Mechanisms of aneuploidy induction in human oogenesis and early embryogenesis

The mechanisms of aneuploidy induction in human oogenesis mainly involve nondisjunction arising during the first and second meiotic divisions. Nondisjunction equally affects both whole chromosomes and chromatids, in the latter case it is facilitated by "predivision" or precocious centromere division. Karyotyping and CGH studies show an excess of hypohaploidy, which is confirmed in studies of preimplantation embryos, providing evidence in favour of anaphase lag as a mechanism. Preferential involvement of the smaller autosomes has been clearly shown but the largest chromosomes are also abnormal in many cases. Overall, the rate of chromosomal imbalance in oocytes from women aged between 30 and 35 has been estimated at 11% from recent karyotyping data but accruing CGH results suggest that the true figure should be considerably higher. Clear evidence has been obtained in favour of germinal or gonadal mosaicism as a predisposing factor. Constitutional aneuploidy in embryos is most frequent for chromosomes 22, 16, 21 and 15; least frequently involved are chromosomes 14, X and Y, and 6. However, embryos of women under 37 are far more likely to be affected by mosaic aneuploidy, which is present in over 50% of 3-day-old embryos. There are two main types, diploid/aneuploid and chaotic mosaics. Chaotic mosaics arise independently of maternal age and may be related to centrosome anomalies and hence of male origin. Aneuploid mosaics most commonly arise by chromosome loss, followed by chromosome gain and least frequently by mitotic nondisjunction. All may be related to maternal age as well as to lack of specific gene products in the embryo. Partial aneuploidy as a result of chromosome breakage affects a minimum of 10% of embryos.     

Mechanisms and chemical induction of aneuploidy in rodent germ cells

The objective of this review is to suggest that the advances being made in our understanding of the molecular events surrounding chromosome segregation in non-mammalian and somatic cell models be considered when designing experiments for studying aneuploidy in mammalian germ cells. Accurate chromosome segregation requires the temporal control and unique interactions among a vast array of proteins and cellular organelles. Abnormal function and temporal disarray among these, and others to be identified, biochemical reactions and cellular organelles have the potential for predisposing cells to aneuploidy. Although numerous studies have demonstrated that certain chemicals (mainly those that alter microtubule function) can induce aneuploidy in mammalian germ cells, it seems relevant to point out that such data can be influenced by gender, meiotic stage, and time of cell-fixation post-treatment. Additionally, a consensus has not been reached regarding which of several germ cell aneuploidy assays most accurately reflects the human condition. More recent studies have shown that certain kinase, phosphatase, proteasome, and topoisomerase inhibitors can also induce aneuploidy in rodent germ cells. We suggest that molecular approaches be prudently incorporated into mammalian germ cell aneuploidy research in order to eventually understand the causes and mechanisms of human aneuploidy. Such an enormous undertaking would benefit from collaboration among scientists representing several disciplines.     

Mechanisms of maternal aneuploidy: FISH analysis of oocytes and polar bodies in patients undergoing assisted conception

We have examined unfertilised oocytes and their first polar bodies (PBs) to determine the way in which the frequency of whole chromosome imbalance compares with that involving single chromatids and whether the precocious separation of chromatids prior to anaphase I affects all pairs of chromosomes. We have applied the technique of fluorescent in situ hybridisation in a three-stage method by using locus-specific probes for chromosomes 13 and 21 and alpha-satellite probes for chromosomes 1, 9, 16, 18 and X to determine the chromosome status of oocytes and their PBs. We obtained analysable results from 127 oocytes and 57 PBs from 72 patients of average age 33 years. Six oocytes and three PBs had extra signals but, of these, three were derived from a single patient, aged 26. Anomalies were seen in chromosomes 13, 16, 18, X and, notably, 21 but none were observed in chromosomes 1 and 9. Half of the anomalies involved additional chromatids rather than whole chromosomes. Since particular chromatids were found to be prematurely separated in the metaphase II oocyte, this may provide further evidence for an additional mechanism of maternal aneuploidy that operates at anaphase II. Detailed analyses of both oocytes and PBs have elucidated possible mechanisms leading to aneuploid gametes in this group of patients with fertility problems.     

