Human Genetics

, Volume 132, Issue 3, pp 245–263 | Cite as

Transmission ratio distortion: review of concept and implications for genetic association studies

  • Lam Opal Huang
  • Aurélie Labbe
  • Claire Infante-Rivard
Review Paper


Transmission ratio distortion (TRD) occurs when one of the two alleles from either parent is preferentially transmitted to the offspring. This leads to a statistical departure from the Mendelian law of inheritance, which states that each of the two parental alleles is transmitted to offspring with a probability of 0.5. A number of mechanisms are thought to induce TRD such as meiotic drive, gametic competition, and embryo lethality. TRD has been extensively studied in animals, but the prevalence of TRD in humans remains largely unknown. Nevertheless, understanding the TRD phenomenon and taking it into consideration in many aspects of human genetics has potential benefits that have not been sufficiently emphasized in the current literature. In this review, we discuss the importance of TRD in three distinct but related fields of genetics: developmental genetics which studies the genetic abnormalities in zygotic and embryonic development, statistical genetics/genetic epidemiology which utilizes population study designs and statistical models to interpret the role of genes in human health, and population genetics which is concerned with genetic diversity in populations in an evolutionary context. From the perspective of developmental genetics, studying TRD leads to the identification of the processes and mechanisms for differential survival observed in embryos. As a result, it is a genetic force which affects allele frequency at the population, as well as, at the organismal level. Therefore, it has implications on genetic diversity of the population over time. From the perspective of genetic epidemiology, the TRD influence on a marker locus is a confounding factor which has to be adequately dealt with to correctly interpret linkage or association study results. These aspects are developed in this review. In addition to these theoretical notions, a brief summary of the empirical evidence of the TRD phenomenon in human and mouse studies is provided. The objective of our paper is to show the potentially important role of TRD in many areas of genetics, and to create an incentive for future research.


Spinal Muscular Atrophy Transmission Disequilibrium Test Meiotic Drive Transmission Ratio Distortion Marker Allele Frequency 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

The study complies with the current laws of Canada.


