Transgenerational dynamics of rDNA copy number in drosophila male germline stem cells
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Abstract
rDNA loci, composed of hundreds of tandemly duplicated arrays of rRNA genes, are known to be among the most unstable genetic elements due to their repetitive nature. rDNA instability underlies aging (replicative senescence) in yeast cells, however, its contribution to the aging of multicellular organisms is poorly understood. In this study, we investigate the dynamics of rDNA loci during aging in the Drosophila male germline stem cell (GSC) lineage, and show that rDNA copy number decreases during aging. Our study further reveals that this age-dependent decrease in rDNA copy number is heritable from generation to generation, yet GSCs in young animals that inherited reduced rDNA copy number are capable of recovering normal rDNA copy number. Based on these findings, we propose that rDNA loci are dynamic genetic elements, where rDNA copy number changes dynamically yet is maintained through a recovery mechanism in the germline.
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Under natural conditions, a decline of rRNA production can be caused by a reduction of rDNA copy number, which occurs due to spontaneous intra-chromatid recombination within the rDNA locus.
“Under natural conditions, a decline of rRNA production can be caused by a reduction of rDNA copy number, which occurs due to spontaneous intra-chromatid recombination within the rDNA locus (100).”
From Impaired function of rDNA transcription initiation machinery leads to derepression of ribosomal genes with insertions of R2 retrotransposon (2022) · cites this paper as [100]
The Introduction (page unavailable) says intrachromatid recombination can cause rDNA copy-number loss, and the Results report copy-number loss during aging in Drosophila male germline stem cells. The paper does not establish that this loss reduces rRNA production; the Discussion instead says that approximately the same number of rDNA copies must be transcribed to meet cellular demand, even when total copy number is lower. (LLM, conf=0.88)
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“Another study demonstrated that rDNA copy number decreases during aging, and that this age-dependent decrease in rDNA copy number is transgenerationally heritable [85].”
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“30 30 − 32 Telomeres, composed of TTAGGG tandem repeats, are located at the ends of linear chromosomes and play a crucial role in maintaining chromosome stability.”
Fefelova, E. A., Pleshakova, I. M., Mikhaleva, E. A., Pirogov, S. A., Poltorachenko, V. A., Abramov, Y. A., Romashin, D. D., Shatskikh, A. S., Blokh, R. S., Gvozdev, V. A., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkab1276 · Cited by 15 · see citing works
“Under natural conditions, a decline of rRNA production can be caused by a reduction of rDNA copy number, which occurs due to spontaneous intra-chromatid recombination within the rDNA locus (100).”
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“A similar phenomenon has been reported as occurring in Drosophila male stem cells, producing sperm with fewer rDNA arrays as the male ages (Lu et al. 2018).”
Kotov, A. A., Bazylev, S. S., Adashev, V. E., Shatskikh, A. S., & Olenina, L. V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084184 · Cited by 12 · see citing works
“Activation of X rDNA probably compensates for the decrease in the number of active copies of Y-linked rDNA, which decreases during aging owing to conflicts between transcription and replication machineries causing rDNA instability [114,123].”
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rDNA subtypes and their transcriptional expression in zebrafish at different developmental stages.
Tao, B.-X., Lo, L.-J., Peng, J.-R., & He, J. (2020) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2020.05.196 · Cited by 11
The implications of satellite DNA instability on cellular function and evolution
Flynn, J. M., & Yamashita, Y. M. (2023) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2023.10.005 · Cited by 13 · see citing works
Self-citationNuclear architecture as an intrinsic regulator of Drosophila female germline stem cell maintenance
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The Y chromosome contributes to sex-specific aging in DrosophilaPreprint
Brown, E. J., Nguyen, A. H., & Bachtrog, D. (2017) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/156042 · Cited by 12 · see citing works
Germline stem cell homeostasis
Nelson, J. O., Chen, C., & Yamashita, Y. M. (2019) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2019.04.006 · Cited by 11 · see citing works
Self-citationrDNA magnification is a unique feature of germline stem cells
Nelson, J. O., Kumon, T., & Yamashita, Y. M. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2314440120 · Cited by 11 · see citing works
“…rDNA CN in the male germline, causing some progeny of bobbed males to regain wild - type characteristics (6, 7). rDNA magnification also likely serves in wild - type animals to maintain rDNA CN through generations to offset spontaneous CN loss that occurs during the aging of individual animals (8).”
