Transmission Ratio Distortion: A Neglected Phenomenon with Many Consequences in Genetic Analysis and Population Genetics

  • Aurélie Labbe
  • Lam Opal Huang
  • Claire Infante-Rivard
Chapter

Abstract

Transmission ratio distortion (TRD) is defined as a statistical departure from the Mendelian 1:1 inheritance ratio and occurs when one of the two alleles from either parent is preferentially transmitted to the offspring (Pardo-Manuel de Villena and Sapienza 2001). This phenomenon is conventionally assessed by the transmission disequilibrium test (TDT) (Spielman et al. 1993), which measures the departure from the expected transmission of an allele from heterozygous parents to affected offspring. In such cases, a departure from Mendelian ratios suggests the presence of linkage and association between the allele and the offspring condition. The TDT and other family-based tests of transmission for linkage disequilibrium and association have been used extensively as one way to provide validation for case–control results while controlling for population structure bias. However, TRD has also been empirically observed in offspring unselected for disease (Infante-Rivard and Weinberg 2005; Naumova et al. 1998; Paterson et al. 2003, 2009; Zollner et al. 2004), which suggests the occurrence of the TRD phenomena in apparently unaffected populations. Although its extent in the human genome is not yet well known, it has also been extensively identified in other species such as mice (LeMaire-Adkins and Hunt 2000; Lyon 2003; Wu et al. 2005), drosophila (Novitski 1951; Sturtevant 1936; Zimmering 1955), and lesser kestrel (Aparicio et al. 2010). Many of the reported TRD loci play a role in tumor suppression and have been found in colon cancer, leukemia, bladder cancer, intestinal adenoma, node-positive breast cancer, and other cancers (De Rango et al. 2007; Eaves et al. 1999; Naumova et al. 2001; Paterson et al. 2009). A number of TRD loci are within gene regions responsible for imprinting (Eversley et al. 2010; Naumova et al. 2001; Yang et al. 2008), such as D12Nds2 on chromosome 12 and H19 on 11p15.5, leading to loss of imprint and embryonic lethality. Many TRD loci have also been linked to abnormal development in neurogenesis, neuronal differentiation, and other cognitive functions in the central and peripheral nervous system (De Rango et al. 2007; Eversley et al. 2010; Naumova et al. 2001; Paterson et al. 2009; Paterson and Petronis 1999; Riess et al. 1997).

