ormouse (discussed below), and somatic insertions canalso occur, although few of the latter have been shownto exert a significant biological effect [49–51]. MutagenicL1 inserts can potentially disrupt normal gene functionor expression by interfering with it directly or by intro-ducing deletions or complex genomic rearrangementsthat are sometimes associated with the integrationprocess [3, 52]. In addition to introducing de novo inser-tions containing L1 sequences, L1 can mobilize flankingA B CFig. 1 Distribution of mouse mutations caused by TE insertions. a Numbers of published mutations caused by different TE types. b Strain bias forIAP and ETn/MusD insertional mutations. c Upper panel – proportion of LINE1 insertional mutations that are full length or near full length. Lowerpanel shows high proportion of B2 SINEs among insertional mutationsGagnier et al. Mobile DNA (2019) 10:15 Page 2 of 22genomic sequences as well. This occurs as a result oftheir incorporation into the nascent L1 mRNA gener-ated by either inaccurate/upstream transcriptional initi-ation (5′ transduction) or inefficient transcriptionaltermination at the L1 3′ polyadenylation site resulting inreadthrough and 3′ transduction [3, 53, 54]. Recent ana-lysis of endogenous L1 expression in human cell linesdetermined that only about a third of expressed L1 locigenerate such readthrough transcripts [55] but a similaranalysis has not been performed for mouse. The unique-ness of these transduced sequences are often useful inidentifying the source L1 element responsible for anewly retrotransposed copy [56].Short interspersed repeats (SINEs)SINE elements are non-autonomous retrotransposons,as they do not encode proteins involved in their amplifi-cation. As with human Alu SINE sequences [57], mouseSINEs have been shown to be retrotransposed by mouseL1 [58]. Only one of the two L1 proteins (ORF2p) is suf-ficient to drive Alu SINE mobilization in tissue culture[57], although ORF1p enhances the process [59]. Bothmouse and human L1s can efficiently mobilize theirnon-orthologous SINEs, suggesting that such a symbi-otic relationship has evolved multiple times [58–62].There are several SINE classes in the mouse genomethat together comprise ~ 8% of the genome [1]. Amongthese are B1, B2, B4/RSINE, ID, and MIR. New muta-genic insertions have been documented for B1 and B2(see below), indicating that at least some copies are stillpotentially active. B1 (like human Alu) is derived from7SL RNA, and B2 is derived from tRNA [3]. B1 and B2SINEs are both present at very high genomic copy num-bers: ~ 560,000 for B1 and ~ 350,000 for B2 [1]. Likemouse L1s and ERVs, these mouse SINEs are insertion-ally polymorphic in inbred strains [17, 63, 64].Cataloging TE-induced mouse mutationsWe assembled lists of mutations caused by TEs by per-using the literature and by querying the Mouse GenomeInformatics (MGI) database of mutant alleles [65]. InOctober 2018 we obtained lists from MGI of all spon-taneous mutant alleles that listed “viral”, “transposon” or“insertion” as the cause and extracted all relevant casesthrough manual curation. To avoid ascertainment bias,we excluded cases where investigators were specificallyscreening for effects of insertionally polymorphic TEs[35, 66, 67]. While such cases can show effects on geneexpression, observable phenotypes due to these inser-tionally polymorphic TE insertions were not reported inthe aforementioned studies. In addition, we excludedcases where the insertion event likely occurred in cul-tured ES cells used to produce transgenic mice. Nearlyall arose spontaneously but two cases of mutationsoccurring during a chemical mutagenesis experiment,but likely not caused by the chemical mutagen, were alsoincluded. This search resulted in a total of 115 TE inser-tion mutations. Ninety-four of these were caused by in-sertions of ERVs/LTR retroelements and 21 were L1 orL1-mediated (Fig. 1). In the case of the ERV mutations,the tables shown here are updates of previously pub-lished lists [1, 20, 68].IAP insertion mutationsThe group of ERVs responsible for the most reportedmutations are the IAP elements. IAP sequences areClass II elements and are highly abundant in the mouse[6, 69]. Different estimates for IAP copy number exist inthe literature but a recent analysis of all sequences anno-tated “IAP” by Repeatmasker [70] found ~ 3000 solitaryLTRs and ~ 2800 full-length or partial full-length ele-ments in the reference C57BL/6 genome [71]. Of the lat-ter, ~ 1000 have 5′ and 3′ LTRs that are 100% identical,indicative of a very young age, and most of these belongto the IAPLTR1 or 1a subtypes [71]. As expected forsuch a young ERV group, IAP elements are highly inser-tionally polymorphic among inbred mouse strains [17,66, 67, 72]. Although ~ 200 IAP sequences (IAPE ele-ments) contain an env gene [73], most do not. Loss ofenv and other specific genetic modifications facilitatedadoption of an intracellular retrotranspositional life cycleby IAPs [74] resulting in their accumulation to highcopy numbers as genomic “super spreaders” [75]. Be-sides the lack of env, there are a few common partly de-leted proviral forms [69] with the most notable beingthe 1Δ1 subtype, which has a 1.9 kb deletion removingpart of gag and pol, resulting in an ORF encoding anovel gag-pol fusion protein. Although retrotransposi-tion of 1Δ1 proviruses is non-autonomous, requiring gagand pol proteins in trans from other IAPs [76], this sub-type is responsible for the great majority of new IAP in-sertion mutations [20]. Interestingly, it has been shownthat the gag-pol fusion protein functions in cis to facili-tate retrotransposition [77]. Together with a generallyhigher level of 1Δ1 transcripts compared to full lengthIAP mRNAs (see below), this cis effect could explainwhy most new insertions are of the 1Δ1 subtype.Although transgenic experiments have shown expres-sion of an IAP LTR only in the male germ line [78], en-dogenous IAP transcription is also detectable inembryogenesis as early as the two cell stage and appearshighest in the morula and blastocyst stages [79]. More-over, at least some IAP elements can be transcribed innormal somatic tissues, particularly in the thymus,where a specific subtype of IAP LTR shows transcrip-tional activity [80, 81]. Notably, the levels of 1Δ1 5.4 kbIAP transcripts are comparable or often more abundantthan full-length IAP transcripts in different tissues or cellGagnier et al. Mobile DNA (2019) 10:15 Page 3 of 22types [69, 80, 82], although the former are present inlower copy numbers [69, 71, 83]. The molecular mecha-nisms underlying the generally higher transcript levels of1Δ1 elements are unknown but one possibility is thatthese elements are more likely to escape the general epi-genetic transcriptional repression of IAPs by DNA methy-lation and repressive histone modifications [84–87].Table 1 lists mouse germ line mutations caused by inser-tions of IAPs. Somatic insertions of IAP elements can alsooccur and cause oncogene or cytokine gene activation inmouse plasmocytomas, myelomas and lymphomas [88–90], likely due to the fact that some IAP LTRs are tran-scriptionally active in lymphoid tissues [80, 81]. Most ofthe germ line insertions occur in gene introns and disrupttranscript processing, notably splicing and polyadenylation(Table 1) [20]. However, several IAP-induced mutationsinvolve ectopic gene transcription promoted by an up-stream or intronic inserted LTR that is regulated by DNAmethylation [20, 91]. In these cases, the IAP is oriented inthe opposite transcriptional direction with respect to thegene and it is an antisense promoter within the LTR thatis responsible for the ectopic gene transcription. For anumber of such cases, including the most well studied Avyallele of agouti [92], variable establishment of epigeneticrepressive marks on the IAP LTR result in variable expres-sivity of the mutant (IAP) allele in genetically