The Retrotransposon-Derived Capsid Genes PNMA1 and PNMA4 Maintain Reproductive Capacity

The Retrotransposon-Derived Capsid Genes PNMA1 and PNMA4 Maintain Reproductive Capacity | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The Retrotransposon-Derived Capsid Genes PNMA1 and PNMA4 Maintain Reproductive Capacity Luke Berchowitz, Thomas Wood, William Henriques, Harrison Cullen, and 17 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4559920/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Apr, 2025 Read the published version in Nature Aging → Version 1 posted You are reading this latest preprint version Abstract The human genome contains 24 gag-like capsid genes derived from deactivated retrotransposons conserved among eutherians. Although some of their encoded proteins retain the ability to form capsids and even transfer cargo, their fitness benefit has remained elusive. Here we show that the gag-like genes PNMA1 and PNMA4 support reproductive capacity during aging. Analysis of donated human ovaries shows that expression of both genes declines normally with age, while several PNMA1 and PNMA4 variants identified in genome-wide association studies are causally associated with low testosterone, altered puberty onset, or obesity. Six-week-old mice lacking either Pnma1 or Pnma4 are indistinguishable from wild-type littermates, but by six months the mutant mice become prematurely subfertile, with precipitous drops in sex hormone levels, gonadal atrophy, and abdominal obesity; overall they produce markedly fewer offspring than controls. These findings expand our understanding of factors that maintain human reproductive health and lend insight into the domestication of retrotransposon-derived genes. Biological sciences/Developmental biology/Ageing Biological sciences/Developmental biology/Germline development Health sciences/Diseases/Reproductive disorders Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files FigS1.pdf FigS2.pdf FigS3.pdf FigS4.pdf FigS5.pdf FigS6.pdf FigS7.pdf FigS8.pdf FigS9.pdf FigS10.pdf FigS11.pdf FigS12.pdf TableS1.xlsx Cite Share Download PDF Status: Published Journal Publication published 22 Apr, 2025 Read the published version in Nature Aging → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4559920","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":324251786,"identity":"4973c3d3-4451-409a-b766-00dbe94bcd73","order_by":0,"name":"Luke 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University","correspondingAuthor":false,"prefix":"","firstName":"Yousin","middleName":"","lastName":"Suh","suffix":""},{"id":324251806,"identity":"323ae1cb-31c6-4c66-af6a-7803604cf622","order_by":20,"name":"Blake Wiedenheft","email":"","orcid":"","institution":"Montana State University","correspondingAuthor":false,"prefix":"","firstName":"Blake","middleName":"","lastName":"Wiedenheft","suffix":""}],"badges":[],"createdAt":"2024-06-10 20:00:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4559920/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4559920/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s43587-025-00852-y","type":"published","date":"2025-04-22T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":59976662,"identity":"36fa7a13-b269-42ce-9fb3-047246ed033e","added_by":"auto","created_at":"2024-07-10 04:56:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":296759,"visible":true,"origin":"","legend":"\u003cp\u003ePNMA1 and PNMA4 are expressed in human ovaries (A) Analysis of uniquely mapping single-cell RNAseq reads for PNMA1-5 loci expressed in MII human oocytes (data from Yuan et al., 2021)38. (B) Human ovaries from young (23-29 years of age, N = 4) and older (49-54 years of age, N = 4) donors were analyzed by single-nuclei RNAseq. Uniquely mapping reads for PNMA1 and PNMA4 loci were assigned to ovarian tissue types based on clustering analysis. Note that the majority of values = 0 and lie underneath the x axis (error bars represent SEM). Total n of each cell type and percentage of positive cells is indicated above the plots. Statistical significance (*p \u0026lt; 0.05) was determined by Mann-Whitney test with Welch’s correction.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4559920/v1/06877a192bde7770274e041b.png"},{"id":59976217,"identity":"fba2f25e-66b0-4437-b58d-1cb8c0b4652c","added_by":"auto","created_at":"2024-07-10 04:48:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":261331,"visible":true,"origin":"","legend":"\u003cp\u003ePNMA1 and PNMA4 are conserved among eutherians (A, B) Architecture of the human PNMA1 and PNMA4. Loci are colored according to domains: capsid domain (CA, magenta), linker (L, lilac), and RNA-binding domain (RBD, purple). The promoter (green) and transcription start sites are shown using arrows. A black triangle on the phylogenetic tree (left) indicates the point of the first expansion of the ancestral PNMA locus leading to PNMA1-5. PNMA1 is universally retained across placental mammals as an intact gene, whereas PNMA4 has experienced lineage-specific pseudogenization (boxed x’s). Conservation at each amino acid is shown with a vertical black line for fifteen eutherian mammals, three marsupials, and two vertebrate outgroups. The histone modification for active transcription (H3K27Ac) in humans is shown along the bottom.