{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T07:17:14Z","timestamp":1765610234103,"version":"build-2065373602"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T00:00:00Z","timestamp":1648598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005690","name":"Universit\u00e4t des Saarlandes","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005690","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>The neural cell adhesion protein neuroligin-4 has puzzled neuroscientists and geneticist alike for almost two decades. Its clinical association with autism spectrum disorders (ASD) is well established, however, its diversification into sex chromosome-specific copies,<jats:italic>NLGN4X<\/jats:italic>and<jats:italic>NLGN4Y<\/jats:italic>, remains uncharted territory. Just recently, the presence of substantial neuroligin-4 sequence differences between humans and laboratory mice, in which<jats:italic>Nlgn4<\/jats:italic>is a pseudoautosomal gene, could be explained as a consequence of dramatic changes affecting the pseudoautosomal region on both sex chromosomes in a subset of rodents, the clade eumuroida. In this study, we describe the presence of sex chromosome-specific copies of neuroligin-4 genes in the Mongolian gerbil (<jats:italic>Meriones unguiculatus<\/jats:italic>) marking the first encounter of its kind in rodents. Gerbils are members of the family Muridae and are closely related to mice and rats. Our results have been incorporated into an extended evolutionary analysis covering primates, rodents, lagomorphs, treeshrews and culogos comprising together the mammalian superorder euarchontoglires. We gathered evidence that substantial changes in neuroligin-4 genes have also occurred outside eumuroida in other rodent species as well as in lagomorphs. These changes feature, e.g., a general reduction of its gene size, an increase in its average GC-content as well as in the third position (GC3) of synonymous codons, and the accumulation of repetitive sequences in line with previous observations. We further show conclusively that the diversification of neuroligin-4 in sex chromosome-specific copies has happened multiple times independently during mammal evolution proving that Y-chromosomal<jats:italic>NLGN4Y<\/jats:italic>genes do not originate from a single common<jats:italic>NLGN4Y<\/jats:italic>ancestor.<\/jats:p>","DOI":"10.3389\/fnmol.2022.838262","type":"journal-article","created":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T12:16:50Z","timestamp":1648642610000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Of Humans and Gerbils\u2014 Independent Diversification of Neuroligin-4 Into X- and Y-Specific Genes in Primates and Rodents"],"prefix":"10.3389","volume":"15","author":[{"given":"Stephan","family":"Maxeiner","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fritz","family":"Benseler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nils","family":"Brose","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriela","family":"Krasteva-Christ","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1038\/s41587-019-0036-z","article-title":"SignalP 5.0 improves signal peptide predictions using deep neural networks.","volume":"37","author":"Almagro Armenteros","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1016\/j.neuron.2007.12.002","article-title":"Structures of neuroligin-1 and the neuroligin-1\/neurexin-1 beta complex reveal specific protein-protein and protein-Ca2+ interactions.","volume":"56","author":"Ara\u00e7","year":"2007","journal-title":"Neuron"},{"key":"B3","first-page":"505","article-title":"Analysis of the genes encoding neuroligins NLGN3 and NLGN4 in Bulgarian patients with autism.","volume":"23","author":"Avdjieva-Tzavella","year":"2012","journal-title":"Genet. Couns."},{"key":"B4","doi-asserted-by":"publisher","first-page":"6421","DOI":"10.1073\/pnas.0801383105","article-title":"Unusually rapid evolution of Neuroligin-4 in mice.","volume":"105","author":"Bolliger","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B5","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.neuron.2005.08.026","article-title":"A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to alpha- and beta-neurexins.","volume":"48","author":"Boucard","year":"2005","journal-title":"Neuron"},{"key":"B6","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/nrn3992","article-title":"From the genetic architecture to synaptic plasticity in autism spectrum disorder.","volume":"16","author":"Bourgeron","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.1111\/j.1460-9568.2007.05842.x","article-title":"Neuroligin-3 is a neuronal adhesion protein at GABAergic and glutamatergic synapses.","volume":"26","author":"Budreck","year":"2007","journal-title":"Eur. J. Neurosci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/jmammal\/gyx147","article-title":"How many species of mammals are there?","volume":"99","author":"Burgin","year":"2018","journal-title":"J. Mammal."},{"key":"B9","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/BF00274192","article-title":"Genetic homology and crossing over in the X and Y chromosomes of Mammals.","volume":"61","author":"Burgoyne","year":"1982","journal-title":"Hum. