Patterns of psychopathology and cognition in sex chromosome aneuploidy

Abstract Background Sex chromosome aneuploidies (SCAs) are a collectively common family of genetic disorders that increase the risk for neuropsychiatric and cognitive impairment. Beyond being important medical disorders in their own right, SCAs also offer a unique naturally occurring model for studying X- and Y-chromosome influences on the human brain. However, it remains unclear if (i) different SCAs are associated with different profiles of psychopathology and (ii) the notable interindividual variation in psychopathology is related to co-occurring variation in cognitive ability. Methods We examined scores for 11 dimensions of psychopathology [Child/Adult Behavior Checklist (CBCL)] and general cognitive ability [full-scale IQ (FSIQ) from Wechsler tests] in 110 youth with varying SCAs (XXY = 41, XYY = 22, XXX = 27, XXYY = 20) and 131 typically developing controls (XX = 59, XY = 72). Results All SCAs were associated with elevated CBCL scores across several dimensions of psychopathology (two-sample t tests comparing the euploidic and aneuploidic groups [all |T| > 9, and p < 0.001]). Social and attentional functioning were particularly sensitive to the carriage of a supernumerary Y-chromosome. In particular, the XYY group evidenced significantly more social problems than both extra-X groups (Cohen’s d effect size > 0.5, Bonferroni corrected p < .05). There was marked variability in CBCL scores within each SCA group, which generally correlated negatively with IQ, but most strongly so for social and attentional difficulties (standardized β, − 0.3). These correlations showed subtle differences as a function of the SCA group and CBCL scale. Conclusions There is domain-specific variation in psychopathology across SCA groups and domain-specific correlation between psychopathology and IQ within SCAs. These findings (i) help to tailor clinical assessment of this common and impactful family of genetic disorders and (ii) suggest that dosage abnormalities of X- and Y-linked genes impart somewhat distinct profiles of neuropsychiatric risk.

Download Full-text

Patterns of Psychopathology and Cognition in Sex Chromosome Aneuploidy

10.21203/rs.3.rs-543874/v1 ◽

2021 ◽

Author(s):

Srishti Rau ◽

Ethan T. Whitman ◽

Kimberly Schauder ◽

Nikhita Gogate ◽

Nancy Raitano Lee ◽

...

Keyword(s):

Cognitive Ability ◽

Y Chromosome ◽

Sex Chromosome ◽

Genetic Disorders ◽

Interindividual Variation ◽

Domain Specific ◽

Medical Disorders ◽

Marked Variability ◽

Increase Risk ◽

Attentional Difficulties

Abstract Background Sex chromosome aneuploidies (SCAs) are a collectively common family of genetic disorders that increase risk for neuropsychiatric and cognitive impairment. Beyond being important medical disorders in their own right, SCAs also offer a unique naturally-occurring model for X- and Y-chromosome influences on the human brain. However, it remains unclear if (i) different SCAs are associated with different profiles of psychopathology, and (ii) the notable interindividual variation in psychopathology is related to co-occurring variation in cognitive ability. Methods We examined scores for 11 dimensions of psychopathology [Child/Adult Behavior Checklist (CBCL)] and general cognitive ability [full-scale IQ (FSIQ) from Wechsler tests] in 110 youth with varying SCAs (XXY = 41, XYY = 22, XXX = 27, XXYY = 20) and 131 typically developing controls (XX = 59, XY = 72). Results All SCAs were associated with elevated CBCL scores across several dimensions of psychopathology, but social and attentional functioning were particularly sensitive to carriage of a supernumerary Y-chromosome. There was marked variability in CBCL scores within each SCA group, which generally correlated negatively with IQ, but most strongly so for social and attentional difficulties. These correlations showed subtle differences as a function of SCA group and CBCL scale. Conclusions There is domain-specific variation in psychopathology across SCA groups, and domain-specific correlation between psychopathology and IQ within SCAs. These findings (i) help to tailor clinical assessment of this common and impactful family of genetic disorders, and (ii) suggest that dosage abnormalities of X- and Y-linked genes impart somewhat distinct profiles of neuropsychiatric risk.

