Trends in Evolutionary Biology 2017; volume 6:6514

Potential impact tions including insertional mutagenesis, of primate-specific SVA generation of deletions at the insertion site, Correspondence: Olga Vasieva, Institute of 3’ or 5’ transduction events, non-allelic Integrative Biology, Department of retrotransposons during homologous recombination and Comparative Genomics, University of the evolution of human exonisation.1-4 More than 10,000 TE inser- Liverpool, Liverpool, L69 7ZB, UK. cognitive function tions occurred in the since Tel.: +44.151.795.4456 - Fax: +44.151.795.4406. human-chimpanzee divergence which were E-mail: [email protected] suggested to have implications on human 1 1 Key words: SVA, retrotransposons, hominoid, Olga Vasieva, Sultan Cetiner, evolution and especially its reproductive, 2 3 brain, evolution. Abigail Savage, Gerald G. Schumann, cognitive and immune functions that Vivien J. Bubb,2 John P. Quinn2 diverged strongly during a relative short Contributions: OV conceived of the study, 1Institute of Integrative Biology, time period.4,5 The large number of such designed and performed the systems analysis, University of Liverpool, UK; TEs in the genome makes an analysis of and drafted the manuscript, SC performed the 2Department of Molecular and Clinical their specific contribution to evolution very computational analysis and took part in draft- ing of the manuscript, AS has performed the Pharmacology, Institute of Translational difficult, and previous studies highlighted retrieval of SVA-associated sets and Medicine, University of Liverpool, UK; the potential role of mainly self-propagating (L1, ERV/ETR) and Alu elements.4 We have helped to draft the manuscript, GGS partici- 3Division of Medical Biotechnology, focused on the functions of in proxim- pated in data analysis and helped to draft the Paul-Ehrlich-Institut, Langen, Germany manuscript, VJB participated in retrieval of ity to the integration sites of the less studied associated gene sets and helped to draft the hominoid-specific composite retrotrans- manuscript, JQ conceived of the study, coordi- posons termed SINE-VNTR-Alu (SVA) ele- nated SVA associated gene set retrieval and 6 ments. SVA elements represent the took part in- drafting of the manuscript. Abstract youngest non-LTR retrotransposon family in humans and the human genome harbors Conflict of interest: the authors declare no The SVA family of hominid-specific approximately 2700 SVAs.7-9 We and others potentialonly conflict of interest. non-LTR retrotransposon comprises the have demonstrated that SVA elements have youngest group of transposable elements in properties of transcriptional regulators of Received for publication: 21 March 2016. the human genome. The propagation of the both in vivo and in Revision received: 24 October 2016. most ancient SVA subfamily took place vitro,8,10,11 and that a significant number of Accepted for publication: 24 October 2016. about 13.5 million years ago, and the SVA elements are located within 10kbuse of the youngest SVA subfamily appeared in the This work is licensed under a Creative major transcriptional start site of many Commons Attribution NonCommercial 4.0 8 human genome after the human/chimpanzee genes. Therefore, SVA insertions estab- License (CC BY-NC 4.0). divergence. Functional analysis of genes lished in the hominoid lineage could be associated with SVA insertions demonstrat- responsible for altering the transcriptome in ©Copyright O. Vasieva et al., 2017 ed their link to multiple ontological cate- a developmental, tissue-specific or stimulus Licensee PAGEPress, Italy gories, with one of the major categories inducible manner, as was already suggested Trends in Evolutionary Biology 2017; 6:6514 being attributed to brain function. Further earlier for Alu elements and demonstrated doi:10.4081/ni.2017.6514 analysis of this subset demonstrated that for LTR sequences of endogenous retro- SVA elements expanded their presence in viruses.4 scriptional regulatory properties both in vivo the human genome at different stages of SVA elements are categorized into sub- and in vitro.7 In this communication, we hominoid evolution and were associated families A to F and F1,11 and their age was wanted to further explore the potential of with progressively evolving behavioral fea- commercialestimated at 13.56 million years (Myrs) for members of the different SVA subfamilies tures that indicate a potential impact of SVA the oldest subfamily (A) and 3.18 Myrs for (A-F1) to modulate specific genes involved propagation on the cognitive ability of a the youngest subfamily (F). Subfamily D is in CNS function. Here, we demonstrate that modern human. Our analysis suggests a by far the largest and encompasses 44% of SVA insertion and subfamily appearance in potential role of SVAs in theNon evolution of all SVAs in the human genome. The subfam- evolution correlate with the acquisition of human and especial- ily termed F1 represents the smallest group certain behavioral traits. ly in the emergence of functional trends rel- covering only 3% of all SVA elements. evant to social and parental behavior. Co- Subfamilies E, F and F1 are human-specific evolution of behavioral features and repro- and correspond to the period since the ductive functions are suggested by our human chimpanzee divergence that occurred Materials and Methods analysis and discussed. ~6 million years ago.5 The implications of SVA insertions for the evolution of other Generation of the list of genes associ- hominoid lineages is quite obvious, because, for instance, the family of gibbon-specific ated with SVA insertions Introduction LAVA retrotransposons, derived from an Genomic coordinates of all SVA loci in SVA A element, has been implicated in the the human genome (Hg19 reference genome Genetic studies have been successful at molecular mechanism underpinning genome sequence) were extracted from the UCSC determining the changes that alter pathways plasticity of the gibbon lineage.12 We have genome browser (http://genome. involved in evolution. Transposable ele- previously examined in detail the SVA inser- ucsc.edu/index.html). This included many ments (TEs), despite long being thought of tions found upstream of the genes PARK7 SVA sequences that were fragmented in the as junk DNA, have impacted the human and FUS, which are genes implicated in neu- Repeat Masker track; therefore, this list was genome during its evolution through a vari- rodegeneration, and demonstrated that the manually annotated to generate a list of ety of mechanisms causing structural varia- SVAs associated with these genes have tran- coordinates of complete SVA sequences

