Transmission ratio distortion: review of concept and implications for genetic association studies
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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.
KeywordsSpinal Muscular Atrophy Transmission Disequilibrium Test Meiotic Drive Transmission Ratio Distortion Marker Allele Frequency
Conflict of interest
The authors declare that they have no conflict of interest.
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- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Lange K (1997) Mathematical and statistical methods for genetic analysis. Springer, New YorkGoogle Scholar
- 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
- 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
- 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