Journal of Molecular Evolution

, Volume 86, Issue 5, pp 312–323 | Cite as

Evolutionary Dynamics of Copy Number and Meiotic Recombination in Murine 5S rDNA: Possible Involvement of Natural Selection

  • Miyu Isobe
  • Mitsuo Nunome
  • Ken Katakura
  • Hitoshi Suzuki
Original Article


We investigated evolutionary trends of the 5S ribosomal RNA gene in the house mouse, Mus musculus. First, we assessed the 5S cluster and copy numbers in eight laboratory strains by pulsed-field gel electrophoresis. The copy numbers in seven lines were estimated to be around 130–170 copies per cluster, with 63 copies in the remaining strain, implying that the copy number can change drastically and has been maintained under certain evolutionary constraints at ~ 140 copies. Second, we addressed the frequency of meiotic recombination mediated by the 5S cluster by performing a mating experiment with laboratory strains, and found that the 5S cluster did not accelerate recombination events. Third, we surveyed recombination events of the 5S-containing chromosome region in wild mice from the Japanese Islands, where the two subspecies lineages, M. m. castaneus and M. m. musculus, are historically mingled, and found that the influence of the 5S cluster on meiotic recombination was limited. Finally, we examined the nucleotide diversity of six genes in the neighboring regions of the 5S cluster and found reduced genetic diversity in the regions on both sides of the cluster, suggesting the involvement of either positive or background selection in the population-level sequence similarity of the 5S clusters. Therefore, the mouse 5S genes are considered to be evolving toward sequence similarity within a given cluster by certain intrachromosomal mechanisms and toward sharing of a specific 5S cluster within a population by certain selective processes.


Mus musculus 5S rDNA Copy number Recombination Natural selection 



We would like to thank Kuniya Abe, Gohta Kinoshita, Motoko Kobayashi, Nobumoto Miyashita, Ritsuko Nakayama, Kazuo Moriwaki, Masahiko Nishimura, Susumu Sakurai, Toshihiko Shiroishi, Toyoyuki Takada, Mie Terashima, Kimiyuki Tsuchiya, Hiromichi Yonekawa, and Shigeharu Wakana for providing valuable comments on an earlier manuscript resulting from this study. We thank two anonymous reviewers for their comments that helped improve the manuscript. This study was supported by a grant-in-aid for Scientific Research (C) to HS (No. 15K07177) from the Japan Society for the Promotion of Science.