Meiosis and sex chromosome aneuploidy: how meiotic errors cause aneuploidy; how aneuploidy causes meiotic errors

As a group, sex chromosome aneuploidies - the 47,XXY, 47,XYY, 47,XXX and 45,X conditions - constitute the most common class of chromosome abnormality in human live-births. Considerable attention has been given to the somatic abnormalities associated with these conditions, but less is known about their meiotic phenotypes; that is, how does sex chromosome imbalance influence the meiotic process. This has become more important with the advent of assisted reproductive technologies, because individuals previously thought to be infertile can now become biological parents. Indeed, there are several recent reports of successful pregnancies involving 47,XXY fathers, and suggestions that cryopreservation of ovarian tissue might impart fertility to at least some Turner syndrome individuals. Thus, the possible consequences of sex chromosome aneuploidy on meiotic chromosome segregation need to be explored.     

植物非整倍体研究进展

非整倍体(aneuploid)是指相对于正常个体(euploid)的染色体组增加、减少一条或若干条染色体的生物个体。由于非整倍体个体存在基因剂量效应的不平衡性(gene-dosage imbalance),非整倍体个体往往会表现严重的表型缺陷(aneuploid syndrom),如发育迟缓,个体矮小,难以繁殖后代等。在人类中,最为典型的例子为导致新生儿智力缺陷的唐氏综合症,由额外的一个21号染色体拷贝(部分拷贝)引起。此外,大多数癌细胞类型表型为严重的非整倍体。在大多情况下,非整倍体对于动物及人类是致命的,而植物对于非整倍体则往往表现出较强的耐受力,特别是在异源多倍体植物中。植物非整倍体对于植物的遗传、育种研究有重要意义,在基因及分子标记的物理位置确定,基因转移,连锁群与染色体的对应关系的确立上具有无可比拟的优势。该文综述了近些年来有关植物非整倍体研究的结果,介绍了非整倍体的几种重要成因和有关非整倍体鉴定手段的变迁,阐述了植物非整倍体对个体表型、基因表达以及表观遗传方面的影响,重点讨论了非整倍体在植物进化、基因组序列测定以及遗传改良方面的潜在作用。同时,探讨了植物非整倍体研究的新思路,以及利用非整倍体促进相关植物遗传改良、育种研究的新方法。     

Comparisons of tests for aneuploidy

The fundamental problems that face us in the development of suitable assay systems for the detection of potentially aneugenic (aneuploidy-inducing) chemicals include: (a) the diversity of cellular targets and mechanisms where perturbations of structure and function may give rise to changes in chromosome number, and (b) the phylogenetic differences that exist between species in their mechanism and kinetics of cell division and their metabolic profiles. A diverse range of assay systems have been developed, which have been shown to have potential for use in the detection of either changes in chromosome number or of perturbations of the events which may be causal in the induction of aneuploidy.

Chromosome number changes may be detected cytologically by karyotypic analysis, or by the use of specialised strains in which aneuploid progeny may be observed due to phenotypic differences with aneuploid parental cells or whole organisms. Techniques for the detection of cellular target modifications range from in vitro studies of tubulin polymerisation to observations of the behaviour of various cellular organelles and their fidelity of action during the division cycle.

The diversity of mechanisms which may give rise to aneuploidy and the qualitative relevance of events observed in experimental organisms compared to man make it unlikely that the detection and risk assessment of the aneugenic activity of chemicals will be possible using a single assay system. Optimal screening and assessment procedures will thus be dependent upon the selection of an appropriate battery of predictive tests for the measurement of the potentially damaging effects of aneuploidy induction.     

How to survive aneuploidy

Aneuploidy, or an abnormal number of chromosomes, adversely affects cell growth, but it is also linked with cancer and tumorigenesis. Now, Torres et al. (2010) help to resolve this paradox by demonstrating that aneuploid yeast cells can evolve mutations in the proteasome protein degradation pathway that alleviate imbalances in protein production and increase the cell's proliferative capacities.     

