Recombination in the pseudoautosomal region in a 47,XYY male

Males with a 47,XYY karyotype generally have chromosomally normal children, despite the high theoretical risk of aneuploidy. Studies of sperm karyotypes or FISH analysis of sperm have demonstrated that the majority of sperm are chromosomally normal in 47,XYY men. There have been a number of meiotic studies of XYY males attempting to determine whether the additional Y chromosome is eliminated during spermatogenesis, with conflicting results regarding the pairing of the sex chromosomes and the presence of an additional Y. We analyzed recombination in the pseudoautosomal region of the XY bivalent to determine whether this is perturbed in a 47,XYY male. A recombination frequency similar to normal 46,XY men would indicate normal pairing within the XY bivalent, whereas a significantly altered frequency would suggest other types of pairing such as a YY bivalent or an XYY trivalent. Two DNA markers, STS/STS pseudogene and DXYS15, were typed in sperm from a heterozygous 47,XYY male. Individual sperm (23,X or Y) were isolated into PCR tubes using a FACStarPlus flow cytometer. Hemi-nested PCR analysis of the two DNA markers was performed to determine the frequency of recombination. A total of 108 sperm was typed with a 38% recombination frequency between the two DNA markers. This is very similar to the frequency of 38.3% that we have observed in 329 sperm from a normal 46,XY male. Thus our results suggest that XY pairing and recombination occur normally in this 47,XYY male. This could occur by the production of an XY bivalent and Y univalent (which is then lost in most cells) or by loss of the additional Y chromosome in some primitive germ cells or spermatogonia and a proliferative advantage of the normal XY cells.     

Aneuploidy in human spermatozoa

We reviewed the frequency and distribution of disomy in spermatozoa obtained by multicolor-FISH analysis on decondensed sperm nuclei in (a) healthy men, (b) fathers of aneuploid offspring of paternal origin and (c) individuals with Klinefelter syndrome and XYY males. In series of healthy men, disomy per autosome is approximately 0.1% but may range from 0.03 (chromosome 8) to 0.47 (chromosome 22). The great majority of authors find that chromosome 21 (0.18%) and the sex chromosomes (0.27%) have significantly elevated frequencies of disomy although these findings are not universal. The total disomy in FISH studies is 2.26% and the estimated aneuploidy (2× disomy) is 4.5%, more than double that seen in sperm karyotypes (1.8%). Increased disomy levels of low orders of magnitude have been reported in spermatozoa of some normal men (stable variants) and in men who have fathered children with Down, Turner and Klinefelter syndromes. These findings suggest that men with a moderately elevated aneuploidy rate may be at a higher risk of fathering paternally derived aneuploid pregnancies. Among lifestyle factors, smoking, alcohol and caffeine have been studied extensively but the compounding effects of the 3 are difficult to separate because they are common lifestyle behaviors. Increases in sex chromosome abnormalities, some autosomal disomies, and in the number of diploid spermatozoa are general features in 47,XXY and 47,XYY males. Aneuploidy of the sex chromosomes is more frequent than aneuploidy of any of the autosomes not only in normal control individuals, but also in patients with sex chromosome abnormalities and fathers of paternally derived Klinefelter, Turner and Down syndromes.     

Analysis of aneuploidy for chromosomes 13, 21, X and Y by multicolour fluorescence in situ hybridisation (FISH) in a 47,XYY male.

The frequency of aneuploid sperm was assessed by fluorescence in situ hybridisation (FISH) in a 47,XYY male previously studied by sperm karyotyping. A total of 20,021 sperm were studied: 10,017 by two-colour FISH for chromosomes 13 and 21 and 10,002 by three-colour FISH for the sex chromosomes using chromosome 1 as an autosomal control for diploidy and lack of hybridisation. Results were compared with more than 500,000 sperm from 18 normal men. The frequencies of X-bearing (49.4%) and Y-bearing sperm (49.8%) were not significantly different from 50% as shown in our sperm karyotyping study. There was no significant increase in the frequency of diploid sperm compared with control donors. There was a significant increase in the frequency of disomy for chromosome 13 (p < 0.0001) and XY disomy (p = 0.0008) compared with control donors. However, since the frequency of disomy was 0.40% for chromosome 13 and 0.55% for XY disomy, it is not surprising that these increases were not discovered previously in our analysis of 75 sperm karyotypes. Our results suggest that the extra Y chromosome is eliminated during spermatogenesis in the majority of cells but that there may be a small but significant increase in the frequency of aneuploid sperm in these men.     

