Maternal Meiotic Division Research Articles

Risk factors for Down syndrome.

Down syndrome (DS) originates, in most of the cases (95%), from a full trisomy of chromosome 21. The remaining cases are due to either mosaicism for chromosome 21 or the inheritance of a structural rearrangement leading to partial trisomy of the majority of its content. Full trisomy 21 and mosaicism are not inherited, but originate from errors in cell divisions during the development of the egg, sperm or embryo. In addition, full trisomy for chromosome 21 should be further divided into cases of maternal origin, the majority, and cases of paternal origin, less than 10%. Among cases of maternal origin, a further stratification should be performed into errors that have occurred or originated during the first meiotic division in the maternal grandmother's body and errors that occurred later in life during the second maternal meiotic division. This complex scenario suggests that our understanding of the risk factors for trisomy 21 should take into account the above stratification as it reflects different individuals and generations in which the first error has occurred. Unfortunately, most of the available literature is focused on maternal risk factors, and the only certain risk factors for the birth of a child with DS are advanced maternal age at conception and recombination errors, even though the molecular mechanisms leading to chromosome 21 nondisjunction are still a matter of debate. This article critically reviews the hypotheses and the risk factors which have been suggested to contribute to the birth of a child with DS, including folate metabolism, dietary, lifestyle, environmental, occupational, genetic and epigenetic factors, with focus on maternal and paternal risk factors, and taking into account the possible contribution of the maternal grandmother and that of the developing trisomic embryo, in a complex scenario depicting the birth of a child with DS as the result of complex gene-environment interactions and selection processes involving different generations.

Polar body cytokinesis

Polar body cytokinesis is the physical separation of a small polar body from a larger oocyte or ovum. This maternal meiotic division shares many similarities with mitotic and spermatogenic cytokinesis, but there are several distinctions, which will be discussed in this review. We synthesize results from many different model species, including those popular for their genetics and several that are more obscure in modern cell biology. The site of polar body division is determined before anaphase, by the eccentric, cortically associated meiotic spindle. Depending on the species, either the actin or microtubule cytoskeleton is required for spindle anchoring. Chromatin is necessary and sufficient to elicit differentiation of the associated cortex, via Ran-based signaling. The midzone of the anaphase spindle serves as a hub for regulatory complexes that elicit Rho activation, and ultimately actomyosin contractile ring assembly and contraction. Polar body cytokinesis uniquely requires another Rho family GTPase, Cdc42, for dynamic reorganization of the polar cortex. This is perhaps due to the considerable asymmetry of this division, wherein the polar body and the oocyte/ovum have distinct fates and very different sizes. Thus, maternal meiotic cytokinesis appears to occur via simultaneous polar relaxation and equatorial contraction, since the polar body is extruded from the spherical oocyte through the nascent contractile ring. As such, polar body cytokinesis is an interesting and important variation on the theme of cell division.

031. THE ORIGIN OF ANEUPLOIDY IN HUMANS: WHERE WE'VE BEEN, WHERE WE'RE GOING

With the advent of the human genome project in the 1990s, DNA markers became available, allowing us to determine the parent and meiotic stage of origin of human aneuploid conditions. This approach has been extensively used to study the origin of trisomies, with one over-arching conclusion: the vast majority of trisomies derive from errors in the development of the egg and, in particular, from nondisjunction occurring in the first maternal meiotic division (MI). However, against this general background, it has also become apparent that there is considerable chromosome-to-chromosome variation. For example, certain aneuploidies (e.g., the XXY condition, or Klinefelter syndrome) are commonly paternal in origin, while others (e.g., trisomy 16, the most common human trisomy) almost always originate from maternal MI errors. Thus, we now know that individual chromosomes behave differently with respect to mechanisms of meiotic nondisjunction. In this presentation, we will summarize results of these parental origin studies of aneuploidy and discuss the involvement of the first identified molecular correlate of nondisjunction – aberrant meiotic recombination – in the genesis of these abnormalities. We will also look forward, discussing the development of mouse models of human aneuploidy, and recent advances in molecular cytogenetics that make it possible to directly analyze human meiosis ‘as it happens’ in fetal oocytes and in spermatocytes.

Incidence, survival, and mortality in Down syndrome in Denmark

The incidence of Down syndrome (DS) has been studied intensively for the two periods 1960-1972 and 1980-1985. The age distribution of birth-giving mothers has changed to older age at child birth from the first to the second period. Non-disjunction studies were carried out in 328 families. Most cases were first maternal meiotic division failures (43%). Nearly 12% were paternal meiotic failures, half of them in first meiosis and half in second. Both newborn infants and fetuses were studied. There was an excess of males, especially among newborn DS children, which was related to a failure at paternal first meiosis. A positive sex ratio was found in all newborn infants as well as in free trisomics as in those with de novo translocations. Survival was studied in the cohort of 278 infants born 1980 to 1985. The highest death-rate occurred between 22 days to 1 year (10.4%), 30 times more than the death probability in the Danish population. There was a significant difference between DS cases with congenital heart defect and those without. The probability of infants without heart disease of reaching the first year was 93.1% and the age of 6 years 88.0%. The probability of survival of children with congenital heart defect was 71.7% and 45.2%, respectively, reflecting also the increasing number of infants born prematurely with low birth weight or small-for-date infants. The predominant heart problems were atrio-ventricular canal defects. Infections and malformations added to the high mortality rate. Three cases of leukemia were significantly more than expected.