Supplementary material

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  1. Boursot P, Auffray JC, Britton-Davidian J, Bonhomme F (1993) The evolution of house mice. Annual Rev Ecol Syst 24:119–152CrossRefGoogle Scholar
  2. Braverman JM, Hudson RR, Kaplan NL, Langley CH, Stephan W (1995) The hitchhiking effect on the site frequency-spectrum of DNA polymorphisms. Genetics 140:783–796PubMedPubMedCentralGoogle Scholar
  3. Campo D, Machado-Schiaffino G, Horreo JL, Garcia-Vazquez E (2009) Molecular organization and evolution of 5S rDNA in the genus Merluccius and their phylogenetic implications. J Mol Evol 68:208–216CrossRefPubMedGoogle Scholar
  4. Charlesworth B, Morgan MT, Charlesworth D (1993) The effect of deleterious mutations on neutral molecular variation. Genetics 134:1289–1303PubMedPubMedCentralGoogle Scholar
  5. Charlesworth B, Sniegowski P, Stephan W (1994) The evolutionary dynamics of repetitive DNA in eukaryotes. Nature 371:215–220CrossRefPubMedGoogle Scholar
  6. Cohen S, Agmon N, Sobol O, Segal D (2010) Extrachromosomal circles of satellite repeats and 5S ribosomal DNA in human cells. Mobile DNA 1:11CrossRefPubMedPubMedCentralGoogle Scholar
  7. Excoffier L, Lischer HEL (2010) Arlequin suite ver 3.5: a new series of programs to perform population genetics analyses under Linux and Windows. Mol Ecol Resour 10:564–567CrossRefPubMedGoogle Scholar
  8. Freire R, Arias A, Ínsua AM, Méndez J, Eirín-López JM (2010) Evolutionary dynamics of the 5S rDNA gene family in the mussel Mytilus: mixed effects of birth-and-death and concerted evolution. J Mol Evol 70:413–426CrossRefPubMedGoogle Scholar
  9. Fujiwara M, Inafuku J, Takeda A, Watanabe A, Fujiwara A, Kohno S, Kubota S (2009) Molecular organization of 5S rDNA in bitterlings (Cyprinidae). Genetica 135:355–365CrossRefPubMedGoogle Scholar
  10. Ganley ARD, Kobayashi T (2007) Highly efficient concerted evolution in the ribosomal DNA repeats: Total rDNA repeat variation revealed by whole-genome shotgun sequence data. Genome Res 17:184–191CrossRefPubMedPubMedCentralGoogle Scholar
  11. Ganley ARD, Kobayashi T (2011) Monitoring the rate and dynamics of concerted evolution in the ribosomal DNA repeats of Saccharomyces cerevisiae using experimental evolution. Mol Biol Evol 28:2883–2891CrossRefPubMedGoogle Scholar
  12. Gaubatz J, Prashad N, Cutter RG (1976) Ribosomal RNA gene dosage as a function of tissue and age for mouse and human. Biochim Biophys Acta 418:358–375CrossRefPubMedGoogle Scholar
  13. Gibbons JG, Branco AT, Godinho SA, Yu S, Lemos B (2015) Concerted copy number variation balances ribosomal DNA dosage in human and mouse genomes. Proc Natl Acad Sci USA 24:2485–2490CrossRefGoogle Scholar
  14. Henderson AS, Atwood KC, Yu MT, Warburton D (1976) The site of 5S RNA genes in primates. Chromosoma 56:29–32CrossRefPubMedGoogle Scholar
  15. Hudson RR, Kreitman M, Aguadé M (1987) A test of neutral molecular evolution based on nucleotide data. Genetics 116:153–159PubMedPubMedCentralGoogle Scholar
  16. Huson DH, Bryant D (2006) Application of phylogenetic networks in evolutionary studies. Mol Biol Evol 23:254–267CrossRefPubMedGoogle Scholar
  17. Ide S, Saka K, Kobayashi T (2013) Rat 109 prevents hyper-amplification of ribosomal RNA genes through histone modification in budding yeast. PLoS Genet 9:e1003410CrossRefPubMedPubMedCentralGoogle Scholar
  18. James SA, West C, Davey RP, Dicks J, Roberts IN (2016) Prevalence and dynamics of ribosomal DNA micro-heterogeneity are linked to population history in two contrasting yeast species. Sci Rep 6:28555CrossRefPubMedPubMedCentralGoogle Scholar
  19. Jensen-Seaman MI, Furey TS, Payseur BA, Lu Y, Roskin KM, Chen C-F, Thomas MA, Haussler D, Jacob HJ (2004) Comparative recombination rates in the rat, mouse, and human genomes. Genome Res 14:528–538CrossRefPubMedPubMedCentralGoogle Scholar
  20. Katakura K, Matsumoto Y, Gomez EA, Furuya M, Hashiguchi Y (1993) Molecular karyotype characterization of Leishmania panamensis. Leishmania mexicana, and Leishmania major-like parasites: agents of cutaneous leishmaniasis in Ecuador. Am J Trop Med Hyg 48:707–715CrossRefPubMedGoogle Scholar