Download Full-text

X and Y Chromosome Complement Influence Adiposity and Metabolism in Mice

Endocrinology ◽

10.1210/en.2012-2098 ◽

2013 ◽

Vol 154 (3) ◽

pp. 1092-1104 ◽

Cited By ~ 50

Author(s):

Xuqi Chen ◽

Rebecca McClusky ◽

Yuichiro Itoh ◽

Karen Reue ◽

Arthur P. Arnold

Keyword(s):

Body Weight ◽

Y Chromosome ◽

Sex Chromosomes ◽

Sex Chromosome ◽

Chromosome Complement ◽

Gonadal Hormones ◽

Xy Model ◽

Second Sex ◽

Metabolic Variables ◽

Novel Model

Abstract Three different models of MF1 strain mice were studied to measure the effects of gonadal secretions and sex chromosome type and number on body weight and composition, and on related metabolic variables such as glucose homeostasis, feeding, and activity. The 3 genetic models varied sex chromosome complement in different ways, as follows: 1) “four core genotypes” mice, comprising XX and XY gonadal males, and XX and XY gonadal females; 2) the XY* model comprising groups similar to XO, XX, XY, and XXY; and 3) a novel model comprising 6 groups having XO, XX, and XY chromosomes with either testes or ovaries. In gonadally intact mice, gonadal males were heavier than gonadal females, but sex chromosome complement also influenced weight. The male/female difference was abolished by adult gonadectomy, after which mice with 2 sex chromosomes (XX or XY) had greater body weight and percentage of body fat than mice with 1 X chromosome. A second sex chromosome of either type, X or Y, had similar effects, indicating that the 2 sex chromosomes each possess factors that influence body weight and composition in the MF1 genetic background. Sex chromosome complement also influenced metabolic variables such as food intake and glucose tolerance. The results reveal a role for the Y chromosome in metabolism independent of testes and gonadal hormones and point to a small number of X–Y gene pairs with similar coding sequences as candidates for causing these effects.

Download Full-text

Telomere-to-telomere assembly of a fish Y chromosome reveals the origin of a young sex chromosome pair

Genome Biology ◽

10.1186/s13059-021-02430-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Lingzhan Xue ◽

Yu Gao ◽

Meiying Wu ◽

Tian Tian ◽

Haiping Fan ◽

...

Keyword(s):

Y Chromosome ◽

Sex Chromosomes ◽

Chromosome Pair ◽

Sex Chromosome ◽

Structural Variations ◽

Recombination Suppression ◽

Chromosome Differentiation ◽

Y Chromosomes ◽

Recent Origin ◽

Mastacembelus Armatus

Abstract Background The origin of sex chromosomes requires the establishment of recombination suppression between the proto-sex chromosomes. In many fish species, the sex chromosome pair is homomorphic with a recent origin, providing species for studying how and why recombination suppression evolved in the initial stages of sex chromosome differentiation, but this requires accurate sequence assembly of the X and Y (or Z and W) chromosomes, which may be difficult if they are recently diverged. Results Here we produce a haplotype-resolved genome assembly of zig-zag eel (Mastacembelus armatus), an aquaculture fish, at the chromosomal scale. The diploid assembly is nearly gap-free, and in most chromosomes, we resolve the centromeric and subtelomeric heterochromatic sequences. In particular, the Y chromosome, including its highly repetitive short arm, has zero gaps. Using resequencing data, we identify a ~7 Mb fully sex-linked region (SLR), spanning the sex chromosome centromere and almost entirely embedded in the pericentromeric heterochromatin. The SLRs on the X and Y chromosomes are almost identical in sequence and gene content, but both are repetitive and heterochromatic, consistent with zero or low recombination. We further identify an HMG-domain containing gene HMGN6 in the SLR as a candidate sex-determining gene that is expressed at the onset of testis development. Conclusions Our study supports the idea that preexisting regions of low recombination, such as pericentromeric regions, can give rise to SLR in the absence of structural variations between the proto-sex chromosomes.

Download Full-text

Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sex chromosome encoded genes

10.1101/2021.05.21.445116 ◽

2021 ◽

Author(s):

Anna Köferle ◽

Andreas Schlattl ◽

Alexandra Hörmann ◽

Fiona Spreitzer ◽

Alexandra M. Popa ◽

...