Rare combination of Becker muscular dystrophy and Klinefelter's syndrome in one patient

Becker muscular dystrophy (BMD) was diagnosed in a male patient with Klinefelter's syndrome (47, XXY karyotype). The BMD was confirmed by (i) immunohistological methods and Western blotting, showing decreased quantity of dystrophin in muscle biopsy specimen and (ii) molecular genetic analysis which demonstrated a homozygous deletion of exons 45–47 within the dystrophin gene on both X-chromosomes. The same deletion was found on one of the X-chromosomes in the patient's mother. It can be deduced therefore that Klinefelter's syndrome in this patient is most likely due to a non-disjunctional error which occurred either during the second maternal meiotic division or during early postzygotic mitotic divisions.

Reduced recombination and paternal age effect in Klinefelter syndrome.

The parental origin of the additional sex chromosome was studied in 47 cases with an XXY sex chromosome constitution. In 23 cases (49%), the error occurred during the first paternal meiotic division. Maternal origin of the additional chromosome was found in the remaining 24 cases (51%). Centromeric homo- versus heterozygosity could be determined in 18 out of the 24 maternally derived cases. According to the centromeric status and recombination rate, the nondisjunction was attributable in 9 cases (50%) to an error at the first maternal meiotic division, in 7 cases (39%) to an error at the second maternal meiotic division and in 2 cases (11%) to a nullo-chiasmata nondisjunction at meiosis II or to postzygotic mitotic error. No recombination, and in particular none in the pericentromeric region, was found in any of the 9 cases due to nondisjunction at the first maternal meiotic division. Significantly increased paternal age was found in the paternally derived cases. Maternal age was significantly higher in the maternally derived cases due to a meiotic I error compared with those due to a meiotic II error. There were no significant clinical differences between patients with respect to the origin of the additional X chromosome.

Trisomy in man.

Trisomy, occurring in at least 4% of pregnancies, is the most common chromosome abnormality in humans. The majority of trisomies are associated with single additional chromosome. The presence of an additional sex chromosome is often associated with physical, behavioral, and intellectual impairment. The presence of an additional autosome is even more serious, being associated with severe mental and physical retardation and frequently with death in infancy. This review discusses the incidence, parental origin, and etiology of human trisomy. The incidence of trisomy varies widely among different chromosomes. This variation appears to reflect a real difference in the frequency of the primary event leading to trisomy as well as in differential selection. Studies of parental origin have shown a 1st maternal meiotic division error to be the most frequent source of the additional chromosome, regardless of the chromosome involved or the maternal age. Although the magnitude of risk varies among chromosomes, increased maternal age is an important risk factor in trisomy. The incidence of trisomy 21 increases from .05% of livebirths at maternal age 20 years to over 3% of all livebirths at age 45 years. The effect of maternal age is most pronounced in double trisomies. It has been hypothesized that the relationship between increasing maternal age and trisomy is due to a gradient in the fetal ovary that affects chiasma freequency. While the basis for the maternal age effect remains unknown, it is almost certainly due to factors acting at or before conception. Epidemiologic studies suggest that maternal irradiation exposure may also lead to trisomy; however, the effective dosage level and the relationship to maternal age remain unknown. No effect of oral contraceptives, spermicides, or fertility drugs on the incidence of trisomy has been documented to date. Understanding of the mechanisms by which trisomies are produced represents a major challenge for human cytogenetics.

The origin of human triploids.

A series of 26 triploid foetuses was ascertained in a survey of spontaneous abortuses and the origin of the additional haploid complement determined in 21 of them by the study of foetal and parental heteromorphisms. In 17 the additional haploid set was paternal in origin, in 3 it was maternal in origin and in one the parental origin could not be determined. The best fit for the data using a maximum-likelihood method was that 66.4% of the triploids were the result of dispermy, 23.6% the result of fertilization of a haploid ovum by a diploid sperm formed by failure of the first meiotic division in the male and 10% the result of a diploid egg formed by failure of the first maternal meiotic division. The possible sources of error inherent in the technique are reviewed and our results compared with previously published data.

A Further Observation of a Recombination within the HL‐A System in an Austrian Family

Abstract. A third case of cross‐over was observed in a Viennese family within the HL‐A system occurring in a maternal meiotic division. The recombination rate is now 3 out of 643 parental meiotic divisions (or 0.467%).

A Further Observation of a Recombination within the HL-A System in an Austrian Family

A third case of cross-over was observed in a Viennese family within the HL-A system occurring in a maternal meiotic division. The recombination rate is now 3 out of 643 parental meiotic divisions (or 0.467%).