Human aneuploidy: Incidence, origin, and etiology

Hassold, Terry; Abruzzo, Michael A.; Adkins, Kenneth; Griffin, Darren K.; Merrill, Michelle; Millie, Elise; Saker, Denise M.; Shen, Joseph; Zaragoza, Michael V.

doi:10.1002/(sici)1098-2280(1996)28:3<167::aid-em2>3.3.co;2-v

Cited by 99 publications

(130 citation statements)

References 0 publications

Supporting

Mentioning

121

Contrasting

Unclassified

Order By: Relevance

“…One etiological factor identified so far is advanced maternal age (reviewed by Griffin 1996;Hassold et al 1996;Eichenlaub-Ritter 1996. It is unclear whether and to what extent exposure to chemical and environmental factors can advance aging effects, modulate the rate of nondisjunction in female meiosis or cause locally and temporally restricted increases in the rate of spontaneous abortion, congenital malformation or occurrence of trisomic conceptuses.…”

Section: Introductionmentioning

confidence: 99%

Trichlorfon exposure, spindle aberrations and nondisjunction in mammalian oocytes

et al. 1998

View full text Add to dashboard Cite

Consumption of trichlorfon-poisoned fish by women in a small Hungarian village has been associated with trisomy resulting from an error of meiosis II in oogenesis. We therefore examined mouse oocytes exposed for 3 h during fertilization to 50 microg/ml trichlorfon. Spindle morphology was not visibly altered by the pesticide. Chromosomes segregated normally at anaphase II with no induction of aneuploidy. However, formation of a spindle was disturbed in many oocytes resuming meiosis I in the presence of trichlorfon. In spite of the spindle aberrations and the failure of bivalents to align properly at the equator, oocytes did not become meiotically arrested but progressed to metaphase II. At this stage, spindles were highly abnormal, and chromosomes were often totally unaligned, unattached or dispersed on the elongated and disorganized spindle. By causing spindle aberrations and influencing chromosome congression, trichlorfon appears, therefore, to predispose mammalian oocytes to random chromosome segregation, especially when they undergo a first division and develop to metaphase II during exposure. This is the first case in which environmentally induced human trisomy can be correlated with spindle aberrations induced by chemical exposure. Our observations suggest that oocytes may not possess a checkpoint sensing displacement of chromosomes from the equator at meiosis I and may therefore be prone to nondisjunction.

show abstract

Section: Introductionmentioning

confidence: 99%

Trichlorfon exposure, spindle aberrations and nondisjunction in mammalian oocytes

et al. 1998

View full text Add to dashboard Cite

show abstract

“…Recently, considerable information has been obtained on the meiotic origin of the additional chromosome in human trisomy. For example, data from DNA polymorphism studies of over 1000 trisomy families are now available on: (1) the parent of origin of nondisjunction, (2) the meiotic stage of the error, and (3) the frequency and placement of recombinational events in the nondisjunctional meioses (reviewed in Hassold et al 1996). The results of these studies suggest that most human trisomy originates in oogenesis, typically at the first meiotic division, and indicate that genetic recombination is an important correlate of nondisjunction.…”

Section: Introductionmentioning

confidence: 99%

Centromeric genotyping and direct analysis of nondisjunction in humans: Down syndrome

1998

View full text Add to dashboard Cite

In species with chiasmate meioses, alterations in genetic recombination are an important correlate of nondisjunction. In general, these alterations fall into one of two categories: either homologous chromosomes fail to pair and/or recombine at meiosis I, or they are united by chiasmata that are suboptimally positioned. Recent studies of human nondisjunction suggest that these relationships apply to our species as well. However, methodological limitations in human genetic mapping have made it difficult to determine whether the important determinant(s) in human nondisjunction is absent recombination, altered recombination, or both. In the present report, we describe somatic cell hybrid studies of chromosome 21 nondisjunction aimed at overcoming this limitation. By using hybrids to "capture" individual chromosomes 21 of the proband and parent of origin of trisomy, it is possible to identify complementary recombinant meiotic products, and thereby to uncover crossovers that cannot be detected by conventional mapping methods. In the present report, we summarize studies of 23 cases. Our results indicate that recombination in proximal 21q is infrequent in trisomy-generating meioses and that, in a proportion of the meioses, recombination does not occur anywhere on 21q. Thus, our observations indicate that failure to recombine is responsible for a proportion of trisomy 21 cases.

show abstract

“…In humans, the most frequently occurring viable aneuploidy is trisomy 21, which is due to chromosome 21 missegregation in female meiosis, with 65 % occurring in meiosis I and 23 % in meiosis II. Trisomy 16 (which is incompatible with life) is in close to 100 % of cases due to missegregation in female meiosis I (Hassold et al 1996;Hassold and Hunt 2001;Nagaoka et al 2012).…”

Section: Introductionmentioning

confidence: 99%

How oocytes try to get it right: spindle checkpoint control in meiosis

Touati

Wassmann

2015

Chromosoma

View full text Add to dashboard Cite

The generation of a viable, diploid organism depends on the formation of haploid gametes, oocytes, and spermatocytes, with the correct number of chromosomes. Halving the genome requires the execution of two consecutive specialized cell divisions named meiosis I and II. Unfortunately, and in contrast to male meiosis, chromosome segregation in oocytes is error prone, with human oocytes being extraordinarily "meiotically challenged". Aneuploid oocytes, that are with the wrong number of chromosomes, give rise to aneuploid embryos when fertilized. In humans, most aneuploidies are lethal and result in spontaneous abortions. However, some trisomies survive to birth or even adulthood, such as the well-known trisomy 21, which gives rise to Down syndrome (Nagaoka et al. in Nat Rev Genet 13:493-504, 2012). A staggering 20-25 % of oocytes ready to be fertilized are aneuploid in humans. If this were not bad enough, there is an additional increase in meiotic missegregations as women get closer to menopause. A woman above 40 has a risk of more than 30 % of getting pregnant with a trisomic child. Worse still, in industrialized western societies, child birth is delayed, with women getting their first child later in life than ever. This trend has led to an increase of trisomic pregnancies by 70 % in the last 30 years (Nagaoka et al. in Nat Rev Genet 13:493-504, 2012; Schmidt et al. in Hum Reprod Update 18:29-43, 2012). To understand why errors occur so frequently during the meiotic divisions in oocytes, we review here the molecular mechanisms at works to control chromosome segregation during meiosis. An important mitotic control mechanism, namely the spindle assembly checkpoint or SAC, has been adapted to the special requirements of the meiotic divisions, and this review will focus on our current knowledge of SAC control in mammalian oocytes. Knowledge on how chromosome segregation is controlled in mammalian oocytes may help to identify risk factors important for questions related to human reproductive health.

show abstract

Human aneuploidy: Incidence, origin, and etiology

Cited by 99 publications

References 0 publications

Trichlorfon exposure, spindle aberrations and nondisjunction in mammalian oocytes

Trichlorfon exposure, spindle aberrations and nondisjunction in mammalian oocytes

Centromeric genotyping and direct analysis of nondisjunction in humans: Down syndrome

How oocytes try to get it right: spindle checkpoint control in meiosis

Contact Info

Product

Resources

About