identicalmice and have been termed metastable epialleles [91, 93].Interestingly, a recent genome-wide screen for other IAPmetastable epialleles in C57BL/6 mice identified ~ 100such loci, with an enrichment of flanking CTCF bindingsites as the primary distinguishing feature [94].IAP activity in C3H miceBecause high numbers of IAP mutations in C3H miceand high IAP insertional polymorphisms among C3Hsubstrains have been noted before [20, 83], we investi-gated the strain of origin for all TE-induced mutations.For IAPs, the strain of origin could not be ascertainedfor three of the 46 cases but, of the remaining 43, a re-markable 84% (36 cases) occurred in a C3H strain or hy-brid involving C3H (Table 1, Fig. 1b). This marked skewis not seen for mutations caused by any other retroele-ments, indicating that ascertainment bias cannot explainthe high frequency of IAP-caused mutations in C3Hmice. While the date of the mutation is difficult to deter-mine in some cases, IAP retrotranspositions in C3Hmice have spanned several decades, with the earliest re-ported cases in the 1950s and the latest in 2014 (Table1). This indicates that the unusual IAP activity has beena characteristic of C3H strains for at least 60 years. In-deed, Frankel et al. have shown that at least 26 1Δ1 IAPinsertions present in C3H/HeJ are absent from thehighly related C3HeB/FeJ substrain [83], again indicativeof ongoing activity of IAPs, particularly the 1Δ1 subtype,in this strain.Although reasons for the numerous IAP insertionalmutations in C3H strains are unknown, it is noteworthythat normal spleen, bone marrow and thymus fromC3H/He mice have much higher levels of IAP tran-scripts compared to C57BL/6 and STS/A mice [95],suggesting that transcriptional deregulation may be in-volved. As well, IAPs are transcriptionally upregulated inradiation-induced acute myeloid leukemia in C3H/Hemice, resulting in new insertions in the leukemic cells,most of which are of the 1Δ1 subtype [95, 96]. Theseobservations, coupled with the fact that most new muta-tions in C3H mice involve the 1Δ1 subtype suggests thatthis IAP subtype is accumulating in the C3H genome ata faster rate than full length elements.Two recent reports illustrate the prudence of consider-ing IAP induced mutations whenever working with C3Hmice (Fig. 2). In the first case, Frankel et al. found thatan IAP insertion in the Pcnx2 gene in C3H/HeJ mice(Pcnx2C3H/HeJ) reduces expression of this gene, which inturn mitigates the effect of an IAP insertion in Gria4(Gria4spkw1) which causes seizures [83]. Hence one IAPinsertion modifies the effect of another (Fig. 2a). In an-other intriguing example, Barau et al. conducted ascreen in C3HeB/FeJ mice using N-ethyl-N-nitrosourea(ENU) mutagenesis to identify genes involved inretrotransposon silencing in the germ line [97]. Theyidentified several lines with the same mutation, indicat-ing it was not induced by ENU but rather was spontan-eous. This mutation was an IAP element inserted in anintron of a gene, annotated as a non-functional pseudo-gene, that formed as a tandem duplication of Dnmt3B.Barau et al. showed that this gene, now termed Dnmt3C,is indeed a functional DNA methyltransferase respon-sible for methylating promoters of young retroelements,including L1 elements and IAPs, in the male germ line[97]. Therefore, an IAP insertion facilitated the discoveryof a gene involved in its own silencing (Fig. 2b).C3H mouse historyThe C3H strain was derived by Leonard Strong from a1920 cross of a Bagg albino female (ancestors to theBALB/c strain) and a male from Little’s strain of “dilutebrowns” (ancestors to the DBA strain) [98]. One of theoriginal female progeny of this mating developed spon-taneous mammary tumors and this trait was selected foror against by subsequent inbreeding to develop the C3Hstrain (highly susceptible to mammary tumors) and theCBA strain (highly resistant). Mouse mammary tumorvirus (MMTV), the transmissible agent responsible forthe early onset mammary tumors in C3H [99, 100], waslater purged from most C3H related strains by pup fos-tering or re-derivation. In particular, the most widelyGagnier et al. Mobile DNA (2019) 10:15 Page 4 of 22Table 1 IAP insertionsaMutation MGI IDb Strain of origin YearmutationaroseLocation &OrientationcMutational mechanism(s) or effects ReferencesaAhvy 1855945 C3H/HeJ ~ 1994 Exon 1C,-c IAP forms 5′-end of transcriptd, Regulation bymethylation[181]aAiapy 1856403 C57BL/6J xC3H male 1992 Intron, − IAP forms 5′-end of transcriptd, Regulation bymethylation[182]Aiy 1855933 C3H/HeJ 1964 Intron 1, − IAP forms 5′-end of transcriptd, transcriptcontains internal IAP sequence[183]aAvy 1855930 C3H/HeJ 1960 Exon 1A, − IAP forms 5′-end of transcriptd, Regulation bymethylation[92, 183]Adamts13s 3579136 unknown, present in several strains ? Intron 23, + IAP causes premature polyadenylation andprotein truncation. Reduced enzyme activitybut no obvious phenotype[184, 185]Ap3d1mh-2J 1856084 C3H/HeJ Before1988Intron 21, + Transcript contains internal IAP sequence,Truncated protein[186]Atcayji-hes 1856898 C3H/HeJ-Tyrc-a 1987 Intron 1, + Transcript contains internal IAP sequence [187]Atp2b2jog 3664103 DSO, derived from C3H/He-Pwhybrid2000 Intron,+ Reduced mRNA levels, likely by terminatingat poly(A) in IAP, also cryptic splicingsuggested[188]Atrnmg 1856081 C3H – Swiss stock cross 1950 Intron 26, − Transcript contains internal IAP sequence,Truncated protein, Likely termination in IAP[189]Atrnmg-L 2156486 C3H/HeJ 1981 Intron 27, + Transcript contains internal IAP sequence,Reduced protein levels, Likely termination inIAP[189]aAxin1Fu 1856035 Bussey stock Before1931Intron 6, − IAP forms 5′-end of transcriptd, Regulation bymethylation, and transcript contains internalIAP sequence, Truncated protein[190, 191]aAxin1Fu-kb 1856037 unknown mid1970s?Exon 7, − IAP forms 5′-end of transcriptd, transcriptcontains internal IAP sequence, Internallydeleted protein[190]Clcc1m1J 5618134 C3H/HeSnJ After1947Intron 2, + Transcripts contains internal IAP sequence,Reduced normal mRNA levels[192]CrygeNo3 3713105 C3H/HeH × 102/E1 F1 Late1990sExon 3, + Reduced mRNA levels, Transcript containsinternal IAP sequence, Truncated protein[193]Dab1scm 1856801 Dc/Le (Dc arose in an obese stockoutcrossed to BALB/c x C3H/Hehybrid. One cross to C3H/HeJ, theninbred.)1991 Intron, − Transcript contains internal IAP sequence,Truncated protein[194, 195]Dnmt3CIAP N C3HeB/FeJFrom chemical induction exp.~ 2014 Last intron, − IAP provides alternate splice acceptor site,resulting in exclusion of Dnmt3C last exon,chimeric Dnmt3C-IAP mRNA[97]Eya1bor 1857803 C3HeB/FeJ 1984 Intron 7, + Transcript contains internal IAP sequence,Reduced mRNA levels[25]Gata3jal 3027100 C3H/HeJ 1990s Intron 3, − Unknown [196]Gpr179nob5 5431477 C3H After1951Intron 1, + Drastically reduces gene expression [197, 198]Gria4spkw1 3580141(QTL)C3H/HeJ 1950–2002Intron 15, + Full-length protein expression is significantlyreduced[199]Gusbmps-2J 2152564 C3H/HeOuJ mid1990s?Intron 8, +, Reduced mRNA size and level, No enzymeactivity detected[200]Hps3coa-6J 1861609 C3H/HeJ 1999? Exon 10, − Transcript contains internal IAP sequence [201]Hps1ep 1856712 C3HeB/FeJ 1957 3′-codingexon, −Transcript contains internal IAP sequence,Protein contains IAP-encoded amino acids[202]Hps6ru-6J 1856410 C3H/HeJ 1995 Unknown, + Kidney: loss of expression, Brain: transcriptcontains IAP sequence[203]Kcnq1vtg-2J 2389447 C3H/HeJCrl-Il2tm1Hor ~ 2000 Exon 2, − IAP fusion transcript likely promoted byantisense LTR. IAP provides 5′ end of 31 bpfused in frame to the gene.