[Trends in Evolutionary Biology 2017; 6:6514] [page 1] Article resulting in a total of 2676 elements encom- associated with an SVA insertion were shown on Figure 1. passing all seven SVA subfamilies.8 The Cardiovascular disease and Glucose toler- A number of behavioral categories coordinates of all known genes and their ance. However the next highest ranked show an evolutionary corresponding pattern transcripts were extracted from the UCSC were Guidance of axons and Synaptic of connection to SVA insertions. The walk- genome browser, and Galaxy software processes (P=1E-5 and P=6E-5 correspond- ing-category-associated group of genes (http://galaxyproject.org/) was used to gen- ingly). The genes classified to the latter cat- ([AGTPBP1 (ATP/GTP binding 1)], erate coordinates of the 10-kb genomic egories were associated with a number of [CACNB4 (Calcium channel, voltage- regions flanking all known transcripts. canonical pathways (such as Synaptic Long dependent, B4 subunit)], [FXN (Frataxin), Finally, the SVA loci were intersected with Term Potentiation or Axonal Guidance SCN8A (Sodium channel, voltage gated, the three lists of genomic coordinates (all Signaling) with no specific enrichment in type VIII alpha subunit)], [ATG7 known genes, 10kb upstream and 10kb any of those top-ranked pathways (Autophagy related 7 homolog)] contain downstream of known genes). Duplicates (Supplementary Material). To better reveal SVA D or F insertions while the functions of were removed from each list individually. functional trends for potential SVA impact climbing activity-associated genes [KCNJ6 For functional enrichment analysis, the on human cognitive function, we focused (Potassium inwardly-rectifying channel, defined SVA coordinates have been used to only on genes relevant to CNS categories J6)] and [HTT (Huntingtin)] are associated produce a shorter list of the Genome (Table 1 and Supplementary Material) and with earlier SVA A and B insertions Reference Consortium Human Build 38 these were re-analyzed by IPA (Supplementary Material). We may specu- (GRCh38) genes directly mapped via (Supplementary Material). The top-ranked late that alteration of the functionality of BIomart Martview service (www. significantly enriched categories (-log(P- these genes overall could have had an biomart.org/biomart/martview/). value)>12) were of morphology and devel- impact on changing from climbing to the opment of forebrain/telencephalon and mul- walking moving mode over the period of Ingenuity pathway analysis tiple categories relevant to axon growth and hominoid evolution. Consistent with that synaptic processes. From the mapped the decline in Nest building activity was Ingenuity Pathway Analysis (IPA) soft- behavioral categories, Learning and Social also speculated to have an enhancing ware (Ingenuity Systems, Inc.) was used to Behavior were the generally most enriched impact on evolution of walking survival investigate biological functions associated only (-log(P-value)>4.6) categories and Nest skills, and we see this category associated with the data sets generated from genes building behavior, Nursing, Sexual behav- with two SVA B and D types. In that respect associated with an SVA insertion.13 The IPA ior, Sexual receptivity of female organism, a modulation of a limited number of genes database is composed of comprehensive Grooming, Emotional behavior, Aggressive in a specific pathway could have a major information on genes and pathway ontolo- behavior, Vocalization and Walking wereuseeffect on the overall pathway. Behavioral gies. The database contains approximately the most significantly enriched categories in characteristics encoded by genes containing 200 canonical pathways as well as 27 high- the SVA B and/or SVA D associated sets of younger SVA elements are generally of a er-order disease and function categories for genes. Social Behavior was the only signif- more executive nature, for instance Core functional enrichment analysis. Right- icantly enriched category attributed to the [CREB1 (cAMP responsive element bind- tailed Fishers Exact statistical tests was used gene sets associated with the youngest SVA ing protein 1)] associated with an SVA E to calculate whether the likelihood of associ- subfamilies F and F1. Many categories insertion, is involved in both vertical and ations between a set of focus genes and a across the sets were mapped by one or two spatial learning and place preference, while category was due to a random chance. The genes. All the defined behavioral categories [PSEN1 (Presenilin-1)] is associated with tool enabled production of graphical net- were presented against the timeline of an SVA F element and plays a role in social works that illustrated mapped genes and occurrence of insertions of the different order recognition, memory and social their functional connections. SVAcommercial subtypes in the human genome as behavior. In this respect, it attracts our Meta-analysis of gene expression Genevestigator software was used to perform a meta-analysis of gene expression in different tissues.14 For each gene/tissue an average level of expression is determinedNon via automated cross-analysis of normalized published Affymetrix microarray data, fil- tered for statistically significant values and stored in the Genevestigator database. The highest and lowest detected average expres- sion levels define a 100-unit scale that is used for presentation of each gene/tissue related average expression value.

