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 human genome 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 gene 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 genes 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 gene expression 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 central nervous system 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 protein 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