[204]Gagnier et al. Mobile DNA (2019) 10:15 Page 5 of 22Table 1 IAP insertions (Continued)aMutation MGI IDb Strain of origin YearmutationaroseLocation &OrientationcMutational mechanism(s) or effects ReferencesLamB3IAP 2179716 C3H (C3Hf/R1 male bred separatelyfrom JAX for decades)~ 1990 Intron/exonjunction (5′),−Transcript contains internal IAP sequence, NomRNA or protein expression[205]Mc1rmpc59H 5791971 C3H.Pde6b 2010 Exon,? Disruption of single exon gene [206]Mgrn1md 1856070 C3H/HeJ ~ 1960 Intron 11, + Reduced mRNA levels, aberrantly sizedtranscripts[207, 208]Mgrn1md-2J 1856072 C3H/HeJ 1978–1993Exon 12, + Reduced mRNA levels, aberrantly sizedtranscripts[207, 208]Mgrn1md-5J 1856519 C3H/HeJ 1978–1993Intron 2, + Not characterized [207, 208]Oprm1IAP N CXBK recomb. Inbred of B6 & Balb Before1984Exon 4,? Decreased mRNA levels, increase in length of3’UTR. Modifies response to opioids[209]Pcnx2C3H/HeJ 6161760 C3H/HeJ After1950Intron 19, + Modifier of Gria4 mutation, reduces Pcnx2expression[83]Pitpnavb 1856642 DBA/2J Early1960sIntron 4, + Transcript contains internal IAP sequence,Reduced mRNA & protein[210]Pla2g6m1J 4412026 C3H/HeJ mid2000sIntron 1,? Reduces normal gene transcripts by ~ 90% [211]Plcd3mNab N C3H mix ~ 2005 Intron 2, − Causes truncated protein, LTR may act asantisense promoter?[212]Pofut1cax 3719000 C3H/HeJ mid2000sIntron 4, Reduced mRNA and protein levels [213]Relnrl-Alb2 1857345 C3H/HeJFrom chemical ind. Exp.~ 1990 Exon 36, − Exon skipping, Reduced mRNA levels [214]Slc35d3IAP 3802578 C3H/HeSn-Rab27aash/JRos 1980s–1990sExon 1, − IAP fusion transcript likely promoted byantisense LTR. IAP provides 5′ end of 18 bpfused in frame to the gene.[215]Spta1sph-Dem 2388936 CcS3/Dem recomb. Con. strainfrom BALB/cHeA and STS/A1991 Intron 10/exon 11junction, +Exon skipping, Reduced protein expression,Reduced α−/β-spectrin dimer and tetramerstability[216]Tal1Hpt 1859843 C57BL/6J x C3HeB/FeJLe-a/a)F1. 1979 Intron 4, + Promotes overexpression of exons 4 and 5,fusion transcripts found.[217]Tnfrsf13cBcmd1 2389403(QTL)A/WySnJ Before1991Exon 3, + Fusion transcripts, Loss of function mutation [218]Tyrcm1OR 2153728 C3Hf/R1 1988 Upstream, − IAP does not form 5′-end of transcript,Reduced mRNA expression[219]Usp14ax-J 1855959 CBA or kreisler stock Early1950sIntron 5, + Transcript contains internal IAP sequence,Reduced mRNA levels,Truncated protein[220]Wnt9bclf1 1856821 A 1920s Downstream,+Produces transcript antisense to Wnt9b. [221, 222]Zfp69IAP N Unknown,present in C57BL/6, NZO,other strains? Intron 3 ofZfp69, +IAP causes premature polyadenylation andalternate splicing. Loss of functional Zfp69 instrains carrying the IAP is protective againstdiabetes.[223]9630033F20Rik N C3H/HeDiSnJ ~ 1985? Exon 5, − Deletion of exon 5, decreased geneexpression. Occurs in “lew” mice with pointmutation in Vamp1 thought to be cause. IAPmay contribute.[224, 225]aVariable phenotype or expression (metastable epiallele)bID number in Mouse Genome Informatics (MGI) database, “N” indicates not present in MGIc- = antisense, + = sense,? = orientation unknowndEctopic expression of IAP-driven transcriptGagnier et al. Mobile DNA (2019) 10:15 Page 6 of 22used C3H substrain C3H/HeJ was re-derived to beMMTV-free at the Jackson Laboratory (JAX) in 1999and all C3H substrains carried at JAX have been free ofMMTV since that time. Because IAP mutations havecontinued to occur in C3H/HeJ mice after removal ofMMTV (Table 1), it is unlikely that activities of the tworetroviral entities are directly related. Various substrainsof C3H, including the commonly used C3H/HeJ, werederived in the late 1940s and early 1950s [101].Interestingly, there is some evidence that C3H/HeJ hasa higher spontaneous mutation rate than most otherstrains. A multi-year study conducted at JAX from 1963to 1969 examined over 7 million mice derived from 28inbred strains for spontaneous observable and heritablemutations [102]. C3H/HeJ had marginally the highestoverall rate of mutations but not remarkably so [102].However, this study also documented mutational casesof “irregular inheritance” where the trait was heritablebut showed very poor penetrance. Of the 35 examples ofsuch cases, 16 (46%) arose in C3H/HeJ, even though thisstrain accounted for only 9.7% of the 7 million mice inthe study [102]. It is tempting to speculate that at leastsome of these unusual cases may involve a new IAP in-sertion behaving as a metastable epiallele [91, 93].ETn/MusD insertion mutationsAfter IAPs, the ETn/MusD group is responsible for thenext highest number of germ line mutations, with 31cases (Fig. 1, Table 2). ETn elements were first describedas repetitive sequences expressed highly in early embryo-genesis [103]. Subsequent expression analyses showedthat ETns are transcribed in two windows of embryonicdevelopment. First during E3.5–7.5 in the inner cellmass and epiblast and second between E8.5–11.5 in vari-ous tissues including the neural tube, olfactory/nasalprocesses and limb buds [103–105]. Although ETns haveLTRs, they have no coding capacity and, hence, theirmode of retrotransposition was initially a mystery. Basedon traces of retroviral homology in canonical ETns, weidentified an ERV group, termed MusD, which is thelikely progenitor of ETn [106, 107] and Ribet et al. dem-onstrated that coding competent MusD elements pro-vide the machinery necessary for ETn elements toretrotranspose [108]. A subsequent phylogenetic analysisof the large betaretrovirus genus classified MusD as be-longing to the Class II ERV-β7 group [14]. One analysisof copy numbers of ETn and MusD in C57BL/6 found~ 240 ETn elements, ~ 100 MusDs and ~ 550 solitaryLTRs [107], and they are highly insertionally poly-morphic [17, 66, 109]. As for IAP elements, loss of theenv gene and other genetic modifications likely resultedin genomic amplification of MusD (and ETn) elementsas intracellular retrotransposons [110]. In another simi-larity to IAPs, most germ line mutations caused by ETn/MusD are due to insertions of the non-autonomous ETn(Table 2), in particular a specific subtype ETnII-β [20].Of the 31 cases, only three are documented to be MusDwhile the rest are ETn (Table 2). The reasons for this arenot clear but ETn transcripts are much more abundantthan MusD transcripts in embryos and ES cells [107,111] and there is evidence that MusD is subject togreater levels of epigenetic suppression [111, 112].ETn/MusD mutations do not show an extreme strainbias as observed for IAP insertions. However, eight mu-tations have occurred in “A” strain mice (Fig. 1b), suchas A/J, and two in the seldom used strain SELH/Bc(Table 2) which has a high incidence of exencephaly[113, 114]. Interestingly, genomic copy number esti-mates in different mouse strains revealed that, whilethere are no detectable differences in MusD numbers,A/J, SELH/Bc and CD-1 mice have two to three timesmore ETnII-β elements compared to C57BL/6 [107].Transcript levels of MusD and ETnII-β in day 7.5 em-bryos are also higher in SELH/Bc and CD-1 comparedto C57BL/6 [107].Nearly all of the ETn mutagenic insertions occur ingene introns, in the same transcriptional direction as thegene, and disrupt normal transcript processing throughutilization of canonical or cryptic signals within the ETn,notably a specific strong splice acceptor site in the LTR,coupled with either a downstream splice donor or polya-denylation signal [20, 45]. This extreme orientation biasfor mutagenic insertions is also observed for the intronicIAP insertions that do not involve IAP promoter activity(Table 1). Such an orientation skew for detrimentalABFig. 