Meiotic behaviour of sex chromosomes investigated by three-colour FISH on 35 142 sperm nuclei from two 47,XYY males

Meiotic segregation of sex chromosomes from two fertile 47,XYY men was analysed by a three-colour fluorescence in situ hybridisation procedure. This method allows the identification of hyperhaploidies (spermatozoa with 24 chromosomes) and diploidies (spermatozoa with 46 chromosomes), and their meiotic origin (meiosis I or II). Alpha-satellite probes specific for chromosomes X, Y and 1 were observed simultaneously in 35 142 sperm nuclei. For both 47,XYY men (24 315 sperm nuclei analysed from one male and 10 827 from the other one) the sex ratio differs from the expected 1:1 ratio (P < 0.001). The rates of disomic Y, diploid YY and diploid XY spermatozoa were increased for both 47,XYY men compared with control sperm (142 050 sperm nuclei analysed from five control men), whereas the rates of hyperhaploidy XY, disomy X and disomy 1 were not significantly different from those of control sperm. These results support the hypothesis that the extra Y chromosome is lost before meiosis with a proliferative advantage of the resulting 46,XY germ cells. Our observations also suggest that a few primary spermatocytes with two Y chromosomes are able to progress through meiosis and to produce Y-bearing sperm cells. A theoretical pairing of the three gonosomes in primary spermatocytes with an extra sex chromosome, compatible with active spermatogenesis, is proposed. Received: 12 April 1996 / Revised: 26 August 1996     

Fertile male mice with three sex chromosomes: Evidence that infertility in XYY male mice is an effect of two Y chromosomes

In the mouse XYY males are sterile, presumably because pairing abnormalities resulting from the presence of three sex chromosomes lead to meiotic breakdown. We have produced male mice, designated XYY^*X, that have three sex chromosome pairing regions but only one intact Y chromosome. Unexpectedly XYY^*X males are fertile, although they are no more efficient in sex chromosome pairing than previously reported XYY males. We conclude that the sterility of XYY males is caused by a combination of the deleterious effect of two Y chromosomes, presumably acting prior to meiosis, and pairing abnormalities resulting in significant meiotic disruption.by P.B. Moens     

Taurodontism and the presence of an extra Y chromosome: study of 47,XYY males and analytical review

A sample of 47,XYY males was examined for taurodontism to provide further information on the effects of chromosome aneuploidies on the trait. The etiology of taurodontism is reviewed in light of recent findings. Two models have been put forward to explain the association of taurodontism with chromosome abnormalities: (1) Taurodontism results from a generalized disruption of developmental homeostasis, and (2) the development of taurodontism reflects a more specific action of the genes. The recent findings in 45,X females indicate that this chromosome aneuploidy does not have any effect on the development of taurodontism, in contrast to the findings of increased frequency of the trait in individuals with extra X chromosomes. The present results in 47,XYY males suggest that the presence of an extra Y chromosome does not cause an increase in the expression of taurodontism. It is concluded that the observed variation in the occurrence of taurodontism in individuals with sex chromosomes aneuploidies does not corroborate the hypothesis of disrupted homeostasis. Instead, the findings indicate that more specific action of gene(s) on the X chromosome is involved. We suggest that the effect of the Y chromosome on growth of both enamel and dentin, possibly in a regulative way, could be involved in the balanced growth of dental structures in 47,XYY males.     

Y-chromosome disomy and trisomy in scarabaeid and cerambycid beetles

In a series of about 500 specimens, including 420 males, of karyotyped Polyphaga beetles, 5 males with chromosome Y aneuploidy were detected. One male of each Dicronorrhina derbyana oberthuri (Scarabaeidae), Agapanthia violacea and Morimus funereus (Cerambycidae) were XYY, and 2 probably related and sterile males of Marmylida marginella (Scarabaeidae) were XYYY. These and literature data suggest that Y chromosome aneuploidies are much more frequent in polyphagan beetles than any other group of animals with an XY/XX sex determinism. The origin of this particularity probably lies in the unique mode of sex chromosome association at meiosis I: it is not synaptic but realized through nucleolar proteins forming the well-known parachute-like structure (Xy(p)). This has 2 possible consequences. The first one is the regular association of several sex chromosomes at metaphase I and segregation at anaphase I. It allows, for instance, XYY (Xyy(p)) males to procreate XYY sons. The second consequence is the occasional remain of nucleolar proteins embedding sex chromosomes in spermatocytes II. We propose that it could impede the correct segregation of Y chromatids after centromere split at anaphase II, and contribute to form YY gametes by XY males and YYY gametes by XYY males. The tendency for increasing the number of Ys would not be strongly limited at the XY level, but only at the XYY level by male infertility at higher Y ploidies.     