Results

Relevance of SVA-associated genes to neural system and cognitive function Figure 1. Behavioral categories attributed to genes associated with SVA insertions at dif- The top ranked categories identified by ferent periods during evolution. IPA for the data set generated from genes

[page 2] [Trends in Evolutionary Biology 2017; 6:6514] Article attention that 3 genes with functions rele- (Supplementary Material). Similarly, all (Puromycin-sensitive aminopeptidase)]), vant to maternity care: Mother preference genes were expressed in testis at above maturation ([LFNG (O-Fucosylpeptide-3- associated gene - [OMP (Olfactory marker average levels. A number of the behavioral Beta-N-acetylglycosyl transferase)]) and protein)] and metabolic functions associat- SVA-associated genes exhibited their high- fertilisation ([CLIC4 (Chloride intracellular ed with Nursing and Feeding categories est expression levels in oocytes: [TIMD4 channel 4)]) of oocytes. Several genes, such ([ACOT11 (Acyl-CoA thioesterase)], (T-cell immunoglobulin and mucin domain as [CYP19A1 (Cytochrome 19A1)], [MKL1 (Megakaryoblastic leukemia containing 4)], [OXT (Oxytocin/ [ABL2 (Non-receptor tyrosine kinase)], (translocation))]), are also associated with Neurophysin I)], [KALRN (Kalirin)], [SHANK1 (SH3-and-multiple-ankyrin the recent SVA F (Supplementary Material). [cyp7B1(Cytochrome 7B1)] and already repeat-domains protein 1)] and already Interestingly, the number of functions asso- mentioned genes MKL1 and ATG7, which mentioned ESR1, CREB1 and NPEPPS ciated with regulation of mating and are enriched for SVA F and SVA F1 inser- also have an association in the IPA knowl- parental behavior is also affected by SVA D tions. Some genes whose expression is edgebase with the following behavioral insertions. Among those genes involved are known to cause a strong neural phenotype, aspects of reproduction: sexual receptivity genes encoding regulators of hormonal such as [GABBR2 (GABA B receptor 2)] of female organism, mating behavior, intro- biosynthesis and response ([CYP19A1 (SVA A) and CREB1 (SVA E), are also mission, mounting and pup retrieval. (Aromatase)], [ESR1 (Oestrogen receptor highly expressed in oocytes. Interestingly, 1)]), metabolism ([LEPR (Leptin receptor)], germ cells are characterized by increased [ATP8A2 ( transporting mobilization of endogenous retrotrans- ATPase 8A2)], [FTO (Alpha-ketoglutarate- posons in general,15 and attribution of SVAs Discussion dependent dioxygenase )]), synaptic func- to genes expressed in these germ cells tion ([SHANK2 (SH3 And Multiple might therefore be relevant for the SVA Retrotransposons have been suggested Ankyrin Repeat Domains 2)], [GPHN mobilization and propagation in this cell to be major drivers of genome evolution, (Gephyrin)]), and immune response type. Analysis of attribution of the gene set both through structural variations such as ([IL1RN (IL1 receptor antagonist)], [OCLN with neuronal and behavioral functions in insertional mutagenesis and modulation of (Occludin)]). Several genes found to be phenotypic reproductive categories (IPA theonly transcriptome.4,16 SVAs can also induce associated with SVA insertions are involved analysis, Supplementary Material) also and exon skipping in multiple ontological categories, e.g. the highlighted their link to spermatogenesis (in which can result in the generation of alter- genes HTT associated with SVA B, or particular, sperm motility [(ADCY10 native transcripts of a gene as documented [BRCA1 (Breast cancer type 1 susceptibili- (Adenylate cyclase 10)]), atrophy of testis by disease causing insertions.17-19 Thus ty protein)], associated with SVA F, could and seminiferous tubules (HTT)), infertilityuse SVA insertions may generate new interac- have been especially significant at particu- in both genders ([STAR (Steroidogenic tions between what would otherwise be dis- lar evolutionary stages whilst having large- acute regulatory protein)], [ABCA1 (ATP- tinct pathways.8,20 In this communication, ly pleiotropic effects (Figure 2). It is indica- binding cassette A1)], [MKKS (McKusick- we suggest a more global involvement of tive that genes with different SVA insertions Kaufman syndrome)], [NPEPPS genes associated with SVA insertions in functionally crosstalk. BRCA1, for instance, is not only linked to DNA repair processes but is also involved in interac- tions with a number of transcription factors, such as ER1, which itself has an SVA inser- tion (Figure 2). As an extreme example of crosstalk between different SVA subtypes are many cases of distinct subtype inser- commercial tions in a single gene (Table 1 and Supplementary Material).

