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The low frequency of recessive disease: insights from ENU mutagenesis, severity of disease phenotype, GWAS associations, and demography: an analytical review

  • Human Genetics ∙ Review
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Abstract

A survey of a select panel of 14 genetic diseases with mixed inheritance confirms that, while autosomal recessive (AR) disease genes are more numerous than autosomal dominant (AD) or X-linked (XL) ones, they make a smaller average contribution to disease. Data collected from N-ethyl-N-nitrosourea (ENU) mutagenesis studies show a similar excess of AR mutations. The smaller AR contribution may partially reflect disease severity, but only in the comparison of AR with AD mutations. On the contrary, XL mutations for the 14 diseases are generally more severe. Genome-wide associations studies (GWAS) data provide fresh insight into the shortage, with a limited negative selection effect mediated by the pleiotropic expression of recessive disease genes in other deleterious phenotypes. Genomic data provide further evidence of purging selection in a past European population bottleneck followed by a dramatic population explosion, now more clearly associated with past climate change. We consider these likely to be the main factors responsible for the low AR to AD/XL inheritance ratio.

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References

  • Acevedo-Arozena A, Wells S, Potter P, Kelly M, Cox RD, Brown SD (2008) ENU mutagenesis, a way forward to understand gene function. Annu Rev Genomics Hum Genet 9:49–69

    Article  CAS  PubMed  Google Scholar 

  • Allan W (1939) Relation of hereditary pattern to clinical severity as illustrated by peroneal atrophy. Arch Intern Med 63:1123–1131

    Article  Google Scholar 

  • Bittles AH, Black ML (2010) Evolution in health and medicine Sackler colloquium: Consanguinity, human evolution, and complex diseases. Proc Natl Acad Sci U S A 107(Suppl 1):1779–1786

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bittles AH, Neel JV (1994) The costs of human inbreeding and their implications for variations at the DNA level. Nat Genet 8:117–121

    Article  CAS  PubMed  Google Scholar 

  • Blekhman R, Man O, Herrmann L, et al (2008) Natural selection on genes that underlie human disease susceptibility. Curr Biol 18:883–889

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Buckley RH (2004) The multiple causes of human SCID. J Clin Invest 114:1409–1411

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chang YF, Imam JS, Wilkinson MF (2007) The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem 76:51–74

    Article  CAS  PubMed  Google Scholar 

  • Charlesworth D, Willis JH (2009) The genetics of inbreeding depression. Nat Rev Genet 10:783–796

    Article  CAS  PubMed  Google Scholar 

  • Coventry A, Bull-Otterson LM, Liu X et al (2010) Deep resequencing reveals excess rare recent variants consistent with explosive population growth. Nat Commun 1:131

    Article  PubMed Central  PubMed  Google Scholar 

  • Dean M, Carrington M, O’Brien SJ (2002) Balanced polymorphism selected by genetic versus infectious human disease. Annu Rev Genomics Hum Genet 3:263–292

    Article  CAS  PubMed  Google Scholar 

  • Erickson RP (2009) Autosomal recessive diseases among the Athabaskans of the southwestern United States: recent advances and implications for the future. Am J Genet A 149A:2602–2611

    Article  Google Scholar 

  • Eriksson A, Betti L, Friend AD, et al (2012) Late Pleistocene climate change and the global expansion of anatomically modern humans. Proc Natl Acad Sci U S A 109:16089–16094

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fu W, O’Connor TD, Jun G et al (2013) Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature 493:216–220

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Furney SJ, Albà MM, López-Bigas N (2006) Differences in the evolutionary history of disease genes affected by dominant or recessive mutations. BMC Genomics 7:165

    Article  PubMed Central  PubMed  Google Scholar 

  • Gabriková D, Bernasovská J, Mačeková S et al (2012) Unique frequencies of HFE gene variants in Roma/Gypsies. J Appl Genet 53:183–187

    Article  PubMed  Google Scholar 

  • Gabrikova D, Mistrik M, Bernasovska J et al (2013) Founder mutations in NDRG1 and HK1 genes are common causes of inherited neuropathies among Roma/Gypsies in Slovakia. J Appl Genet 54:455–460

    Article  CAS  PubMed  Google Scholar 

  • Hartong DT, Berson EL, Dryja TP (2006) Retinitis pigmentosa. Lancet 368:1795–1809

    Article  CAS  PubMed  Google Scholar 

  • Hrabé de Angelis MH, Flaswinkel H, Fuchs H et al (2000) Genome-wide, large-scale production of mutant mice by ENU mutagenesis. Nat Genet 25:444–447

    Article  PubMed  Google Scholar 

  • Inoue K, Ohyama T, Sakuragi Y et al (2004) Translation of SOX10 3’ untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain. Hum Mol Genet 16:3037–3046

    Article  Google Scholar 

  • Kääriäinen H (1987) Polycystic kidney disease in children: a genetic and epidemiological study of 82 Finnish patients. J Med Genet 24:474–481

    Article  PubMed Central  PubMed  Google Scholar 

  • Keinan A, Clark AG (2012) Recent explosive human population growth has resulted in an excess of rare genetic variants. Science 336:740–743

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Keinan A, Mullikin JC, Patterson N, Reich D (2007) Measurement of the human allele frequency spectrum demonstrates greater genetic drift in East Asians than in Europeans. Nat Genet 39:1251–1255