BackgroundSelf-citationRibosomal DNA replication time coordinates completion of genome replication and anaphase in yeast
Kwan, E. X., Alvino, G. M., Lynch, K. L., Levan, P. F., Amemiya, H. M., Wang, X. S., Johnson, S., Sanchez, J. C., Miller, M. A., Croy, M., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112161 · Cited by 16 · see citing works
Under the magnifying glass: The ups and downs of rDNA copy number
Kindelay, S. M., & Maggert, K. A. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.05.006 · Cited by 10 · see citing works
The retrotransposon <i>R2</i> maintains <i>Drosophila</i> ribosomal DNA repeats
Nelson, J. O., Slicko, A., & Yamashita, Y. M. (2021) · doi:10.1101/2021.07.12.451825 · Cited by 7 · see citing works
Self-citationHuang, B., & Hu, X. (2025) · Aging and Disease · doi:10.14336/ad.2025.0541 · Cited by 8 · see citing works
“Human 45S rDNA is located between the short arms and satellite regions of the acrocentric chromosomes 13, 14, 15, 21, and 22.”
InfluentialEllis, D., Martín, F. R., Rodríguez‐López, M., Cotobal, C., Sun, X.-M., Jeffares, D. C., Marguerat, S., Tallada, V. A., & Bähler, J. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/522524 · Cited by 1 · see citing works
“Work in other systems has shown that copy numbers of rDNA repeats decrease with age, and instability in this region is linked with ageing and longevity (Spivey et al. 2017; Kobayashi 2014; Lu et al. 2018).”
BackgroundAssessing Human Ribosomal DNA Variation and Its Association With Phenotypic Outcomes
Rodríguez-Algarra, F., Whittaker, E., del Castillo, S., & Rakyan, V. K. (2025) · BioEssays · doi:10.1002/bies.202400232 · Cited by 8 · see citing works
“This phenomenon has been observed in various organisms, particularly in yeast [61, 190] and flies [191], and would be consistent with rDNA loss through increased locus instability [192, 193].”
Kindelay, S. M., & Maggert, K. A. (2024) · Genetics · doi:10.1093/genetics/iyae063 · Cited by 6 · see citing works
RNA polymerase II-mediated rDNA transcription mediates rDNA copy number expansion in Drosophila
Watase, G. J., & Yamashita, Y. M. (2024) · PLoS Genetics · doi:10.1371/journal.pgen.1011136 · Cited by 5 · see citing works
Self-citationEllis, D., Martín, F. R., Rodríguez‐López, M., Cotobal, C., Sun, X.-M., Saintain, Q., Jeffares, D. C., Marguerat, S., Tallada, V. A., & Bähler, J. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009784 · Cited by 10 · see citing works
Functions of RNAi Pathways in Ribosomal RNA Regulation
Shatskikh, A. S., Fefelova, E. A., & Klenov, M. S. (2024) · Non-Coding RNA · doi:10.3390/ncrna10020019 · Cited by 3 · see citing works
“Moreover, rDNA copy number varies even within cells of the same organism and depends on age [27–29].”
BackgroundQiu, G., Fu, M., Zheng, X., & Huang, C. (2024) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.13151 · Cited by 3 · see citing works
Vitale, M., Kranjc, N., Leigh, J., Kyrou, K., Courty, T., Marston, L., Grilli, S., Crisanti, A., & Bernardini, F. (2024) · bioRxiv · doi:10.1371/journal.pgen.1011303 · Cited by 3
Kolesnikova, T. D., Klenov, M. S., Nokhova, A. R., Lavrov, S. A., Pokholkova, G. V., Schubert, V., Maltseva, S. V., Cook, K. R., Dixon, M. J., & Zhimulev, I. F. (2022) · Cells · doi:10.3390/cells11233872 · Cited by 4 · see citing works
“rDNA clusters are dynamic genetic elements in which the rDNA copy number can change over generations or cell divisions, subject to the control of a recovery mechanism in the germline [16].”
BackgroundChavan, A., Skrutl, L., Uliana, F., Pfister, M., Brändle, F., Tirián, L., Baptista, D., Handler, D., Burke, D. F., Sintsova, A., et al. (2025) · PLoS Biology · doi:10.1371/journal.pbio.3002984 · Cited by 5 · see citing works
Sadler, D. E., Watts, P. C., & Uusi‐Heikkilä, S. (2024) · Scientific Reports · doi:10.1038/s41598-024-63030-x · Cited by 2 · see citing works
“Quantifying processes that drive variation in telomere length and rDNA copy number is important as maintenance of these loci is thought to be essential to genome integrity 35,109,110 and the rate of molecular aging 89,111 .”
BackgroundRevising the Central Dogma: Regulated, Dynamic, and System-Dependent Information Coding and Decoding
Tan, C., & Anderson, E. (2024) · BIO-Complexity · doi:10.5048/bio-c.2024.3 · Cited by 2
“D. melanogaster has also been found to be able to adjust its rDNA copy numbers [104,105].”