Meta-analysis of anatomical rele- vance of SVA-associated behavioralNon gene expression Forebrain and hindbrain were con- firmed to be the sites of high expression of the majority of the genes attributed to behavioral phenotypes. High expression levels of the majority of genes associated with all 7 SVA subtypes were also found Figure 2. Functional networks reconstructed from SVA-associated genes and classified in outside of the CNS which indicates a neuronal and behavioral categories. Fx-labels correspond to gene-attributed functions pleotropic multi-tissue effect of the genes and diseases. Solid lines - experimentally validated functional interactions, dashed lines - with behavioral phenotypes and suggests protein binding. The color intensities of blocks correspond to types of intragenic SVA insertions increasing in the order: B, D, F. Blue lettering indicates the genes associated their coordinated evolution. Potential posi- with neuronal and behavioral categories. ACOT11(Acyl-CoA thioesterase 11), tive selection of SVA-associated genes [CDK5RAP2 (CDK5 regulatory subunit associated protein 2)], [DIXDC1( DIX domain could be attributed, among other factors, to containing 1)], [E2F (Elongation factor 2)], ESR1 (Estrogen receptor1), [FANCA their direct effect on an organism’s repro- (Fanconi anemia protein A)], [FANCD2 (Fanconi anemia protein D2)], [HdaC (Histone duction. Nearly 80% of all genes associated deacetylase)], MSH2(MutS homolog 2)], [NPM1 (Nucleophosmin)], [POLA1(Polymerase (DNA directed), alpha 1, catalytic subunit)], [RBL1 with members of the SVA A and B subtypes (Retinoblastoma-like 1)], VPS35 (Vacuolar protein sorting 35 homolog)]. were highly expressed in placental chorion

[Trends in Evolutionary Biology 2017; 6:6514] [page 3] Article

only use Behavior Neurological disease Neurological Psychological disease Psychological Nervous system development and function and development system Nervous commercial

