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The mystery of the mystery of common genetic diseases

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Abstract

Common monogenic genetic diseases, ones that have unexpectedly high frequencies in certain populations, have attracted a great number of conflicting evolutionary explanations. This paper will attempt to explain the mystery of why two particularly extensively studied common genetic diseases, Tay Sachs disease and cystic fibrosis, remain evolutionary mysteries despite decades of research. I review the most commonly cited evolutionary processes used to explain common genetic diseases: reproductive compensation, random genetic drift (in the context of founder effect), and especially heterozygote advantage. The latter process has drawn a particularly large amount of attention, having so successfully explained the elevated frequency of sickle cell anemia in malaria-endemic areas. However, the empirical evidence for heterozygote advantage in other common genetic diseases is quite weak. I introduce and illustrate the significance of a hierarchy of genetic disease phenomena found within the genetic disease explanations, which include the phenomena: single mutation variants of a common genetic disease, single genetic diseases, and classes of diseases with related phenotypic effects. I demonstrate that some of the confusion over the explanations of common genetic diseases can be traced back to confusions over which phenomena are being explained. I proceed to briefly evaluate the existing evidence for two common human genetic diseases: Tay Sachs disease and cystic fibrosis. The above considerations will ultimately shed light on why these diseases’ evolutionary explanations remain so deeply unresolved after so such a great volume of research.

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Notes

  1. Founder effect is properly a subcategory of bottleneck effects, which can occur at times other than the founding of the population, with similar consequences.

  2. However, the use of a deterministic model has the effect of discounting drift as a mere matter of basic model structure choice.

  3. This process can also extend beyond 1:1 replacement, becoming “reproductive over-compensation”, wherein sibships in disease-affected families are actually larger than the population’s average (Koeslag, et al. 1984).

  4. An exception to this general tendency of biochemical linkages is a recent paper by Poolman and Galvani (2007). The paper uses epidemiological models to argue that TB is a viable candidate HA selective agent for CF. Regrettably, a dearth of TB data for non-European areas limits the paper’s ability to account for CF’s Europe-centered increase in frequency.

  5. This research could be either prospective or retrospective is design, so long as fitness is accurately ascertained. Of course, ethical considerations would set serious constraints on any prospective study design.

References

  • Bowersox J (1998) Cystic fibrosis protects against typhoid fever (news release). National Institutes of Health, Bethesda

    Google Scholar 

  • Bowman J (1964) Comments on abnormal erythrocytes and malaria. Am J Trop Med Hyg 13(suppl):159–161

    Google Scholar 

  • Bowman JE, Carson PE, Frischer H, Powell RD, Colwell EJ, Legters LJ et al (1971) Hemoglobin and red cell enzyme variation in some populations of the Republic of Vietnam with comments on the malria hypothesis. Am J Phys Anthropol 34(3):313–324

    Article  Google Scholar 

  • Bromberger S (1966) Why-questions. In: Colodny RG (ed) Mind and cosmos: essays in contemporary science and philosophy. University of Pittsburgh Press, Pittsburgh, pp 86–111

    Google Scholar 

  • Calafell F, Cutting G, Dodge J, Des Georges M, Dörk T, Durie P et al (2004) The molecular genetic epidemiology of cystic fibrosis: report of a joint meeting of WHO/ECFTN/ICF(M)A/ECFS Genoa, Italy, 19 June 2002. World Health OrganizationChronic Diseases and Health Promotion Human Genetics Programme, Geneva

    Google Scholar 

  • Charrow J (2004) Ashkenazi jewish genetic disorders. Familial Cancer 3(3–4):201–206

    Article  Google Scholar 

  • Chase GA, McKusick VA (1972) Controversy in human genetics: founder effect in tay-sachs disease. Am J Hum Genet 24(3):339–340

    Google Scholar 

  • Diamond JM (1988) Diamond replies. Nature 331(6158):666

    Article  Google Scholar 

  • Diamond J (1991) Curse and blessing of the Ghetto. Discover 12:60–65

    Google Scholar 

  • Diamond J (1994) Human genetics. Jewish lysosomes. Nature 368(6469):291–292

    Article  Google Scholar 

  • Flint J, Harding RM, Clegg JB, Boyce AJ (1993) Why are some genetic diseases common? Hum Genet 91(2):91–117