Total aneuploidy and age-related sex chromosome aneuploidy in cultured lymphocytes of normal men and women

Summary In PHA-cultured lymphocytes, about 8% of metaphases from 32 women were aneuploid compared to 4% of metaphases from 35 men. A significant part of this aneuploidy was characterized by sex chromosome involvement: in women, the loss or gain of X chromosomes; in men, the gain of X chromosomes and the loss or gain of Y chromosomes. The incidence of this aneuploidy was positively age-related for both sexes. Premature division of the X-chromosome centromere was closely associated with X-chromosome aneuploidy in women and men, and appeared to be the mechanism of nondisjunction causing this aneuploidy. Premature centromere division (PCD) indicated a dysfunction of the X-chromosome centromere with aging, and this dysfunction was the basic cause of age-related aneuploidy. A similar mechanism of nondisjunction may operate for the Y chromosome of men, but could not be clearly demonstrated because of the low incidence of Y-chromosome aneuploidy.The balance of the aneuploidy was characterized by chromosome loss and the involvement of all chromosome groups. It was consistent with chromosome loss from metaphase cells damaged during preparation for cytogenetic examination.     

Stable variants of sperm aneuploidy among healthy men show associations between germinal and somatic aneuploidy

Repeated semen specimens from healthy men were analyzed by sperm fluorescence in situ hybridization (FISH), to identify men who consistently produced elevated frequencies of aneuploid sperm and to determine whether men who were identified as stable variants of sperm aneuploidy also exhibited higher frequencies of aneuploidy in their peripheral blood lymphocytes. Seven semen specimens were provided by each of 15 men over a 2-year period and were evaluated by the X-Y-8 multicolor sperm FISH method (i.e., approximately 1,050,000 sperm were analyzed from 105 specimens). Three men were identified as stable aneuploidy variants producing significantly higher frequencies of XY, disomy X, disomy Y, disomy 8, and/or diploid sperm over time. In addition, one man and three men were identified as sperm-morphology and sperm-motility variants, respectively. Strong correlations were found between the frequencies of sperm with autosomal and sex-chromosome aneuploidies and between the two types of meiosis II diploidy; but not between sperm aneuploidy and semen quality. A significant association was found between the frequencies of sex-chromosome aneuploidies in sperm and lymphocytes in a subset of 10 men (r2=0.67, P=.004), especially between XY sperm and sex-chromosome aneuploidy in lymphocytes (r2=0.70, P=.003). These findings suggest that certain apparently healthy men can produce significantly higher frequencies of both aneuploid sperm and lymphocytes. Serious long-term somatic and reproductive health consequences may include increased risks of aneuploidy-related somatic diseases and of having children with paternally transmitted aneuploidies, such as Klinefelter, Turner, triple-X, and XYY syndromes.     

Hyperthermia-induced embryonic aneuploidy in mice

Chromosomal aneuploidy, as an effect of elevated ambient temperature during early gestation, was studied in 650 eight-day embryos from 60 females of two different mouse stocks. Exposure of treatment females to 34 C and 50% relative humidity during days 5 and 6 of gestation caused an increase in embryo chromosomal hyperploidy. No embryo sex interaction with the percent hyperploidy was found.     

Tetraploidy, aneuploidy and cancer

Aneuploidy is one of the most obvious differences between normal and cancer cells. However, there remains debate over how aneuploid cells arise and whether or not they are a cause or consequence of tumorigenesis. One proposed route to aneuploid cancer cells is through an unstable tetraploid intermediate. Supporting this idea, recent studies demonstrate that tetraploidy promotes chromosomal aberrations and tumorigenesis in vivo. These tetraploid cells can arise by a variety of mechanisms, including mitotic slippage, cytokinesis failure, and viral-induced cell fusion. Furthermore, new studies suggest that there might not be a ploidy-sensing checkpoint that permanently blocks the proliferation of tetraploid cells. Therefore, abnormal division of tetraploid cells might facilitate genetic changes that lead to aneuploid cancers.     