2 Effects of IAP insertions in C3H mice. a An IAP insertion inGria4 in C3H/HeJ causes seizures associated with spike-wavedischarges but seizure episodes are much more frequent when theallele is crossed into another strain. The modifying effect in C3H/HeJis due to another IAP insertion in Pcnx2, which reduces thedetrimental effect of the Gria4 mutation. b A new IAP insertion inthe previously unknown Dnmt3c gene was detected in a C3HeB/FeJcolony during a screen for genes involved in retrotransposonsilencing in the male germ line. See text for references. Black boxesare gene exons and green arrows and lines represent IAP LTRs andinternal sequences. Numbers of exons/introns and distances are notto scaleGagnier et al. Mobile DNA (2019) 10:15 Page 7 of 22Table 2 ETn/MusD insertionsMutation MGI IDa Strain of origin Location & Orientation# Mutational mechanisms or effects ReferencesAdcy1brl 1857405 ICR Intron 14, +# Transcripts contain ETn sequence,Transcripts terminate within the ETn[226, 227]Bloc1s5mu 1856106 Stock-t Intron 3, + Transcripts contain internal ETnsequence[228]Cacna1fnob2 3605845 AXB6/PgnJ Exon 2, + Premature termination and alternativesplicing within ETn[229, 230]Cacng2stg 1856548 A/J Intron 2, + Transcripts contain ETn sequence,Probable termination within ETn[231, 232]Cacng2stg-wag 1856386 MRL/MpJ-Faslpr/J Intron 1, + Transcripts contain ETn sequence,Probable termination within ETn[231, 232]Cacng2stg-3J 2155891 BALB/cJ Intron 2, + Transcripts contain internal ETnsequence[231, 232]Clcn1adr 1856316 A2G Intron 12, + Transcripts contain ETn sequence,Termination within ETn[233]Dsg4hage 3766998 Recom. inbred of MRL/lpr x BXSB Intron 8, + Aberrant splicing in ETn causes in frameadditional exon of 63 amino acids[234]Dysf prmd 3055150 A/J Intron 4,+ ETn fixed in A/J strain. Aberrant splicing,No detectable dysferlin protein[235]EdarDl-slk 1856017 Stock Tyrp1b Dock7m Rb(4.6)2Bnr unknown Transcripts contain ETn sequence,Termination within ETn[236]Eml1heco 5560734 NOR-ICR Intron 22, + Aberrant splicing and prematuretermination, transcripts contain ETnsequence[237, 238]Etn3Ppd 3665247 CD-1 1.6 kb 3′ of Dusp9 gene, − Upregulates Dusp9 in ES cells, causesphenotype in Polypodia mutant[120]Faslpr 1856334 MRL/Mp Intron 2, + Transcripts contain ETn sequence,Termination within ETn[21, 239, 240]Fbxw4Dac 1857833 SM/Ckc 10 kb 5′ of exon 1, − No evident difference in size orabundance of transcript, MusD*insertion[121–123]Fbxw4Dac-2J 1857834 MRL/MpJ Intron 5, + Small amounts of normal transcript,MusD* insertion disrupts a conservedmotif in intron[121–123]Fig4plt1 3716838 ‘mixed’ (129/Ola, C57BL/6J, C3H & SJL) Intron 18, + Abnormal splicing from exon18 to SAsite of EtnII, very low abundance oftranscript[241]Fignfi 1856870 Random bred Intron 2, + Transcripts contain ETn sequence,Probable termination within ETn[242]Foxn1nu-Bc 1856110 SELH/Bc Intron, − Transcripts contain internal ETnsequence[113]Gli3pdn 1856282 Jcl:ICR Intron 3, + 5 alternatively spliced transcriptscontain ETn sequence, three terminatewithin ETn, two terminate as wild-type[243]Hk1dea 2151848 A/J Intron 4, + Probable aberrant splicing of ETnsequences into mRNA, Decreasedhexokinase activity[244]Hsf4ldis1 3056560 RIIIS/J Intron 9, + ETn alters splicing resulting in achimeric truncated protein, and causesat least 100 fold up-regulation of thetranscript[245]Lepob-2J 1858048 SM/Ckc-Fbxw4Dac Intron 1, + Transcripts contain ETn sequence,Probable termination within ETn, Lossof leptin expression.[23]MipCat-Fr 1857104 A/J Intron 3, + Transcripts contain ETn sequence,Termination within ETn, LTR sequencetranslated to protein domain[246, 247]Gagnier et al. Mobile DNA (2019) 10:15 Page 8 of 22insertions is indeed expected, given that fixed/olderERVs have an antisense bias in genes [115, 116], presum-ably reflecting the fact that such insertions are less likelyto be potentially deleterious and selected against.In an attempt to mechanistically understand theseorientation biases, we modeled splicing events involvingintronic ERVs (using computationally predicted spliceand polyadenylation motifs) and surprisingly found simi-lar predicted frequencies of alternate splicing caused bysense or antisense ERVs [45]. However, actual splicingpatterns of human mRNAs with intronic ERVs suggeststhat suppression of splicing within antisense-orientedERVs occurs, possibly via steric hindrance due to anneal-ing of sense-oriented ERV mRNAs [45]. This scenariowould be analogous to gene therapy approaches whereoligonucleotides that anneal to and suppress the use ofmutagenic splice sites are used to redirect splicing andrestore gene function [117]. Although unproven, such amechanism could contribute to the general antisensebias for neutral/fixed ERV insertions and the oppositebias for mutagenic insertions.Unlike for IAPs, there are no documented cases of ETnpromoters causing a phenotype by driving ectopic geneexpression (Table 2). This is likely due at least in part tothe fact that ETn/MusD LTRs are normally only transcrip-tionally active in embryogenesis, responding to embryonictranscription factors [118, 119], so their promoter/enhan-cer activity would be silent in somatic tissues where mostobservable but non-lethal phenotypes manifestthemselves. There is, however, at least one case where en-hancer effects of an ETn insertion are likely responsiblefor a mutant phenotype. In this example, an ETn insertiondownstream of the Dusp9 gene upregulates this gene andalso causes malformations in Polypodia mice, although adirect link between Dusp9 deregulation and malforma-tions has not been shown [120].There is an intriguing but complex story involving twoof the three documented MusD insertions [121–123].Both of these cause the dactylaplasia (Dac) embryoniclimb malformation phenotype by insertions within(Fbxw4Dac-2J) or upstream (Fbxw4Dac) of the Fbxw4gene. Both are full length MusD elements that share99.6% identity and have occurred in different mousestrains. In the former case (Fbxw4Dac-2J), the intronic,sense oriented MusD severely reduces the amount ofnormal Fbxw4 transcripts, likely via typical transcriptprocessing disruption or via physical disruption of aconserved, and hence potentially regulatory, ~ 1.5 kb re-gion within the intron [123], although neither mechan-ism has been formally demonstrated. In the other Dacmutation (Fbxw4Dac, also termed Dac1J) the MusD isinserted 10 kb upstream of the Fbxw4 gene in antisenseorientation. However, no effects on the size or abun-dance of Fbxw4 transcripts are evident in mice carryingthis insertion, so the mechanism by which it causes dac-tylaplasia remains unclear [121–123].Interestingly, the Dac phenotype is modified by an un-linked polymorphic locus mdac (modifier ofTable 2 ETn/MusD insertions (Continued)Mutation MGI IDa Strain of origin Location & Orientation# Mutational mechanisms or effects ReferencesRubieSWR-J 5568608 SWR/J Intron 1, + Aberrant splicing and prematurepolyadenylation of the long non-codingRNA transcript Rubie which is proposedto regulate Bmp4 expression[248]Sgk3fz-ica 3032837 Swiss Intron 6, + Aberrant splicing, transcript containsETn sequence[249, 250]Sil1wz 3055918 Recomb. inbred CXB5/ByJ Intron 7, + Aberrant splicing and prematuretermination. Transcript contains ETnsequence[251]Slc6a5m1J 5086232 NOD.Cg-Emv30b Prkdcscid/Dvs Intron 5, + MusD* insertion, Inclusion of 183 bp ofMusD sequence in mRNA, completeloss of protein[252]Ttc7fsn 1856879 A/J Intron 14, + Transcripts contain internal ETnsequence[253]TWis 1857760 A/J splice donor of exon 7, − 8 alternatively spliced transcripts, 4contain ETn sequence, 1 terminateswithin ETn, 7 terminate as wild-type, 5have exon skipping[254, 255]Tyrc-Bc3 1856303 SELH/Bc Exon 1, − Transcripts probably contain ETnsequence, Probable termination in ETn[113]Zhx2BALB/cJ 3623885 BALB/cJ Intron 1, + Transcripts contain ETn sequence,Termination within ETn[256, 257]aID number in Mouse Genome Informatics (MGI) database, “N” indicates not present in MGI#- = antisense, + = sense,? = orientation unknown*MusD insertions are bolded. All others are ETnsGagnier et al. Mobile DNA (2019) 10:15 Page 9 of 22dactylaplasia) [124]. In strains homozygous for the mdacallele (eg. BALB/c and A/J), the dactylaplasia phenotypeis observed if the mice carry either dac mutation. How-ever, in strains carrying the other allele Mdac (eg. CBA,C3H or C57BL), the phenotypic effects of the dac muta-tions are not observed [122, 124]. Although the identityof mdac is still unknown, it could be a gene involved inepigenetic regulation of MusD. In mdac/mdac mice, the5′ LTR of the Dac1J MusD element is unmethylated andenriched in active histone marks whereas this LTR isheavily methylated and enriched in repressive histonemarks in mice carrying the Mdac allele [122]. Moreover,ectopic MusD transcript expression is observed in em-bryos and limb buds of dactylaplasia mdac/mdac mice,but not in wildtype mdac/mdac mice, suggesting thatthe increased MusD expression is due to transcription ofthe Dac1J MusD element itself, rather than general up-regulation of MusDs in the genome [122]. The mdacTable 3 MLV InsertionsMutation MGI IDa Strain of origin ERV location, orientationb Mutational mechanisms or effects ReferencesAbcb1amds 3044239 CF-1 Solitary MLV LTR, Intron 22, − Transcripts contain viral sequence, Exon skipping,Disruption of gene function.