Analysis of two 47,XXX males reveals X-Y interchange and maternal or paternal nondisjunction

Summary Two cases of 47,XXX males were studied, one of which has been published previously (Bigozzi et al. 1980). Analysis of X-linked restriction fragment length polymorphisms revealed that in this case, one X chromosome was of paternal and two were of maternal origin, whereas in the other case, two X chromosomes were of paternal and one of maternal origin. Southern blot analysis with Y-specific DNA probes demonstrated the presence of Y short arm sequences in both XXX males. In one case, the results obtained pointed to a paracentric inversion on Yp of the patient's father. In situ hybridization indicated that the Y-specific DNA sequences were localized on Xp22.3 in one of the three X chromosomes in both cases. The presence of Y DNA had no effect on random X inactivation. It is concluded that both XXX males originate from aberrant X-Y interchange during paternal meiosis, with coincident nondisjunction of the X chromosome during maternal meiosis in case 1, and during paternal meiosis II in case 2.     

Patchy fur (Paf), a semidominant X-linked gene associated with a high level of X-Y nondisjunction in male mice

Several X-linked mutations that have associated sex chromosomal nondisjunction have been identified in the mouse. We describe a new semidominant X-linked mutation called patchy fur (Paf) that produces an abnormal coat. It maps to the distal end of the murine X chromosome very near the XY pseudoautosomal region. The degree of severity in affected mice is hemizygous males greater than homozygous females greater than heterozygous females. An unusual feature of Paf is that either the mutation itself or an inseparable chromosomal abnormality causes delayed disjunction of the X and Y chromosomes at meiotic metaphase I, which in turn results in approximately 19% XO progeny and slightly less than 1% XXY progeny from Paf/Y males. The effect occurs only in male carriers and thus must extend into the proximal end of the XY pairing region.     

Association between nondisjunction and maternal age in meiosis-II human oocytes.

The relationship between advanced maternal age and increased risk of trisomic offspring is well known clinically but not clearly understood at the level of the oocyte. A total of 383 oocytes that failed fertilization from 107 patients undergoing in vitro fertilization were analyzed by FISH using X-, 18-, and 13/21-chromosome probes simultaneously. The corresponding polar bodies were also analyzed in 188 of these oocytes. The chromosomes in the oocyte and first polar body complement each other and provide an internal control to differentiate between aneuploidy and technical errors. Two mechanisms of nondisjunction were determined. First, nondisjunction of bivalent chromosomes resulting in two univalents going to the same pole and, second, nondisjunction by premature chromatid separation (predivision) of univalent chromosomes producing either a balanced (2 + 2) or unbalanced (3 + 1) distribution of chromatids into the first polar body and M-II oocytes. Balanced predivision of chromatids, previously proposed as a major mechanism of aneuploidy, was found to increase significantly with time in culture (P < .005), which suggests that this phenomenon should be interpreted carefully. Unbalanced predivision and classical nondisjunction were unaffected by oocyte aging. In comparing oocytes from women <35 years of age with oocytes from women > or = 40 years of age, a significant increase (P < .001) in nondisjunction of full dyads was found in the oocytes with analyzable polar bodies and no FISH errors. Premature predivision of chromatids was also found to cause nondisjunction, but it did not increase with maternal age.     

An abnormal terminal X-Y interchange accounts for most but not all cases of human XX maleness

To determine if human XX maleness results from an abnormal chromosomal X-Y interchange, we studied the inheritance of the paternal pseudoautosomal region in nine patients. Those six patients in whom Y-specific DNA was found (Y(+)) inherited the entire pseudoautosomal region from the paternal Y chromosome and lost that of the paternal X chromosome. Moreover, in three Y(+) cases, we observed the deletion of a paternal Xp locus tightly linked to the pseudoautosomal region. These results definitively show that an abnormal and terminal X-Y interchange during paternal meiosis causes Y(+)XX maleness. In contrast, no abnormal X-Y interchange was observed in any of the three Y(-) cases analyzed, suggesting that maleness can occur in the absence of any Y-specific DNA.     

The impact of imprinting: Prader-Willi syndrome resulting from chromosome translocation, recombination, and nondisjunction.