Increased incidence of disomic sperm nuclei in a 47,XYY male assessed by fluorescent in situ hybridization (FISH)

Using triple-colour fluorescent in situ hybridization in decondensed sperm heads, we assessed the sex-chromosome distribution in spermatozoa from a 47,XYY male compared with controls. The incidence of spermatozoa with 24,XY (0.30%) and 24,YY (1.01%) disomy was significantly higher than in our control series. Diploid meiocytes present in the ejaculate were mainly 47,XYY (60.6–86.7%), and haploid meiocytes were mainly 24,XY (78.1%).These results suggest that, although the extra Y chromosome is thought to be eliminated during spermatogenesis, XYY germ cells can complete meiosis and produce disomic spermatozoa. Received: 5 August 1996 / Revised: 2 October 1996     

A comparison of the frequency of sperm chromosome abnormalities in men with mild,moderate, and severe oligozoospermia

Infertile men undergoing intracytoplasmic sperm injection have an increased frequency of chromosome abnormalities in their sperm. Men with low sperm concentration (oligozoospermia) have an increased risk of sperm chromosome abnormalities. This study was initiated to determine whether men with severe oligozoospermia (<10(6) sperm/ml) have a higher frequency of chromosome abnormalities in their sperm compared with men with moderate (1-9 x 10(6) sperm/ml) or mild (10-19 x 10(6) sperm/ml) oligozoospermia. Multicolor fluorescence in situ hybridization analysis was performed using DNA probes specific for chromosomes 13, 21, X, and Y (with chromosome 1 as an autosomal control for the sex chromosomes). Aneuploidy and disomy frequencies were assessed from a total of 603,011 sperm from 30 men: 10 in each of the categories. The mean frequencies of disomy for the patients with mild, moderate, and severe oligozoospermia were 0.17%, 0.24%, and 0.30%, respectively, for chromosome 13 and 0.22%, 0.44%, and 0.58%, respectively, for chromosome 21. For the sex chromosomes, the mean frequencies of disomy for mild, moderate, and severe oligozoospermia were 0.25%, 1.04%, and 0.68%, respectively, for XY, 0.047%, 0.08%, and 0.10%, respectively, for XX, and 0.04%, 0.06%, and 0.09%, respectively, for YY. The frequencies for diploidy also increased from 0.4% for mild to 1.20% for moderate to 1.24% for severe oligozoospermia. There was a significant inverse correlation between the frequency of sperm chromosome abnormalities and the sperm concentration for XY, XX, and YY disomy and diploidy. These results demonstrate that men with severe oligozoospermia have an elevated risk for chromosome abnormalities in their sperm, particularly sex chromosome abnormalities.     

Incidence of 47,XYY males: Implications of the production of 47,XYY offspring by 47,XYY males

Abstract

Chromosomally normal 46,XY males can have 47,XYY male offspring as a result of fertilization of a normal ovum by a YY spermatozoon, produced by nondisjunction in the second meiotic division or by mitotic nondisjunction of the Y chromosome in early stages of embryonic development of a 46,XY fetus. If such meiotic and mitotic nondisjunctions were random events and if these were the only source of 47,XYY males in the population, the incidence of 47,XYY males would remain constant. Two cases have been reported, however, in which 47,XYY males produced 47,XYY male offspring. If there are 47,XYY males who are a source of 47,XYY males in the population, there is the possibility that the incidence of 47,XYY males is changing. A discrete‐generation model is presented which describes (1) the change in incidence of 47,XYY males from one generation to the next; (2) the incidence at equilibrium; and (3) the incidence as a function of the probability that a 47.XYY male has a 47,XYY offspring, and as a function of the mean number of offspring of 47,XYY males relative to the mean number of offspring of 46,XY males.     