Non ESR1, GABRA2, GABRG3, GABRG3, GABRA2, ESR1, LRPAP1, LRP4, IL1RN, GOLPH3, NRXN1, MYH9, MTOR, MSH2, PDE4D, PCMT1, PARK7, TENM4, SCN8A,SYTL4, PEX5, GFRA2, GLRA3, GNAQ,GOLPH3, GNAQ,GOLPH3, GLRA3, GFRA2, LEPR, IL1RN, IL1RAPL1, GPR98, MTOR, MSH2, LRPAP1, LRP4, OTOGL, OCLN, NRXN1, MYH9, PDGFRA, PDE4D, PCMT1, PARK7, PHF8PIGV, PEX5, PDS5B, RAB7A, PUS1, PTPN9, PNPT1POR, SCN8A, RPGRIP1L, RMND1, RBL1, SYTL4, SPTBN1, SPRN, SNTB2, SIL1, TRPV1, TRIOBP, TENM4, TAOK1, TAF1, VAMP7, ULK4, UBR1, UBE4B, ZDHHC9 YWHAE, XK, VPS35, TRPV3, UBE4B, UBR1,ULK4, VAMP7, VPS35 VAMP7, UBR1,ULK4, UBE4B, TRPV3, IL1RN, LEPR, LRPAP1, MOS, MTOR, MTOR, MOS, LRPAP1, LEPR, IL1RN, NFATC3, NIPBL, NRXN1, OCLN, PARK7, PARK7, OCLN, NRXN1, NIPBL, NFATC3, NRXN1, OXT, PTPRD DNAJC1, DYSF, FGF12, ASPA, BRAF, C9, CACNB4, MYO1B, PDE9A, UBR1 CTSS, PARK2, PSEN1, SLMAP PSEN1, PARK2, CTSS, UBR1 PDE9A, MYO1B, CACNB4, C9, BRAF, ASPA, FGF12, DYSF, DNAJC1, PTPRD OXT, NRXN1, TACR3, TRPM6, UBR1, PIGL, PNKD, PTPN9, CFB, CNTNAP2, CPA6, TMC1, VAPB, VPS35 VAPB, TMC1, CPA6, CNTNAP2, CFB, PTPN9, PNKD, PIGL, UBR1, TRPM6, TACR3, DDIT3, CYP19A1, CRB1, SIL1, RORA, RAB7A, ZDHHC15 YARS, PBX3, PRKG1, SCN8A, SHANK2, SYTL4, SYTL4, SHANK2, SCN8A, PRKG1, PBX3, L1RN, JARID2, KIF15, LEPR, LILRB3, LPAR4, LPAR4, LILRB3, LEPR, KIF15, JARID2, L1RN, MAPK1, RCAM, NRXN1, FGF12, LRRK2, MKKS, CACNB4, CNTNAP2, CYP19A1, MYH10, OMP, PARK2, CYP7B1, MKL1 CYP7B1, PARK2, OMP, MYH10, CYP19A1, CNTNAP2, CACNB4, MKKS, LRRK2, FGF12, NRXN1, RCAM, MAPK1, OXT, SEC24D, TACR3, NPEPPS, SLC16A2 ESR1, F2RL1, FTO, FXN, GABRA2, PDE11A, PSEN1 PDE11A, GABRA2, FXN, FTO, F2RL1, ESR1, SLC16A2 NPEPPS, TACR3, SEC24D, OXT, VEZT VAMP7, UBR1, TRPV1, LRP4, LRPAP1, MOS, MTOR, MYH9, NCOR1, NCOR1, MYH9, MTOR, MOS, LRPAP1, LRP4, TIMD4, UBR1, USF1 GABRG3, GFRA2, GNAQ, GPHN, GPHN, GNAQ, GFRA2, GABRG3, USF1 UBR1, TIMD4, NFATC3, NIPBL, NRXN1, NRXN2, OCLN, PARK7, PARK7, OCLN, NRXN2, NRXN1, NIPBL, NFATC3, POR, PEX5, PDS5B, PDGFRA, PCMT1, PBX3, SCN8A, RPGRIP1L, RGS11, RBL1, PTPN9, PRKG1, SYNE2, SPTBN1, SNTB2, SLC17A5, SIL1, SHANK2, UBE4B, TRPV3, TRPV1, TENM4, TACC2, SYTL4, YWHAE VEZT, VAMP7, UTRN, ULK4, ULK1, UBR1, NR1H2, NRCAM, NRXN1, OXT, CAMK1D, CNTNAP2, CRB1, CYP19A1, PDE11A, PPARD, PSEN1, PSEN1, PPARD, PDE11A, CYP19A1, CRB1, CNTNAP2, CAMK1D, OXT, NRXN1, NRCAM, NR1H2, PARD3, PDS5B, PRPH2, RPGRIP1L, DDIT3, DIXDC1, EIF2B3, EIF4G3, ELMO1, ZEB1 TENM4, ROBO2. RBL1, ELMO1, EIF4G3, EIF2B3, DIXDC1, DDIT3, RPGRIP1L, PRPH2, PDS5B, PARD3, SMAD2, TACR3, TRPM6, ERBB2IP, ESR1, F2RL1, FAIM2, FER, FGD4, FGD4, FER, FAIM2, F2RL1, ESR1, ERBB2IP, TRPM6, TACR3, SMAD2, UBR1, UBR2, UTRN FTO, FXN, GFRA2, GNAQ, GPHN, IL1RAPL1, IL1RAPL1, GPHN, GNAQ, GFRA2, FXN, FTO, UTRN UBR2, UBR1, LOC440040, LRRK2, MFN2, CFB, CRB1, CYP19A1, SLC30A10 SPTLC1, VPS35 SPTLC1, SLC30A10 MFN2, CYP19A1, LRRK2, CRB1, CFB, LOC440040, VAMP1 ELMO1, STAR, EIF2B3, PNKD, DDIT3, SLC16A2, SLC25A12, SLC25A12, SLC16A2, ELMO1, EIF2B3, FGD4, F2RL1, ESR1, VAMP1, TFAP2B, STAR, GABRG3, GABRA, FXN, FUS, WDR62 