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Gene Conversion Amongst Alu SINE Elements

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Gene Conversion Amongst Alu SINE Elements G C A T T A C G G C A T genes Article Gene Conversion amongst Alu SINE Elements Liliya Doronina 1,* , Olga Reising 1 and Jürgen Schmitz 1,2,* 1 Institute of Experimental Pathology, ZMBE, University of Münster, 48149 Münster, Germany; [email protected] 2 EvoPAD-RTG, University of Münster, 48149 Münster, Germany * Correspondence: [email protected] (L.D.); [email protected] (J.S.) Abstract: The process of non-allelic gene conversion acts on homologous sequences during recom- bination, replacing parts of one with the other to make them uniform. Such concerted evolution is best described as paralogous ribosomal RNA gene unification that serves to preserve the essential house-keeping functions of the converted genes. Transposed elements (TE), especially Alu short interspersed elements (SINE) that have more than a million copies in primate genomes, are a sig- nificant source of homologous units and a verified target of gene conversion. The consequences of such a recombination-based process are diverse, including multiplications of functional TE internal binding domains and, for evolutionists, confusing divergent annotations of orthologous transposable elements in related species. We systematically extracted and compared 68,097 Alu insertions in various primates looking for potential events of TE gene conversion and discovered 98 clear cases of Alu–Alu gene conversion, including 64 cases for which the direction of conversion was identified (e.g., AluS conversion to AluY). Gene conversion also does not necessarily affect the entire homolo- gous sequence, and we detected 69 cases of partial gene conversion that resulted in virtual hybrids of two elements. Phylogenetic screening of gene-converted Alus revealed three clear hotspots of the process in the ancestors of Catarrhini, Hominoidea, and gibbons. In general, our systematic Citation: Doronina, L.; Reising, O.; screening of orthologous primate loci for gene-converted TEs provides a new strategy and view of a Schmitz, J. Gene Conversion amongst post-integrative process that changes the identities of such elements. Alu SINE Elements. Genes 2021, 12, 905. https://doi.org/10.3390/ Keywords: gene conversion; partial gene conversion; transposable elements; Alu subfamily conver- genes12060905 sion; homoplasy Academic Editor: Manuel A. Garrido-Ramos 1. Introduction Received: 9 May 2021 Genomes of most eukaryotic organisms contain a large number of repetitive sequences, Accepted: 8 June 2021 a notable portion of which is composed of transposable elements (TE). For example, TEs Published: 11 June 2021 occupy up to 69% of human genomes [1]. Despite the large numbers of TEs, only a few “master-copies” can actively propagate [2,3]. Accumulating changes in master copies leads Publisher’s Note: MDPI stays neutral to new subfamilies and types of TEs that commonly differ by several diagnostic sites and with regard to jurisdictional claims in published maps and institutional affil- spread in limiting activity waves through the genome [4]. iations. Due to their repetitive nature, high similarity, and large quantities in the genome, TEs present a significant substrate for non-allelic gene conversion. Gene conversion is a process whereby the genetic material of a donor sequence unidirectionally replaces that of a homologous acceptor sequence via recombination after a double-strand DNA break. Thus, gene conversion can proliferate mutations among TEs independently of Copyright: © 2021 by the authors. the activity of the master-copy, leading to TE homogenization, a phenomenon known Licensee MDPI, Basel, Switzerland. as concerted evolution [5]. Earlier retrotransposon studies reported a few cases of gene This article is an open access article distributed under the terms and conversion between TE copies. For example, Kass and colleagues [6] described a case conditions of the Creative Commons of gene conversion that changed a younger human Alu SINE to an older element. Roy Attribution (CC BY) license (https:// et al. [7] suggested that gene conversion is responsible for ~10–20% of the variation in creativecommons.org/licenses/by/ the young AluYa5 subfamily. A whole-genome gene conversion analysis among Alus in 4.0/). humans [8] focused on non-diagnostic mutations in Alu sequences revealed significant Genes 2021, 12, 905. https://doi.org/10.3390/genes12060905 https://www.mdpi.com/journal/genes Genes 2021, 12, x FOR PEER REVIEW 2 of 9 Genes 2021, 12, 905 2 of 10 diagnostic mutations in Alu sequences revealed significant levels of gene conversion, es- pecially amonglevels neighboring of gene Alu conversion,s. The authors especially found among that gene neighboring conversionAlu actss. The on authorsAlus found that within a