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-4559920/v1/2804e9bb2bc2f01e2d676a85.png"},{"id":59976659,"identity":"01aca23a-4ec4-4484-b24a-6ee3795c7ff9","added_by":"auto","created_at":"2024-07-10 04:56:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2294378,"visible":true,"origin":"","legend":"\u003cp\u003eMale mice lacking Pnma1 or Pnma4 prematurely lose reproductive capacity (A) Wild type male control mice (gray), Pnma1-/- (cyan), or Pnma4-/- (purple) were crossed biweekly to CF-1 female fertility tester mice (N = 5 pairs for each genotype-timepoint combination). Pup numbers for each cross were recorded. (B, C) Testes (n above graph) from control (pooled wild type and heterozygous, gray), Pnma1-/- (cyan), Pnma4-/- (purple), or Pnma1-/- Pnma4-/- double mutant (red) mice were weighed. Representative images and 389 quantifications are shown. (D) Sperm counts from dissected cauda epididymides. The number of individuals (N) for each genotype and age are shown above. (E) Serum testosterone (from N individual males) at the indicated ages. (F) PAS-stained tubule sections from 6-month-old mouse testes; devoid tubules are indicated by yellow arrowheads. (G) Devoid tubules (from n testes) as percentage of total. (H) Sections from 12-month-old testes were analyzed by TUNEL and DAPI staining. TUNEL397 positive cells are indicated by yellow arrowheads. (I) Percent TUNEL-positive cells per tubule (n indicated by genotype to the right). Statistical significance (*p \u0026lt; 0.05) was determined by one-way ANOVA with correction for multiple comparisons and student’s t-test. Error bars indicate SEM.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-4559920/v1/a34f10d22fcc13ffc30d0c70.png"},{"id":59976660,"identity":"40fe28cc-9222-47cb-944a-691637b729a4","added_by":"auto","created_at":"2024-07-10 04:56:48","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2714045,"visible":true,"origin":"","legend":"\u003cp\u003eFemale mice lacking Pnma1 or Pnma4 have age-dependent reproductive defects (A) Wild type female wild type mice (gray), Pnma1-/- (cyan), or Pnma4-/- (purple) were crossed to B6D21/J male fertility tester mice (N = 5 pairs for each genotype-timepoint combination). Pup numbers for each cross are plotted over time. (B) PAS-stained ovarian sections from 3-month-old mouse ovaries. Black arrows denote antral follicles, yellow arrows denote abnormal follicles, and green arrows denote follicular cysts. (C) Representative images of ovaries from the four genotypes. (D) Ovaries (n above graph) from control (pooled wild type and heterozygous, gray), Pnma1-/- (cyan), Pnma4-/- (purple), or Pnma1-/- Pnma4-/- double mutant (red) mice were weighed. (E) The number of antral follicles at the indicated ages per mm2. The number of individuals (N) for each genotype and age are shown. (F) The number of follicular cysts per mm2 by age and genotype (N’s in graph). (G) Germinal vesicle (GV) oocytes were collected from six-414 month-old females and meiotically induced. Meiotic progression was analyzed by tubulin immunofluorescence. Percentage of meiosis II oocytes was recorded. (H) GV oocytes were collected from seven-month-old wild-type and double mutant mouse ovaries. We injected mRNA encoding mClover-MAP4 (microtubule-binding protein) and H2B419 mScarlet (histone) and imaged oocytes live for ~18 hours, recording (I) the time from nuclear envelope breakdown (NEBD) to anaphase I and (J) lagging chromosome percentages. Statistical significance (*p \u0026lt; 0.05) was determined by determined by one-way ANOVA with correction for multiple comparisons and student’s t-test. Error bars indicate SEM.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-4559920/v1/e93f85295ec07c2801dd8055.png"},{"id":59976228,"identity":"184c68f6-9252-4105-8e21-9a13c644bacc","added_by":"auto","created_at":"2024-07-10 04:48:48","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":959619,"visible":true,"origin":"","legend":"\u003cp\u003ePnma1 and Pnma4 mutants gain abdominal fat with age (A) Body weights (N above graph) of control (pooled wild type and heterozygote, gray), Pnma1-/- (cyan), Pnma4-/- (purple), or Pnma1-/- Pnma4-/- double mutant (red) at the indicated ages. (B) Representative images of abdominal fat at six months in each genotype. (C) Food intake of 3-month wild type, Pnma1-/-, Pnma4-/-, or Pnma1-/- Pnma4-/- double mutant mice (N = 10 mice) was monitored daily for 7 days. Statistical significance (*p \u0026lt; 0.05) was determined by one-way ANOVA with correction for multiple comparisons. Error bars indicate SEM.