  21. Kellogg EA, Appels R (1995) Intraspecific and interspecific variation in 5S RNA genes are decoupled in diploid wheat relatives. Genetics 140:325–343PubMedPubMedCentralGoogle Scholar
  22. Kobayashi T (2011) How does genome instability affect lifespan? Genes Cells 16:617–624CrossRefPubMedPubMedCentralGoogle Scholar
  23. Kodama S, Nunome M, Moriwaki K, Suzuki H (2015) Ancient onset of geographical divergence, interpopulation genetic exchange, and natural selection on the Mc1r coat-colour gene in the house mouse (Mus musculus). Biol J Linn Soc 114:778–794CrossRefGoogle Scholar
  24. Kuwayama T, Nunome M, Kinoshita G, Abe K, Suzuki H (2017) Heterogeneous genetic makeup of the Japanese house mouse (Mus musculus) created by multiple independent introductions and spatio-temporally diverse hybridisation processes. Biol J Linn Soc 122:661–674CrossRefGoogle Scholar
  25. Liao D, Pavelitz T, Kidd JR, Kidd KK, Weiner AM (1997) Concerted evolution of the tandemly repeated genes encoding human U2 snRNA (the RNU2 locus) involves rapid intrachromosomal homogenization and rare interchromosomal gene conversion. EMBO J 16:588–598CrossRefPubMedPubMedCentralGoogle Scholar
  26. Librado P, Rozas J (2009) DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics 25:1451–1452CrossRefPubMedGoogle Scholar
  27. Little RD, Braaten DC (1989) Genomic organization of human 5S rDNA and sequence of one tandem repeat. Genomics 4:376–383CrossRefPubMedGoogle Scholar
  28. Lomholt B, Frederiksen S, Jensen LR, Christensen K, Hallenberg C (1996) 5S rRNA genes in Macaca fascicularis map to chromosome 1p in three loci. Mamm Genome 7:451–453CrossRefPubMedGoogle Scholar
  29. Matsuda Y, Moriwaki K, Chapman VM, Hoi-Sen Y, Akbarzadeh J, Suzuki H (1994) Chromosomal mapping of mouse 5S rRNA genes by direct R-banding fluorescence in situ hybridization. Cytogenet Cell Genet 66:246–249CrossRefPubMedGoogle Scholar
  30. Maynard Smith J, Haigh J (1974) The hitch-hiking effect of a favourable gene. Genet Res 23:23–35CrossRefGoogle Scholar
  31. Nagylaki T (1984) Evolution of multigene families under interchromosomal gene conversion. Proc Natl Acad Sci USA 81:3796–3800CrossRefPubMedPubMedCentralGoogle Scholar
  32. Nagylaki T, Petes TD (1982) Intrachromosomal gene conversion and the maintenance of sequence homogeneity among repeated genes. Genetics 100:315–337PubMedPubMedCentralGoogle Scholar
  33. Nei M, Rooney AP (2005) Concerted and birth-and-death evolution of multigene families. Annu Rev Genet 39:121–152CrossRefPubMedPubMedCentralGoogle Scholar
  34. Nielsen R (2005) Molecular signatures of natural selection. Annu Rev Genet 39:197–218CrossRefPubMedGoogle Scholar
  35. Nunome M, Ishimori C, Aplin KP, Yonekawa H, Moriwaki K, Suzuki H (2010) Detection of recombinant haplotypes in wild mice (Mus musculus) provides new insights into the origin of Japanese mice. Mol Ecol 19:2474–2489PubMedGoogle Scholar
  36. Ohta T (1980) Evolution and variation of multigene families. Springer, BerlinCrossRefGoogle Scholar
  37. Petes TD, Botstein D (1977) Simple Mendelian inheritance of the reiterated ribosomal DNA of yeast. Proc Natl Acad Sci USA 74:5091–5095CrossRefPubMedPubMedCentralGoogle Scholar
  38. Pinhal D, Yoshimura TS, Araki CS, Martins C (2011) The 5S rDNA family evolves through concerted and birth-and-death evolution in fish genomes: an example from freshwater stingrays. BMC Evol Biol 11:151CrossRefPubMedPubMedCentralGoogle Scholar
  39. Richard GF, Kerrest A, Dujon B (2008) Comparative genomics and molecular dynamics of DNA repeats in eukaryotes. Microbiol Mol Biol Rev 72:686–727CrossRefPubMedPubMedCentralGoogle Scholar
  40. Rooney AP, Ward TJ (2005) Evolution of large ribosomal RNA multigene family in filamentous fungi: birth and death of a concerted evolution paradigm. Proc Natl Acad Sci USA 102:5084–5098CrossRefPubMedPubMedCentralGoogle Scholar
  41. Schlotterer C, Hauser MT, von Haeseler A, Tautz D (1994) Comparative evolutionary analysis of rDNA ITS regions in Drosophila. Mol Biol Evol 11:513–522PubMedGoogle Scholar