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1523\/JNEUROSCI.0404-20.2020","article-title":"An Autism- Associated Mutation Impairs Neuroligin-4 Glycosylation and Enhances Excitatory Synaptic Transmission in Human Neurons.","volume":"41","author":"Cast","year":"2021","journal-title":"J. Neurosci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1016\/j.neuron.2007.05.029","article-title":"Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2.","volume":"54","author":"Chubykin","year":"2007","journal-title":"Neuron"},{"key":"B12","doi-asserted-by":"publisher","first-page":"10881","DOI":"10.1093\/nar\/16.22.10881","article-title":"Multiple sequence alignment with hierarchical clustering.","volume":"16","author":"Corpet","year":"1988","journal-title":"Nucleic Acids Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1038\/nature13151","article-title":"Origins and functional evolution of Y chromosomes across mammals.","volume":"508","author":"Cortez","year":"2014","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.conb.2007.01.011","article-title":"Neurexin-neuroligin signaling in synapse development.","volume":"17","author":"Craig","year":"2007","journal-title":"Curr. Opin. Neurobiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1093\/jmammal\/gyy179","article-title":"Rodent systematics in an age of discovery: Recent advances and prospects.","volume":"100","author":"D\u2019El\u00eda","year":"2019","journal-title":"J. Mammal."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.0030198","article-title":"Meiotic pairing and segregation of achiasmate sex chromosomes in eutherian mammals: the role of SYCP3 protein.","volume":"3","author":"De la Fuente","year":"2007","journal-title":"PLoS Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1111\/j.1558-5646.1985.tb00420.x","article-title":"Confidence limits on phylogenies: an approach using the bootstrap.","volume":"39","author":"Felsenstein","year":"1985","journal-title":"Evolution"},{"key":"B18","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1038\/ejhg.2008.63","article-title":"The human pseudoautosomal regions: a review for genetic epidemiologists.","volume":"16","author":"Flaquer","year":"2008","journal-title":"Eur. J. Hum. Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1662","DOI":"10.1002\/mrd.20903","article-title":"Differences of the porcine amelogenin X and Y chromosome genes (AMELX and AMELY) and their application for sex determination in pigs.","volume":"75","author":"Fontanesi","year":"2008","journal-title":"Mol. Reprod. Dev."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1016\/j.cell.2004.11.035","article-title":"Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins.","volume":"119","author":"Graf","year":"2004","journal-title":"Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/nrg.2015.2","article-title":"Evolution of vertebrate sex chromosomes and dosage compensation.","volume":"17","author":"Graves","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1292\/jvms.62.1109","article-title":"Sex determination by simultaneous amplification of equine SRY and amelogenin genes.","volume":"62","author":"Hasegaw","year":"2000","journal-title":"J. Vet. Med. Sci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/ng1136","article-title":"Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.","volume":"34","author":"Jamain","year":"2003","journal-title":"Nat. Genet."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1073\/pnas.0711555105","article-title":"Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism.","volume":"105","author":"Jamain","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2016.69","article-title":"Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder.","volume":"6","author":"Kilaru","year":"2016","journal-title":"Transl. Psychiatry"},{"key":"B26","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.conb.2017.04.003","article-title":"Organizers of inhibitory synapses come of age.","volume":"45","author":"Krueger-Burg","year":"2017","journal-title":"Curr. Opin. Neurobiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.1093\/molbev\/msy096","article-title":"MEGA X: Molecular Evolutionary Genetics Analysis across Computing Platforms.","volume":"35","author":"Kumar","year":"2018","journal-title":"Mol. Biol. Evol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"11435","DOI":"10.1523\/JNEUROSCI.2946-10.2010","article-title":"Alternative splicing of neuroligin regulates the rate of presynaptic differentiation.","volume":"30","author":"Lee","year":"2010","journal-title":"J. Neurosci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1007\/BF01371335","article-title":"Forensic application of a rapid and quantitative DNA sex test by amplification of the X-Y homologous gene amelogenin.","volume":"106","author":"Mannucci","year":"1994","journal-title":"Int. J. Legal Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1093\/molbev\/msaa014","article-title":"Evolution of the Autism-Associated Neuroligin-4 Gene Reveals Broad Erosion of Pseudoautosomal Regions in Rodents.","volume":"37","author":"Maxeiner","year":"2020","journal-title":"Mol. Biol. Evol."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.aanat.2021.151765","article-title":"Of mice and men - and guinea pigs?","volume":"238","author":"Maxeiner","year":"2021","journal-title":"Ann. Anat."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1186\/s13293-019-0279-x","article-title":"Novel human sex-typing strategies based on the autism candidate gene NLGN4X and its male-specific gametologue NLGN4Y.","volume":"10","author":"Maxeiner","year":"2019","journal-title":"Biol. Sex Differ."},{"key":"B33","doi-asserted-by":"publisher","first-page":"2348","DOI":"10.1126\/science.1067179","article-title":"Resolution of the early placental mammal radiation using Bayesian phylogenetics.","volume":"294","author":"Murphy","year":"2001","journal-title":"Science"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006940","article-title":"Functional significance of rare neuroligin 1 variants found in autism.","volume":"13","author":"Nakanishi","year":"2017","journal-title":"PLoS Genet."},{"key":"B35","doi-asserted-by":"publisher","first-page":"759.e","DOI":"10.1016\/j.neuron.2020.03.008","article-title":"A Cluster of Autism- Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y.","volume":"106","author":"Nguyen","year":"2020","journal-title":"Neuron"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.58668","article-title":"Alternative splicing at neuroligin site A regulates glycan interaction and synaptogenic activity.","volume":"9","author":"Oku","year":"2020","journal-title":"Elife"},{"key":"B37","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1002\/ajmg.a.37977","article-title":"Neuroligin 2 nonsense variant associated with anxiety, autism, intellectual disability, hyperphagia, and obesity.","volume":"173","author":"Parente","year":"2017","journal-title":"Am. J. Med. Genet. A."