rangegene of about conversion 10 kb, inversely acts on Alupropors withintional a to range their ofdistance about 10from kb, one inversely another. proportional to Most studies oftheir gene distance conversion from between one another. TEs focused Most studies on Alu of SINEs gene conversionin primates. between How- TEs focused ever, similar effectson Alu wereSINEs also in reported primates. for However, LTRs in similarother mammals effects were [9,10] also and reported in plants for LTRs in other [11]. mammals [9,10] and in plants [11]. As the vast majorityAs the vastof genomic majority TEs of genomic are neutral TEs to are the neutral effects to theof natural effects ofselection, natural selection, gene gene conversionconversion does not doesusually not have usually a crucial have aimpact crucial on impact the organism. on the organism. However, However, TE TE gene gene conversionconversion can have canan haveadaptive an adaptive effect in effectrewiring in rewiring regulatory regulatory networks networks (reviewed (reviewed in [12]). in [12]). For example,For example, gene conversion gene conversion among among ISX TEs ISX might TEs mightbe responsible be responsible for optimizing for optimizing binding binding sites forsites the for dosage the dosage compensation compensation complex complex in Drosophila in Drosophila [13]. [13]. Gene conversionGene may conversion also directly may influenc also directlye the influenceevolution the of evolutionTEs [12,14]. of TEsTransfer- [12,14]. Transferring ring mutationsmutations to master to copies master may copies increase mayincrease or reduce or reducetheir activity, their activity, as proposed as proposed for for example example for thefor Alu theYh3a3AluYh3a3 subfamily subfamily [15]. [Moreover,15]. Moreover, gene gene conversion conversion might might lead leadto the to the formation formation of newof new TE families TE families or help or help maintain maintain them them in endosymbiont in endosymbiont genomes genomes byby pre- preventing their venting their degradationdegradation and and loss loss [16]. [16]. The extent of sequenceThe extent similarity of sequence between similarity donor between and acceptor donor and loci acceptor positively loci positivelyinflu- influences ences the frequencythe frequency of gene ofconversion, gene conversion, and reaches and reaches an optimum an optimum at 89%–100% at 89%–100% [17,18]. [17, 18]. Therefore, Therefore, a substantiala substantial number number of gene of gene conversion conversion events events involves involves young young TEs TEsof the of same the same subfamily. subfamily. AluAlu elementselements are arethe themost most abundant abundant TEs TEs in primate in primate genomes genomes and and have have served served as a model as a model groupgroup for TE-based for TE-based gene gene conversion conversion studies studies e.g., [7,8]. e.g., Alu [7,8s]. evolvedAlus evolved from 7 SL from 7 SL RNA RNA around 65around million 65 years million ago years in the ago ancestral in the ancestrallineage of lineage primates of primatesand consist and of consist di- of dimeric 0 0 meric sequencessequences of about of300 about nt (merged 300 nt (merged 5′- and 3 5′-monomers- and 3 -monomers [19]). They [19 ]).diverged They diverged into into three three subfamilies/types—thesubfamilies/types—the oldest Alu oldestJ, the AluAluJ,S, the andAlu theS, andyoungest the youngest AluY. MoreAluY. than More a than a million million Alu copiesAlu copiesare distributed are distributed across the across human the humangenome, genome, occupying occupying about 11% about of ge- 11% of genomic nomic space [20].space Because [20]. Becausegene conversion gene conversion also acts on also relatively acts on relativelyshort sequences short sequences(begin- (beginning ning with 10 ntwith [17]), 10 not nt [only17]), are not entire only areAlu entiresequencesAlu sequences substituted, substituted, but also partial but also Alu partial– Alu–Alu 0 0 Alu gene conversiongene conversion occurs, resulting occurs, in resulting hybrid elements in hybrid (e.g., elements hybrids (e.g., with hybrids 5′-Alu withS and 5 -AluS and 3 - 3′-AluY [21,22],Alu FigureY[21 1).,22 ], Figure1). Figure 1. SchematicFigure 1. representationSchematic representation of Alu–Alu geneof Alu conversion.–Alu gene conversion. (A) shows three (A) shows different three scenarios different of scenarios gene conversion: in of gene conversion: in which a 5′-end Alu monomer, a complete Alu, or a 3′-end Alu monomer were which a 50-end Alu monomer, a complete Alu, or a 30-end Alu monomer were converted. (B) Representative gene conversion converted. (B) Representative gene conversion at orthologous AluS loci leading to 5′-end AluY, at orthologous AluS loci leading to 50-end AluY, AluY, and 30-end AluY in the common ancestor of great apes (grey area;
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