[258, 259]Aifm1Hq 1861097 CF-1 Intron 1, + 80% decrease in transcript and protein levels,Aberrant splicing[260]Hrhr 1856057 HRS/J Intron 6, + Transcripts contain viral sequence, Probabletermination within LTR[24, 137]Lamc2jeb 3609880 129X1/SvJ Solitary MLV LTR,intron 18, +Aberrant splicing and premature termination,low level of normal transcripts[261]Lmf1cld 1856820 M. m. musculus Intron 7,? Transcripts contain ERV sequence, Terminationwithin ERV[262]Myo5ad 1856004 Fancy mice Intron, + Shortened and abnormally spliced transcriptsthat vary among tissues[135]Pde6brd1 1856373 unknown Intron 1, − Associated with nonsense mutation in genebut effect of ERV is unclear[263]aID number in Mouse Genome Informatics (MGI) databaseb- = antisense, + = sense,? = orientation unknownTable 4 Other ERV InsertionsMutation MGI IDa Strain of Origin ERV, Location, Orientationb Mutational mechanisms or effects ReferencesAgtpbp1pcd-2J 1856536 SM/J ERV-β2/ETnERV3, Intron 13, + Greatly reduced full length gene transcripts [264]Etn2Sd 1857746 Danforth’s posteriorduplication stockERVβ-2/ETnERV3, 12 kb upstream, + Overexpression of Ptf1a and twoneighboring genes, acts as an enhancer[140–142]Nox3het 1856606 GL/Le Presumed ERVβ-2/ETnERV3, Intron 12, + Transcripts show aberrant splicing fromNox3 into retroviral element[139, 265]Prph2Rd2 1856523 O20/A ERVβ-2/ETnERV3, Exon 2, − Transcripts contain entire ERV, codingsequence disruption[266, 267]Ednrbs 1856148 Fancy mice ERVβ-4, Intron 1, + Aberrant splicing and prematurepolyadenylation[268]a 1855937 Fancy mice VL30, Intron 1, −;ERVβ-4 within VL30, +Smaller gene mRNA and levels 8 fold lowerthan in wild-type.Aberrant splicing and prematuretermination within the ERVβ-4[22, 143]Dock7m 1856946 JAX Dilute Brown MERV-L, Exon 18, + Frameshift and premature termination [269, 270]Fgf5go-moja 6147688 ICR Partial MTA MaLR, Intron 2, − 498 bp insertion is combined with 9.3 kbdeletion of exon 3 and flanking sequence,no detectable transcripts[158]Grm1crv4 3664783 BALB/c/Pas MERV-L solitary LTR, intron 4, + Aberrant splicing and prematuretermination, transcripts contain LTRsequence[271]Npc1m1N 1857409 BALB/c Partial MERV-L, Exon 9 824 bp partial and rearranged MERV-L com-bined with 703 bp deletion. Transcriptscontain MERV-L sequence, decreased ex-pression, premature truncation[159]aID number in Mouse Genome Informatics (MGI) databaseb- = antisense, + = sense,? = orientation unknownGagnier et al. Mobile DNA (2019) 10:15 Page 10 of 22locus has been mapped to a 9.4 Mb region betweenmarkers D13Mit310 and D13Mit113 on chromosome 13[122, 124]. Interestingly, this region includes a cluster ofKRAB-ZFP (zinc finger protein) transcription factorgenes. KRAB-ZFP genes are found in multiple clustersin the genome, are rapidly evolving and highly poly-morphic in mice [125, 126] and some are involved inepigenetic silencing of ERVs [126]. Hence, it is temptingto speculate that the identity of mdac is such a gene.MLV insertion mutationsThe murine leukemia virus (MLV or MuLV) group isthe most well characterized ERV group in the mouseand has caused seven documented spontaneous muta-tions (Fig. 1a,Table 3). MLV is also likely responsible forretrotransposing the non-autonomous VL30 ERV in-volved in the non-agouti mutation that will be discussedin the next section. MLVs are Class I elements, belong-ing to the gamma retrovirus genus, entered the mousegenome less that 1.5 million years ago and still containsinfectious members [127]. MLV loci are highly insertion-ally polymorphic among strains [128, 129] with copynumbers of ~ 20 for xenotropic MLV and ~ 40 for poly-tropic MLV [9]. Ecotropic copies, i.e. those able to infectonly mouse cells (and not those of other species) basedon env protein recognition of a cellular receptor, arepresent in very few copies in various strains [127]. Newgerm line insertions appear to occur primarily throughoocyte reinfection, rather than intracellular retrotranspo-sition [130], which has likely kept MLV copy numberslow. Ever since it was first reported that exogenous MLVcan integrate into the germ line [131], MLV andMLV-based vectors have been widely used for many ap-plications including insertional mutagenesis screens,gene therapy and oncogene discovery [132–134].All of the MLV mutation-causing insertions occur ingene introns and affect normal gene transcript process-ing to varying degrees (Table 3). The very firstERV-induced mutation to be described, over 35 yearsago, was an MLV insertion causing the dilute coat colormutation (Myo5ad) in DBA/2J mice [135]. This mutationcan revert due to homologous recombination betweenthe 5′ and 3′ LTR of the full length provirus, leaving asolitary LTR at the locus [136]. Phenotypic reversion bythis mechanism also occurs for the hairless mutation(Hrhr), another of the first documented cases caused byan MLV insertion [137].Insertional mutations by other class II ERVsIn addition to the ERVs discussed above, members offive other ERV groups have caused mouse mutations(Table 4). Like the IAP and ETn/MusD groups, two ofthe groups, ERV-β2 and ERV-β4, belong to Class II orthe betaretrovirus genus as defined by pol homology[14]. Both of these groups are heterogeneous and rela-tively low in copy number. The ERV-β2 group includesmouse mammary tumor virus (MMTV) but the ERVsresponsible for the four cases of mutations belong to adifferent ERV-β2 cluster which has internal sequencesannotated in Repbase [138] primarily as “ETnERV3”with LTRs annotated as “RLTR13A” [14]. The full ERVwas not sequenced for the Nox3het mutation but we pre-sume it to be an ERV-β2 since the limited LTR sequenceprovided matched RLTR13A or RLTR13B [139]. For theother three ERV-β2 cases in Table 4, their full sequenceshave been published and they are 96–99% identical toeach other with the major differences being internal de-letions in the Agtpbp1pcd-2J and Prph2Rd2 elements withrespect to the longer Etn2Sd ERV insertion (D. Mager,unpublished observations).The above cases highlight the continual difficultiesand confusion with ERV annotation. As an example, theERV insertion causing the allele termed “Etn2Sd”, wherethe ERV likely acts as an enhancer, was reported to bean “ETn” element [140–142]. However, as discussedabove, this is misleading since “ETnERV3” is a separateentity compared to the more well-known ETn/MusDgroup, an important distinction but likely generally over-looked. Interestingly, when the reference C57Bl/6 gen-ome was analyzed in 2004, less than 15 ERV loci fallinginto the ERV-β2 group were found and none were fullycoding competent [14]. Moreover, all of the ERV-β2sdiscussed above also lack full open reading frames.Nonetheless, the presence of these elements at sites ofnew mutations in other strains suggests such strainshave or had coding-competent members to provide pro-teins in trans, allowing retrotransposition of defective el-ements. The strains in which the ERV-β2 mutationsarose (Table 4) do not share close relationships so theorigin of any active autonomous copies is unknown.The ERV-β4 group [14] has been involved in two knownmutations and both occurred in old “fancy mice” (Table4). One of these mutations (Ednrbs) was caused by inser-tion of a 5 kb non-coding competent element