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Frequency of Human Disease Mutations and Spermatogonial Stem Cell Function

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The Biology of Mammalian Spermatogonia

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Abstract

Some human disease mutations enter the human population each generation as a result of de novo germline base substitutions that immediately affect children born to normal parents. In some cases the frequency of these mutations exceeds the well-documented germline mutation rate 100–1000 fold. Recent technologies have made it possible to estimate the frequency of single base disease mutations in both sperm and testes from normal men. The evidence confirms that, although unaffected, the men have high enough frequencies of these mutations in semen and testis to explain the high sporadic disease incidence. The explanation for the high frequency initially was ascribed to the idea that the affected nucleotide site was a mutation hot spot with a mutation rate per cell division at that site far greater than the rate at other sites. Recent evidence rules out this hot spot model. An alternative model suggests that any of these types of rare disease mutations can confer upon a single testis stem cell a selective advantage. Over time, a disproportionate increase of mutant stem cells over the wild-type stem cells occurs that increases the disease mutation frequency in sperm. The evidence against the hot spot model and for the selection model is reviewed and the functional consequences of these disease mutations on testis stem cell proliferation is also summarized. Finally, the consequence of these mutations is considered within the context of the paternal age effect and the human genetic load.

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References

  • Ahmed Z, Schuller AC, Suhling K, Tregidgo C, Ladbury JE (2008) Extracellular point mutations in FGFR2 elicit unexpected changes in intracellular signalling. Biochem J 413:37–49

    Article  CAS  PubMed  Google Scholar 

  • Araki T, Chan G, Newbigging S, Morikawa L, Bronson RT et al (2009) Noonan syndrome cardiac defects are caused by PTPN11 acting in endocardium to enhance endocardial-mesenchymal transformation. Proc Natl Acad Sci U S A 106:4736–4741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arighi E, Borrello MG, Sariola H (2005) RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev 16:441–467

    Article  CAS  PubMed  Google Scholar 

  • Arnheim N, Calabrese P (2009) Understanding what determines the frequency and pattern of human germline mutations. Nat Rev Genet 10:478–488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caires K, Broady J, McLean D (2010) Maintaining the male germline: regulation of spermatogonial stem cells. J Endocrinol 205:133–145

    Article  CAS  PubMed  Google Scholar 

  • Campbell CD, Eichler EE (2013) Properties and rates of germline mutations in humans. Trends Genet 29:575–584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carlson KM, Bracamontes J, Jackson CE, Clark R, Lacroix A et al (1994) Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet 55:1076–1082

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen L, Li D, Li C, Engel A, Deng CX (2003) A Ser252Trp [corrected] substitution in mouse fibroblast growth factor receptor 2 (Fgfr2) results in craniosynostosis. Bone 33:169–178

    Article  CAS  PubMed  Google Scholar 

  • Chevalier N, Barlier A, Roche C, Mograbi B, Camparo P et al (2010) RET gene mutations are not involved in the origin of human testicular seminoma. Int J Androl 33:848–852

    Article  CAS  PubMed  Google Scholar 

  • Chiarini-Garcia H, Hornick JR, Griswold MD, Russell LD (2001) Distribution of type A spermatogonia in the mouse is not random. Biol Reprod 65:1179–1185

    Article  CAS  PubMed  Google Scholar 

  • Choi SK, Yoon SR, Calabrese P, Arnheim N (2008) A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations. Proc Natl Acad Sci U S A 105:10143–10148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi SK, Yoon SR, Calabrese P, Arnheim N (2012) Positive selection for new disease mutations in the human germline: evidence from the heritable cancer syndrome multiple endocrine neoplasia type 2B. PLoS Genet 8:e1002420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clermont Y (1966) Renewal of spermatogonia in man. Am J Anat 118:509–524

    Article  CAS  PubMed  Google Scholar 

  • Crow JF (1997) The high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci U S A 94:8380–8386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crow JF (2000) The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet 1:40–47

    Article  CAS  PubMed  Google Scholar 

  • Dance M, Montagner A, Salles JP, Yart A, Raynal P (2008) The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway. Cell Signal 20:453–459

    Article  CAS  PubMed  Google Scholar 

  • Drost JB, Lee WR (1995) Biological basis of germline mutation: comparisons of spontaneous germline mutation rates among drosophila, mouse, and human. Environ Mol Mutagen 25:48–64