Analysis of sperm chromosome complements from a man heterozygous for a pericentric inversion of chromosome 1

Human sperm chromosomes were studied in a man heterozygous for a pericentric inversion of chromosome (1)(p31q12). Q-banded pronuclear chromosomes were analyzed after in vitro penetration of golden hamster oocytes. A total of 159 sperm were examined: 54% bearing the inverted chromosome 1 and 46% the normal chromosome 1. These frequencies are not significantly different from the theoretical 11 ratio. There were no recombinant sperm with duplications or deficiencies, suggesting that a pairing loop failed to form or that crossing-over was suppressed. The frequency of abnormalities unrelated to the inversion was 5% for numerical, 8.8% for structural, 2.5% for numerical and structural, values not significantly different from control donors studied in our lab. The frequencies of X- and Y-bearing sperm were 46% and 54%, respectively, not significantly different from the expected value of 50%. This is the fifth pericentric inversion studied by human sperm chromosome analysis; recombinant chromosomes have been observed in two of the five cases. Some of the factors associated with an increased risk of recombinant sperm appear to be inversion size greater than 30% of the chromosome and chromosome breakpoints in G-light bands.     

Effects of the Y chromosome on quantitative growth: an anthropometric study of 47,XYY males

The aim of the study was to investigate the effects of the Y chromosome on different body and head dimensions of 47,XYY males, and especially its effect on their body proportions. From seven adult 47,XYY males 25 anthropometric measurements were recorded and compared with four male relatives and 42 control males. In most dimensions 47,XYY males were larger than the normal males, the difference being mainly between 0.5 and 1.5 S.D. units. The body proportions of 47,XYY males were found to be similar to those of the normal males when the effect of size was allowed for. It is concluded that the extra Y chromosome in 47,XYY males causes an increase in their growth without affecting the body proportions. This finding suggests that the Y chromosome contains gene(s) which affects growth by increasing its quantitative outcome. This effect may be mediated by a direct action of the Y chromosome on the cells. It also may seem that the Y chromosomal gene(s) influence the development of the sex difference in height and body size.     

The 47,XYY male, Y chromosome, and tooth size.

Permanent teeth of 12 individuals with a 47,XYY chromosome constitution have been examined. The tooth sizes of 47,XYY males were found to be larger than those of control males and females. In many instances the differences were statistically significant. Using these results, it was possible to conclude that a factor or factors which influence excess growth of 47,XYY males probably are in effect during prenatal life, but without doubt must be in effect very early in postnatal life. The time period needed for the achievement of final excess growth is relatively short, in the case of first permanent molars probably only from 2 1/2 to 3 1/2 years. On the basis of the finding that the Y chromosome apparently carries genes affecting tooth sizes in normal males [1], it was suggested that gene products of the extra Y chromosome could cause the observed size difference between normal and 47,XYY males. The nature of the influence of one versus two Y chromosomes on growth was discussed in terms of the possible influence of the Y chromosome on the cell divisions within the developing tooth germ.     

Incidence of major chromosome aberrations in 12,319 newborn infants in Tokyo

Summary In order to ascertain the frequency of chromosome aberrations among newborn infants in Japan, a chromosome survey of a large number of newborn infants is in progress. A consecutive series of 12,319 newborn babies, 6382 male and 5937 female, have been screened for clinical manifestations of autosomal aberrations and for sex chromatin and sex chromosome aberrations. Chromosome studies were carried out on 694 infants with suspected chromosome aberrations. The clinically abnormal infants were screened by conventional staining, and banding techniques have been used in the part of the study performed since 1974. Of the clincally abnormal infants, 25 had abnormal karyotypes, including two males with a 47,XXY complement, one female with a 45,X complement, three male infants with a 47,XYY complement, two with trisomy 13 syndrome, three with trisomy 18 (including one case of mosaicism), eleven with Down's syndrome (including one case of mosaicism), one with B5p partial trisomy, one with cri-du-chat syndrome, and one with Y/D translocation. The overall results are comparable to those of previous population cytogenetic studies only in the autosomal trisomies and sex chromosome abnormalities and in that the observed frequencies were comparable to those found in studies in Caucasians.To whom offprint requests should be sent     

Sex chromosome configurations in pachytene spermatocytes of an XYY mouse

Karyotypic investigation of a phenotypically normal but sterile male mouse showed the presence of an XYY sex chromosome constitution. The synaptic behaviour of the three sex chromosomes was examined in 65 pachytene cells. The sex chromosomes formed a variety of synaptic configurations: an XYY trivalent (40%); an XY bivalent and Y univalent (38.5%); an X univalent and YY bivalent (13.8%); or X, Y, Y univalence (7.7%). There was considerable variation in the extent of synapsis and some of the associations clearly involved nonhomologous pairing. These observations have been compared with previously published information on chromosome configurations at metaphase I from other XYY males.     

