XYY spermatogenesis in XO/XY/XYY mosaic mice

The relative frequencies of XYY and XY cells in XO/XY/XYY mosaic mice were compared between somatic cells (bone marrow) and spermatogonia, and between spermatogonia and pachytene or MI spermatocytes. The results indicated there was no selection either for or against XYY spermatogonia. There was, however, a strong selection against XYY spermatocytes during pachytene, with their almost total elimination by the first meiotic metaphase. At pachytene, most XYY cells had trivalent or X univalent/YY bivalent configurations. These findings are contrasted with previous studies of XYY spermatogenesis in mice and are discussed with respect to a model that invokes sex-chromosome univalence as the cause of XYY spermatogenic failure.     

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.     

Evidence that sex chromosome asynapsis, rather than excess Y gene dosage, is responsible for the meiotic impairment of XYY mice

There is extensive evidence for the existence of a meiotic checkpoint that acts to eliminate spermatocytes that fail to achieve full sex chromosome synapsis at the pachytene stage of the first meiotic prophase. XYY mice are nearly always sterile, with clear signs of meiotic impairment, and sex chromosome asynapsis has been proposed to underlie this impairment. However, a study of XYY*(X) mice (mice having three sex chromosomes but only a single dose of Y genes) revealed that these mice are fertile, and thus implicated Y gene dosage as a major factor in the sterility of XYY mice. To address this question further, sex chromosome synapsis and spermatogenic proficiency were compared between XYY*(X) and XYY mice generated in the same litters. This established that differences in spermatogenic proficiency within and between the two genotypes correlated with the frequency of radial trivalent formation (full sex chromosome synapsis); XYY*(X) males, as a group, had double the radial trivalent frequency of XYY males. This observation provides strong support for the view that sex chromosome asynapsis (or some consequence thereof), rather than Y gene dosage, is the major factor leading to the meiotic impairment of XYY mice.     

Behavioral phenotypes in males with XYY and possible role of increased NLGN4Y expression in autism features

The male sex chromosome disorder, 47,XYY syndrome (XYY), is associated with increased risk for social‐emotional difficulties, attention‐deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). We hypothesize that increased Y chromosome gene copy number in XYY leads to overexpression of Y‐linked genes related to brain development and function, thereby increasing risk for these phenotypes. We measured expression in blood of two Y genes NLGN4Y and RPS4Y in 26 boys with XYY and 11 male controls and evaluated whether NLGN4Y expression correlates with anxiety, ADHD, depression and autistic behaviors (from questionnaires) in boys with XYY. The XYY cohort had increased risk of ASD behaviors on the social responsiveness scale (SRS) and increased attention deficits on the Conners' DSM‐IV inattention and hyperactive scales. In contrast, there was no increase in reported symptoms of anxiety or depression by the XYY group. Peripheral expression of two Y genes in boys with XYY vs. typically developing controls was increased twofold in the XYY group. Results from the SRS total and autistic mannerisms scales, but not from the attention, anxiety or depression measures, correlated with peripheral expression of NLGN4Y in boys with XYY. Males with XYY have social phenotypes that include increased risk for autism‐related behaviors and ADHD. Expression of NLGN4Y, a gene that may be involved in synaptic function, is increased in boys with XYY, and the level of expression correlates with overall social responsiveness and autism symptoms. Thus, further investigation of NLGN4Y as a plausible ASD risk gene in XYY is warranted.     

Sizes of deciduous teeth in 47,XYY males.

Deciduous teeth of six 47,XYY males have been examined, and the tooth sizes were found to be larger than those of controls. We concluded that a factor or factors which influence excess dental growth in 47,XYY males are probably in effect before the age of a few months. The time needed for the achievement of final tooth growth excess seems to be limited to a 9--18 month period. It also became evident that excess dental growth of 47,XYY individuals is a developmentally stable process, and the Y chromosome apparently regulates quantitative variation of the teeth in normal males [2]. These observations on tooth sizes in 47,XYY males suggest a chromosomal influence on dental determination.     

Sperm chromosome complements in a 47,XYY man

Summary Human sperm chromosomes from a 47,XYY male were examined using the direct method of sperm chromosome analysis with two modifications in the semen processing. A total of 75 sperm complements was karyotyped and all of these contained one sex chromosome. The percentages of X-and Y-bearing sperm were 53% and 47%, respectively. There were 10 sperm with autosomal chromosomal abnormalities. The frequencies of numerical (4.0%), structural (10.6%), and total (13.3%) abnormalities were not significantly different from the frequencies observed in normal donors in our laboratory. Our results do not support the suggestion that XYY males have an increased risk of aneuploid progeny as a result of secondary non-disjunction or interchromosomal effects. They do support the hypothesis that one Y chromosome is eliminated in the germ cells of XYY males. However since our study provides the first information on sperm chromosomes in an XYY male, further studies on other XYY men are required.     

Cardiac functioning and blood pressure of 47,XYY and 47,XXY men in a double-blind, double-matched population survey.