    Article  CAS  PubMed  Google Scholar 

  • Ebata KT, Yeh JR, Zhang X, Nagano MC (2011) Soluble growth factors stimulate spermatogonial stem cell divisions that maintain a stem cell pool and produce progenitors in vitro. Exp Cell Res 317:1319–1329

    Article  CAS  PubMed  Google Scholar 

  • Ellegren H (2007) Characteristics, causes and evolutionary consequences of male-biased mutation. Proc Biol Sci 274:1–10

    Article  CAS  PubMed  Google Scholar 

  • Eswarakumar VP, Monsonego-Ornan E, Pines M, Antonopoulou I, Morriss-Kay GM et al (2002) The IIIc alternative of Fgfr2 is a positive regulator of bone formation. Development 129:3783–3793

    CAS  PubMed  Google Scholar 

  • Germain D, Frank DA (2007) Targeting the cytoplasmic and nuclear functions of signal transducers and activators of transcription 3 for cancer therapy. Clin Cancer Res 13:5665–5669

    Article  CAS  PubMed  Google Scholar 

  • Giannoulatou E, McVean G, Taylor IB, McGowan SJ, Maher GJ et al (2013) Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline. Proc Natl Acad Sci U S A 110:20152–20157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glaser RL, Jabs EW (2004) Dear old dad. Sci Aging Knowl Environ 2004:re1

    Article  Google Scholar 

  • Goriely A, Hansen RM, Taylor IB, Olesen IA, Jacobsen GK et al (2009) Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat Genet 41:1247–1252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goriely A, McVean GA, Rojmyr M, Ingemarsson B, Wilkie AO (2003) Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line. Science 301:643–646

    Article  CAS  PubMed  Google Scholar 

  • Goriely A, Wilkie AO (2012) Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am J Hum Genet 90:175–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gotoh N (2008) Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer Sci 99:1319–1325

    Article  CAS  PubMed  Google Scholar 

  • Griswold MD, Oatley JM (2013) Concise review: defining characteristics of mammalian spermatogenic stem cells. Stem Cells 31:8–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grossmann KS, Rosario M, Birchmeier C, Birchmeier W (2010) The tyrosine phosphatase Shp2 in development and cancer. Adv Cancer Res 106:53–89

    Article  CAS  PubMed  Google Scholar 

  • Hamra FK (2015) Diagnosing spermatogonial stemness. Biol Reprod 92:119

    Article  PubMed  PubMed Central  Google Scholar 

  • Hara K, Nakagawa T, Enomoto H, Suzuki M, Yamamoto M et al (2014) Mouse spermatogenic stem cells continually interconvert between equipotent singly isolated and syncytial states. Cell Stem Cell 14:658–672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hart KC, Robertson SC, Donoghue DJ (2001) Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, Stat activation, and phosphatidylinositol 3-kinase activation. Mol Biol Cell 12:931–942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hastings IM (1989) Potential germline competition in animals and its evolutionary implications. Genetics 123:191–197

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hastings IM (1991) Germline selection: population genetic aspects of the sexual/asexual life cycle. Genetics 129:1167–1176

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heller CG, Clermont Y (1963) Spermatogenesis in man: an estimate of its duration. Science 140:184–186

    Article  CAS  PubMed  Google Scholar 

  • Itoh N, Ornitz DM (2004) Evolution of the Fgf and Fgfr gene families. Trends Genet 20:563–569

    Article  CAS  PubMed  Google Scholar 

  • Kanatsu-Shinohara M, Shinohara T (2013) Spermatogonial stem cell self-renewal and development. Annu Rev Cell Dev Biol 29:163–187

    Article  CAS  PubMed  Google Scholar 

  • Kaucher AV, Oatley MJ, Oatley JM (2012) NEUROG3 is a critical downstream effector for STAT3-regulated differentiation of mammalian stem and progenitor spermatogonia. Biol Reprod 86(164):161–111

    Google Scholar 

  • Klein AM, Nakagawa T, Ichikawa R, Yoshida S, Simons BD (2010) Mouse germ line stem cells undergo rapid and stochastic turnover. Cell Stem Cell 7:214–224