  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. Bauer H, Véron N, Willert J, Herrmann BG (2007) The t-complex-encoded guanine nucleotide exchange factor Fgd2 reveals that two opposing signaling pathways promote transmission ratio distortion in the mouse. Genes Dev 21:143–147. doi: 10.1101/gad.414807 PubMedCrossRefGoogle Scholar
  3. Bauer H, Schindler S, Charron Y, Willert J, Kusecek B, Herrmann BG (2012) The nucleoside diphosphate kinase gene Nme3 acts as quantitative trait locus promoting non-mendelian inheritance. PLoS Genet 8. doi: 10.1371/journal.pgen.1002567
  4. 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
  5. Bettencourt C, Fialho RN, Santos C, Montiel R, Bruges-Armas J, Maciel P, Lima M (2008) Segregation distortion of wild-type alleles at the Machado-Joseph disease locus: a study in normal families from the Azores islands (Portugal). J Hum Genet 53:333–339. doi: 10.1007/s10038-008-0261-7 PubMedCrossRefGoogle Scholar
  6. 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
  7. Bodmer W, Bonilla C (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet 40:695–701PubMedCrossRefGoogle Scholar
  8. 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
  9. Casellas J, Gularte RJ, Farber CR, 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 191:247–259. doi: 10.1534/genetics.111.135988 PubMedCrossRefGoogle Scholar
  10. 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
  11. 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
  12. 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. Mammal Genome 13:24–29CrossRefGoogle Scholar
  13. Crow JF (1988) The ultraselfish gene. Genetics 118:389PubMedGoogle Scholar
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. Gorlov IP, Gorlova OY, Sunyaev SR, Spitz MR, Amos CI (2008) Shifting paradigm of association studies: value of rare single-nucleotide polymorphisms. Am J Human Genet 82:100–112CrossRefGoogle Scholar
  22. 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
  23. Haig D, Grafen A (1991) Genetic scrambling as a defence against meiotic drive. J Theor Biol 153:531–558PubMedCrossRefGoogle Scholar
  24. 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
  25. Hastings IM (1991) Germline selection: population genetic aspects of the sexual/asexual life cycle. Genetics 129:1167–1176PubMedGoogle Scholar
  26. Haston CK, Humes DG, Lafleur M (2007) X chromosome transmission ratio distortion in Cftr ± intercross-derived mice. BMC Genet 8:23. doi: 10.1186/1471-2156-8-23 PubMedCrossRefGoogle Scholar
  27. Henckaerts L, Vlietinck R, Derom C, Boonen S, Rutgeerts P, Vermeire S (2010) Transmission ratio distortion of DLG5 R30Q: evidence for prenatal selection? Inflamm Bowel Dis 16:910–911. doi: 10.1002/ibd.21109 PubMedCrossRefGoogle Scholar
  28. Honeywell C, Argiropoulos B, Douglas S, Blumenthal AL, Allanson J, McGowan-Jordan J, McCready ME (2012) Apparent transmission distortion of a pericentric chromosome one inversion in a large multi-generation pedigree. Am J Med Genet A 158A:1262–1268. doi: 10.1002/ajmg.a.35286 PubMedCrossRefGoogle Scholar
  29. Huang L, Labbe A, Infante-Rivard C (2011) Impact of transmission ratio distortion on the interpretation of genetic association studies and evolution of population parameters. In: 6th Annual Genetic Epidemiology and Statistical Genetic MeetingGoogle Scholar
  30. Hurst GD, Werren JH (2001) The role of selfish genetic elements in eukaryotic evolution. Nat Rev Genet 2:597–606. doi: 10.1038/35084545 PubMedCrossRefGoogle Scholar
  31. 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
  32. 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
  33. Klopocki E, Lohan S, Doelken SC, Stricker S, Ockeloen CW, Soares Thiele de Aguiar R, Lezirovitz K, Mingroni Netto RC, Jamsheer A, Shah H, Kurth I, Habenicht R, Warman M, Devriendt K, Kordass U, Hempel M, Rajab A, Makitie O, Naveed M, Radhakrishna U, Antonarakis SE, Horn D, Mundlos S (2012) Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion. J Med Genet 49:119–125. doi: 10.1136/jmedgenet-2011-100409 PubMedCrossRefGoogle Scholar
  34. Kryukov GV, Pennacchio LA, Sunyaev SR (2007) Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am J Human Genet 80:727–739CrossRefGoogle Scholar
  35. Lange K (1997) Mathematical and statistical methods for genetic analysis. Springer, New YorkGoogle Scholar
  36. LeMaire-Adkins R, Hunt PA (2000) Nonrandom segregation of the mouse univalent X chromosome: evidence of spindle-mediated meiotic drive. Genetics 156:775PubMedGoogle Scholar
  37. 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
  38. Liu LY, Schaub MA, Sirota M, Butte AJ (2012) Transmission distortion in Crohn’s disease risk gene ATG16L1 leads to sex difference in disease association. Inflamm Bowel Dis 18:312–322. doi: 10.1002/ibd.21781 PubMedCrossRefGoogle Scholar
