Meiotic drive at the myotonic dystrophy locus?

Carey, Nessa; Johnson, Keith; Nokelainen, Pekka; Peltonen, Leena; Ml, Savontaus; Juvonen,; Anvret, Maria; Grandell, Ulla; Chotai, K; Robertson, E. Graeme

doi:10.1038/ng0294-117

Cited by 46 publications

(29 citation statements)

References 16 publications

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“…The proposed model provides a mechanism accounting for the persistence of mutable genes despite a significant biological disadvantage (reduced fitness) associated with their full expression (Carey et al, 1994). The model is consistent with recent evidence of trinucleotide repeat sequences associated with schizophrenia (Morris et al, 1995;O'Donovan et al, 1995).…”

Section: New Mutations and A Proposed Mutational Modelsupporting

confidence: 67%

Reproductive fitness in familial schizophrenia

Bassett¹,

McAlduff²,

Bury³

et al. 1995

Schizophrenia Research

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Background-Reproductive fitness is an important factor in understanding inheritance in genetic disorders. The purpose of this study was to determine whether fitness is reduced in familial schizophrenia (FS) and if fitness in siblings differs from the norm.Method-The number of offspring in 36 subjects with RDC schizophrenia or schizoaffective disorder (SZ) and their 101 siblings from large FS families was compared with age-adjusted census figures.Results-Fitness in the SZ group was significantly reduced: 23% of expected in males and 51% of expected in females. Fitness of unaffected siblings was within census expectations. However, female siblings with schizophrenia spectrum features had increased fitness over census norms. Reduced fitness was correlated with low marital rates, poor functioning and positive symptoms.Conclusions-These results indicate that reduced fitness is an important genetic force in FS and is likely inherent to the illness. Sex differences are important and would need to be considered when examining maternal and paternal transmission of schizophrenia. The results support a proposed high mutation rate for schizophrenia, consistent with a dynamic mutation mechanism.

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Section: New Mutations and A Proposed Mutational Modelsupporting

confidence: 67%

Reproductive fitness in familial schizophrenia

Bassett¹,

McAlduff²,

Bury³

et al. 1995

Schizophrenia Research

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“…These results support the observation, of TRD in favour of Group II repeats, in the live-born offspring of couples with at least one parent with Group I/Group II genotype (56% Group II, N ¼ 150/266 transmissions; P ¼ 0.04, exact binomial test) 3 (Supplementary Information, see Table S3). …”

Section: Discussionsupporting

confidence: 76%

“…4,6,7 Moreover, preferential transmission of the larger of the two (CTG) n repeats in the normal-size range from parents to live-born offspring has been found in families with no DM1. 3,5,19 The mechanism of such preferential transmission of larger DMPK alleles remains unclear. In principle, TRD may result from events that occur before (meiotic drive or preferential survival of gametes), at the time of, or after fertilisation (embryonic death).…”

Section: Introductionmentioning

confidence: 99%

“…Based on the functional importance of the (CTG) 19 -37 repeats for the aetiology of DM1 and the evidence for their preferential transmission, 3 we have selected the same cutoff point. To simplify our terminology, we will refer to smaller normal-size DMPK alleles with (CTG) 5 -18 as Group I repeats, and to larger normal-size alleles with (CTG) 19 -37 as Group II repeats.…”

Section: Introductionmentioning

confidence: 99%

“…13 The human dystrophia myotonica-protein kinase (DMPK) gene is located in chromosome region 19q13. 3 and contains a (CTG) n repeat in its 3 0 untranslated region. 14,15 Expansion of this repeat causes dystrophia myotonica 1 (DM1 [MIM 160900] Online Mendelian Inheritance in Man http://www.ncbi.nlm.nih.gov/Omim), an autosomal dominant disorder, which is the most common form of adult muscular dystrophy.…”

Section: Introductionmentioning

confidence: 99%

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Transmission ratio distortion in the myotonic dystrophy locus in human preimplantation embryos

et al. 2006

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One form of myotonic dystrophy, dystrophia myotonica 1 (DM1), is caused by the expansion of a (CTG) n repeat within the dystrophia myotonica-protein kinase (DMPK) gene located in chromosome region 19q13.3. Unaffected individuals carry alleles with repeat size (CTG) 5 -37 , premutation carriers (CTG) 38 -49 and DM1 affected individuals (CTG) 50 -6000 . Preferential transmission both of expanded repeats from DM1-affected parents and larger DMPK alleles in the normal-size range have been reported in live-born offspring. To determine the moment in development when transmission ratio distortion (TRD) for larger normal-size DMPK alleles is generated, the transmission from heterozygous parents with one repeat within the (CTG) 5 -18 range (Group I repeat) and the other within the (CTG) 19 -37 range (Group II repeat) to human preimplantation embryos was analysed. A statistically significant TRD of 59% (95% confidence interval of 54 -64) in favour of Group II repeats from both mothers and fathers was observed in preimplantation embryos, which remained significant when female embryos were considered separately. In contrast, no significant TRD was detected for repeats from informative Group I/Group I parents. Our analysis showed that Group II repeats specifically were preferentially transmitted in human preimplantation embryos. We suggest that TRD, in Group II repeats at the DMPK locus, is likely to result from events occurring at or around the time of fertilisation.

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