    Article  CAS  PubMed  Google Scholar 

  • Klein AM, Simons BD (2011) Universal patterns of stem cell fate in cycling adult tissues. Development 138:3103–3111

    Article  CAS  PubMed  Google Scholar 

  • Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P et al (2012) Rate of de novo mutations and the importance of father's age to disease risk. Nature 488:471–475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • L'Hote CG, Knowles MA (2005) Cell responses to FGFR3 signalling: growth, differentiation and apoptosis. Exp Cell Res 304:417–431

    Article  PubMed  Google Scholar 

  • Lee J, Kanatsu-Shinohara M, Morimoto H, Kazuki Y, Takashima S et al (2009) Genetic reconstruction of mouse spermatogonial stem cell self-renewal in vitro by Ras-cyclin D2 activation. Cell Stem Cell 5:76–86

    Article  CAS  PubMed  Google Scholar 

  • Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141:1117–1134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lew ED, Furdui CM, Anderson KS, Schlessinger J (2009) The precise sequence of FGF receptor autophosphorylation is kinetically driven and is disrupted by oncogenic mutations. Sci Signal 2:ra6

    Article  PubMed  PubMed Central  Google Scholar 

  • Lim J, Maher GJ, Turner GD, Dudka-Ruszkowska W, Taylor S et al (2012) Selfish spermatogonial selection: evidence from an immunohistochemical screen in testes of elderly men. PLoS One 7:e42382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Q, Sommer SS (2004) Detection of extremely rare alleles by bidirectional pyrophosphorolysis-activated polymerization allele-specific amplification (Bi-PAP-A): measurement of mutation load in mammalian tissues. BioTechniques 36:156–166

    CAS  PubMed  Google Scholar 

  • Luria SE, Delbruck M (1943) Mutations of bacteria from virus sensitivity to virus resistance. Genetics 28:491–511

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maher GJ, Goriely A, Wilkie AO (2014) Cellular evidence for selfish spermatogonial selection in aged human testes. Andrology 2:304–314

    Article  CAS  PubMed  Google Scholar 

  • Maher GJ, McGowan SJ, Giannoulatou E, Verrill C, Goriely A et al (2016a) Visualizing the origins of selfish de novo mutations in individual seminiferous tubules of human testes. Proc Natl Acad Sci U S A 113:2454–2459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maher GJ, Rajpert-De Meyts E, Goriely A, Wilkie AO (2016b) Cellular correlates of selfish spermatogonial selection. Andrology 4:550–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin LA, Assif N, Gilbert M, Wijewarnasuriya D, Seandel M (2014) Enhanced fitness of adult spermatogonial stem cells bearing a paternal age-associated FGFR2 mutation. Stem Cell Rep 3:219–226

    Article  CAS  Google Scholar 

  • Masumura K, Toyoda-Hokaiwado N, Ukai A, Gondo Y, Honma M et al (2016) Estimation of the frequency of inherited germline mutations by whole exome sequencing in ethyl nitrosourea-treated and untreated gpt delta mice. Genes Environ 38:10

    Article  PubMed  PubMed Central  Google Scholar 

  • Mohammadi M, Olsen SK, Ibrahimi OA (2005) Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev 16:107–137

    Article  CAS  PubMed  Google Scholar 

  • Mohi MG, Neel BG (2007) The role of Shp2 (PTPN11) in cancer. Curr Opin Genet Dev 17:23–30

    Article  CAS  PubMed  Google Scholar 

  • Muller J, Skakkebaek NE (1992) The prenatal and postnatal development of the testis. Bailliere Clin Endocrinol Metab 6:251–271

    Article  CAS  Google Scholar 

  • Mulligan LM (2014) RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer 14:173–186

    Article  CAS  PubMed  Google Scholar 

  • Neel BG, Chan G, Dhanji S (2010) SH2 domain-containing protein-tyrosine phosphatases. In: Bradshaw RA, Dennis EA (eds) Handbook of cell signaling, 2nd edn. Academic Press, Amsterdam; San Diego, CA, pp 771–810

    Chapter  Google Scholar 

  • Nistal M, Codesal J, Paniagua R, Santamaria L (1987) Decrease in the number of human Ap and Ad spermatogonia and in the Ap/Ad ratio with advancing age. New data on the spermatogonial stem cell. J Androl 8:64–68