whose in-ternal sequence is classified as “ERV-β4_1B-I (internal)” inRepbase [138] but half of the sequence in the middle ofthe element actually lacks homology to retroviruses (un-published observations). Fifteen to 20 sequences closelyrelated to the Ednrbs element exist in the C57BL/6 refer-ence genome and, since they contain LTRs and parts ofthe 5′ and 3′ internal sequences highly similar to theERV-β4 element discussed below, it is likely that this smallnon-autonomous group has amplified using retroviralproteins provided by coding competent ERV-β4 elements.The other mutation case involving an ERV-β4 is com-plex. The a (non-agouti) allele of the agouti gene is oneof many agouti alleles affecting coat color [143], includ-ing four caused by IAP insertions (Table 1). The a alleleGagnier et al. Mobile DNA (2019) 10:15 Page 11 of 22is fixed in the reference strain C57BL/6 and is re-sponsible for its black coat color. Molecularcharacterization of non-agouti in the early 1990s re-vealed that it was caused by a 5.5 kb VL30 ERV inser-tion in the first intron of the agouti gene withanother reported ~ 5.5 kb segment flanked by 526 bpdirect repeats found within the VL30 [22, 143]. Ourperusal of the fully sequenced reference C57BL/6genome shows that the sequence within the VL30 is~ 9.3 kb. The mutation is reported to be caused by aVL30, which belongs to a well-studied medium re-petitive non-autonomous Class I ERV group that isco-packaged with MLV, allowing its retrotransposi-tion [144, 145]. Although VL30 is insertionally poly-morphic among inbred strains [17], this is the onlyreported VL30-caused mutation. The nature of theinsertion within the VL30 was not known at thetime of analysis, but the C57BL/6 sequence shows itto be an ERV-β4 (coordinates of the full ~ 14.7 kbVL30/ERV-β4 insertion are chr2:155014951–155,029,651, GRCm38/mm10). Hence two ERV inser-tion events contributed to the non-agouti mutation,a VL30 insertion followed by insertion of an ERV-β4within it (Fig. 3). The non-agouti a allele reverts at ahigh frequency to “black and tan” (at) orwhite-bellied agouti (Aw) [22, 143]. Molecular ana-lyses by Bulman et al. showed that the at allele con-tains the VL30 element with a single ERV-β4 LTRand the Aw allele contain just one VL30 LTR[22](Fig. 3). Therefore, normal agouti gene expres-sion can be partly restored by homologous recom-bination between the LTRs of the VL30 or theERV-β4, as has also been observed for MLV muta-tions (discussed above). Notably, the ERV-β4 elementinvolved in the non-agouti a allele is the only fullycoding competent ERV-β4 copy in the C57BL/6 gen-ome [14].Insertions by MERV-L/MaLR elementsThe Class III MERV-L LTR retrotransposon group hasalso caused a few mutations (lower part of Table 4).MERV-L is a large, recently amplified group in themouse with coding competent members but lacking anenv gene [146–148]. These retrotransposons are highlyexpressed in the 2-cell embryo [79, 149], create viral-likeparticles [150] and ~ 700 full length or near full lengthelements exist in the reference C57BL/6 genome [148].Therefore, the fact that there are only three reportedgerm line mutations caused by MERV-L insertions issomewhat paradoxical. Despite the high transcript leveland particle formation by MERV-L at the two cell stage,it appears that any fully retrotranspositionally competentmembers are very rare or effectively blocked from com-pleting retrotransposition by host defense mechanisms.Indeed, MERV-L elements amplified in two major burstsin mouse evolution, approximately 2 and 10 millionyears ago [147] and it is possible that host genetic adap-tations as a result of a host-virus “arms race” [151] haveeffectively repressed further MERV-L expansion. Inter-estingly, MERV-L and associated MT MaLR LTRs havebeen co-opted to drive expression of genes and othertranscripts involved in early embryogenesis and zygoticgenome activation [79, 152–154] and there is evidencethat MERV-L expression is important for embryonic de-velopment [155].Insertion of a partial MTA MaLR element, belongingto a large young group of non-autonomous retrotran-sposons related to MERV-L [15, 156], and also highlyexpressed in early embryogenesis [153, 157], has contrib-uted to a mutation in the Fgf5 gene [158]. However, thiscase and the MERV-L insertion causing the Npc1m1Nmutation [159] are both partial elements and arecoupled with genomic deletions, so the order of eventsresulting in these mutations is unclear. It is noteworthythat two of the four cases associated with Class IIIMERV-L/MaLR mutagenic insertions involve rearrange-ments of the ERV itself as well as genomic deletions.Interestingly, MaLR elements are associated with forma-tion of independent hypervariable minisatellite sequencearrays in both human and mouse [160, 161], suggestingthat these elements may foster genomic recombinationand rearrangements.LINE1 insertion mutationsOur literature and MGI database search resulted in a listof 12 germ line mutations caused by L1 insertions(Table 5, Fig. 1). Of the 11 where the length and/or se-quence of the insertion was published, five are fulllength (or nearly full length) and six are partial elements,with the shortest being only 81 bp. All five full length in-sertions belong to the L1MdTf family, subtypes I or II,which are among the youngest L1 subfamilies, each withFig. 3 Three alleles of the agouti gene involving ERV insertions. Thea (non-agouti) mutant allele is fixed in the reference strain C57BL/6.It involves a VL30 ERV and an ERV-β4 inserted within it. Partialphenotypic reversion of non-agouti occurs frequently. The at (blackand tan) allele results from recombination between the LTRs of theERV-β4. The Aw (white-bellied agouti) allele results fromrecombination between the VL30 LTRs. See text for references. Genestructure in black is shown to very rough scale. Green arrows andlines are the LTRs and internal VL30 sequences. Purple arrows andline depict the ERV-β4Gagnier et al. Mobile DNA (2019) 10:15 Page 12 of 22over 1000 full length elements in C57BL/6 [34]. (Notethat some revisions and updates to L1 subfamily classifi-cation and nomenclature have occurred [34]). In twocases, the source L1 element could be identified due toinclusion of flanking transduced sequence at the new in-sertion site. In the Nr2e3rd7 mutant allele, the L1insertion includes 28 bp of 5′ transduced sequence,allowing the source element to be traced to the L1 atchr4:21650298–21,656,544 (GRCm38/mm10) [162]. Theother case (Lama2dy-Pas) is interesting in that it involvesan IAP LTR and an L1 [163]. While not reported as anL1 3′ transduction event in the original paper [163], ourTable 5 L1 InsertionsMutation MGI IDa Strain of origin L1 length, location and orientationb Mutational mechanisms or effects ReferencesAtp7aMo-ca 2387450 unknown 81 bp L1, exon 10, − Aberrant splicing causing in-frame lossof 10 amino acids[272]Dab1yot 1857750 Chimera of 129 and C57BL/6 Rearranged partial L1MdTf, intron Partial gene deletion and atypical962 bp L1 insertion[273]Frem1heb 1856897 AKR/J Unknown length L1, exon 17, + Transcript and protein truncation [274]Glrbspa 1856363 Random-bred stock Full length L1MdTf_I intron 6, − Reduced expression of normal transcriptand exon skipping[275–277]Lama2dy-Pas 6220701 Non-inbred Agouti Nearly full length L1MdTf_II and3′ transduction, intron 34, +Transcript contains internal IAP sequence,Truncated protein.L1-mediated retrotransposition eventinvolving an L1 and 3′ transduced IAP LTR[163]Lystbg 1855968 C3H/Rl X 101/R1 (from radiation exp.) 1.1 kb 5′ truncated L1, intron, + Two alternatively spliced transcriptscontaining L1 sequence results in twotruncated forms of the protein[278, 279]Mitfmi-bw 1856089 C3H Full length L1MdTf_II, intron 3, + Decreased expression and exon skippingof two isoforms and abolished expressionof the third isoform[280]Nr2e3rd7 1859180 77-2C2a-special- JAX Full length L1MdTf_I with 28 bp5′ transduction, exon 5, −Accumulation of incompletely splicedtranscripts.