},{"key":"B38","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1016\/j.neuron.2009.08.023","article-title":"Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin.","volume":"63","author":"Poulopoulos","year":"2009","journal-title":"Neuron"},{"key":"B39","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1159\/000443157","article-title":"The Eutherian Pseudoautosomal Region.","volume":"147","author":"Raudsepp","year":"2015","journal-title":"Cytogenet. Genome Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1093\/oxfordjournals.molbev.a040454","article-title":"The neighbor-joining method: a new method for reconstructing phylogenetic trees.","volume":"4","author":"Saitou","year":"1987","journal-title":"Mol. Biol. Evol."},{"key":"B41","first-page":"303","article-title":"The human enamel protein gene amelogenin is expressed from both the X and the Y chromosomes.","volume":"50","author":"Salido","year":"1992","journal-title":"Am. J. Hum. Genet."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1073\/pnas.96.3.1100","article-title":"Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses.","volume":"96","author":"Song","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1093\/molbev\/msz312","article-title":"Molecular Evolutionary Genetics Analysis (MEGA) for macOS.","volume":"37","author":"Stecher","year":"2020","journal-title":"Mol. Biol. Evol."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1186\/2040-2392-3-8","article-title":"Identification of rare X-linked neuroligin variants by massively parallel sequencing in males with autism spectrum disorder.","volume":"3","author":"Steinberg","year":"2012","journal-title":"Mol. Autism"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0183070","article-title":"Muroid rodent phylogenetics: 900-species tree reveals increasing diversification rates.","volume":"12","author":"Steppan","year":"2017","journal-title":"PLoS One"},{"key":"B46","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/j.cell.2017.10.024","article-title":"Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits.","volume":"171","author":"S\u00fcdhof","year":"2017","journal-title":"Cell"},{"key":"B47","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1126\/science.1146221","article-title":"A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice.","volume":"318","author":"Tabuchi","year":"2007","journal-title":"Science"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.1093\/oxfordjournals.molbev.a003995","article-title":"Evolutionary distance estimation under heterogeneous substitution pattern among lineages.","volume":"19","author":"Tamura","year":"2002","journal-title":"Mol. Biol. Evol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"11030","DOI":"10.1073\/pnas.0404206101","article-title":"Prospects for inferring very large phylogenies by using the neighbor-joining method.","volume":"101","author":"Tamura","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B50","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1078\/0171-9335-00410","article-title":"Neuroligin 2 is exclusively localized to inhibitory synapses.","volume":"83","author":"Varoqueaux","year":"2004","journal-title":"Eur. J. Cell Biol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"4938","DOI":"10.1002\/cne.22499","article-title":"Alternative splicing of neuroligin and its protein distribution in the outer plexiform layer of the chicken retina.","volume":"518","author":"Wahlin","year":"2010","journal-title":"J. Comp. Neurol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1093\/molbev\/mss267","article-title":"Gene survival and death on the human Y chromosome.","volume":"30","author":"Wilson Sayres","year":"2013","journal-title":"Mol. Biol. Evol."},{"key":"B53","doi-asserted-by":"crossref","DOI":"10.56021\/9780801882210","author":"Wilson","year":"2005","journal-title":"Mammal Species of the World. A Taxonomic and Geographic Reference"},{"key":"B54","doi-asserted-by":"publisher","first-page":"4133","DOI":"10.1007\/s11033-014-3284-5","article-title":"Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients.","volume":"41","author":"Xu","year":"2014","journal-title":"Mol. Biol. Rep."},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1111\/age.12063","article-title":"Sex identification of dog by PCR based on the differences in the AMELX and AMELY genes.","volume":"44","author":"Yan","year":"2013","journal-title":"Anim. Genet."},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1111\/age.12823","article-title":"Sex identification in horses (Equus caballus) based on the gene pair NLGN4X\/NLGN4Y.","volume":"50","author":"Zaffalon","year":"2019","journal-title":"Anim. Genet."},{"key":"B57","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/0022-5193(65)90083-4","article-title":"Molecules as documents of evolutionary history.","volume":"8","author":"Zuckerkandl","year":"1965","journal-title":"J. Theor. Biol."}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2022.838262\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,19]],"date-time":"2023-11-19T12:10:44Z","timestamp":1700395844000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2022.838262\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,30]]},"references-count":57,"alternative-id":["10.3389\/fnmol.2022.838262"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2022.838262","relation":{},"ISSN":["1662-5099"],"issn-type":[{"type":"electronic","value":"1662-5099"}],"subject":[],"published":{"date-parts":[[2022,3,30]]},"article-number":"838262"}}