    Article  Google Scholar 

  • Frisch A, Colombo R, Michaelovsky E, Karpati M, Goldman B, Peleg L (2004) Origin and spread of the 1278insTATC mutation causing Tay-Sachs disease in Ashkenazi Jews: genetic drift as a Robust and Parsimonious hypothesis. Hum Genet 114(4):366–376

    Article  Google Scholar 

  • Gabriel SE, Brigman KN, Koller BH, Boucher RC, Stutts MJ (1994) Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. Science 266(5182):107–109

    Article  Google Scholar 

  • Gallego Romero I, Ober C (2008) CFTR mutations and reproductive outcomes in a population isolate. Hum Genet 122(6):583–588

    Article  Google Scholar 

  • Gould SJ, Lewontin RC (1979) The Spandrels of San Marco and the Panglossian Paradigm: a critique of the adaptationist programme. Proc R Soc Lond Ser B Biol Sci 205(1161):581–598

    Article  Google Scholar 

  • Harris EE, Malyango AA (2005) Evolutionary explanations in medical and health profession courses: are you answering your students’ “Why” questions? BMC Med Educ 5(1):16

    Google Scholar 

  • Hastings IM (2000) Models of human genetic disease: how biased are the standard formulae? Genet Res 75(1):107–114

    Article  Google Scholar 

  • Högenauer C, Santa Ana CA, Porter JL, Millard M, Gelfand A, Rosenblatt RL et al (2000) Active intestinal chloride secretion in human carriers of cystic fibrosis mutations: an evaluation of the hypothesis that heterozygotes have subnormal active intestinal chloride secretion. Am J Hum Genet 67(6):1422–1427

    Article  Google Scholar 

  • Jorde LB, Lathrop GM (1988) A test of the heterozygote-advantage hypothesis in cystic fibrosis carriers. Am J Hum Genet 42(6):808–815

    Google Scholar 

  • Knudson AG, Jr, Wayne L, Hallett WY (1967) On the selective advantage of cystic fibrosis heterozygotes. Am J Hum Genet 19(3 Pt 2):388–392

    Google Scholar 

  • Koeslag JH, Schach SR, Melzer CW (1984) Tay-Sachs disease and the persistence of lethal autosomal recessive genes in human populations. S Afr Med J 66(3):87–89

    Google Scholar 

  • Lewis LG, Cohen MB (1995) A selective advantage for cystic fibrosis carriers. J Pediatr Gastroenterol Nutr 21(1):117–118

    Article  Google Scholar 

  • Lewontin RC (1953) The effect of compensation on populations subject to natural selection. Am Nat 87(837):375–381

    Article  Google Scholar 

  • Livingstone FB (1971) Malaria and human polymorphisms. Annu Rev Genet 5:33–64

    Article  Google Scholar 

  • Lloyd EA (1994) The structure and confirmation of evolutionary theory. Princeton University Press, Princeton

    Google Scholar 

  • Meals RA (1971) Paradoxical frequencies of recessive disorders in Ashkenazic Jews. J Chronic Dis 23:547–558

    Article  Google Scholar 

  • Modiano G, Ciminelli BM, Pignatti PF (2007) Cystic fibrosis and lactase persistence: a possible correlation. Eur J Hum Genet 15(3):255–259

    Article  Google Scholar 

  • Myrianthopoulos NC, Aaronson SM (1971). Population dynamics of Tay Sachs Disease. II. What confers the selective advantage upon the jewish heterozygote? Paper presented at the symposium on sphingolipidoses and allied disorders, New York

  • Myrianthopoulos NC, Aronson SM (1966) Population dynamics of Tay-Sachs Disease. I. Reproductive fitness and selection. Am J Hum Genet 18(4):313–327