[162]Pde6ccpfl1 2657247 Recom. Inbred CXB1/ByJ 1.5 kb insertion of truncated L1 &likely 3′ transduction, Intron 4, −Aberrant splicing within inserted sequencecauses inclusion of extra 116 bp exon andframe shift.[164]Relnrl-Orl 1856416 BALB/c Full length L1MdTf_I exon 59, + 220 bp deletion in mRNA due to skippingof exon containing L1[281]Scn8amed 1856078 PCT 180 bp 5′ truncated L1, Exon 2, − Skipping of exon containing L1, loss of functional protein [282]Ttnmdm 1856953 C57BL/6J 2.4 kb L1, exon 3, + 779 bp gene deletion and L1 insertion causesexon loss or chimeric transcripts[283]aID number in Mouse Genome Informatics (MGI) databaseb- = antisense, + = sense,? = orientation unknownABFig. 4 a Transduction of IAP LTR by an L1. A full length L1MdTf element interrupted by an IAP ERV exists in intron 3 of the Akr1c14 gene onchromosome 13. This L1 is the source element responsible for the Lama2dy-Pas mutation, with the newly inserted sequence polyadenylated in theIAP LTR. Thick orange lines are L1 genomic sequences and thin orange lines represent L1 RNA. The IAP LTRs and internal sequences are in green.Genes and number of exons are not to scale. b B2 insertion causing gene upregulation. The TNFBPSM1 mutation is a B2 insertion (in yellow) in the3′ UTR of Tnf, causing Tnf upregulation due to polyadenylation within the B2 which removes the negative regulatory ARE (AU rich element) fromthe Tnf mRNA. Mice with this mutation have heart disease and arthritis due to overexpression of TNF. B2 is yellow and thicker black boxes arecoding sequencesGagnier et al. Mobile DNA (2019) 10:15 Page 13 of 22perusal of the inserted sequence (Genbank accessionAJ277888) revealed that the L1 has transduced the IAPLTR, with the inserted sequence polyadenylated withinthe 5′ LTR (Fig. 4a). The source L1 has a 3.7 kb partlydeleted IAP element inserted within it, so that ~ 700 bpof the 3′ end of the L1 occurs on the other side of theIAP (coordinates of the source L1/IAP arechr13:4065522–4,076,041, GRCm38/mm10). Another L1insertion (Pde6ccpfl1), which occurred in a recombinantinbred strain established from a C57Bl/6 and BALB/cintercross, has the classical molecular structure of a 3′transduction event [164]. However, there is no L1 elem-ent in either the sequenced C57BL/6 or BALB/c ge-nomes at the original location of the transducedsequence (unpublished observations), which occurs inan intron of the Diaph2 gene [164]. Therefore, the sim-plest explanation is that an L1 inserted in the Diaph2gene in the particular mouse colony being used and thenretrotransposed again, creating the Pde6ccpfl1 allele.L1 insertions have occurred in a variety of geneticbackgrounds, with no evident strain bias. The muta-tional effects of these insertions are as expected, with in-tronic L1s affecting splicing and exonic cases physicallydisrupting the coding sequence. Interestingly of the 12L1 cases, half occur in gene exons and half in introns(Table 5), which is more skewed toward exons comparedto the ERV insertions discussed above (Tables 1-4). It isa reasonable assumption that truncated (and henceshorter) L1 insertions might be less likely to affect tran-script processing if inserted in an intron. (See also dis-cussion of SINE insertions below). Indeed, the twoshortest L1 insertions of 81 and 180 bp both occur inexons (Table 5). However, two of the five full length L1s,which are similar to size to ERVs, also occur in exons.SINE and other LINE1-mediated insertion mutationsMembers of two mouse SINE families, B1 and B2, havecaused documented mutations (Table 6). Also includedin this Table is a presumed L1-mediated insertion ofCenpw cDNA into an exon of Poc1a [165]. It is note-worthy that, although higher numbers of B1 elementshave accumulated during mouse evolution [1], seven ofthe eight mutation-causing SINE insertions are B2 withno evident strain bias (Table 6, Fig. 1c). In accord with thepreponderance of B2- over B1-caused mutations, retro-transposition assays in vitro showed a higher retrotranspo-sition rate for B2 compared to B1, although the assayswere conducted in human cells [58]. It is possible that B2is currently the more active family in inbred strains, con-tains some members more efficient at utilizing the L1 ret-rotransposition machinery and/or are moretranscriptionally active in the germ line. Interestingly,Dewannieux et al. [58] found that most B1 elements havea nucleotide mutation compared to Alu elements and 7SLRNA (from which both B1 and Alu were derived) andnoted that this highly conserved nucleotide is critical for7SL RNA interaction with SRP9/14 proteins [166]. As hasbeen shown for Alu elements [167], this interaction is ex-pected to enhance L1-mediated retrotransposition of B1.Indeed, replacement of this nucleotide in several tested B1elements resulted in a much higher retrotransposition ratein culture [58]. Therefore, B1 elements harboring this mu-tation have become the most prevalent in the genome des-pite the fact that the mutation lowered their ability toretrotranspose. Although the evolutionary trajectoryresulting in B1 prevalence is unknown, it has been sug-gested that, during mouse evolution, such B1 elementshave been selectively retained to minimize harm to thehost [58].Table 6 SINEs and other L1-mediated insertionsMutation MGI IDa Strain of origin Insertion type,location, andorientationbMutational mechanisms or effects ReferencesAtcayji 1856574 Bagg albino B1, exon 4, + B1 insertion causes protein truncation and rare exon skipping [187, 284]ComtB2i 4819952 Strain variant, likely origin inLathrop stockB2, 3′ UTR, + Premature polyadenylation leads to shortened 3’UTR and increasedprotein expression. Associated with behavioral difference.[170, 171]Gsdma3Dfl 2385837 BALB/c B2, exon 7, + B2 causes premature termination, transcript includes B2 sequence [285]Ndufs4fky 4942335 Male Dnmt3L +/− x femaletransgenic RIP-mOVA C57BL/6B2, exon 3, + B2 insertion causes exon skipping and premature termination [286]Nrcamm1J 5444298 B6.129P2-Cnr2tm1Dgen/J B2, exon 26, − Aberrant splicing and premature termination [287]Poc1acha 2135614 DBA.B6-Ahvy/a x DBA/2J Gene cDNA, exon 8,−L1 mediated insertion of Cenpw cDNA in exon 8. Exon 8 is skipped,reading frame preserved[165]Ptpn6me-B24947257 BALB/c B2, exon 6, + Replacement of exon 6 sequence with B2 sequence, reading framepreserved[288]Slc27a4wrfr 2445864 (129X1/SvJ x 129S1/Sv)F1 B2, exon 3, − Coding sequence disruption, no mRNA or protein detected [289]TnfBpsm1 5795894 C57BL/6 B2, 3’UTR, + Premature polyadenylation leads to shortened 3’UTR and geneoverexpression[172]aID number in Mouse Genome Informatics (MGI) databaseb- = antisense, + = sense,? = orientation unknownGagnier et al. Mobile DNA (2019) 10:15 Page 14 of 22Unlike the ERV mutation-causing insertions, wheremost cases occur in introns (Tables 1-4), all such mouseSINE insertions have occurred in exons (Table 6), whichrepresent a much smaller genomic space. The marked biastoward exonic insertions also occurs for disease-causingAlus [4]. This could simply be due to the fact that SINEsare shorter and therefore new insertions are much lesslikely to significantly disrupt gene expression if insertedinto an intron. Indeed, although SINEs, particularly Alus,can cause alternative splicing and exonization [168], bothhuman and mouse SINEs are relatively enriched in introns[169] and show less evidence of selection against intronicinsertions compared to ERVs or L1s [68].As is the case for mutation-causing human Alu in-sertions [4], most of the mouse SINE insertions dir-ectly disrupt the gene’s coding sequence, causingexon skipping, protein ablation, truncations or aminoacid replacements (Table 6). However, in the ComtB2iallele, which is a strain variant present in C57BL/6and a few other strains [170, 171] and in theTnfBpsm1 mutation [172], a B2 element inserted intothe 3′ UTR causes gene