TRISOMICS IN SOLANUM CHACOENSE: FERTILITY AND CYTOLOGY

Twenty trisomic plants found in the progeny 3x x 2x crosses in Solatium chacoense and their F₁ trisomies obtained by 2x + 1 X 2x crosses were studied with respect to their fertility and cytology. The female transmission of the extra chromosome in the trisomics varied from 2 to 60 %. The transmission frequencies of F₁ trisomies were similar to their parent trisomies in most of the lines. The transmission through the pollen ranged from 0 to 20 %. Female and male fertility of the parent trisomies was high. They produced an average of 37 seeds per pollination as the female or as the male parent. The F₁ trisomies produced about half the seed set of their parent trisomies. The extra chromosomes of six trisomies were identified by pachytene analysis. They were isochromosomes for the long arms of chromosomes I, IV and IX and the short arms of IV, IX and XII. Chromosome morphology of the extra chromosomes in pachytene stage was described. A chromosome association of 12 II + 1 I was found in 66 % of the cells at MI. About 29 % of the cells had one trivalent and 5 % had three or five univalents. The frequency of trivalent formation was not affected by the length of the extra chromosome. The possibility of univalent shift in secondary trisomies was discussed.     

Mosaic trisomies in human spontaneous abortions

Summary Data from a cytogenetic survey of spontaneous abortions were examined to determine the incidence and origin of mosaic trisomies in this population. The overall frequency of mosaicism among trisomies was approximately 5%, but the level of mosaicism varied significantly among trisomies, being much higher for the nonacrocentric than for the acrocentric trisomies. Evidence from chromosome heteromorphism analysis suggests that the extra chromosome in mosaic trisomies usually has a meiotic origin.This work was supported by Grant HD 07879 and Fellowship HD 05576 from the National Institutes of Health     

The Influence of Whole-Arm Trisomy on Gene Expression in Drosophila

The biochemical consequences of extensive aneuploidy in Drosophila have been examined by measuring the levels of specific proteins in larvae trisomic for entire chromosome arms. By far the most common effect is a reduction in gene product levels (per gene template) by one-third from the diploid quantity, consistent with the model that concentration-dependent repressors of these loci reside on the duplicated chromosome arms. Most loci appear sensitive to such repression in one or more of the trisomies examined, suggesting that such regulatory loci might be quite common. Repression of gene-product levels in trisomies may significantly contribute to their inviability. Few loci are activated in trisomies implying that most factors necessary for gene expression are in excess. While autosomal trisomies can repress the expression of both X-linked and autosomal loci, X-chromosomal trisomies have little effect on most autosomal genes. A family of genes coding for larval serum proteins do not respond similarly in trisomies, suggesting that regulation operates on a process which is not common to their coordinate regulation. Finally, Adh genes transposed to new chromosomal positions maintain their ability to be repressed in 3L trisomies suggesting that this response to regulation involves a closely linked cis-acting regulatory element.     

Maternal Age-Specific Rates for Trisomy 21 and Common Autosomal Trisomies in Fetuses from a Single Diagnostic Center in Thailand

To provide maternal age-specific rates for trisomy 21 (T21) and common autosomal trisomies (including trisomies 21, 18 and 13) in fetuses. We retrospectively reviewed prenatal cytogenetic results obtained between 1990 and 2009 in Songklanagarind Hospital, a university teaching hospital, in southern Thailand. Maternal age-specific rates of T21 and common autosomal trisomies were established using different regression models, from which only the fittest models were used for the study. A total of 17,819 records were included in the statistical analysis. The fittest models for predicting rates of T21 and common autosomal trisomies were regression models with 2 parameters (Age and Age²). The rate of T21 ranged between 2.67 per 1,000 fetuses at the age of 34 and 71.06 per 1,000 at the age of 48. The rate of common autosomal trisomies ranged between 4.54 per 1,000 and 99.65 per 1,000 at the same ages. This report provides the first maternal age-specific rates for T21 and common autosomal trisomies fetuses in a Southeast Asian population and the largest case number of fetuses have ever been reported in Asians.     