GABBR2, ULK4 CACNA2D4, HLA-DRB1, HTT, ABCA1, APBB2, ARNT, CFLAR, ADORA3, ALOX5, ANKRD11, ANXA2, CASP8, CREB1, HUWE1, APLP2, BRCA1, ACOT11,RAD54L, ACOT11,RAD54L, HUWE1, CREB1, BRCA1, CASP8, APLP2, ANXA2, ANKRD11, ALOX5, ADORA3, CFLAR, ARNT, APBB2, ABCA1, HTT, HLA-DRB1, CACNA2D4, ULK4 GABBR2, AARS2, ARL13B, BBS9, ACSL4, CACNA2D4, CCM2, CLCN3, ABCA1, ABHD12, APBB2, ADAM19, ADORA3, AHI1, ADIPOQ, ANXA2, ATP2C1, BRAT1, ALDH7A1, APAF1, APLP2, BRCA1, ATG7, BRCA1, ACOT11, APLP2, APAF1, ALDH7A1, BRAT1, ATP2C1, ANXA2, ADIPOQ, RAP2, CDK5, ERBB3, EIF2B4, AHI1, CTSS, ADORA3, CECR2, ADAM19, APBB2, HMBOX1, CLCN3, ABHD12, CCM2, ABCA1, CACNA2D4, DST, ACSL4, CREB1, CASP8, BBS9, ARL13B, AARS2, ANKRD11, POLA1, ALOX5, CYP7B1, LRP2, AIP, KDM6A, IFT140, CFLAR, HDAC8, NBAS, HDAC4, MYO1B, ARNT,ATF2, GRID1, HUWE1, FAF1, DST, DYX1C1, CLN6, CASP6, ATP7A, ASPA, ARHGAP35, FGF12, DYSF, DNAJC1, IGBP1, IGBP1, PARK2, ORC6, HTT, RAD54L, NEU1, PTPN9, MS4A1, HLA-DRB1, KCNJ6, GABBR2, FAF1, PDXDC2P, PDE9A, OPHN1, SV2C RANBP2, PSEN1, SLMAP, PPARD, PCSK5, BBS5, VAV2 ATXN2, UBR1, SNX2, LAMA2, ATRX, RNF135, KDM6A, HYOU1, OXT, REEP1,NRXN1, PLCB4, NRCAM, NR1H2, MKS1,PHB, C9, BRWD3, BRAF, LPIN1, LOC440040, PRPH2, PDS5B, TRA, PARP1, TAF1, PARD3, SMO, RTTN, SPTLC1, SLC30A10, SERAC1, CASK, PARG, CAMTA1, MKKS, MFN2, CACNB4, LRRK2, SMAD2, RPGRIP1L, PTPRD, UNC13B ULK4, ADCY10 AKAP9, CASP6, ARHGAP5, CLCN3, ALPL, APBB2, ATF2, HEY2, ABL2, ADAM19, AGTPBP1, ADIPOQ, ANXA2, ATP2C1, CASP8, APAF1, APLP2, BRCA1, ATG7, CDK5RAP2, CDK5RAP2, ATG7, BRCA1, APLP2, CASP8, APAF1, ATP2C1, ANXA2, ADIPOQ, AGTPBP1, ADAM19, ABL2, HEY2, ATF2, APBB2, ALPL, CLCN3, CASP6, ARHGAP5, AKAP9, ADCY10 SVA_A SVA_B SVA_C SVA_D SVA_E SVA_F SVA_F1 SVA_F SVA_E SVA_D SVA_C SVA_B SVA_A GABBR2 KCNJ6, PLCB4 CLCN3, HDAC4, HTT, ABCA1, ABHD12, ATF2, ABL2, AGTPBP1, ATP7A, ATP8A2, CREB1, OPHN1, UBR1 APLP2, KALRN, LEF1, ACOT11, ATG7, ATG7, ACOT11, LEF1, KALRN, APLP2, UBR1 OPHN1, CREB1, ATP8A2, ATP7A, AGTPBP1, ABL2, ATF2, ABHD12, ABCA1, HTT, HDAC4, CLCN3, PLCB4 KCNJ6, GABBR2 GABBR2, KCNJ6, PHB, CNTN4, DCLK1, DST, FBXL20, HYOU1, LAMA2, LRRK2, AHI1, ALOX5, ANK2, CLIC4, CREB1, DST, LFNG, CLIC4, EIF2B4, ERBB3, FSTL1, CYP7B1, HTR1E, HTR1E, CYP7B1, FSTL1, ERBB3, EIF2B4, LFNG, CLIC4, DST, CREB1, CLIC4, LRRK2, ANK2, LAMA2, ALOX5, AHI1, HYOU1, FBXL20, DST, DCLK1, CNTN4, PHB, KCNJ6, GABBR2, PLCB4, SMO, TRA, GRID1, HDAC2, HDAC4, MKKS, PARG, PTPN9, ARHGAP35, ASPA, ATP7A, ATP8A2, OPHN1, UBR1, VAV2 KALRN, LEF1, LRP2, LRRC4C, PTPN9, SV2C PTPN9, LRRC4C, LRP2, LEF1, KALRN, VAV2 UBR1, OPHN1, ATP8A2, ATP7A, ASPA, ARHGAP35, PTPN9, PARG, MKKS, HDAC4, TRA, HDAC2, SMO, GRID1, PLCB4, ULK4, UNC13B HTT, MAPK1, MYO5A, NCOR1, RORA, SIL1, STAR ATRX, ATXN2, BRAF, C2CD3, CACNB4, MYH10, NPM1, OMP, PARK2, PARK2, OMP, NPM1, MYH10, CACNB4, C2CD3, BRAF, NCOR1, ATXN2, MYO5A, ATRX, MAPK1, STAR SIL1, HTT, RORA, UNC13B ULK4, Table 1. Genes associated insertions with and Table SVA classified to 4 categories relevant to neural system function.