    Google Scholar 

  • O’Brien SJ (1991) Ghetto legacy. Curr Biol 1(4):209–211

    Article  Google Scholar 

  • Peach SL, Borriello SP, Gaya H, Barclay FE, Welch AR (1986) Asymptomatic carriage of clostridium difficile in patients with cystic fibrosis. J Clin Pathol 39(9):1013–1018

    Article  Google Scholar 

  • Pier GB, Grout M, Zaidi T, Meluleni G, Mueschenborn SS, Banting G et al (1998) Salmonella typhi uses CFTR to enter intestinal epithelial cells. Nature 393(6680):79–82

    Article  Google Scholar 

  • Poolman EM, Galvani AP (2007) Evaluating candidate agents of selective pressure for cystic fibrosis. J R Soc Interface 4(12):91–98

    Article  Google Scholar 

  • Qin J, Calabrese P, Tiemann-Boege I, Shinde DN, Yoon S-R, Gelfand D et al (2007) The molecular anatomy of spontaneous germline mutations in human testes. PLoS Biol 5(9):e224

    Article  Google Scholar 

  • Risch N, Tang H, Katzenstein H, Ekstein J (2003) Geographic distribution of disease mutations in the Ashkenazi Jewish population supports genetic drift over selection. Am J Hum Genet 72(4):812–822

    Article  Google Scholar 

  • Rodman DM, Zamudio S (1991) The cystic fibrosis heterozygote—advantage in surviving cholera? Med Hypotheses 36(3):253–258

    Article  Google Scholar 

  • Rotter JI, Diamond JM (1987) What maintains the frequencies of human genetic diseases? Nature 329(6137):289–290

    Article  Google Scholar 

  • Schaffner KF (1993) Discovery and explanation in biology and medicine. University of Chicago Press, Chicago

    Google Scholar 

  • Spyropoulos B, Moens PB, Davidson J, Lowden JA (1981) Heterozygote advantage in Tay Sachs carriers? Am J Hum Genet 33(3):375–380

    Google Scholar 

  • Stiehm ER (2006) Disease versus disease: how one disease may ameliorate another. Pediatrics 117(1):184–191

    Article  Google Scholar 

  • Temple D (1988) The contrast theory of why-questions. Philos Sci 55(1):141–151

    Article  Google Scholar 

  • van de Vosse E, Ali S, de Visser AW, Surjadi C, Widjaja S, Vollaard AM et al (2005) Susceptibility to typhoid fever is associated with a polymorphism in the cystic fibrosis transmembrane conductance regulator (CFTR). Hum Genet 118(1):138–140

    Article  Google Scholar 

  • van Fraassen BC (1990) The scientific image. Oxford University Press, New York

    Google Scholar 

  • Walsh DM, Lewens T, Ariew A (2002) The trials of life: natural selection and random drift. Philos Sci 69(3):452–473

    Article  Google Scholar 

  • Wright SW, Morton NE (1968) Genetic studies on cystic fibrosis in Hawaii. Am J Hum Genet 20(2):157–169

    Google Scholar 

  • Zlotogora J (1994) High frequencies of human genetic diseases: founder effect with genetic drift or selection? Am J Med Genet 49(1):10–13

    Article  Google Scholar 

  • Zlotogora J (1998) Selection for carriers of recessive diseases: a common phenomenon? Am J Med Genet 80(3):266–268

    Article  Google Scholar 

Download references

Acknowledgments

I am deeply grateful for the many helpful suggestions offered by the Indiana University Biology Studies Reading Group. I would like to especially thank Elisabeth Lloyd for her paramount patience and wisdom throughout the writing and revising of the paper, as well as Michael Wade for his detailed and insightful advice on both the biology and the philosophy. I am also very grateful for the invaluable comments and suggestions provided by Kim Sterelny and an anonymous reviewer.

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  1. Indiana University History and Philosophy of Science Department, 3000 S. Walnut Street Pike, Apt. B8, Bloomington, IN, 47401, USA

    Sean A. Valles

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Valles, S.A. The mystery of the mystery of common genetic diseases. Biol Philos 25, 183–201 (2010). https://doi.org/10.1007/s10539-009-9184-8

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