Analysis of nucleolar organizing regions in parents of trisomic spontaneous abortions

Summary Nucleolar organizing region (NOR) variants of parents of karyotyped spontaneous abortions were examined to fest the hypothesis that double NORs are important in the genesis of acrocentric trisomies. We were unable to detect any significant difference in the frequency or types of NOR variants between parents of acrocentric trisomies and parents of other types of spontaneous abortions, nor did we identify a double NOR in either group. Thus, it seems unlikely that double NORs are of major significance in the etiology of acrocentric trisomies.     

Triple trisomy in a 17-week-old fetus

Summary Autosomal trisomies account for the majority of chromosome abnormalities associated with spontaneous miscarriages. Occasionally, double autosomal trisomies are found to be present in abortuses. This report describes the second occurrence of triple trisomy associated with fetal demise.     

On the possible effects of homeostatic shifts in human embryonic development

Possible etiological factors of congenital malformations as well as of human trisomies are considered in the framework of the repressor hypothesis. In this approach gene expression is envisaged from the point of view of the functional variations of the total activation energy for normal gene expression in homeostatic equilibrium. We restrict our attention to variations of the total activation energy under the effect of temperature gradients. We discuss the evidence that hyperthermia may be an etiological factor for trisomies in humans.Also at the Instituto Internacional de Estudios Avanzados Apartado 17606, Parque Central, Caracas 1015-A, Venezuela.     

A cytogenetic study directly from chorionic villi of 140 spontaneous abortions

Summary Spontaneous abortions were studied by analyzing chromosomes directly from chorionic villi. The frequency and the type of anomalies detected among 140 abortuses are in good agreement with those observed by others using conventional tissue cultures. Abnormal karyotypes were found in 48.6% of the cases. Trisomy predominated (66.2%), followed by polyploidy (22.1%), monosomy X (7.4%), and structural anomalies (4.4%). Among the trisomies, the most prevalent were of chromosome 22 (22.2%), 16(22.2%), and 13 (9.5%). The relative frequencies of trisomies, monosomy X, and the different chromosomes involved in trisomies seem to differ between our study and those in which tissue cultures were analyzed. Our low frequency of 45,XO karyotypes and the shift to trisomies of chromosomes whose involvement increases steeply with maternal age are considered due to the approximately 3 year higher mean maternal age in our sample. The sex ratio (male to female) in chromosomally abnormal abortuses was 1.28, which is nearly identical to the 1.2 found in earlier studies. Surprisingly, in chromosomally normal abortions males were significantly outnumbered by females (sex ratio 0.76). Since maternal cell contamination cannot have influenced the sex ratio in our study, we consider it worthwhile to investigate whether failures associated with X inactivation are responsible for pregnancy wastage of some euploid female conceptuses. Knowledge of the karyotypes may serve as a prerequisite for the investigation of non-chromosomal genetic causes of pregnancy wastage.     

The relationship of maternal age and trisomy among trisomic spontaneous abortions

The relationship between maternal age and trisomy was examined by comparing mean ages of 954 trisomic spontaneous abortions with those of live births ascertained at the same study center. The overall mean for trisomy was highly significantly elevated over that of the newborns. The age effect was most pronounced for trisomies involving the small chromosomes, with trisomies 13, 14, 15, 16, 17, 18, 20, 21, and 22 all having significantly increased ages by comparison with the control population. However, the majority of trisomies involving large or medium-sized chromosomes also had elevated mean maternal ages, suggesting that most, if not all, human trisomies are associated with increasing age of the mother. Additional variation in the age effect was observed among trisomies involving similar-sized chromosomes, indicating that factors other than chromosome size also influence the relationship between increasing age and trisomy.     