    Article  CAS  PubMed  Google Scholar 

  • Nistal M, Paniagua R (1984) Testicular and epididymal pathology. Thieme-Stratton, New York

    Google Scholar 

  • Oatley JM, Brinster RL (2008) Regulation of spermatogonial stem cell self-renewal in mammals. Annu Rev Cell Dev Biol 24:263–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oatley JM, Kaucher AV, Avarbock MR, Brinster RL (2010) Regulation of mouse spermatogonial stem cell differentiation by STAT3 signaling. Biol Reprod 83:427–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pauli RM (1993) Achondroplasia. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A et al (eds) GeneReviews(R). University of Washington, Seattle, WA

    Google Scholar 

  • Penrose L (1955) Paternal age and mutation. Lancet 269:312–313

    Article  CAS  PubMed  Google Scholar 

  • Phillips BT, Gassei K, Orwig KE (2010) Spermatogonial stem cell regulation and spermatogenesis. Philos Trans R Soc Lond Ser B Biol Sci 365:1663–1678

    Article  CAS  Google Scholar 

  • Pohl E, Gromoll J, Kliesch S, Wistuba J (2016) An alternative interpretation of cellular ‘selfish spermatogonial selection’-clusters in the human testis indicates the need for 3-D-analyses. Andrology 4:213–217

    Article  CAS  PubMed  Google Scholar 

  • Puri P, Phillips BT, Suzuki H, Orwig KE, Rajkovic A et al (2014) The transition from stem cell to progenitor spermatogonia and male fertility requires the SHP2 protein tyrosine phosphatase. Stem Cells 32:741–753

    Article  CAS  PubMed  Google Scholar 

  • Qin J, Calabrese P, Tiemann-Boege I, Shinde DN, Yoon SR et al (2007) The molecular anatomy of spontaneous germline mutations in human testes. PLoS Biol e224:5

    Google Scholar 

  • Risch N, Reich EW, Wishnick MM, McCarthy JG (1987) Spontaneous mutation and parental age in humans. Am J Hum Genet 41:218–248

    CAS  PubMed  PubMed Central  Google Scholar 

  • Runeberg-Roos P, Saarma M (2007) Neurotrophic factor receptor RET: structure, cell biology, and inherited diseases. Ann Med 39:572–580

    Article  CAS  PubMed  Google Scholar 

  • Sayres MA, Makova KD (2011) Genome analyses substantiate male mutation bias in many species. BioEssays 33:938–945

    Article  PubMed Central  Google Scholar 

  • Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225

    Article  CAS  PubMed  Google Scholar 

  • Segurel L, Quintana-Murci L (2014) Preserving immune diversity through ancient inheritance and admixture. Curr Opin Immunol 30:79–84

    Article  CAS  PubMed  Google Scholar 

  • Segurel L, Wyman MJ, Przeworski M (2014) Determinants of mutation rate variation in the human germline. Annu Rev Genomics Hum Genet 15:47–70

    Article  CAS  PubMed  Google Scholar 

  • Shinde DN, Elmer DP, Calabrese P, Boulanger J, Arnheim N et al (2013) New evidence for positive selection helps explain the paternal age effect observed in achondroplasia. Hum Mol Genet 22(20):4117–4126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith-Hicks CL, Sizer KC, Powers JF, Tischler AS, Costantini F (2000) C-cell hyperplasia, pheochromocytoma and sympathoadrenal malformation in a mouse model of multiple endocrine neoplasia type 2B. EMBO J 19:612–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takashima S, Kanatsu-Shinohara M, Tanaka T, Morimoto H, Inoue K et al (2015) Functional differences between GDNF-dependent and FGF2-dependent mouse spermatogonial stem cell self-renewal. Stem Cell Rep 4:489–502

    Article  CAS  Google Scholar 

  • Thisse B, Thisse C (2005) Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev Biol 287:390–402

    Article  CAS  PubMed  Google Scholar 

  • van Alphen MM, van de Kant HJ, de Rooij DG (1988) Depletion of the spermatogonia from the seminiferous epithelium of the rhesus monkey after X irradiation. Radiat Res 113:473–486

    Article  PubMed  Google Scholar 

  • Vogel F, Motulsky AG (1997) Human genetics: problems and approaches. Springer, Berlin; New York