  42. Scoles GJ, Gill BS, Xin ZY, Clarke BC, McIntyre CL, Chapman C, Appels R (1998) Frequent duplication and deletion events in the 5S RNA genes and the associated spacer regions of the Triticeae. Plant Syst Evol 160:105–122CrossRefGoogle Scholar
  43. Smith GP (1976) Evolution of repeated DNA sequences by unequal crossover. Science 191:528–535CrossRefPubMedGoogle Scholar
  44. Sørensen PD, Frederiksen S (1991) Characterization of human 5S ribosomal RNA genes. Nucleic Acids Res 19:4147–4151CrossRefPubMedPubMedCentralGoogle Scholar
  45. Sørensen PD, Lomholt B, Frederiksen S, Tommerup N (1991) Fine mapping of human 5S rRNA genes to chromosome 1q42.11 to q42.13. Cytogenet Cell Genet 57:26–29CrossRefPubMedGoogle Scholar
  46. Stage DE, Eickbush TH (2007) Sequence variation within the rRNA loci of 12 Drosophila species. Genome Res 17:1888–1897CrossRefPubMedPubMedCentralGoogle Scholar
  47. Stephens M, Scheet P (2005) Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet 76:449–462CrossRefPubMedPubMedCentralGoogle Scholar
  48. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989CrossRefPubMedPubMedCentralGoogle Scholar
  49. Stults DM, Killen MW, Pierce HH, Pierce AJ (2008) Genomic architecture and inheritance of human ribosomal RNA gene clusters. Genome Res 18:13–18CrossRefPubMedPubMedCentralGoogle Scholar
  50. Suzuki H, Moriwaki K, Sakurai S (1994a) Sequences and evolutionary analysis of mouse 5S rDNAs. Mol Biol Evol 11:704–710PubMedGoogle Scholar
  51. Suzuki H, Tsuchiya K, Sakaizumi M, Wakana S, Sakurai S (1994b) Evolution of restriction sites of ribosomal DNA in natural populations of the field mouse, Apodemus speciosus. J Mol Evol 38:107–112CrossRefPubMedGoogle Scholar
  52. Suzuki H, Sakurai S, Matsuda Y (1996) Rat rDNA spacer sequences and chromosomal assignment of the genes to the extreme terminal region of chromosome 19. Cytogenet Cell Genet 72:1–4CrossRefPubMedGoogle Scholar
  53. Suzuki H, Nunome M, Kinoshita G, Aplin KP, Vogel P, Kryukov AP, Jin M-L, Han S-H, Maryanto I, Tsuchiya K, Ikeda H, Shiroishi T, Yonekawa H, Moriwaki K (2013) Evolutionary and dispersal history of Eurasian house mice Mus musculus clarified by more extensive geographic sampling of mitochondrial DNA. Heredity 111:375–390CrossRefPubMedPubMedCentralGoogle Scholar
  54. Takada T, Ebata T, Noguchi H, Keane TM, Adams DJ, Narita T, Shin T, Fujisawa H, Toyoda A, Abe K, Obata Y (2013) The ancestor of extant Japanese fancy mice contributed to the mosaic genomes of classical inbred strains. Genome Res 23:1329–1338CrossRefPubMedPubMedCentralGoogle Scholar
  55. Takada T, Yoshiki A, Obata Y, Yamazaki Y, Shiroishi T (2015) NIG_MoG: a mouse genome navigator for exploring intersubspecific genetic polymorphisms. Mamm Genome 26:331–337CrossRefPubMedGoogle Scholar
  56. Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28:2731–2739CrossRefPubMedPubMedCentralGoogle Scholar
  57. Vierna J, Gonzalez-Tizon A, Martinez-Lage A (2009) Long-term evolution of 5S ribosomal DNA seems to be driven by birth-and-death processes and selection in Ensis razor shells (mollusca: Bivalvia). Biochem Genet 47:635–644CrossRefPubMedGoogle Scholar
  58. Vizoso M, Vierna J, González-Tizón AM, Martínez-Lage A (2011) The 5S rDNA gene family in mollusks: characterization of transcriptional regulatory regions, prediction of secondary structures, and long-term evolution, with special attention to Mytilidae mussels. J Hered 102:433–447CrossRefPubMedGoogle Scholar
  59. Yu S, Lemos B (2016) A portrait of ribosomal DNA contacts with Hi-C reveals 5S and 45S rDNA anchoring points in the folded human genome. Genome Biol Evol 8:3545–3558CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Graduate School of Earth ScienceHokkaido UniversitySapporoJapan
  2. 2.Avian Bioscience Research Center, Graduate School of Bioagricultural SciencesNagoya UniversityNagoyaJapan
  3. 3.Graduate School of Veterinary MedicineHokkaido UniversitySapporoJapan

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