Tissue-Specific Placental Mosaicism for Autosomal Trisomies in Human Spontaneous Abortuses: Mechanisms of Formation and Phenotypical Effects

The frequencies of autosomal trisomies in extraembryonic human tissues were estimated in the cases of different abnormalities of prenatal development, from the confined placental mosaicism (CPM) with either relatively normal embryogenesis or restricted intrauterine growth to spontaneous abortion. A tissue-specific compartmentalization was found to be characteristic of cell lines with trisomies for individual autosomes. Analysis of various phenotypical effects of chromosomal aberrations associated with mosaicism is necessarily required to understand the mechanisms and factors responsible for tissue chromosomal mosaicism. Based on analysis of the cell karyotype during prenatal diagnosing of chromosome aberrations in tissues of both extraembryonic and embryonic origin, in 1996, Wolstenholme proposed a model of CPM for individual chromosomes. According to the model, the distribution of cell lines with autosomal trisomies between extraembryonic tissues depends on the ratio between meiotic and mitotic mutations early in embryonic development. However, the model cannot be used to study tissue chromosomal mosaicism in spontaneous abortions, because little information is available on cell karyotype in embryonic tissues themselves after intrauterine fetal death. In this work, a model of tissue-specific chromosomal mosaicism was suggested based on the data on cell karyotype determined in extraembryonic tissues alone, which can be helpful in evaluating the contribution of tissue chromosomal differences into the etiology of early intrauterine death. Along with the experimental evidence, comparative analysis of the two models indicated that the meiotic chromosome nondisjunction plays the major role in trisomy formation and the resultant spontaneous arrest of embryonic development. Other factors responsible for tissue-specific distribution of chromosomal aberrations are also discussed. These are differences in cell proliferative activity, as well as changes in compartmentalization and migration of cells with abnormal karyotypes.     

Placental mosaicism and intrauterine survival of trisomies 13 and 18.

Cytogenetic analysis of 14 placentas from live newborn infants or from terminated pregnancies with trisomies 13 and 18 revealed that all were mosaic. The mosaicism was confined to the cytotrophoblast and not detected in villous stroma, chorionic plate, or amnion. The percentage of cells with a normal karyotype varied from 12% to 100%, the average being 70%. No such confined mosaicism could be detected in 12 placentas of trisomy 21 fetuses. These findings suggest that a postzygotic loss of a trisomic chromosome in a progenitor cell of trophectoderm facilitates the intrauterine survival of trisomy-13 and -18 conceptuses. They also imply that it is placental function which determines the intrauterine survival and that the mother plays no active role in rejection of trisomic conceptions. The combination of both a pre- and post-zygotic cell division defect in viable trisomy-13 and -18 conceptions points to the possibility of a genetic predisposition to such events. The detection of only a diploid cell line in the cytotrophoblast of some pregnancies with trisomies 13 and 18 also suggests that direct preparation is unreliable for prenatal diagnosis of these trisomies on chorionic villi sampling and that long-term villous culture should be used.     

Tissue-specific placental mosaicism for autosomal trisomies in spontaneous human abortuses: mechanisms of formation and phenotypic effects]

The frequencies of autosomal trisomies in extraembryonic human tissues were estimated in the cases of different abnormalities of prenatal development, from the confined placental mosaicism (CPM) with either relatively normal embryogenesis or restricted intrauterine growth to spontaneous abortion. A tissue-specific compartmentalization was found to be characteristic of cell lines with trisomies for individual autosomes. Analysis of various phenotypical effects of chromosomal aberrations associated with mosaicism is necessarily required to understand the mechanisms and factors responsible for tissue chromosomal mosaicism. Based on analysis of the cell karyotype during prenatal diagnosing of chromosome aberrations in tissues of both extraembryonic and embryonic origin, in 1996, Wolstenholme proposed a model of CPM for individual chromosomes. According to the model, the distribution of cell lines with autosomal trisomies between extraembryonic tissues depends on the ratio between meiotic and mitotic mutations early in embryonic development. However, the model cannot be used to study tissue chromosomal mosaicism in spontaneous abortions, because little information is available on cell karyotype in embryonic tissues themselves after intrauterine fetal death. In this work, a model of tissue-specific chromosomal mosaicism was suggested based on the data on cell karyotype determined in extraembryonic tissues alone, which can be helpful in evaluating the contribution of tissue chromosomal differences into the etiology of early intrauterine death. Along with the experimental evidence, comparative analysis of the two models indicated that the meiotic chromosome nondisjunction plays the major role in trisomy formation and the resultant spontaneous arrest of embryonic development. Other factors responsible for tissue-specific distribution of chromosomal aberrations are also discussed. These are differences in cell proliferative activity, as well as changes in compartmentalization and migration of cells with abnormal karyotypes.     