[page 4] [Trends in Evolutionary Biology 2017; 6:6514] Article

CNS-relevant pathways. Our data has estab- SVA trans-mobilization.28 2. Hancks DC, Ewing AD, Chen JE, et al. lished that more primitive behavioral char- Behavioral trends caused by SVA inser- Exon-trapping mediated by the human acteristics (as climbing, for example) are tions in genes expressed in brain could be retrotransposon SVA. Genome Res prominent for the genes associated with the thus linked to a higher rate of an inheritable 2009;19:1983-91. older SVA subtypes A and B and later inser- SVA trans-mobilization. Thus, being sub- 3. Hancks DC, Kazazian HH, Jr. SVA tions are more related to younger trends, jected to positive or negative selection at retrotransposons: evolution and genetic such as walking. Overall, results revealed a particular stages of hominoid evolution, instability. Semin Cancer Biol striking correlation between the timing of those behavioral trends could be associated 2010;20:234-45. SVA insertions (Figure 1) and functional with waves of heritable SVA propagation in 4. Oliver KR, Green WK. Mobile DNA significance of these associated genes at the genome. The mechanisms of accelera- and the TE-Thrust hypothesis: support- particular stages of hominoid evolution.21 tion and inhibition of propagation of SVAs ing evidence from primates. Mobile This may not be surprising but could be may be common for all TE, and the wavy DNA 2011,2:8. consistent with the lineage variation of the nature of this process have been mentioned 5. Mills RE, Bennett EA, Iskow RC, et al. phylogenic tree for primates (Figure 1). It earlier.4 Genes associated with both neu- Recently mobilized transposons in the attracts our attention, particularly, that a ronal and reproductive phenotypes as well human and chimpanzee genomes. Am J number of behavioral characteristics rele- as with TE trans-mobilization properties Hum Genet 2006;78:671-9. vant to maternity care such as Nursing, could be in the first line of the TE-driven 6. Ostertag EM, Goodier JL, Zhang Y, Feeding, Nest Building, Mother Preference, evolutionary changes. Interestingly, genes Kazazian HH, Jr. SVA elements are non were populated by SVA-associated genes involved in CNS and reproductive functions autonomous retrotransposons that cause during the last 6 Myrs of hominoid evolu- and DNA repair are associated with differ- disease in humans. Am J Hum Genet tion (Figure 1). Provided these structural ent autonomous and non-autonomous TE 2003;73:1444-51. changes are functionally significant, they elements,4 that potentially make a cumula- 7. Wang H, Xing J, Grover D, et al. SVA can correspond to a consistent neotenisation tive evolutionary impact. elements: a hominid-specific retropo- of hominoids and development of a family- son family. J Mol Biol 2005;354:994- based social structure.21 Another example is only1007. Nest Building Behavior that is associated 8. Savage AL, Bubb VJ, Breen G, Quinn with SVA types B and D and is known to Conclusions JP. Characterisation of the potential decline with evolution of hominoids due to function of SVA retrotransposons to a switch to ground-sleeping.22 This decline Our systems analysis suggests an modulate gene expression patterns. was speculated to be also an enhancer of impact of SVA retrotransposition onuse evolu- BMC Evol Biol 2013;13:101. walking survival skills, innovation, proce- tion and performance of human cognitive 9. Cordaux R, Batzer MA. The impact of dural memories and gender specification. functions. Data revealed that insertions of retrotransposons on human genome The associated insertions can suggestively members of the older SVA subtypes A-C evolution. Nat Rev Genet 2009;10:691- play a suppressive or deleterious role in this occurred in genes involved in more primi- 703. behavioral trend. Some of the SVA inser- tive characteristics whereas younger SVA 10. Savage AL, Wilm TP, Khursheed K, et tions could also have a gender-specific D-F1 insertions were present in genes al. An evaluation of a SVA retrotranspo- influence on cognitive functions. The linked to more sophisticated human-specif- son in the FUS promoter as a transcrip- BRCA1 gene, for instance, which is associ- ic traits. The presence of SVAs in multiple tional regulator and its association to ated with an SVA F insertion and is one of genes within a network may allow for a ALS. PLoS ONE 2014;9:e90833. the hubs in SVA integrated functional net- concerted response to an environmental 11. Zabolotneva AA, Bantysh O, Suntsova work (Figure 2), was shown to be in a cross stimulus modulated by factors targeting MV, et al. Transcriptional regulation of talk with the estrogen receptor ESR1.23,24 commercialSVA regulatory sequences. Potential posi- human-specific SVAF(1) retrotrans- BRCA1 is also known to have a strong role tive feedbacks in SVA-associated functional posons by cis-regulatory MAST2 in the control of brain size,25,26 especially in networks and crosstalk between cognitive sequences. Gene 2012;505:128-36. regions responsible for learning, memory, and reproductive functions would lead to 12. Carbone L, Harris RA, Gnerre S, et al. muscle control and balance. Interestingly, waves of SVA trans-mobilization in the Gibbon genome and the fast karyotype structurally related PGR (progesterone-Non course of hominoid evolution. Considering evolution of small apes. Nature dependent transcription factor) binding sites that genetic polymorphisms in the human 2014;513:195-201. were shown to be enriched in ancient mam- population are associated with SVA inser- 13. Gietzen D. Ingenuity Pathways Analysis malian TEs linked to evolution of pregnan- tions and that the youngest SVA insertions (IPA) 2010 [cited 2013]. Available from: cy,27 and LTR and Alu elements were also are documented in human brain and germ http://www.usc. shown to be strongly associated with genes line tissues, it can be suggested that SVAs edu/hsc/nml/assets/bioinfo/IPA/Data%20 relevant to reproduction.4 have a modulatory impact on recent human Analysis%20training%20Handouts.pdf. Moderate expression of the majority of behavioral trends and susceptibilities to 14. Hruz T, Laule O, Szabo G, et al. behavioral-SVA-associated genes in male psychiatric disorders. Genevestigator V3: a reference expres- germ cells (in contrast to less than 10% sion database for the meta-analysis of though strongly, expressed in oocyte) could transcriptomes. Advances in make this cell type a particular source of Bioinformatics 2008;2008:420747 trans-mobilized SVA elements which are References 15. Levin HL, Moran JV. Dynamic interac- inheritable and passed on to following gen- tions between transposable elements erations. This hypothesis would be support- 1. Muotri AR, Marchetto MC, Coufal NG, and their hosts. Nat Rev Genet ed by a strong expression of L1 retrotrans- Gage FH. The necessary junk: new 2011;12:615-27. posons in this niche which are known to functions for transposable elements. 16. Thompson P, Macfarlan TS, Lorincz provide the protein machinery required for Hum Mol Genet 2007;16:R159-67. MC. Long terminal repeats: from para-