BackgroundReplication fork blocking deficiency leads to a reduction of rDNA copy number in budding yeast
Murai, T., Yanagi, S., Hori, Y., & Kobayashi, T. (2024) · iScience · doi:10.1016/j.isci.2024.109120 · Cited by 3 · see citing works
“10,43 In fact, in flies, a protein for efficient copy number recovery was identified, 44 and further research is awaited.”
BackgroundMethodEpigenetic inheritance across multiple generations
Thamban, T., Agarwaal, V., Basu, A., Rajeev, R., Sinha, A., Dwivedi, A. P., & Khosla, S. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-816363-4.00019-5 · Cited by 5 · see citing works
Nucleolar stress causes the entry into replicative senescence in budding yeast
Morlot, S., Jia, S., Léger-Silvestre, I., Matifas, A., Gadal, O., & Charvin, G. (2018) · bioRxiv · doi:10.1101/297093 · Cited by 1
Nucleolar expansion: A biomolecular condensate mortality timer
Gutierrez, J., & Tyler, J. K. (2026) · Geromedicine · doi:10.70401/geromedicine.2026.0017 · Cited by 1
“However, rDNA instability greatly increases with age, as observed in yeast [42,43] , Drosophila [44,45] , mice [46] and human aging [47] , as well as in age-related disease [48] and progeroid contexts [49] . rDNA instability can be easily detected during yeast aging [43] , due to the presence of a…”
Genome-wide DNA methylation profiles and ribosomal DNA copy number at birth
Barth, K., Alfano, R., Plusquin, M., Wang, C.-R., Nawrot, T., & Martens, D. (2026) · Epigenetics · doi:10.1080/15592294.2026.2633818 · Cited by 1
“However, evidence suggests that the genes mus-101 and mei-41 , both involved in the homologous recombination repair, are required for germline rDNA maintenance and the rapid expansion of rDNA copies in Drosophila [50].”
Plasticity and stringency: rethinking stem cell division modes
Bener, M. B., & Inaba, M. (2026) · Biochemical Society Transactions · doi:10.1042/bst20250202 · Cited by 1 · see citing works
“Subsequent studies confirmed that when parents with reduced rDNA copy number produce offspring, this reduction is inherited by F1 progeny but gradually restored within approximately 10 days [63].”
Urban, J. A., Ringwalt, D., Urban, J. M., Xue, W., Gleason, R. J., Zhao, K.-J., & Chen, X. (2025) · Genome Research · doi:10.1101/gr.280809.125 · Cited by 1
“In Drosophila germ cells, rDNA copy number decreases during aging yet can be restored in GSCs of young males in the following generation (Lu et al. 2018; Watase et al. 2022; Nelson et al. 2023).”
Gu, T., Gracheva, E., Lee, M., Leung, W., Bieser, S., Nielsen, A., Smiley, A. T., Vuong, N. N. T., Walther, M., Reuter, G., et al. (2025) · Genetics · doi:10.1093/genetics/iyaf275 · Cited by 3 · see citing works
“In a subsequent version of the experiment, each TRiP line was crossed to lacO flies with and without the da-GAL4 driver to provide more consistent controls.”
Phenotypic tolerance for rDNA copy number variation within the natural range of C. elegans
Hall, A. N., Morton, E. A., Walters, R., Cuperus, J., & Queitsch, C. (2025) · bioRxiv · doi:10.1101/2025.03.21.644675 · Cited by 1
“It is in contrast, however, to other reports of rDNA copy number maintenance or rapid copy number recovery after loss (30,31,33,91), although these losses were below the natural copy number range and subsequent gains restored natural-range copy numbers. rDNA copy number did not correlate with rRNA…”
The RNA-binding protein Modulo promotes neural stem cell maintenance in Drosophila
Parra, A. S., & Johnston, C. A. (2024) · PLoS ONE · doi:10.1371/journal.pone.0309221 · Cited by 1 · see citing works
Nelson, J. O., Slicko, A., Raz, A. A., & Yamashita, Y. M. (2024) · bioRxiv · doi:10.1101/2024.02.28.582629 · Cited by 1
“RNA FISH samples were prepared using an R2 Stellaris probe set (Biosearch Technologies) as previously described (Lu et al. 2018).”
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Self-citationGheflat, S., Sadeghi, A., Bandehpour, M., Ramezani, K., & Kazemi, B. (2019) · Iranian journal of pharmaceutical research · doi:10.22037/ijpr.2019.14650.12567 · Cited by 1
Coordination of genome replication and anaphase entry by rDNA copy number in S. cerevisiaePreprint
Kwan, E. X., Alvino, G. M., Lynch, K. L., Levan, P. F., Amemiya, H. M., Wang, X. S., Johnson, S., Sanchez, J. C., Miller, M. A., Croy, M., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.02.25.432950 · Cited by 2 · see citing works
“…been associated recently with more physiologically relevant rDNA copy number variants that are sufficient for ribosome biogenesis (Gibbons et al., 2014; Ide et al., 2010; Lu et al., 2018; Michel et al., 2005; Paredes et al., 2011; Picart-Picolo et al., 2020; Wang and Lemos, 2017; Xu et al., 2017).”