Keyword(s):

Y Chromosome ◽

Therapeutic Strategy ◽

Sex Chromosome ◽

De Novo ◽

Chromosome Loss ◽

Potential Candidate ◽

Loss Of Function ◽

Male Patients ◽

Tumour Cell Lines ◽

Paralog Gene

Genetic networks are characterized by extensive buffering. During tumour evolution, disruption of these functional redundancies can create de novo vulnerabilities that are specific to cancer cells. In this regard, paralog genes are of particular interest, as the loss of one paralog gene can render tumour cells dependent on a remaining paralog. To systematically identify cancer-relevant paralog dependencies, we searched for candidate dependencies using CRISPR screens and publicly available loss-of-function datasets. Our analysis revealed >2,000 potential candidate dependencies, several of which were subsequently experimentally validated. We provide evidence that DNAJC15-DNAJC19, FAM50A-FAM50B and RPP25-RPP25L are novel cancer relevant paralog dependencies. Importantly, our analysis also revealed unexpected redundancies between sex chromosome genes. We show that chrX- and chrY- encoded paralogs, as exemplified by ZFX-ZFY, DDX3X-DDX3Y and EIF1AX-EIF1AY, are functionally linked so that tumour cell lines from male patients with Y-chromosome loss become exquisitely dependent on the chrX-encoded gene. We therefore propose genetic redundancies between chrX- and chrY- encoded paralogs as a general therapeutic strategy for human tumours that have lost the Y-chromosome.

Download Full-text

The evolution of the Y chromosome with X-Y recombination.

Genetics ◽

10.1093/genetics/119.3.711 ◽

1988 ◽

Vol 119 (3) ◽

pp. 711-720

Author(s):

A G Clark

Keyword(s):

Natural Selection ◽

Y Chromosome ◽

Meiotic Recombination ◽

Population Genetic ◽

Sex Chromosome ◽

Genetic Model ◽

Chromosome Polymorphism ◽

Significant Finding ◽

Special Cases ◽

Theoretical Population

Abstract A theoretical population genetic model is developed to explore the consequences of X-Y recombination in the evolution of sex chromosome polymorphism. The model incorporates one sex-determining locus and one locus subject to natural selection. Both loci have two alleles, and the rate of classical meiotic recombination between the loci is r. The alleles at the sex-determining locus specify whether the chromosome is X or Y, and the alleles at the selected locus are arbitrarily labeled A and a. Natural selection is modeled as a process of differential viabilities. The system can be expressed in terms of three recurrence equations, one for the frequency of A on the X-bearing gametes produced by females, one for each of the frequency of A on the X- and Y-bearing gametes produced by males. Several special cases are examined, including X chromosome dominance and symmetric selection. Unusual equilibria are found with the two sexes having very different allele frequencies at the selected locus. A significant finding is that the allowance of recombination results in a much greater opportunity for polymorphism of the Y chromosome. Tighter linkage results in a greater likelihood for equilibria with a large difference between the sex chromosomes in allele frequency.

Download Full-text

The detection of female cell activity in male sex chromosome chimeric Rideau Arcott sheep, using the Xist gene product as a marker

SURG Journal ◽

10.21083/surg.v1i2.414 ◽

2008 ◽

Vol 1 (2) ◽

pp. 20-25

Author(s):

Okimi Peters ◽

W. Allan King

Keyword(s):

Y Chromosome ◽

Sex Chromosome ◽

Cell Activity ◽

Xist Gene ◽

Specific Gene ◽

Xist Expression ◽

Female Cell ◽

Male Sex ◽

Polymerase Chain ◽

Xy Female

The detection of the SRY (Sex-determining region on the Y chromosome) gene is a popular method used for the identification of freemartins (XX/XY female chimeras). This method relies on the fact that the SRY gene is a Y chromosome specific gene and is thus normally only present in males therefore detecting its presence in a female indicates the presence of male cells (XY cells) within the female. This concept can be extrapolated to the male counterparts of freemartins with regards to the Xist gene. This gene is normally only widely expressed in females and can be used as a marker for identifying females. Therefore, detecting Xist gene expression in males (in tissues other than the testes, as the Xist gene is expressed exclusively in the testes of males) may indicate that these males contain transcriptionally competent female cells and thus necessarily labels them as sex-chromosome chimeras. In the present study four previously identified male sex chromosome chimeras were screened for the expression of the Xist gene using reverse transcription Polymerase Chain Reaction (PCR), and it was detected in three of the four chimeras. Xist expression was not detected in one of the chimeras because the proportion of female cells in its blood is significantly low and thus it is likely that the blood sample used in the study did not possess female cells. None-the-less it was concluded that the detection of Xist expression in male sex chromosome chimeras can be used as an indication of the presence and transcriptional competence of female cells within them.

