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.     

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.     

Rapid detection of sex chromosomal aneuploidies by QF-PCR: application in 200 men with severe oligozoospermia or azoospermia

Klinefelter syndrome is the most common genetic cause of severe male factor infertility. Cytogenetic evaluation of metaphase chromosomes generally has a long turnaround time. We describe a reliable molecular genetic method that can be completed in 2 working days to identify the presence of any extra X chromosomes. The quantitative fluorescent (QF) 5-plex PCR includes the amplification of amelogenin, which is present on both sex chromosomes in a biallelic form, a polymorphic short tandem repeat (STR) on the pseudoautosomal region of X and Y (X22), two polymorphic X-specific STRs (DXS6803, DXS6809), and a Y-specific marker (SY134), in a single tube. The presence of an extra X chromosome is recognized either by a supernumerary peak or an increased peak area based on criteria we have developed. The application of the method on 200 patients resulted in the identification of 14 patients (7%) with Klinefelter syndrome or a variant form (2 SRY-positive 46,XX men), as well as an additional patient with 47,XYY karyotype. The QF-PCR method, along with Y chromosome microdeletion testing, can be used as a first-step genetic analysis in azoospermic or severely oligozoospermic patients for the rapid identification of sex chromosome aneuploidies.     

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.     

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.     

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.     

The tricky path to recombining X and Y chromosomes in meiosis

Sex chromosomes are the Achilles' heel of male meiosis in mammals. Mis-segregation of the X and Y chromosomes leads to sex chromosome aneuploidies, with clinical outcomes such as infertility and Klinefelter syndrome. Successful meiotic divisions require that all chromosomes find their homologous partner and achieve recombination and pairing. Sex chromosomes in males of many species have only a small region of homology (the pseudoautosomal region, PAR) that enables pairing. Until recently, little was known about the dynamics of recombination and pairing within mammalian X and Y PARs. Here, we review our recent findings on PAR behavior in mouse meiosis. We uncovered unexpected differences between autosomal chromosomes and the X-Y chromosome pair, namely that PAR recombination and pairing occurs later, and is under different genetic control. These findings imply that spermatocytes have evolved distinct strategies that ensure successful X-Y recombination and chromosome segregation.     

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     

Correlation between the number of sex chromosomes and the H-Y antigen titer

Summary H-Y antigen was studied serologically on blood cells and cultured fibroblasts of patients with numerical aberrations of the sex chromosomes. As compared with normal males, patients with the karyotypes 48,XXXY and 49,XXXXY have reduced H-Y antigen titrs; a tendency toward reduced titers can also be detected in the 47,XXY Klinefelter syndrome. The existence of an intermediary titer was further substantiated by a quantitative absorption test applied to cells with the 49,XXXXY karyotype. It appears that in the presence of one Y chromosome, the H-Y antigen titer decreases with an increasing number of X chromosomes. In contrast, the H-Y antigen titer is increased if, at a given number of X chromosomes, the number of Y chromosomes is increased, as in the 47,XYY male. Consequently, patients with 48,XXYY chromosomes are in the male control range. The findings are interpreted under the hypothesis of a controlling or modifying influence of the sex chromosomes on the titer of H-Y antigen.     

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.     

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.     

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 .     

The XXYY Variant of Klinefelter's Syndrome

Three males with an XXYY sex chromosome complex are described. These patients, together with five XXYY subjects recorded in the literature, show the clinical features of Klinefelter''s syndrome. Taking into consideration the findings in XYY and XXXYY individuals, it appears that the addition of a Y chromosome to XY, XXY and XXXY complexes has a variable and as yet not clearly delineated harmful effect. For example, a 44 + XXYY complement of chromosomes may prove to have significant manifestations in skeletal maturation and predispose to vascular and cutaneous abnormalities of the lower extremities in older patients. But when two Y chromosomes are present, the phenotype does not differ markedly from that resulting from the presence of a single Y chromosome in the sex chromosome complex. This finding is compatible with the view that the Y chromosome of man is relatively inert, compared with the autosomes, except for genes that function in male sex determination.     

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.     

47,XXX females,sex chromosomes,and tooth crown structure

Summary Enamel thickness of the maxillary permanent central incisors and canines in seven Finnish 47,XXX females, their first-degree male and female relatives, and control males and females from the general population were determined from radiographs. The results showed that enamel in the teeth of 47,XXX females was clearly thicker than that of normal controls. On the other hand, the thickness of dentin (distance between mesial and distal dentinoenamel junctions) in 47,XXX females' teeth was about the same as that in normal control females, but clearly reduced as compared with that in control males. It is therefore obvious that in the triple-X chromosome complement the extra X chromosome is active in amelogenesis, whereas it has practically no influence on the growth of dentin. The calculations based on present and previous results in 45,X females and 47,XYY males indicate that the X chromosome increases metric enamel growth somewhat more effectively than the Y chromosome. Possibly, halfway states exist between active and repressed enamel genes on the X chromosome. The Y chromosome seems to promote dental growth in a holistic fashion.     

The Origin of the Achiasmatic XY Sex Chromosome System in Cacopsylla peregrina (Frst.) (Psylloidea, Homoptera)

The status of an extra univalent, if it is a B chromosome or an achiasmatic Y chromosome, associating with the X chromosome in male meiosis of Cacopsylla peregrina (Frst.) (Homoptera, Psylloidea) was analysed. One extra univalent was present in all males collected from three geographically well separated populations, it was mitotically stable, and showed precise segregation from the X chromosome. These findings led us to propose that the univalent represents in fact a Y chromosome. The behaviour of the X and Y chromosomes during meiotic prophase suggested that their regular segregation was based on an achiasmatic segregation mechanism characterised by a 'touch and go' pairing of segregating chromosomes at metaphase I. To explain the formation of the achiasmatic Y within an insect group with X0 sex chromosome system, it was suggested that the Y chromosome has evolved from a mitotically stable B chromosome that was first integrated into an achiasmatic segregation system with the X chromosome, and has later become fixed in the karyotype as a Y chromosome.     

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.     

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     

Chromosomal mosaicism on amniotic interphase nuclei detected by multiprobe FISH

So far classical prenatal detection of chromosome aberrations has been limited to the evaluation of metaphase by means of time-consuming cytogenetic techniques. The MultiVision PGT test enables a simultaneous detection of aneuploidies of chromosomes 13,18, 21, X, and Y, even 24 h after amniocentesis. In the presented case, this test detected prenatally a chromosomal mosaicism 69,XYY[35]/46,XY[65]. This result was not confirmed after birth, by the same test on blood smear. The discrepancy is difficult to explain.