Keywords

Leukemia Recombination Adenoma Hunt Plasminogen 

References

  1. Aparicio JM, Ortego J, Calabuig G, Cordero PJ (2010) Evidence of subtle departures from Mendelian segregation in a wild lesser kestrel (Falco naumanni) population. Heredity 105:213–219PubMedCrossRefGoogle Scholar
  2. Becker T, Jansen S, Tamm S, Wienker TF, Tummler B, Stanke F (2007) Transmission ratio distortion and maternal effects confound the analysis of modulators of cystic fibrosis disease severity on 19q13. Eur J Hum Genet 15:774–778PubMedCrossRefGoogle Scholar
  3. Blyth K, Vaillant F, Jenkins A, McDonald L, Pringle MA, Huser C, Stein T, Neil J, Cameron ER (2010) Runx2 in normal tissues and cancer cells: a developing story. Blood Cells Mol Dis 45:117–123. doi: 10.1016/j.bcmd.2010.05.007 PubMedCrossRefGoogle Scholar
  4. Bodmer W, Bonilla C (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet 40:695–701PubMedCrossRefGoogle Scholar
  5. Botta A, Tacconelli A, Bagni I, Giardina E, Bonifazi E, Pietropolli A, Clementi M, Novelli G (2005) Transmission ratio distortion in the spinal muscular atrophy locus: data from 314 prenatal tests. Neurology 65:1631–1635PubMedCrossRefGoogle Scholar
  6. Casellas J, Gularte RJ, Varona L, Mehrabian M, Schadt EE, Lusis AJ, Attie AD, Yandell BS, Medrano JF (2012) Genome scans for transmission ratio distortion regions in mice. Genetics 191(1):247–259PubMedCrossRefGoogle Scholar
  7. Chevin LM, Hospital F (2006) The hitchhiking effect of an autosomal meiotic drive gene. Genetics 173:1829–1832. doi: 10.1534/genetics.105.052977 PubMedCrossRefGoogle Scholar
  8. Cirulli ET, Goldstein DB (2010) Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet 11:415–425PubMedCrossRefGoogle Scholar
  9. Croteau S, Andrade MF, Huang F, Greenwood CM, Morgan K, Naumova AK (2002) Inheritance patterns of maternal alleles in imprinted regions of the mouse genome at different stages of development. Mammalian Genome 13:24–29PubMedCrossRefGoogle Scholar
  10. De Rango F, Dato S, Bellizzi D, Rose G, Marzi E, Cavallone L, Franceschi C, Skytthe A, Jeune B, Cournil A (2007) A novel sampling design to explore gene-longevity associations: the ECHA study. Eur J Hum Genet 16:236–242PubMedCrossRefGoogle Scholar
  11. Dean NL, Loredo-Osti JC, Fujiwara TM, Morgan K, Tan SL, Naumova AK, Ao A (2006) Transmission ratio distortion in the myotonic dystrophy locus in human preimplantation embryos. Eur J Hum Genet 14:299–306PubMedCrossRefGoogle Scholar
  12. Deng L, Zhang D, Richards E, Tang X, Fang J, Long F, Wang Y (2009) Constructing an initial map of transmission distortion based on high density HapMap SNPs across the human autosomes. J Genet Genomics 36:703–709. doi: 10.1016/s1673-8527(08)60163-0 PubMedCrossRefGoogle Scholar
  13. Dudding TE, Attia J, Infante-Rivard C (2004) Addendum to: the association between adverse pregnancy outcomes and maternal factor V Leiden genotype. A meta-analysis. Thromb Haemaost 92:434Google Scholar
  14. Dudding TE, Attia J (2004) The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis. Thromb Haemost 91:700–711PubMedGoogle Scholar
  15. Eaves IA, Bennett ST, Forster P, Ferber KM, Ehrmann D, Wilson AJ, Bhattacharyya S, Ziegler AG, Brinkmann B, Todd JA (1999) Transmission ratio distortion at the INS-IGF2 VNTR. Nat Genet 22:324PubMedCrossRefGoogle Scholar
  16. Evans D, Morris A, Cardon L, Sham P (2006) A note on the power to detect transmission distortion in parent-child trios via the transmission disequilibrium test. Behav Genet 36:947–950PubMedCrossRefGoogle Scholar
  17. Eversley CD, Clark T, Xie Y, Steigerwalt J, Bell TA, de Villena FP, Threadgill DW (2010) Genetic mapping and developmental timing of transmission ratio distortion in a mouse interspecific backcross. BMC Genet 11:98. doi: 10.1186/1471-2156-11-98 PubMedCrossRefGoogle Scholar
  18. Friedrichs F, Brescianini S, Annese V, Latiano A, Berger K, Kugathasan S, Broeckel U, Nikolaus S, Daly MJ, Schreiber S, Rioux JD, Stoll M (2006) Evidence of transmission ratio distortion of DLG5 R30Q variant in general and implication of an association with Crohn disease in men. Hum Genet 119:305–311PubMedCrossRefGoogle Scholar
  19. Gorlov IP, Gorlova OY, Sunyaev SR, Spitz MR, Amos CI (2008) Shifting paradigm of association studies: value of rare single-nucleotide polymorphisms. Am J Hum Genet 82:100–112PubMedCrossRefGoogle Scholar
  20. Greenwood CM, Morgan K (2000) The impact of transmission-ratio distortion on allele sharing in affected sibling pairs. Am J Hum Genet 66:2001–2004PubMedCrossRefGoogle Scholar