Maternal Folate Polymorphisms and the Etiology of Human Nondisjunction

Attempts to identify genetic contributors to human meiotic nondisjunction have met with little, if any, success. Thus, recent reports linking Down syndrome to maternal polymorphisms at either of two folate metabolism enzymes, methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), have generated considerable interest. In the present report, we asked whether variation at MTHFR (677C-->T) or MTRR (66A-->G) might be associated with human trisomies other than trisomy 21. We analyzed maternal polymorphisms at MTHFR and MTRR in 93 cases of sex-chromosome trisomy, 44 cases of trisomy 18, and 158 cases of autosomal trisomies 2, 7, 10, 13, 14, 15, 16, 18, or 22, and compared the distributions of genotypes to those of control populations. We observed a significant increase in the MTHFR polymorphism in mothers of trisomy 18 conceptuses but were unable to identify any other significant associations. Overall, our observations suggest that, at least for the sex chromosomes and for a combined set of autosomal trisomies, polymorphisms in the folate pathway are not a significant contributor to human meiotic nondisjunction.     

Trisomy: Chromosome competition or maternal strategy?: Increase of trisomy incidence with increasing maternal age does not result from competition between chromosomes

Axelrod and Hamilton (Science 211:1390, 1981) suggested that trisomies may result from an end-game strategy between chromosomes competing to get on the gamete as the mother approaches menopause. We tested this hypothesis by reviewing studies of the parental origin of the extra chromosome in trisomy 21 births. These data show that there is no significant rise in trisomy 21 conceptions as the mother ages. The increase in trisomies with maternal age results not from an increase in nondisjunctions, but from a decrease in rejection of trisomy zygotes, which may be adaptive for the mother towards the end of her reproductive life. This decreasing rate of rejection may result from the changing inclusive benefits of two maternal strategies as menopause approaches.     

The increase in aneuploidy of embryos Is associated with pathological morphology of the sperm

Chromosomes of embryos of couples with reduced number of morphologically normal sperm cells (less than 4%) and couples with a normal level of morphologically normal sperm cells (over 4%) has revealed significant differences. In the group with a low level of normal spermatozoa, the frequency of embryos with normal chromosomes is significantly reduced and incidence of sex chromosome trisomies and autosomal monosomies and trisomies is increased; a tendency to decrease has been found for the frequency of male embryos. The obtained data may be useful to establish additional criteria for preimplantation genetic screening in the case of male infertility.     

Genetic analysis of rye (Secale cereale L.) Genetics of male sterility of the G-type

Summary The genetics and relationships between the genes in rye located in the nucleus and cytoplasm of the male sterility of the G-type were investigated. A factor inducing male sterility was found in the cytoplasms or rye cv Schlägler alt and rye cv Norddeutscher Champagner. Monogenic inheritance was observed in linkage tests. Using primary trisomies of rye cv Esto, the nuclear gene ms1 was found to be located on chromosome 4R. Modifying genes, probably masked in normal cytoplasm but expressed in male-sterility-inducing cytoplasm together with gene ms1, were located on chromosomes 3R (ms2) and 6R (ms3). Mono-, di-, and trigenic inheritance types were found in backcross progenies of trisomies.     