Spermatogenesis in an infertile XYY man

Summary Testicular histology and meiosis has been studied in an XYY male patient identified at an infertility clinic. This man was found to have an XYY sex chromosome complement in 15% of spermatogonial metaphases. There was no clear evidence of 2 Y chromosomes at diakinesis but there appeared to be a slight excess of sperm with a fluorescent Y body.     

Sequence analysis of long FMR1 arrays in the Japanese population: insights into the generation of long (CGG) n tracts

Sperm chromosome abnormalities were assessed in testicular cancer patients before and after treatment with BEP (bleomycin, etoposide, cisplatin). The frequencies of disomy for chromosomes 1, 12, X, Y and XY were assessed along with diploid frequencies and sex ratios by multicolour fluorescence in situ hybridization (FISH). For each cancer patient, a minimum of 10 000 sperm was assessed for each chromosome probe before and after chemotherapy (CT). Data was analysed “blindly” by coding the slides. A total of 161 097 sperm were analyzed, 80 445 before and 80 642 after treatment. The mean disomy frequencies were 0.11% pre-CT vs 0.06% post-CT for chromosome 1, 0.18% vs 0.15% for chromosome 12, 0.10% vs 0.9% for the X chromosome, 0.13% vs 0.10% for the Y chromosome and 0.25% vs 0.20% for XY sperm. There was no significant difference in the frequency of disomy pre-CT vs post-CT for any chromosome except that chromosome 1 demonstrated a significant decrease after CT. The “sex ratios” and frequency of diploid sperm were also not significantly different in pre- and post-CT samples with 50.2% X-bearing sperm pre-CT and 50.5% X post-CT and 0.14% diploid sperm pre-CT vs 0.15% diploid sperm post-CT. There was no significant donor heterogeneity among the cancer patients. None of the values in the cancer patients differed significantly from 10 normal control donors. Thus our study suggests that BEP chemotherapy does not increase the risk of numerical chromosomal abnormalities in human sperm. Received: 11 June 1996 / Revised: 8 August 1996     

Chromosome studies in a neonatal population

The results of chromosome studies on 6809 consecutive newborn infants are presented. One hundred and one (1.48%) were heterozygous for a marker chromosome, the significance of which is not at present clear. Twenty-two infants (0.32%) had a major chromosome abnormality. Only six of these infants (0.09%) had a clinically recognizable abnormal phenotype (Down''s syndrome). The occult chromosome abnormalities included five sex chromosome abnormalities (one 47,XYY; two 47,XXY; two 47,XXX) and 11 balanced translocations. Seven of these were t(DqDq) and four were reciprocal translocations. The results of the present survey are combined with four other similar neonatal surveys in which a total of 23,328 newborns have been screened. Of these, 117 (0.5%; range 0.65-0.32%) had major chromosome abnormalities. The majority of these (72.7%) would not have been detected at birth without chromosome studies, an important fact in the context of prenatal diagnosis of chromosome disease and the early ascertainment of high-risk families.     

Analysis of the chromosome complement in outbred mouse sperm fertilizing in vitro

The chromosome complements in a population of mouse sperm from random-bred ICR donors were analyzed at first-cleavage metaphase after in vitro fertilization (IVF) of oocytes from females of the same strain. The sperm were aged as donations occurred within an average of 31 days, either since last mating or at arrival at the animal facility in the case of virgin males. Of a total of 598 sperm complements studied from 22 sexually mature males aged 10–26 weeks old, there was one diploid complement (0.17%). The frequencies of hyperhaploidy and structural aberrations that were studied in 338 complements were 4.4% and 3.6%, respectively, giving an overall frequency of 8.0%. The hyperhaploid complements consisted of n + 1, n + 2, n + 3, and n + 7 counts, while the structural abnormalities were of the chromosome type and included large and small fragments and a possible translocation. This is the highest frequency of sperm chromosome abnormalities reported for mouse sperm obtained from males under physiological conditions and fertilized in vitro or in vivo. Sperm aging, strain, and/or technique differences are among the factors that may be responsible for this high frequency. Since the 8.0% frequency of hyperhaploidy and structural abnormalities is similar to the frequency reported for human sperm after IVF, the outbred murine in vitro fertilization system may be a useful model to study the origin of human sperm chromosome abnormalities.