  21. Haig D, Grafen A (1991) Genetic scrambling as a defence against meiotic drive. J Theor Biol 153:531–558PubMedCrossRefGoogle Scholar
  22. Hanchard N, Rockett K, Udalova I, Wilson J, Keating B, Koch O, Nijnik A, Diakite M, Herbert M, Kwiatkowski D (2005) An investigation of transmission ratio distortion in the central region of the human MHC. Genes Immun 7:51–58CrossRefGoogle Scholar
  23. Hastings IM (1991) Germline selection: population genetic aspects of the sexual/asexual life cycle. Genetics 129:1167–1176PubMedGoogle Scholar
  24. Huang LO, Labbe A, Infante-Rivard C (2013) Transmission ratio distortion: review of concept and implications for genetic association studies. Hum Genet 132(3):245–263PubMedCrossRefGoogle Scholar
  25. Imboden M, Swan H, Denjoy I, Van Langen IM, Latinen-Forsblom PJ, Napolitano C, Fressart V, Breithardt G, Berthet M, Priori S, Hainque B, Wilde AAM, Schulze-Bahr E, Feingold J, Guicheney P (2006) Female predominance and transmission distortion in the long-QT syndrome. N Engl J Med 355:2744–2751PubMedCrossRefGoogle Scholar
  26. Infante-Rivard C, Rivard GE, Yotov W, Génin E, Guiguet M, Weinberg C, Gauthier R, Feoli-Fonseca JC (2002) Absence of association of thrombophilia polymorphisms with intrauterine growth retardation. N Engl J Med 347:19–24PubMedCrossRefGoogle Scholar
  27. Infante-Rivard C, Lévy E, Rivard GE, Guiguet M, Feoli-Fonseca JC (2003) Small babies receive the cardiovascular protective apolipoprotein ε2 allele less frequently than expected. J Med Gen 40:626–629CrossRefGoogle Scholar
  28. Infante-Rivard C, Weinberg CR (2005) Parent-of-origin transmission of thrombophilic alleles to intrauterine growth-restricted newborns and transmission-ratio distortion in unaffected newborns. Am J Epidemiol 162:891–897. doi: 10.1093/aje/kwi293 PubMedCrossRefGoogle Scholar
  29. Infante-Rivard C, Rivard GE, Guiguet M, Gauthier R (2005) Thrombophilic polymorphisms and intrauterine growth restriction. Epidemiology 16:281–287PubMedCrossRefGoogle Scholar
  30. Infante-Rivard C (2010) Genetic association between paraoxonase 1 gene (PON1) single nucleotide polymorphisms and small-for-gestational age outcome in related and unrelated subjects. Am J Epidemiol 171:999–1006PubMedCrossRefGoogle Scholar
  31. 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 80:727–739PubMedCrossRefGoogle Scholar
  32. Lange K (1997) Mathematical and statistical methods for genetic analysis. Springer, New YorkCrossRefGoogle Scholar
  33. Lemire M, Roslin NM, Laprise C, Hudson TJ, Morgan K (2004) Transmission-ratio distortion and allele sharing in affected sib pairs: a new linkage statistics with reduced biais, with application to chromosome 6q25.3. Am J Hum Genet 75(4):571–586.PubMedCrossRefGoogle Scholar
  34. LeMaire-Adkins R, Hunt PA (2000) Nonrandom segregation of the mouse univalent X chromosome: evidence of spindle-mediated meiotic drive. Genetics 156:775PubMedGoogle Scholar
  35. Li B, Leal SM (2009) Discovery of rare variants via sequencing: implications for the design of complex trait association studies. PLoS Genet 5:e1000481PubMedCrossRefGoogle Scholar
  36. Liddell D (1976) Practical tests of 2 × 2 contingency tables. J Royal Stat Soc 25(4):295–304Google Scholar
  37. Lyon MF (2003) Transmission ratio distortion in mice. Annu Rev Genet 37:393–408PubMedCrossRefGoogle Scholar
  38. Maher B (2008) Personal genomes: the case of the missing heritability. Nature 456:18–21. doi: 10.1038/456018a PubMedCrossRefGoogle Scholar
  39. Meyer WK, Arbeithuber B, Ober C, Ebner T, Tiemann-Boege I, Hudson RR, Przeworski M (2012) Evaluating the evidence for transmission distortion in human pedigrees. Genetics 191:215–232. doi: 10.1534/genetics.112.139576 PubMedCrossRefGoogle Scholar
  40. Naumova A, Olien L, Bird L, Slamka C, Fonseca M, Verner A, Wang M, Leppert M, Morgan K, Sapienza C (1995) Transmission ratio distortion of X chromosomes among male offspring of females with skewed X inactivation. Dev Genet 17:198–205PubMedCrossRefGoogle Scholar
  41. Naumova AK, Greenwood CM, Morgan K (2001) Imprinting and deviation from Mendelian transmission ratios. Genome 44:311–320PubMedCrossRefGoogle Scholar
  42. Naumova AK, Leppert M, Barker DF, Morgan K, Sapienza C (1998) Parental origin-dependent, male offspring-specific transmission-ratio distortion at loci on the human X chromosome. Am J Hum Genet 62:1493–1499PubMedCrossRefGoogle Scholar