Prader-Willi syndrome (PWS) is most often the result of a deletion of bands q11.2-q13 of the paternally derived chromosome 15, but it also occurs either because of maternal uniparental disomy (UPD) of this region or, rarely, from a methylation imprinting defect. A significant number of cases are due to structural rearrangements of the pericentromeric region of chromosome 15. We report two cases of PWS with UPD in which there was a meiosis I nondisjunction error involving an altered chromosome 15 produced by both a translocation event between the heteromorphic satellite regions of chromosomes 14 and 15 and recombination. In both cases, high-resolution banding of the long arm was normal, and FISH of probes D15S11, SNRPN, D15S10, and GABRB3 indicated no loss of this material. Chromosome heteromorphism analysis showed that each patient had maternal heterodisomy of the chromosome 15 short arm, whereas PCR of microsatellites demonstrated allele-specific maternal isodisomy and heterodisomy of the long arm. SNRPN gene methylation analysis revealed only a maternal imprint in both patients. We suggest that the chromosome structural rearrangements, combined with recombination in these patients, disrupted normal segregation of an imprinted region, resulting in uniparental disomy and PWS.     

Recombination and maternal age-dependent nondisjunction: molecular studies of trisomy 16.

Trisomy 16 is the most common human trisomy, occurring in > or = 1% of all clinically recognized pregnancies. It is thought to be completely dependent on maternal age and thus provides a useful model for studying the association of increasing maternal age and nondisjunction. We have been conducting a study to determine the parent and meiotic stage of origin of trisomy 16 and the possible association of nondisjunction and aberrant recombination. In the present report, we summarize our observations on 62 spontaneous abortions with trisomy 16. All trisomies were maternally derived, and in virtually all the error occurred at meiosis I. In studies of genetic recombination, we observed a highly significant reduction in recombination in the trisomy-generating meioses by comparison with normal female meioses. However, most cases of trisomy 16 had at least one detectable crossover between the nondisjoined chromosomes, indicating that it is reduced--and not absent--recombination that is the important predisposing factor. Additionally, our data indicate an altered distribution of crossing-over in trisomy 16, as we rarely observed crossovers in the proximal long and short arms. Thus, it may be that, at least for trisomy 16, the association between maternal age and trisomy is due to diminished recombination, particularly in the proximal regions of the chromosome.     

Heterologous interchange and nondisjunction of distributively paired chromosomes in Drosophila melanogaster mature oocytes

In the mature oocyte C(1)-4 and Y-4 interchanges do not direct disjunction of the centromeres of the involved heterologs. C(1)-4 detachments are recovered in either sex and almost every time ($\text{13}\text{14}$) with a free fourth chromosome that is the sister of the involved four. Y-4 fragments are recovered preferentially in males ($\text{28}\text{28}$) and with a free, sister four ($\text{26}\text{28}$). In the mature oocyte segregation patterns are determined and C(1)-4 and Y-4 interchange usually involve heterologs segragating to the same pole.     

Isolation of sequences from Xp22.3 and deletion mapping using sex chromosome rearrangements from human X-Y interchange sex reversals

A repeated DNA element (STIR) interspersed in Xp22.3 and on the Y chromosome has been used as a tag to isolate seven single-copy probes from the human sex chromosomes. The seven probes detect X-specific loci located in Xp22.3. Using a panel of X-chromosomal deletions from X-Y interchange sex reversals (XX males and XY females), these X-specific loci and some additional ones were mapped to four contiguous intervals of Xp22.3, proximal to the pseudoautosomal region and distal to STS. The construction of this deletion map of the terminal part of the human X chromosome can serve as a starting point for a long-range physical map of Xp22.3 and for a more accurate mapping of genetic diseases located in Xp22.3.     

Methylation levels of maternal and paternal genomes during preimplantation development.