upregulation, which under-lies the phenotype. This effect is due to a shortened3′ UTR caused by premature polyadenylation withinthe B2 and a resultant replacement or disruption ofnegative regulatory motifs within the UTR, whichhas been directly shown for TnfBpsm1 [172] (Fig. 4b).Concluding remarksThis review has provided a comprehensive catalog anddiscussion of mouse mutations caused by insertions ofERVs, LINEs and SINEs. It is clear that, among these TEtypes, ERV insertion mutations are the most prevalent(Fig. 1a). Through an accounting of all independentspontaneous mutant alleles in mouse, it was previouslyestimated that ERV insertions comprise 10–12% of allpublished spontaneous mutations [1, 20]. Another previ-ous report estimated that L1 insertions account for 2–3% of mouse mutations [173], suggesting a relative ratioof ERV to L1 insertion mutations of 4 to 6. Our updatednumbers (94 ERV cases and 12 L1 cases) reveal a some-what higher ratio of approximately eight. If the nineSINE insertion cases reported here are included, the ra-tio of ERV to “L1-mediated” insertion mutations is ~ 4.5.Since both human and mouse have active L1s, we canattempt to compare relative L1 recent “activity” basedsolely on the number of documented mutations due toL1 insertions. Both bioinformatics and functional studies[31–33] suggest that the typical inbred mouse genomeharbors roughly 20–30 times more retrotranspositionallycompetent L1s compared to human (~ 3000 versus ~100–150). All else being equal, one might then expectthe frequency of L1 insertional mutations to be 20–30times higher in mouse. Recent reviews onretrotransposons in human disease report 22 cases of L1insertions causing heritable mutations/diseases [4, 174].To put these numbers in context, it should be remem-bered that many more mutations have been described inhuman compared to mouse. The Human Gene MutationDatabase [175], lists ~ 240,000 entries as of January2019. In contrast, the MGI database [65], lists only ~2100 spontaneous mutant alleles as of the same date,and many of these are non-independent entries or re-vertant cases. While comparing such overall numbers isfraught with caveats, they are however still useful to il-lustrate the point that the mouse “mutational space” isvastly understudied compared to human. Hence, therelatively low number of 12 mouse L1 mutations (whencompared to the number of human L1 mutations) is notunexpected but rather simply appears low when viewedagainst the high numbers of ERV mutations. Indeed thisnumber is approximately in line with expectations whencompared to human, given the much higher number ofactive L1s but much lower numbers of all characterizedmutations in mouse.In considering L1-mediated insertion mutations as afraction of all mutations, the numbers reported heresuggest a frequency of 3–5% in mouse, building onthe previous L1 estimate of 2–3% [173] and includingthe SINE cases. There have been various estimates forthe frequency of L1-mediated mutations in human,with an early estimate of 1 in 600 (0.16%) reportedby Kazazian [176]. A more recent study of thespectrum of mutations in a single gene found that TEinsertions caused 0.4% of all mutations in NF-1 [177],although it is unclear if this figure can be extrapo-lated to all genes. In any case, these estimates suggestthat the contribution of L1 activity to overall muta-tional burden is at least 10 fold higher in mouse.Concerning mouse ERVs, there are several distinctERV groups currently able to retrotranspose at least insome strains, including the low copy number and poorlycharacterized ERV-β2 and ERV-β4 groups [14], previ-ously not known to be active. Unpublished transcrip-tome analysis indicates that expression of both thesegroups is readily detectable in early embryonic stages(Julie Brind’Amour and Matt Lorincz, personal commu-nication) but little else is known about them. The factthat new insertions have been found for such low copynumber ERV groups indicates they are still mutagenic insome strains and worthy of further investigation.Another point worth emphasizing is that, althoughIAP ERVs are young and have accumulated to high copynumbers in inbred strains, they perhaps do not deservethe often used designation as the currently “most active”group of mouse ERVs. This is likely true only in C3Hmice and, if this strain is removed from consideration, amodest seven IAP-caused mutations can be documentedGagnier et al. Mobile DNA (2019) 10:15 Page 15 of 22to have occurred in strains unrelated to C3H (Table 1,\Fig. 1b). This number of mutations places IAP recent“activity” more on a par with the low copy number MLVand ERV-β2 groups and suggests that the genomic ex-pansion of IAPs in most strains has largely ceased, likelydue to host defense mechanisms [86, 151, 178–180]gaining the upper hand. Exclusive of the C3H strain, theETn/MusD group accounts for the most mutagenic ERVinsertions. One possible reason for the high IAP-inducedmutations in C3H mice could be a slight relaxation ofrepression in the germ line, so it would seem prudentfor investigators to consider including this strain in stud-ies to investigate the regulation of IAPs. This extremestrain bias for IAP activity also illustrates the difficultyin attempting to compare de novo TE insertion muta-tion rates in the “outbred” human population with thosein the artificial environment of inbred mice. Nonethe-less, the primary difference between human and mousein terms of TE-induced insertional mutations is clearlythe lack of ongoing ERV activity in modern humans.AbbreviationsDac: Dactylaplasia; ERV: Endogenous retrovirus; ETn: Early transposon;IAP: Intracisternal A type particle; JAX: The Jackson Laboratory; L1: LINE-1family; LINE: Long interspersed element; LTR: Long terminal repeat;MaLR: Mammalian apparent LTR retrotransposon; MLV: Murine leukemiavirus; ORF: Open reading frame; SINE: Short interspersed element;TE: Transposable elementAcknowledgementsWe thank Rita Rebollo for help with figures and for making suggestions onthis review. We also thank Diana Juriloff for advice on mouse history andJonathan Stoye for reading the MLV section. We apologize to authors if wefailed to mention relevant work.FundingRelevant work in the Mager lab is currently funded by the Natural Sciencesand Engineering Council of Canada. V. Belancio is funded by NIH grantsR21AG055387 and R01AG057597 and the Brown Foundation.Availability of data and materialsThis is a review article. Data sharing not applicable to this article as nodatasets were generated or analyzed during the current study.Authors’ contributionsLG and DLM compiled data and VLP and DLM wrote the manuscript. Allauthors read and approved the final manuscript.Ethics approval and consent to participateNot applicable. This is a review article on mouse.Consent for publicationNot applicableCompeting interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Terry Fox Laboratory, BC Cancer and Department of Medical Genetics,University of British Columbia, V5Z1L3, Vancouver, BC, Canada. 2Departmentof Structural and Cellular Biology, Tulane University School of Medicine,Tulane Cancer Center, Tulane Center for Aging, New Orleans, LA 70112, USA.Received: 29 January 2019 Accepted: 1 April 2019References1. Consortium MGS. Initial sequencing and comparative analysis of the mousegenome. Nature. 2002;420:520–62.2. Belancio VP, Hedges DJ, Deininger P. Mammalian non-LTR retrotransposons:for better or worse, in sickness and in health. Genome Res. 2008;18(3):343–58.3. Richardson SR, Doucet AJ, Kopera HC, Moldovan JB, Garcia-Perez JL, MoranJV. 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Endogenous retroviruses
Long terminal repeats
Long interspersed elements
Short interspersed elements
Germ line mutation
Inbred mice
Insertional mutagenesis
Transcriptional interference
Mouse germ line mutations due to retrotransposon insertions
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