[Trends in Evolutionary Biology 2017; 6:6514] [page 5] Article

sitic elements to building blocks of the 22. Coolidge FL. The effects of the tree-to- neural progenitors. Development transcriptional regulatory repertoire. ground sleep transition in the evolution 2009;136:1859-68. Mol Cell 2016;62:766-76. of cognition in early Homo. Before 27. Lynch VJ, Nnamani MC, Kapusta A, et 17. Hancks DC, Kazazian HH, Jr. Active Farming 2006;4:11-8. al. Ancient transposable elements trans- human retrotransposons: variation and 23. Gorrini C, Gang BP, Bassi C, et al. formed the uterine regulatory landscape disease. Curr Opin Genet Dev Estrogen controls the survival of and transcriptome during the evolution 2012;22:191-203. BRCA1-deficient cells via a PI3K- of mammalian pregnancy. Cell Rep 18. Kaer K, Speek M. Retroelements in NRF2-regulated pathway. Proc Natl 2015;10:551-61. human disease. Gene 2013;518:231-41. Acad Sci USA 2014;111:4472-7. 28. Raiz J, Damert A, Chira et al. The non- 19. Nakamura Y, Murata M, Takagi Y, et al. 24. Kang HJ, Yi YW, Kim HJ, et al. autonomous retrotransposon SVA is SVA retrotransposition in exon 6 of the BRCA1 negatively regulates IGF-1 trans-mobilized by the human LINE-1 coagulation factor IX gene causing expression through an estrogen-respon- protein machinery. Nucleic Acids Res severe hemophilia B. Int J Hematol sive element-like site. Cell Death Dis 2012;40:1666-83. 2015;102:134-9. 2012;3:e336. 29. Zamudio N, Bourchis D. Transposable 20. Quinn JP, Bubb VJ. SVA retrotrans- 25. Pao GM, Zhu Q, Perez-Garcia CG, et elements in the mammalian germline: a posons as modulators of gene expres- al. Role of BRCA1 in brain develop- comfortable niche or a deadly trap sion. Mob Genet Elements ment. Proc Natl Acad Sci USA quest. Heredity 2010;105:92-104. 2014;4:e32102. 2014;111:E1240-E8. 30. Han JS, Szak ST, Boeke JD. 21. Hrdy SB. Evolutionary context of 26. Pulvers JN, Huttner WB. Brca1 is Transcriptional disruption by the L1 human development: the cooperative required for embryonic development of retrotransposon and implications for breeding model. Carter CS, ed. the mouse cerebral cortex to normal mammalian transcriptomes. Nature Cambridge: M.I.T. Press; 2005. size by preventing apoptosis of early 2004;429:268-74. only use

commercial

Non

[page 6] [Trends in Evolutionary Biology 2017; 6:6514]