BackgroundProgrammed Aging Theory Defeats Damage Accumulation Theory of Aging
Huang, B.-L. (2026) · Ageing and Longevity Research · doi:10.53941/alr.2026.100002
“Fortunately, evidence has shown that telomere DNA and rDNA lost in somatic cells can be replenished in early embryonic cells or germ cells [78–80].”
Feasibility Analysis of Mainstream Aging Theories and Intervention
Huang, B. (2026) · Ageing and Longevity Research · doi:10.53941/alr.2026.100001 · Cited by 1 · see citing works
“For example, in fruit flies with a 40-day lifespan, the rDNA array is shortened by half [21].”
Ataxin-2 regulates the synaptonemal complex to ensure chromosome pairing during female meiosis
Monteiro, V. L., Wang, Z.-Y., Santé, J. F., Janakiraman, S., Roselli, C., Bakthavachalu, B., Ramaswami, M., Smibert, C. A., & Hurd, T. (2026) · bioRxiv · doi:10.1093/genetics/iyag213
Urban, J. A., Ringwalt, D., Urban, J. M., Xue, W., Gleason, R. J., Zhao, K.-J., & Chen, X. (2025) · bioRxiv · doi:10.1101/2025.04.19.649648
“In Drosophila germ cells, rDNA copy number decreases during aging, yet can be restored in GSCs of young males in the following generation (Lu et al. 2018; Nelson et al. 2023; Watase et al. 2022).”
Phenotypic tolerance for rDNA copy number variation within the natural range of C. elegans
Hall, A. N., Morton, E. A., Walters, R., Cuperus, J. T., & Queitsch, C. (2025) · PLoS Genetics · doi:10.1371/journal.pgen.1011759 · Cited by 1 · see citing works
“It is in contrast, however, to other reports of rDNA copy number maintenance or rapid copy number recovery after loss (30,31,33,88), although these losses were below the natural copy number range and subsequent gains restored natural-range copy numbers. rDNA copy number did not correlate with rRNA…”
Piwi and piRNAs repress transcription of aberrant rRNA genes containing retrotransposon fragmentsPreprint
Fefelova, E. A., Shatskikh, A. S., Mikhaleva, E. A., Abramov, Y. A., Lavrov, S. A., Пирогов, С. А., Poltorachenko, V. A., Ilin, A. A., Zamore, P. D., & Klenov, M. S. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.30.651568
Nelson, J. O., Slicko, A., Raz, A. A., & Yamashita, Y. M. (2025) · Nature Communications · doi:10.1038/s41467-024-55725-6 · Cited by 4 · see citing works
“2F, and Supplemental Data 1).”
InfluentialSelf-citationBlokhina, Y. P., & Buchwalter, A. L. (2024) · PLoS ONE · doi:10.1371/journal.pone.0310626 · Cited by 1 · see citing works
Zylstra, A., Hadj‐Moussa, H., Horkai, D., Whale, A. J., Piguet, B., & Houseley, J. M. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.07.14.500009
“…variation might be relevant to animal ageing and pathology as rDNA copy number variation has been reported during Drosophila and mouse ageing (Lu et al., 2018; Watada et al., 2020), in human neurodegenerative disorders (Hallgren et al., 2014), and in cancer (Stults et al., 2008; Valori et…”
BackgroundNiehaus, C. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-85679-9.00029-5
- Authors
- Lu, K. L., Nelson, J. O., Watase, G. J., Warsinger-Pepe, N., & Yamashita, Y. M.
- Affiliations
- University of Michigan (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Yamashita, Yukiko M
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2018-02-13
- Volume
- 7
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5811208
- OpenAlex
- W2760826592
- Cited by
- 77
- References
- 69
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 10 · 2023: 14 · 2022: 10 · 2021: 7 · 2020: 8 · 2019: 10 · 2018: 4 · 2017: 1
- FWCI
- 2.85
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences
- National Institute on Aging
- National Institute of Child Health and Human Development
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- rDNA copy number, ribosomal DNA, germline stem cells, male germline, aging, replicative senescence, transgenerational inheritance, Drosophila
- MeSH terms
- Aging, Animals, DNA, Ribosomal, Drosophila, Germ Cells, Male, Stem Cells, Genetic Variation, Gene Dosage, Genomic Instability
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