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Results for “Nondisjunction, Genetic”

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At least 19 recordsLinked to original sources
PubMed1981

Inbreeding and the genetic control of nondisjunction.

We have studied the frequency of trisomics in newly formed zygotes and the proportion of trisomics, k, coming from consanguineous marriages by assuming that recessive genes at a single locus or multiple loci are responsible for the induction of nondisjunction. For mitotic nondisjunction, the value of k increases as the magnitude of consanguinity of the parents increases, but the opposite relationship holds for meiotic nondisjunction. Therefore, it is important to distinguish mitotic and meiotic types in the genetic study of nondisjunction. This seems to be one of the simplest tests for detecting the genetic control of nondisjunction.

Consanguinity↗
PubMed1999

Genetic variation in rates of nondisjunction: association of two naturally occurring polymorphisms in the chromokinesin nod with increased rates of nondisjunction in Drosophila melanogaster.

Genetic variation in nondisjunction frequency among X chromosomes from two Drosophila melanogaster natural populations is examined in a sensitized assay. A high level of genetic variation is observed (a range of 0.006-0.241). Two naturally occurring variants at the nod locus, a chromokinesin required for proper achiasmate chromosome segregation, are significantly associated with an increased frequency of nondisjunction. Both of these polymorphisms are found at intermediate frequency in widely distributed natural populations. To account for these observations, we propose a general model incorporating unique opportunities for meiotic drive during female meiosis. The oötid competition model can account for both high mean rates of female-specific nondisjunction in Drosophila and humans as well as the standing genetic variation in this critical fitness character in natural populations.

Animals↗
PubMed1993

Requiem for distributive segregation: achiasmate segregation in Drosophila females.

The segregation of achiasmate chromosome pairs at meiosis I is not brought about by a single 'distributive system' as previously thought, but rather by two separate mechanisms. One system uses the pairing of proximal heterochromatic sequences to mediate the segregation of achiasmate homologs-an observation that, at long last, defines a function for heterochromatin. The other system facilitates the segregation of heterologous chromosomes, by an as yet undiscovered mechanism.

Animals↗
PubMed2006

A molecular model for sporadic human aneuploidy.

Aneuploidy is a leading cause of birth defects and a significant contributor to infertility in humans. Maternal age is the only well-established risk factor for gametic aneuploidy in the general population, with the underlying cause(s) yet to be identified. Here we present an extension of the 'two-hit' model for sporadic human aneuploidy. An important implication of this model is that the genetic makeup of an individual will influence the threshold where recombinationally at-risk oocytes (hit-1 events) become sensitive to the effects of advancing age (hit-2 events). Consequently, the age-related risk of gametic aneuploidy in many individuals is likely to differ significantly from the population average, and single nucleotide polymorphisms (SNPs) associated with altered risk should be identifiable.

Adult↗
PubMed1996

Susceptible chiasmate configurations of chromosome 21 predispose to non-disjunction in both maternal meiosis I and meiosis II.

The cause of non-disjunction of chromosome 21 remains largely unknown. Advanced maternal age is associated with both maternal meiosis I (MI) and meiosis II (MII) non-disjunction events. While reduced genetic recombination has been demonstrated in maternal MI errors, the basis for MII errors remains uncertain. We studied 133 trisomy 21 cases with maternal MII errors to test the hypothesis that segregation at MII may also be influenced by genetic recombination. Our data support a highly significant association: MII non-disjunction involves increased recombination that is largely restricted to proximal 21q. Thus, while absence of a proximal recombination appears to predispose to non-disjunction in MI, the presence of a proximal exchange predisposes to non-disjunction in MII. These findings profoundly affect our understanding of trisomy 21 as they suggest that virtually all maternal non-disjunction results from events occurring in meiosis I.

Adult↗
PubMed2001

Multipoint genetic mapping with trisomy data.

Trisomy is the most common genetic abnormality in humans and is the leading cause of mental retardation. Although molecular studies that use a large number of highly polymorphic markers have been undertaken to understand the recombination patterns for chromosome abnormalities, there is a lack of multilocus approaches to incorporating crossover interference in the analysis of human trisomy data. In the present article, we develop two statistical methods that simultaneously use all genetic information in trisomy data. The first approach relies on a general relationship between multilocus trisomy probabilities and multilocus ordered-tetrad probabilities. Under the assumption that no more than one chiasma exists in each marker interval, we describe how to use the expectation-maximization algorithm to examine the probability distribution of the recombination events underlying meioses that lead to trisomy. One limitation of the first approach is that the amount of computation increases exponentially with the number of markers. The second approach models the crossover process as a chi(2) model. We describe how to use hidden Markov models to evaluate multilocus trisomy probabilities. Our methods are applicable when both parents are available or when only the nondisjoining parent is available. For both methods, genetic distances among a set of markers can be estimated and the pattern of overall chiasma distribution can be inspected for differences in recombination between meioses exhibiting trisomy and normal meioses. We illustrate the proposed approaches through their application to a set of trisomy 21 data.

Algorithms↗
PubMed1993

SID1-1: a mutation affecting meiotic sister-chromatid association in yeast.

Meiotic chromosome segregation must occur with high fidelity in order to prevent the generation of deleterious aneuploidies. In meiosis I, homologous chromosomes pair, then migrate to opposite poles of the spindle. This process uses a collection of unique structures and mechanisms that have yet to be thoroughly characterized. To acquire a collection of informative meiotic mutants, we carried out a novel genetic screen in Saccharomyces cerevisiae. This screen was designed to identify dominant mutants in which meiosis I chromosome segregation occurs with decreased fidelity. One mutant recovered using this screen, SID1-1 (sister disjunction), showed an incidence of spores disomic for a marked chromosome III that was 25-fold greater than the wild-type level. Crossing-over is slightly, but not dramatically, reduced in SID1-1. Both recombinant and nonrecombinant chromosomes segregate with reduced fidelity in the presence of SID1-1. We present evidence that the mutant is defective in sister-chromatid association.

