If components of this system such as a human homolog of NOD degrade, achiasmate bivalents or bivalents with distal-only exchanges may be preferentially affected; e. Failure to resolve connections between homologues results in segregation of both to the same pole, producing eggs with missing or additional whole chromosomes Bc. The evidence that environmental factors contribute to aneuploidy is growing, and the technology to address this concern is in hand. The nod gene in Drosophila melanogaster encodes a kinesin-like protein required for normal meiotic segregation 15 , 22 , Strikingly, in the male, almost all chromosomes are joined by at least one crossover 17 , but the same does not apply to the female. Lister LM, et al.
Homologous chromosomes that are not associated with one another for example, owing to failure to recombine. Susceptible chiasmate configurations of chromosome 21 predispose to nondisjunction in both maternal meiosis I and meiosis II. In humans, the introduction of the contraceptive pill raised concerns about an increase in chromosomally abnormal conceptions among women who became pregnant while taking the earliest form of this contraceptive This balancing of tension requires chiasmata to hold the two homologs together. Although recessive loss-of-function nod alleles affect only the segregation of achiasmate bivalents, a dominant allele nod DTW impairs the segregation of both chiasmate and achiasmate bivalents at MI 16 ,
Gabriel AS, et al. These observations contrast sharply with data from naturally occurring pregnancies, where most aneuploid abnormalities involve a single chromosome and are attributable to errors at maternal meiosis I. Related articles in Web of Science Google Scholar.
A Bivalents joined only by distally placed chiasmata may be susceptible to premature separation at MI.
Human aneuploidy: mechanisms and new insights into an age-old problem
Initially, we summarize recent observations on the incidence and aetiology of human aneuploidy from studies of eggs and embryos. Indeed, in many situations, female fertility is maintained, whereas the male is sterile reviewed in Ref. The latter event could result in precocious sister chromatid separation at MI. Following fertilization by either procedure, embryos may be cultured in vitro for several days before being transferred or frozen.
For example, an exchange of meiotic origin in the central euchromatin 4 ensures regular disjunction, while a proximal DSB-repair event in the heterochromatin 5 may cause nondisjunction, either by interlocking the homologs at anaphase I or by compromising the integrity of the centromere.
One explanation may be that the precipitating event occurs at MI, with aberrant segregation occurring at both divisions Fig. Note that in this panel, we have followed segregation of only one of the two homologues; that is, the homologue on the right at anaphase I. Musacchio A, Salmon ED. Mad2 is required for inhibiting securin and cyclin B degradation following spindle depolymerisation in meiosis I mouse oocytes.
The relationship between the two known aetiological agents — altered recombination and maternal age — is entirely dependent on chromosomal context: Our understanding of the human meiotic process, and of factors which affect meiotic chromosome segregation, is much less advanced. Finally, cases of trisomy 21 of maternal MII origin are associated with increased recombination, despite the fact that this condition is clearly maternal age-dependent.
As the oroblem equational segregation of chromosomes that nondisjoin at MI has been documented in a number of experimental systems for review see 1332this may represent an important potential mechanism for nondisjunction in many organisms.
Not all observations from natural conceptions, however, are replicated by the ART studies. In fact, the majority of chromosome misbehavior disotders ord mutants appears to be precocious sister chromatid separation at the thinklng rather than the second meiotic division Inheritance of DNA polymorphisms has been used to determine the parent and meiotic stage of origin of trisomies.
Most trisomies are maternally derived, but as shown here, the relative contribution of maternal meiosis I and meiosis II errors varies widely among chromosomes.
Because age-related increases in human trisomies begin at least a decade before the onset of menopause, the relevance of the mouse data to the human situation is uncertain.
Aneuploidy & chromosomal rearrangements (article) | Khan Academy
During the past decade, however, crtiical studies in the mouse and accumulating data from ART have provided compelling evidence of links to endocrine-disrupting chemicals or to exogenous hormones. Typically, chromosome-specific FISH probes for a subset of chromosomes involved in clinically relevant trisomies for example, chromosomes 13, 18, 21 and the sex chromosomes are hybridized to biopsied polar bodies or blastomeres, and the FISH signals are counted to infer the chromosome constitution of the embryo.
Harlap S, et al. White YA, et al.
Open in a separate window. Three abnormal crossover configurations have been linked to human trisomies: Increasing nondisjunction with maternal age: Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Intriguingly, recent studies in the mouse demonstrate that a true metaphase I, with all chromosomes properly aligned at the spindle equator, is not required for anaphase onset in the oocyte 70 — When followed by a normal MII, the resulting disomic gamete would contain nondisjoined chromosomaal having genetically different centromeres; thus nondisjunction would be scored as occurring at MI.
Chiasma frequency and maternal age in mammals. We have previously proposed that age impairs the ability of human females to form a normal meiotic spindle 18perhaps through the time-dependent decay of an important component on which spindle function is dependent.
Similarly, there has been relatively little evidence for a significant increase in the frequency of zero-exchange events in either maternal uniparental disomy 15, based on studies of 27 cases 45 or maternal MI trisomy 18, based on studies of 16 cases