Lifestyle factors and sperm aneuploidy

Different environmental and lifestyle factors may interfere with the normal disjunction of sister chromatids/chromosomes during meiosis and may cause aneuploidy. The aim of the study was to examine the association between lifestyle factors and sperm aneuploidy. The study population consisted of 212 healthy men under 45 years of age attending an infertility clinic for diagnostic purposes and who had a normal semen concentration of 20–300 × 10⁶ mL or slight oligozoospermia (semen concentration of 15–20 × 10⁶/mL). All participants were interviewed and provided a semen sample. Sperm aneuploidy was assessed using multicolor FISH (DNA probes specific for chromosomes X, Y, 18, 13, 21). Results from the study suggest that lifestyle factors are related to sperm aneuploidy. A positive relationship was found between coffee drinking everyday and the lack of chromosome X or Y, as well as coffee drinking 1–6 times per week and additional chromosome 18. Wearing boxer shorts decrease the copy number changes in the whole chromosome 18, the number of additional chromosome 18 and the lack of chromosome 13. Additionally, obesity (BMI 30–40 kg/m²) was positively associated with additional chromosome 21 after being adjusted for potential confounders. These findings demonstrate that changing the men's lifestyle habits may contribute to reduction of the incidence of sperm aneuploidy. It is necessary that men continue to follow sensible health advice concerning excess weight, coffee drinking and wearing tight fitting underwear. As this is the first such study to examine different lifestyle factors and sperm aneuploidy, the results need to be confirmed on larger population.     

Targeting aneuploidy for cancer therapy

Tumor cells frequently display an abnormal number of chromosomes, a phenomenon known as aneuploidy. Tang et al. (2011) now show that aneuploid cells are particularly sensitive to compounds that induce proteotoxic and energy stress. Could this vulnerability lead to new cancer therapies?     

Fertility and aneuploidy in autopolyploidAnthoxanthum

An autopolyploid series comprising 2x, 3x and 4x was obtained by colchicining the diploid speciesA. ovatum Lag. The autotriploid, used as seed and pollen parent, was back-crossed to diploid and tetraploid. No significant overall difference was observed in fertility, but there was a tendency for particular pair crosses to the diploid as female parent to show higher levels of seed-setting. This may be associated with the relatively large proportion of haploid pollen that functions when the triploid is used as the male parent.The effectiveness, in part, of the freely liberated pollen of autotriploidAnthoxanthum in producing progeny, contrasts with the total failure of manually liberated allotriploidDactylis pollen. Triploid sterility may well relate to degree of hybridity.Genetic unbalance induced by aneuploidy was considered to be more relevant than the genetic ratio in seeds, as an explanation of the type of interploid progeny obtained inAnthoxanthum.Cytological material in this paper was submitted by the junior author in partial satisfaction of the requirements for the degree of M.Sc. in the University of Wales.     

Inherited aneuploidy: germline mosaicism

Germline mosaicism has been thought to be a rare cause of aneuploidy in the human population. Recent evidence from cytological and population studies suggests otherwise. Approximately 5% of young couples with a Down syndrome child show evidence of germinal mosaicism. Molecular cytogenetic analysis of oocytes has proved germinal or gonadal mosaicism for trisomies of chromosomes 13 and 21 in several studies involving both oocytes and first polar bodies. Most recently direct analysis of fetal ovarian pre-meiotic, meiotic, and stromal cells proved low level trisomy 21 mosaicism in every sample tested. Based upon this evidence, germinal or gonadal mosaicism is likely to make a significant contribution to aneuploidy in the human population, particularly where younger women are concerned.     

Chemically-induced aneuploidy in mammalian oocytes

The ability of certain chemicals to elevate the frequency of aneuploidy above spontaneous levels in mammalian experimental models prompts the concern that a similar situation might exist in humans. Validation of experimental models for aneuploidy studies is in progress since there is much to be learned about the causes and mechanisms of chemically-induced aneuploidy. Several biological variables have been shown to influence the results from aneuploidy assays. In this review, we examine these variables as they relate to female germ cell aneuploid assays. Also, we have found that the aneuploidy results obtained from different cell types, sexes, and experimental models cannot necessarily be expected to agree due to certain anatomic and physiologic differences and the end points measured.