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kenneson A, Kolor K, Yang Q, Olney RS, Rasmussen SA, Friedman JM (2006) Trends and racial disparities in muscular dystrophy deaths in the United States, 1983–1998: an analysis of multiple cause mortality data. Am J Med Genet A 140:2289–2297

    Article  PubMed  Google Scholar 

  • Krawczak M, Ball EV, Cooper DN (2008) Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes. Am J Hum Genet 63:474–488

    Article  Google Scholar 

  • Kryukov GV, Pennacchio LA, Sunyaev SR (2007) Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am J Hum Genet 80:727–739

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lohmueller KE, Indap AR, Schmidt S et al (2008) Proportionally more deleterious genetic variation in European than in African populations. Nature 451:994–997

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lynch M (2010) Rate, molecular spectrum, and consequences of human mutation. Proc Natl Acad Sci U S A 107:961–968

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • MacArthur DG, Balasubramanian S, Frankish A et al (2012) A systematic survey of loss-of-function variants in human protein-coding genes. Science 335:823–828

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Marth GT, Czabarka E, Murvai J, Sherry ST (2004) The allele frequency spectrum in genome-wide human variation data reveals signals of differential demographic history in three large world populations. Genetics 166:351–372

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McQuillan R, Eklund N, Pirastu N, et al (2012) Evidence of inbreeding depression on human height. PLoS Genet 8(7):e1002655

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mitchison NA, Clarke B (2008) From ENU mutagenesis to population genetics. Mamm Genome 19:221–225

    Article  PubMed  Google Scholar 

  • Mitchison NA, Bhattacharya S, Tuddenham EG (2011) Human congenital diseases with mixed modes of inheritance have a shortage of recessive disease. A demographic scenario? Ann Hum Genet 75:688–693

    Article  PubMed  Google Scholar 

  • Morriss-Kay GM (2010) The evolution of human artistic creativity. J Anat 216:158–176

    Article  PubMed Central  PubMed  Google Scholar 

  • Mort M, Ivanov D, Cooper DN, Chuzhanova NA (2008) A meta-analysis of nonsense mutations causing human genetic disease. Hum Mutat 29:1037–1047

    Article  CAS  PubMed  Google Scholar 

  • Morton NE, Crow JF, Muller HJ (1956) An estimate of the mutational damage in man from data on consanguineous marriages. Proc Natl Acad Sci U S A 42:855–863

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nelson J, Crowhurst J, Carey B, Greed L (2003) Incidence of the mucopolysaccharidoses in Western Australia. J Med Genet A 123A(3):310–313

    Article  Google Scholar 

  • Nguyen N, Judd LM, Kalantzis A, Whittle B, Giraud AS, van Driel IR (2011) Random mutagenesis of the mouse genome: a strategy for discovering gene function and the molecular basis of disease. Am J Physiol Gastrointest Liver Physiol 300:G1–G11

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pelak K, Shianna KV, Ge D et al (2010) The characterization of twenty sequenced human genomes. PLoS Genet 6(9):e1001111

    Article  PubMed Central  PubMed  Google Scholar 

  • Pettigrew HD, Teuber SS, Gershwin ME (2009) Clinical significance of complement deficiencies. Ann N Y Acad Sci 1173:108–123

    Article  CAS  PubMed  Google Scholar 

  • Peyvandi F, Spreafico M (2008) National and international registries of rare bleeding disorders. Blood Transfus 6(Suppl 2):s45–s48

    PubMed Central  PubMed  Google Scholar 

  • Saporta AS, Sottile SL, Miller LJ, Feely SM, Siskind CE, Shy ME (2011) Charcot–Marie–Tooth disease subtypes and genetic testing strategies. Ann Neurol 69:22–33

    Article  PubMed Central  PubMed  Google Scholar 

  • Sohocki MM, Daiger SP, Bowne SJ et al (2001) Prevalence of mutations causing retinitis pigmentosa and other inherited retinopathies. Hum Mutat 17:42–51

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sowińska-Seidler A, Socha M, Jamsheer A (2014) Split-hand/foot malformation - molecular cause and implications in genetic counseling. J Appl Genet 55(1):105–115

    Google Scholar 

  • Vogel F (1984) Clinical consequences of heterozygosity for autosomal-recessive diseases. Clin Genet 25:381–415

    Article  CAS  PubMed  Google Scholar 

  • Weiss J, Hurley LA, Harris RM et al (2012) ENU mutagenesis in mice identifies candidate genes for hypogonadism. Mamm Genome 23:346–355

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Williamson SH, Hernandez R, Fledel-Alon A, Zhu L, Nielsen R, Bustamante CD (2005) Simultaneous inference of selection and population growth from patterns of variation in the human genome. Proc Natl Acad Sci U S A 102:7882–7887

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, University of Arizona, Tucson, AZ, 85724, USA

    Robert P. Erickson

  2. Division of Infection and Immunity, University College London, London, UK

    N. Avrion Mitchison

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  1. Robert P. Erickson
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  2. N. Avrion Mitchison
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Correspondence to Robert P. Erickson.

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Erickson, R.P., Mitchison, N.A. The low frequency of recessive disease: insights from ENU mutagenesis, severity of disease phenotype, GWAS associations, and demography: an analytical review. J Appl Genetics 55, 319–327 (2014). https://doi.org/10.1007/s13353-014-0203-3

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  • DOI: https://doi.org/10.1007/s13353-014-0203-3

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