    Book  Google Scholar 

  • von Kopylow K, Staege H, Schulze W, Will H, Kirchhoff C (2012a) Fibroblast growth factor receptor 3 is highly expressed in rarely dividing human type A spermatogonia. Histochem Cell Biol 138:759–772

    Article  CAS  Google Scholar 

  • von Kopylow K, Staege H, Spiess AN, Schulze W, Will H et al (2012b) Differential marker protein expression specifies rarefaction zone-containing human Adark spermatogonia. Reproduction 143:45–57

    Article  Google Scholar 

  • Walter CA, Intano GW, McMahan CA, Kelner K, McCarrey JR et al (2004) Mutation spectral changes in spermatogenic cells obtained from old mice. DNA Repair (Amst) 3:495–504

    Article  CAS  Google Scholar 

  • Wang Y, Spatz MK, Kannan K, Hayk H, Avivi A et al (1999) A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3. Proc Natl Acad Sci U S A 96:4455–4460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Xiao R, Yang F, Karim BO, Iacovelli AJ et al (2005) Abnormalities in cartilage and bone development in the Apert syndrome FGFR2+/S252W mouse. Development 132:3537–3548

    Article  CAS  PubMed  Google Scholar 

  • Weinberg W (1912) Zur Verebung des Zwergwuches. Archiv Rassen-und Gesellschafts-Hygie Biolne 9:710–718

    Google Scholar 

  • Wells SA Jr, Santoro M (2009) Targeting the RET pathway in thyroid cancer. Clin Cancer Res 15:7119–7123

    Article  CAS  PubMed  Google Scholar 

  • Yang QE, Oatley JM (2014) Spermatogonial stem cell functions in physiological and pathological conditions. Curr Top Dev Biol 107:235–267

    Article  CAS  PubMed  Google Scholar 

  • Yoon SR, Choi SK, Eboreime J, Gelb BD, Calabrese P et al (2013) Age-dependent germline mosaicism of the most common noonan syndrome mutation shows the signature of germline selection. Am J Hum Genet 92:917–926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoon SR, Qin J, Glaser RL, Jabs EW, Wexler NS et al (2009) The ups and downs of mutation frequencies during aging can account for the Apert syndrome paternal age effect. PLoS Genet 5:e1000558

    Article  PubMed  PubMed Central  Google Scholar 

  • Yoshida S (2010) Stem cells in mammalian spermatogenesis. Develop Growth Differ 52:311–317

    Article  CAS  Google Scholar 

  • Yoshida S (2012) Elucidating the identity and behavior of spermatogenic stem cells in the mouse testis. Reproduction 144:293–302

    Article  CAS  PubMed  Google Scholar 

  • Yoshida S, Sukeno M, Nabeshima Y (2007) A vasculature-associated niche for undifferentiated spermatogonia in the mouse testis. Science 317:1722–1726

    Article  CAS  PubMed  Google Scholar 

  • Zhang T, Oatley J, Bardwell VJ, Zarkower D (2016) DMRT1 is required for mouse spermatogonial stem cell maintenance and replenishment. PLoS Genet 12:e1006293

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang W, Chan RJ, Chen H, Yang Z, He Y et al (2009) Negative regulation of Stat3 by activating PTPN11 mutants contributes to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia. J Biol Chem 284:22353–22363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M et al (2006) Receptor specificity of the fibroblast growth factor family. J Biol Chem 281:15694–15700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou QG, Griswold MD (2008) Regulation of spermatogonia. In: T. S. R. Community (ed) StemBook

    Google Scholar 

Download references

Acknowledgments

Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R01GM36745. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Molecular and Computational Biology Program, University of Southern California, 1050 Childs Way, Los Angeles, CA, 90089-2910, USA

    Norman Arnheim & Peter Calabrese

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Correspondence to Norman Arnheim .

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  1. Centre for Reproductive Biology, School of Molecular Biosciences, Washington State University, Pullman, Washington, USA

    Jon M. Oatley

  2. School of Molecular Biosciences, Washington State University, Pullman, Washington, USA

    Michael D. Griswold

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Arnheim, N., Calabrese, P. (2017). Frequency of Human Disease Mutations and Spermatogonial Stem Cell Function. In: Oatley, J., Griswold, M. (eds) The Biology of Mammalian Spermatogonia. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-7505-1_8

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