\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-4559920/v1/94496e8cbda351bf896d60d7.png"},{"id":59977716,"identity":"60e99f10-b044-4548-802d-a785f6ddb8e5","added_by":"auto","created_at":"2024-07-10 05:20:48","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":3083079,"visible":true,"origin":"","legend":"\u003cp\u003ePNMA proteins form capsid-like structures that can exit human cells (A, B) Top panels depict TEM micrographs of negatively stained recombinant PNMA1 (A) and PNMA4 (B) protein. Bottom panels depict 2D class averages from cryoSPARC. (C) Experimental setup: 3V5-tagged PNMA1, PNMA4, and ARC (control exported capsid) expression plasmids were transfected into HEK-293T cells. mCherry (control non-capsid) was co438 expressed from the transfected plasmid. Culture medium was collected, spun, and filtered to remove cells and debris. Filtrate was fractionated over a 20% sucrose cushion to enrich for capsids, which fractionate as large particles at the bottom of the cushion (pellet). Sucrose, meniscus, spun media, and pellet fractions were collected. Unfractionated 441 media input and cell lysate samples were also collected. (D) PNMA, PNMA4, ARC (anti-V5), and mCherry protein levels by immunoblot. Untransfected controls (control input) are at the far right of each blot. Asterisks (*) mark the cross-reacting BSA band (abundant in growth medium). Note the presence of BSA in the untransfected controls and absence of BSA in pellet/lysate. (E) Experimental setup: Lysate was prepared from ten testes from wild type C57BL6/J mice were collected at 3 months. Lysate was fractionated by velocity step gradient (38,000 rpm, 3 hours) over a double sucrose cushion (25% and 70%). Capsid-like structures migrate to the interface between 25%-70% sucrose (70% meniscus). The 70% meniscus was further fractionated by isopycnic (equilibrium) centrifugation on an iodixanol step gradient; the photograph shows the centrifuge tube after this step.\u003c/p\u003e","description":"","filename":"Fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-4559920/v1/90fb8dec7aed78c2eb4623ef.png"},{"id":59976234,"identity":"4b8bf7ac-8e78-4555-9026-e910f2c34253","added_by":"auto","created_at":"2024-07-10 04:48:49","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":231971,"visible":true,"origin":"","legend":"\u003cp\u003eModel for PNMA1 and PNMA4 function.\u003c/p\u003e","description":"","filename":"Fig7.png","url":"https://assets-eu.researchsquare.com/files/rs-4559920/v1/5db8467742b715f22876cf68.png"},{"id":81179198,"identity":"5a4930bc-e56d-435d-a6d7-836b1510febe","added_by":"auto","created_at":"2025-04-23 07:05:38","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2873907,"visible":true,"origin":"","legend":"","description":"","filename":"Pnmapaper061024.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4559920/v1_covered_7038b5fc-00d9-4572-8803-4fb941939f0b.pdf"},{"id":59976219,"identity":"060f19bc-958f-4b3b-97f5-d27d8b4527d9","added_by":"auto","created_at":"2024-07-10 04:48:48","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":534560,"visible":true,"origin":"","legend":"","description":"","filename":"FigS1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4559920/v1/3c1492c6fe0d01fa168b902c.pdf"},{"id":59976988,"identity":"7a43fff5-8582-4f35-aa35-736ab06eadda","added_by":"auto","created_at":"2024-07-10 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Capacity\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature 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Although some of their encoded proteins retain the ability to form capsids and even transfer cargo, their fitness benefit has remained elusive. Here we show that the gag-like genes PNMA1 and PNMA4 support reproductive capacity during aging. Analysis of donated human ovaries shows that expression of both genes declines normally with age, while several PNMA1 and PNMA4 variants identified in genome-wide association studies are causally associated with low testosterone, altered puberty onset, or obesity. Six-week-old mice lacking either Pnma1 or Pnma4 are indistinguishable from wild-type littermates, but by six months the mutant mice become prematurely subfertile, with precipitous drops in sex hormone levels, gonadal atrophy, and abdominal obesity; overall they produce markedly fewer offspring than controls. These findings expand our understanding of factors that maintain human reproductive health and lend insight into the domestication of retrotransposon-derived genes.","manuscriptTitle":"The Retrotransposon-Derived Capsid Genes PNMA1 and PNMA4 Maintain Reproductive Capacity","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-10 04:48:43","doi":"10.21203/rs.3.rs-4559920/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-aging","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nataging","sideBox":"Learn more about [Nature Aging](https://www.nature.com/nataging/)","snPcode":"","submissionUrl":"","title":"Nature Aging","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"837e6156-03e3-4a39-9cab-5c42f37f6d85","owner":[],"postedDate":"July 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":34372315,"name":"Biological sciences/Developmental biology/Ageing"},{"id":34372316,"name":"Biological sciences/Developmental biology/Germline development"},{"id":34372317,"name":"Health sciences/Diseases/Reproductive disorders"}],"tags":[],"updatedAt":"2025-04-23T07:05:23+00:00","versionOfRecord":{"articleIdentity":"rs-4559920","link":"https://doi.org/10.1038/s43587-025-00852-y","journal":{"identity":"nature-aging","isVorOnly":false,"title":"Nature Aging"},"publishedOn":"2025-04-22 04:00:00","publishedOnDateReadable":"April 22nd, 2025"},"versionCreatedAt":"2024-07-10 04:48:43","video":"","vorDoi":"10.1038/s43587-025-00852-y","vorDoiUrl":"https://doi.org/10.1038/s43587-025-00852-y","workflowStages":[]},"version":"v1","identity":"rs-4559920","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4559920","identity":"rs-4559920","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}