Alleles↗
PubMed1980

Evidence for genetic control of nondisjunction in man.

Data on factors associated with the occurrence of Down syndrome in a highly inbred population were evaluated to investigate the presence of a genetic control of nondisjunction in man. In Kuwait, close consanguinity occurs in 40% of marriages. In its main obstetric hospital, 20 trisomic Down babies out of 11,614 singleton births were delivered over a 12-month period. Chi-square analyses indicate the occurrence of Down syndrome to be linked to two independent factors: consanquinity of parents and maternal age. The relative risk is approximately four times greater for closely related than for nonrelated parents (P less than .005); a possible explanation for this is the existence of a gene that induces mitotic nondisjunction in the homozygous fertilized ovum. An alternative explanation is the existence of an autosomal recessive gene which results in meiotic nondisjunction in the homozygous parents. Consanguinity is usually perpetuated in certain families, or sections of the population, and parents in highly inbred families have a higher probability to be homozygotes for that gene.

Adult↗
PubMed1998

Chromosomal drive and the evolution of meiotic nondisjunction and trisomy in humans.

Trisomy is a genetic abnormality of considerable medical importance. The most familiar example is trisomy 21, which causes Down Syndrome [Cummings, M. R. (1988) Human Heredity: Principles and Issues (West Publishing Company, New York)]. In a classic paper, Axelrod and Hamilton [Axelrod, R. & Hamilton, W. D. (1981) Science 211, 1390-1396] offered a chromosomal drive (CD) hypothesis based on the game iterated prisoner's dilemma (IPD) to explain the evolution of an increased frequency of trisomic pregnancies with maternal age. In this paper we explore this hypothesis and its predictions in detail. On closer examination we find that IPD does not provide an adequate model for the CD hypothesis. Therefore, we develop a more suitable model and explore the conditions necessary for it to explain maternal age-dependent trisomy. Our results demonstrate that a relationship between the decay of a female's reproductive potential and chromosomal drive must exist for the CD hypothesis to work. With appropriate parameter values, a comparison of model predictions with empirical estimates for the age-dependence of trisomy reveals a striking correspondence. We point out a close correspondence between other predictions made by the CD hypothesis and empirical observations, as well.

Animals↗
PubMed1993

A short chromosomal region with major roles in yeast chromosome III meiotic disjunction, recombination and double strand breaks.

A multicopy plasmid was isolated from a yeast genomic library, whose presence resulted in a twofold increase in meiotic nondisjunction of chromosome III. The plasmid contains a 7.5-kb insert from the middle of the right arm of chromosome III, including the gene THR4. Using chromosomal fragments derived from chromosome III, we determined that the cloned region caused a significant, specific, cis-acting increase in chromosome III nondisjunction in the first meiotic division. The plasmid containing this segment exhibited high spontaneous meiotic integration into chromosome III (in 2.4% of the normal meiotic divisions) and a sixfold increase (15.5%) in integration in nondisjunctant meioses. Genetic analysis of the cloned region revealed that it contains a "hot spot" for meiotic recombination. In DNA of rad50S mutant cells, a strong meiosis-induced double strand break (DSB) signal was detected in this region. We discuss the possible relationships between meiosis-induced DSBs, recombination and chromosome disjunction, and propose that recombinational hot spots may be "pairing sites" for homologous chromosomes in meiosis.

Chromosomes, Fungal↗
PubMedDate not supplied

Meiotic and mitotic nondisjunction: lessons from preimplantation genetic diagnosis.

Direct testing of the outcome of the first and second meiotic divisions has become possible with the introduction of preimplantation genetic diagnosis (PGD) for aneuploidies. Testing of oocytes by fluorescent in situ hybridization (FISH) analysis of the first and second polar bodies showed that more than half of oocytes from the IVF patients aged 35 years and older had chromosomal abnormalities, which originated from errors in meiosis I or meiosis II, or both: 41.9% of oocytes were aneuploid after meiosis I and 37.3% aneuploid after meiosis II, with 29.1% of these oocytes having both meiosis I and meiosis II errors. As a result, one third of oocytes detected as normal after meiosis I contained the meiosis II errors, and two thirds of those with meiosis II errors were already abnormal following meiosis I. Although the rates of chromosomal abnormalities deriving from meiosis I and II were comparable, meiosis I errors predominantly resulted in extra chromosome (chromatid) material in oocytes, in contrast to a random distribution of extra and missing chromatids after meiosis II. The majority of meiosis I abnormalities were represented by chromatid errors, which seem to be the major source of chromosomal abnormalities in the resulting embryos. Approximately one third of aneuploid oocytes deriving from sequential errors in the first and second meiotic divisions resulted in a balanced karyotype, representing a possible phenomenon of "aneuploidy rescue" during the second meiotic division. However, the majority of the embryos resulting from such oocytes appeared to be abnormal for the same or different chromosome(s), or were mosaic, suggesting a possible predisposition of the resulting embryos to further mitotic errors. Although the origin of a high frequency of mosaicism at the cleavage stage is not sufficiently understood, the mosaic embryos may originate from the chromosomally abnormal oocytes, as a result of a "trisomy rescue" mechanism during the first mitotic divisions, which renders polar body FISH analysis to have important clinical value for reliable pre-selection of aneuploidy-free embryos for transfer.

Animals↗