  43. Novitski E (1951) Non-random disjunction in Drosophila. Genetics 36:267PubMedGoogle Scholar
  44. Pardo-Manuel de Villena F, Sapienza C (2001) Nonrandom segregation during meiosis: the unfairness of females. Mamm Genome 12:331–339. doi: 10.1007/s003350040003 PubMedCrossRefGoogle Scholar
  45. Paterson A, Sun L, Liu XQ (2003) Transmission ratio distortion in families from the Framingham Heart Study. BMC Genet 4:S48PubMedCrossRefGoogle Scholar
  46. Paterson A, Waggott D, Schillert A, Infante-Rivard C, Bull S, Yoo Y, Pinnaduwage D (2009) Transmission-ratio distortion in the Framingham Heart Study. BMC Proc 3(Suppl 7):S51PubMedCrossRefGoogle Scholar
  47. Paterson AD, Petronis A (1999) Transmission ratio distortion in females on chromosome 10p11 p15. Am J Med Genet 88:657–661PubMedCrossRefGoogle Scholar
  48. Polaski A (1998) Dynamic balance of segregation distortion and selection maintains normal allele sizes at the myotonic dystrophy locus. Math Biosci 147:93–112CrossRefGoogle Scholar
  49. Riess O, Epplen JT, Amoiridis G, Przuntek H, Schols L (1997) Transmission distortion of the mutant alleles in spinocerebellar ataxia. Hum Genet 99:282–284PubMedCrossRefGoogle Scholar
  50. Santos PSC, Höhne J, Schlattmann P, König IR, Ziegler A, Uchanska-Ziegler B (2009) Assessment of transmission distortion on chromosome 6p in healthy individuals using tagSNPs. Eur J Hum Genet 17:1182–1189PubMedCrossRefGoogle Scholar
  51. Sazhenova EA, Lebedev IN (2008) Epimutations of the KCNQ1OT1 imprinting center of chromosome 11 in early human embryo lethality. Genetika 44:1609–1616PubMedGoogle Scholar
  52. Shemer R, Birger Y, Riggs AD, Razin A (1997) Structure of the imprinted mouse Snrpn gene and establishment of its parental-specific methylation pattern. Proc Natl Acad Sci U S A 94:10267–10272PubMedCrossRefGoogle Scholar
  53. Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52:506PubMedGoogle Scholar
  54. Sturtevant A (1936) Preferential segregation in triplo-IV females of Drosophila melanogaster. Genetics 21:444PubMedGoogle Scholar
  55. The HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320. doi: 10.1038/nature04226 CrossRefGoogle Scholar
  56. Tiwari HK, Barnholtz-Sloan J, Wineinger N et al (2008) Review and evaluation of methods correcting for population stratification with a focus on underlying statistical principles. Hum Hered 66(2):67–86PubMedCrossRefGoogle Scholar
  57. Weinberg CR, Wilcox AJ, Lie RT (1998) A log-linear approach to case-parent-triad data: assessing effects of disease genes that act either directly or through maternal effects and that may be subject to parental imprinting. Am J Hum Genet 62:969–978PubMedCrossRefGoogle Scholar
  58. Weinberg CR (1999) Methods for detection of parent-of-origin effects in genetic studies of case-parents triads. Am J Hum Genet 5(1):229–235CrossRefGoogle Scholar
  59. Westendorp R, van Dunne FM, Kirkwood T, Helmerhorst FM, Huizinga T (2001) Optimizing human fertility and survival. Nat Med 7:873PubMedCrossRefGoogle Scholar
  60. Wu G, Hao L, Han Z, Gao S, Latham KE, de Villena FPM, Sapienza C (2005) Maternal transmission ratio distortion at the mouse Om locus results from meiotic drive at the second meiotic division. Genetics 170:327PubMedCrossRefGoogle Scholar
  61. Yang L, Andrade MF, Labialle S, Moussette S, Geneau G, Sinnett D, Belisle A, Greenwood CM, Naumova AK (2008) Parental effect of DNA (cytosine-5) methyltransferase 1 on grandparental-origin-dependent transmission ratio distortion in mouse crosses and human families. Genetics 178:35–45PubMedCrossRefGoogle Scholar
  62. Zhou JY, Hu YQ, Lin S et al (2009) Detection of parent-of-origin effects based on complete and incomplete nuclear families with multiple affected children. Hum Hered 67(1):1–12PubMedCrossRefGoogle Scholar
  63. Zimmering S (1955) A genetic study of segregation in a translocation heterozygote in Drosophila. Genetics 40:809PubMedGoogle Scholar
  64. Zollner S, Wen X, Hanchard NA, Herbert MA, Ober C, Pritchard JK (2004) Evidence for extensive transmission distortion in the human genome. Am J Hum Genet 74:62–72PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Aurélie Labbe
    • 1
    • 2
  • Lam Opal Huang
    • 1
  • Claire Infante-Rivard
    • 1
  1. 1.Department of Epidemiology, Biostatistics and Occupational HealthMcGill UniversityMontréalCanada
  2. 2.Douglas Mental Health University InstituteMontrealCanada

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