Download Full-text

Meiotic Behavior of Achiasmate Sex Chromosomes in the African Pygmy Mouse Mus mattheyi Offers New Insights into the Evolution of Sex Chromosome Pairing and Segregation in Mammals

Genes ◽

10.3390/genes12091434 ◽

2021 ◽

Vol 12 (9) ◽

pp. 1434

Author(s):

Ana Gil-Fernández ◽

Marta Ribagorda ◽

Marta Martín-Ruiz ◽

Pablo López-Jiménez ◽

Tamara Laguna ◽

...

Keyword(s):

Dna Repair ◽

Y Chromosome ◽

Sex Chromosomes ◽

Sex Chromosome ◽

Mammalian Species ◽

Evolutionary Process ◽

Small Region ◽

Pseudoautosomal Region ◽

Evolution Of Sex ◽

African Pygmy Mouse

X and Y chromosomes in mammals are different in size and gene content due to an evolutionary process of differentiation and degeneration of the Y chromosome. Nevertheless, these chromosomes usually share a small region of homology, the pseudoautosomal region (PAR), which allows them to perform a partial synapsis and undergo reciprocal recombination during meiosis, which ensures their segregation. However, in some mammalian species the PAR has been lost, which challenges the pairing and segregation of sex chromosomes in meiosis. The African pygmy mouse Mus mattheyi shows completely differentiated sex chromosomes, representing an uncommon evolutionary situation among mouse species. We have performed a detailed analysis of the location of proteins involved in synaptonemal complex assembly (SYCP3), recombination (RPA, RAD51 and MLH1) and sex chromosome inactivation (γH2AX) in this species. We found that neither synapsis nor chiasmata are found between sex chromosomes and their pairing is notably delayed compared to autosomes. Interestingly, the Y chromosome only incorporates RPA and RAD51 in a reduced fraction of spermatocytes, indicating a particular DNA repair dynamic on this chromosome. The analysis of segregation revealed that sex chromosomes are associated until metaphase-I just by a chromatin contact. Unexpectedly, both sex chromosomes remain labelled with γH2AX during first meiotic division. This chromatin contact is probably enough to maintain sex chromosome association up to anaphase-I and, therefore, could be relevant to ensure their reductional segregation. The results presented suggest that the regulation of both DNA repair and epigenetic modifications in the sex chromosomes can have a great impact on the divergence of sex chromosomes and their proper transmission, widening our understanding on the relationship between meiosis and the evolution of sex chromosomes in mammals.

Download Full-text

From brain determination to testis determination: evolution of the mammalian sex-determining gene

Reproduction Fertility and Development ◽

10.1071/rd01093 ◽

2001 ◽

Vol 13 (8) ◽

pp. 665 ◽

Cited By ~ 20

Author(s):

Jennifer A. Marshall Graves

Keyword(s):

Y Chromosome ◽

Sex Chromosome ◽

Critical Role ◽

Dominant Gene ◽

Comparative Gene Mapping ◽

Good Account ◽

Mole Vole ◽

Sex Chromosome System ◽

Testis Determination ◽

Autosome Pair

In mammals, sex is determined by an XY male:XX female sex chromosome system in which a male-dominant gene on the Y chromosome (SRY) determines testis formation. Sex chromosomes evolved from an ordinary autosome pair as the Y chromosome was progressively degraded. The Y chromosome has lost nearly all of its 1500 original genes, and those that survived did so because they evolved a critical role in male determination or differentiation. SRY is typical of Y-borne genes. Comparative gene mapping and sequencing shows that SRY arose quite recently as a degraded version of the SOX3 gene on the X chromosome. SOX3 is expressed predominantly in brain, and so is more likely to be a brain-determining than a testis-determining gene. The male-dominant action of SRY may be an illusion, as its structure suggests that it works by interfering with the action of a related gene, which in turn inhibits testis development. This hypothesis can give a good account of how a brain-determining gene acquired a role in testis determination via differential dosage of SOX3. SRY has no central role in sex determination and it can be replaced as a trigger and lost, as have many other Y-borne genes in recent evolutionary history. The absence of SRY in two species of the mole vole (Ellobius) suggests that its useful life is already running out.

Download Full-text