The methylation status of three highly repeated sequences was studied in sperm, eggs and preimplantation embryos with different combinations of parental chromosomes. High levels of methylation of the IAP and MUP sequence families were found in sperm and in eggs, whereas the L1 repeat was found to be highly methylated in sperm but only about 42% methylated in eggs. To assess how the two parental genomes behaved during preimplantation development, normal, fertilised embryos were compared with parthenogenetic embryos where the chromosomes are exclusively of maternal origin. It was observed that the high levels of methylation at the IAP and MUP sequences were retained through early development, with the first signs of demethylation at the IAP sequences apparent on both parental chromosomes in the blastocyst. Methylation at the sperm-derived L1 sequences dropped to about the same level as that of the egg-derived sequences by the late 2-cell stage, both then remain at this intermediate level until around the time of cavitation when levels fell to about 10% in the blastocyst. High levels of DNA methylase were detected in germinal vesicle and metaphase II oocytes; these high levels were maintained in fertilised and parthenogenetic embryos through into the morula and then declined to be undetectable in the blastocyst. Our comparison of maternal and paternal genomes suggests that methylation levels at repeat sequences are remarkably similar at the time of fertilisation or, as in the case of the L1 sequences, they become so during the first few cell cycles. Hence, there do not appear to be global methylation differences between the genomes that are retained through preimplantation development.(ABSTRACT TRUNCATED AT 250 WORDS)     

Partial trisomy 16q resulting from maternal translocation

Summary A 3 1/2-year-old male with partial trisomy of the long arm of chromosome 16 resulting from a maternal balanced translocation is described. Karyotype: 46,XY,-22,der(22),t(16;22)(q21;p12)mat.     

Concurrence of fragile X and Klinefelter syndromes: report of a new case of paternal nondisjunction

The concurrence of fragile X and Klinefelter syndromes would be expected occasionally. Therefore, the analysis of the literature showed that the concurrence of both conditions was found at least 16 times. Among them, only seven cases were analyzed for the parental origin of the extra chromosome X, suggesting that the maternal nondisjunction was preferentially inherited. We present the third patient with the concurrence of fragile X and Klinefelter syndromes, in which the parental origin of the supernumerary chromosome X was paternal. This finding reinforces that the parent-of-origin predisposition of the concurrence of the fragile X and Klinefelter syndromes is a pure coincidence.     

Predator-induced maternal and paternal effects independently alter sexual selection

Parental experience alters survival-related phenotypes of offspring in both adaptive and nonadaptive ways, yielding rapid inter- and transgenerational fitness effects. Yet, fitness comprises survival and reproduction, and parental effects on mating decisions could alter the strength and direction of sexual selection, affecting long-term evolutionary trajectories. We used a full factorial design in which threespine stickleback (Gasterosteus aculeatus) mothers, fathers, both, or neither were exposed to a model predator at developmentally appropriate times to test for predator-induced maternal, paternal, and joint parental effects on daughters’ mating behavior. We tested the responsiveness, preferences, and mate choices of adult daughters in no-choice trials with wild-caught males who had varied sexual signals. Maternal and paternal predator exposure independently yielded daughters who preferred males who were intermediate in conspicuousness (with duller nuptial coloration and who courted less vigorously), relaxing the typical preference for the most conspicuous males. The combined effects of maternal and paternal predator exposure were not cumulative; when both parents were predator exposed, single-parent effects on mate preferences were reversed. Thus, we cannot assume that maternal and paternal effects additively combine to produce “parental” effects. Further, joint parental predator exposure yielded daughters who were three times less likely to mate at all. Stress-induced intergenerational parental effects on reproductive decisions such as those observed here may potentiate rapid transgenerational responses to novel and changing mating environments.     

Complete elimination of maternal mitochondrial DNA during meiosis resulting in the paternal inheritance of the mitochondrial genome in Chlamydomonas species

Summary. The non-Mendelian inheritance of organellar DNA is common in most plants and animals. In the isogamous green alga Chlamydomonas species, progeny inherit chloroplast genes from the maternal parent, as paternal chloroplast genes are selectively eliminated in young zygotes. Mitochondrial genes are inherited from the paternal parent. Analogically, maternal mitochondrial DNA (mtDNA) is thought to be selectively eliminated. Nevertheless, it is unclear when this selective elimination occurs. Here, we examined the behaviors of maternal and paternal mtDNAs by various methods during the period between the beginning of zygote formation and zoospore formation. First, we observed the behavior of the organelle nucleoids of living cells by specifically staining DNA with the fluorochrome SYBR Green I and staining mitochondria with 3,3′-dihexyloxacarbocyanine iodide. We also examined the fate of mtDNA of male and female parental origin by real-time PCR, nested PCR with single zygotes, and fluorescence in situ hybridization analysis. The mtDNA of maternal origin was completely eliminated before the first cell nuclear division, probably just before mtDNA synthesis, during meiosis. Therefore, the progeny inherit the remaining paternal mtDNA. We suggest that the complete elimination of maternal mtDNA during meiosis is the primary cause of paternal mitochondrial inheritance. Correspondence and reprints: Laboratory of Cell and Functional Biology, Faculty of Science, University of the Ryukyus, Nishihara, Okinawa 901-0213, Japan.     