This paper reports the electrocardiogram measures and blood pressure of 12 men with 47,XYY, 14 men with 47,XXY, and 52 matched controls with 46,XY. The abnormal karyotypes were identified in a systematic population search for XYY and XXY men. The subjects and their matched controls were examined in a double-blind fashion. Electrocardiogram measures of 47,XYY and 47,XXY men were found to differ from those of 46,XY controls. The XYYs had longer P-R intervals, shorter QRS complexes, and nonsignificantly longer R-R intervals than their matched controls. The XXYs showed longer R-R intervals and trends for for prolonged P-R intervals and shorter QRS complexes when compared with their controls. Trends toward increased within-group variability in the XYY and XXY groups were observed in five of six variance tests, suggesting that the sex chromosome aneuploids have a cardiac condition anomaly. Blood pressure measures of 47,XYY and 47,XXY men were found not to differ from those of 46,XY men. None of the measures revealed a significant difference between the XYYs and the XXYs.     

The XYY condition in a wild mammal: an XY/XYY mosaic common shrew (Sorex araneus)

XY/XYY sex-chromosome mosaicism was demonstrated in both bone marrow and germ cells of a wild adult common shrew. Secondary sexual characteristics were those of a normal male, but the testes were small, and the sperm count was only about 3% of normal. Most of the seminiferous tubule cross-sections examined revealed serious spermatogenic impairment and a reduced diameter. A range of sex-chromosome pairing configurations was observed in XYY primary spermatocytes, including configurations involving the X and both Y chromosomes in a linear or radial array. The presence of metaphase II (MII) spreads with an XY sex-chromosome complement indicated that XYY primary spermatocytes could contribute products to MII. Following Burgoyne (1979) and Burgoyne and Biddle (1980), a number of models of spermatocyte loss were tested. The data indicated that there was an association between the sex-chromosome complement of primary spermatocytes and their contribution to MII. The best fit to the observed MII frequency data was provided by a model which assumed that all XYY primary spermatocytes with a univalent Y chromosome and a high proportion of XYY primary spermatocytes with an unpaired X chromosome failed to contribute products to MII.     

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.     

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.     

Brain morphology in children with 47,XYY syndrome: a voxel‐ and surface‐based morphometric study

The neurocognitive and behavioral profile of individuals with 47,XYY is increasingly documented; however, very little is known about the effect of a supernumerary Y‐chromosome on brain development. Establishing the neural phenotype associated with 47,XYY may prove valuable in clarifying the role of Y‐chromosome gene dosage effects, a potential factor in several neuropsychiatric disorders that show a prevalence bias toward males, including autism spectrum disorders. Here, we investigated brain structure in 10 young boys with 47,XYY and 10 age‐matched healthy controls by combining voxel‐based morphometry (VBM) and surface‐based morphometry (SBM). The VBM results show the existence of altered gray matter volume (GMV) in the insular and parietal regions of 47,XYY relative to controls, changes that were paralleled by extensive modifications in white matter (WM) bilaterally in the frontal and superior parietal lobes. The SBM analyses corroborated these findings and revealed the presence of abnormal surface area and cortical thinning in regions with abnormal GMV and WMV. Overall, these preliminary results demonstrate a significant impact of a supernumerary Y‐chromosome on brain development, provide a neural basis for the motor, speech and behavior regulation difficulties associated with 47,XYY and may relate to sexual dimorphism in these areas .     

Dermatoglyphics of the XYY Syndrome

The presence of an extra Y chromosome in Man results in a condition termed the XYY Syndrome. Such individuals are tall, exhibit aggressive behavior, and may be mentally retarded. XYY patients are usually discovered after they have committed a crime. Even though relatively few XYY patients have been recorded so far in the literature the incidence of this condition in US males has been estimated at 1 in 300. Thus the majority of XYY's lead normal lives, directing their excess aggression into legal channels. For those who do not do so, the earlier corrective educational therapy is constituted the better the result. Since dermatoglyphics are affected by chromosomal aberrations there is a need to examine the dermatoglyphics of XYY patients in order to establish specific dermatoglyphic features that can be used for diagnosis at birth.     

Testosterone production by XYY subjects.

A study of plasma concentration (P1T, ng/ml), metabolic clearance rate (MCRT, L/day) and blood production rate (PBT, mg/day) was done on seven XYY subjects of various ages and four pair-matched control XY subjects by a radioinfusion technique of 1,2-3H-testosterone. Although MCRT showed no significant difference between the groups, P1T and PBT were significantly lower (P less than 0.05) in XYY subjects. Therefore, increased aggressive behavior of the XYY subjects can not be attributed to increased levels or production rates of testosterone.     

Prader-Willi syndrome and polygonosomal abnormalities in males:about a Prader-Willi/47,XYY patient

We herein report a male patient known as having a XYY karyotype. At the age of 26 years a Prader-Willi syndrome (PWS) was diagnosed. Before that time the whole symptomatology was ascribed to the XYY syndrome. This is the first reported association of PWS and polygonosomal abnormality in a male adult (whose height is above average).     

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.     

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     

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