The Origin of Abnormalities in Recurrent Aneuploidy/Polyploidy

Recurrent miscarriage due to sporadic chromosomal abnormalities may simply be a consequence of the dramatic increase of trisomic conceptions with increased maternal age. However, it is also possible that some couples are at increased risk of abnormalities as a result of gonadal mosaicism, factors affecting chromosome structure and segregation, increased sperm aneuploidy in the male partner, or accelerated "aging" of the ovaries. We report cytogenetic and molecular findings from 122 spontaneous abortions (SAs) from 54 couples who were ascertained as having two or more documented aneuploid or polyploid SAs. The distribution of abnormalities in this group was similar to those from 307 SAs that involved chromosome abnormalities and were diagnosed at the same center but did not involve documented recurrent aneuploidy/polyploidy. Although recurrence of the same abnormality was observed in eight families, this number was equal to that expected by chance, indicating that gonadal mosaicism is rarely the explanation for recurrence. The origin of the abnormality was determined in 37 SAs from 23 of the couples in the study. A maternal meiotic origin was involved in 30 trisomies and in 1 triploid SA; 3 additional maternal trisomies were of possible somatic origin. A paternal origin was found in the remaining two trisomies and in one triploid SA. In addition, one double trisomy was the consequence of both a maternal and a paternal meiotic error. These results confirm that the etiology of trisomy is predominantly a result of meiotic errors related to increased maternal age, regardless of whether the couple has experienced one or multiple aneuploid SAs. Furthermore, this is true even when a second SA involves the same abnormality. Nonetheless, these data do not exclude some population variability in risk for aneuploidy.     

A model relating the incidence of meiotic trisomy to maternal age

A model is developed to explain the well-documented increase in the incidence of meiotic trisomies with increasing maternal age. This theoretical framework applies to all chromosomes, of which trisomy 21 (responsible for Down's syndrome in humans) is considered as a special case; the model can also be readily extended to trisomies of other mammals. The basic mechanism proposed links the hormonal environment of the oocyte to the durations of certain stages of meiosis. Changes in the hormonal environment, especially through aging, can slow the overall rate of meiosis, lengthening the interval from the resumption of meiosis in dictyotene until anaphase I. This extends the period in which homologous chromosomes are vulnerable to premature separation, increasing the probability of an unequal distribution of chromosomes in the first meiotic division. Testable predictions of the model are presented and discussed.     

Cytogenetic analysis of 750 spontaneous abortions with the direct-preparation method of chorionic villi and its implications for studying genetic causes of pregnancy wastage

Altogether, 750 cases of spontaneous abortion between the fifth and 25th week of gestation were analyzed cytogenetically by the direct-preparation method using chorionic villi. The majority of cases (68%) were derived from early abortions before the 12th week of gestation. The frequency of abnormal karyotypes was 50.1%; trisomy was predominant (62.1%), followed by triploidy (12.4%), monosomy X (10.5%), tetraploidy (9.2%), and structural chromosome anomalies (4.7%). Among trisomies, chromosomes 16 (21.8%), 22 (17.9%), and 21 (10.0%) were prevalent. The frequency of chromosomally abnormal abortions increased with maternal age but only because of an increase of trisomy. Polyploidy and monosomy X, however, decreased. Mean maternal age was significantly increased for trisomies 16, 21, and 22 and was highest for trisomies 18 and 20. The results obtained are within the range of variability reported earlier from tissue culture-type studies. A consistent feature during our study is the excess of females in chromosomally normal abortions (male:female sex ratio 0.71). According to the methodology applied, maternal cell contamination and undetected 46,XX molar samples cannot have influenced the sex ratio. However, a bias introduced by social status or maternal age cannot be excluded. With the more rapid and convenient direct preparation of chorionic villi, reliable cytogenetic data on causes of spontaneous abortions can be obtained.