Hyperthermia of male Drosophila melanogaster meiocytes induces abnormalities in both paternal and maternal sex chromosome sets of the offspring

Nondisjunction and loss of sex chromosomes caused by exposure of male Drosophila melanogaster to heat shock (HS) (37 degrees C for 1 h) has been studied to determine the role of mutation l(1)ts403 (sbr10) in the control of chromosome segregation during cell division. Hyperthermia of males at the pupal stage has been demonstrated to increase the number of offspring with abnormalities of not only paternal, but also maternal sex chromosome sets. According to the criterion used, there is a temperature-sensitive period of spermatogenesis, which presumably coincides with meiosis. Phenotypes of some individuals correspond to the presence of two sex chromosomes of obtained from the same parent. The frequency of abnormal chromosome sets in the offspring of male carriers of the sbr10 mutation is about two times higher than in the offspring of males without this mutation.     

No evidence for a paternal interchromosomal effect from analysis of the origin of nondisjunction in Down syndrome patients with concomitant familial chromosome rearrangements.

The parental origin of the extra chromosome 21 was determined with DNA polymorphisms in seven families in whom the proband and one of the parents carried an additional chromosome rearrangement (balanced translocation or pericentric inversion) not involving chromosome 21. The balanced rearrangement was inherited from the mother in two families and from the father in five families, whereas the additional chromosome 21 was derived from the mother in all seven families. These findings are not in agreement with the hypothesis of a paternal interchromosomal effect. The latter would imply that a balanced rearrangement in the father would favor nondisjunction during meiosis in the germ cells.     

Trisomy 9p resulting from maternal 9/21 translocation

Summary The clinical picture found in a child with trisomy 9p confirmed that this chromosomal syndrome is a entity, which arises from maternal translocation t(9;21).     

An analysis of white-mottled mutants inDrosophila hydei,with observations on X-Y exchanges in the male

Chromosomes and phenotypes of four different sex-linkedwhite-mottled mutants of the position-effect variogation type were studied. Three mutants (w ^m1,w ^m2,w ^m3) are X-chromosomal rearrangements which shift the w⁺ locus into a position close to heterochromatin, but which have different ouchromatic and heterochromatic breaks. The fourth, a spontaneous derivative ofw ^m1, is an insertional duplication of part of the X chromosome, including thew ⁺ andN ⁺loci. The duplicated segment is inserted into the distal part of the long arm of the heterochromatic Y chromosome. It is designated,w ^m CoY, orXw ^m Co when transferred to the X chromosome.Three chromosomal types (w ^m1,w ^m CoY) and (Xw ^m Co) having the same cuchromatic break near thew ⁺ locus, cause large-spotted eyes whereas two others (w ^m2,w ^m3) produce a popper-and-salt type of mottling. From the position of the various eu- and heterochromatic breaks, it appears that the distance of thew ⁺ locus to the point of reunion with heterochromatin, rather than the amount or type of adjoining heterochromatin, dietates the phenotypic action of the displacedw ⁺ locus, in the sense of a spreading effect on two proposed functional subunits within thew ⁺ locus.The pigmentation background against which the mottling effect is produced, i.e., a givenw-allele with its characteristic colour, or other eye colour mutations, does not seem to affect the type of mottling. Drosopterins and ommochromes react in the same way to modifing factors like temperature and supernumerary Y chromosomes. Two mutants (w ^m2 andw ^m CoY) while reacting in the same manner to Y chromosomes showed an opposite temperature response.By exchange between the heterochromatin of the Y and X chromosome inw/w ^m CoY males thew ^m Co duplication was transferred between the sex chromosomes with a certain regularity. It is not yet known wether the exchanges are mitotic or meiotic in origin but their heterochromatic nature has been demonstrated cytologically.