  39. Magee AC, Hughes AE (1998) Segregation distortion in myotonic dystrophy. J Med Genet 35:1045–1046PubMedCrossRefGoogle Scholar
  40. Maher B (2008) Personal genomes: the case of the missing heritability. Nature 456:18–21. doi: 10.1038/456018a PubMedCrossRefGoogle Scholar
  41. Martin-DeLeon PA, Zhang H, Morales CR, Zhao Y, Rulon M, Barnoski BL, Chen H, Galileo DS (2005) Spam1-associated transmission ratio distortion in mice: elucidating the mechanism. Reprod Biol Endocrinol 3:32. doi: 10.1186/1477-7827-3-32 PubMedCrossRefGoogle Scholar
  42. 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
  43. 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
  44. 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
  45. Naumova AK, Greenwood CM, Morgan K (2001) Imprinting and deviation from Mendelian transmission ratios. Genome 44:311–320PubMedCrossRefGoogle Scholar
  46. Novitski E (1951) Non-random disjunction in Drosophila. Genetics 36:267PubMedGoogle Scholar
  47. 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
  48. Paterson AD, Petronis A (1999) Transmission ratio distortion in females on chromosome 10p11 p15. Am J Med Genet 88:657–661PubMedCrossRefGoogle Scholar
  49. Paterson A, Sun L, Liu XQ (2003) Transmission ratio distortion in families from the Framingham Heart Study. BMC Genet 4:S48PubMedCrossRefGoogle Scholar
  50. Paterson A, Waggott D, Schillert A, Infante-Rivard C, Bull S, Yoo Y, Pinnaduwage D (2009) Transmission-ratio distortion in the Framingham Heart Study 2009. BioMed Central Ltd., London, p S51Google Scholar
  51. Polanski A (1998) Dynamic balance of segregation distortion and selection maintains normal allele sizes at the myotonic dystrophy locus* 1. Math Biosci 147:93–112PubMedCrossRefGoogle Scholar
  52. 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
  53. Santos PS, Hohne J, Schlattmann P, Konig IR, Ziegler A, Uchanska-Ziegler B (2009) Assessment of transmission distortion on chromosome 6p in healthy individuals using tagSNPs. Eur J Hum Genet 17:1182–1189. doi: 10.1038/ejhg.2009.16 PubMedCrossRefGoogle Scholar
  54. Sazhenova EA, Lebedev IN (2008) Epimutations of the KCNQ1OT1 imprinting center of chromosome 11 in early human embryo lethality. Genetika 44:1609–1616PubMedGoogle Scholar
  55. Schulz R, Underkoffler LA, Collins JN, Oakey RJ (2006) Nondisjunction and transmission ratio distortion of Chromosome 2 in a (2.8) Robertsonian translocation mouse strain. Mamm Genome 17:239–247. doi: 10.1007/s00335-005-0126-8 PubMedCrossRefGoogle Scholar
  56. 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 USA 94:10267–10272PubMedCrossRefGoogle Scholar
  57. Shoubridge C, Gardner A, Schwartz CE, Hackett A, Field M, Gecz J (2012) Is there a Mendelian transmission ratio distortion of the c.429_452dup (24 bp) polyalanine tract ARX mutation? Eur J Human Genet. doi: 10.1038/ejhg.2012.61
  58. 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
  59. Sturtevant A (1936) Preferential segregation in triplo-IV females of Drosophila melanogaster. Genetics 21:444PubMedGoogle Scholar
  60. Taveau M, Stockholm D, Marchand S, Roudaut C, Le Bert M, Richard I (2004) Bidirectional transcriptional activity of the Pgk1 promoter and transmission ratio distortion in Capn3-deficient mice. Genomics 84:592–595. doi: 10.1016/j.ygeno.2004.04.011 PubMedCrossRefGoogle Scholar
  61. The International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320. doi: 10.1038/nature04226 CrossRefGoogle Scholar
  62. Underkoffler LA, Mitchell LE, Abdulali ZS, Collins JN, Oakey RJ (2005) Transmission ratio distortion in offspring of mouse heterozygous carriers of a (7.18) Robertsonian translocation. Genetics 169:843–848. doi: 10.1534/genetics.104.032755 PubMedCrossRefGoogle Scholar
  63. Veron N, Bauer H, Weisse AY, Luder G, Werber M, Herrmann BG (2009) Retention of gene products in syncytial spermatids promotes non-Mendelian inheritance as revealed by the t complex responder. Genes Dev 23:2705–2710. doi: 10.1101/gad.553009 PubMedCrossRefGoogle Scholar
  64. Weinberg CR (1999) Methods for detection of parent-of-origin effects in genetic studies of case-parents triads. Am J Hum Genet 65:229–235PubMedCrossRefGoogle Scholar
  65. Westendorp R, van Dunne FM, Kirkwood T, Helmerhorst FM, Huizinga T (2001) Optimizing human fertility and survival. Nat Med 7:873PubMedCrossRefGoogle Scholar
  66. 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 170:327–334. doi: 10.1534/genetics.104.039479 PubMedCrossRefGoogle Scholar
  67. 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
  68. Zimmering S (1955) A genetic study of segregation in a translocation heterozygote in Drosophila. Genetics 40:809PubMedGoogle Scholar
  69. 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-Verlag Berlin Heidelberg 2012

Authors and Affiliations

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

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