High expression of the mammalian X chromosome in brain

doi:10.1016/j.brainres.2006.08.053

Brain Research

Volume 1126, Issue 1, 18 December 2006, Pages 46-49

https://doi.org/10.1016/j.brainres.2006.08.053 Get rights and content

Abstract

Divergence between the sex chromosomes has led to loss and differentiation of Y-linked genes and haplo-insufficiency for X-linked genes in males. A mechanism of dosage compensation, for which we recently found evidence in mammals, evolved to restore a balanced expression of the genome by doubling the transcriptional output from the X chromosome. X inactivation would then serve to avoid hyper-transcription of X-linked genes in females by silencing one X chromosome. We also found that, compared to the rest of the genome, the X chromosome contains an excess of genes highly expressed in brain tissues. The exceptionally important role of the X chromosome in brain function, evident from the prevalence of X-linked forms of mental retardation, is discussed in view of sex chromosome regulation and evolution and sexual reproduction.

Section snippets

Acknowledgments

This work was supported by grants from the National Institutes of Health. We thank M.K. Cheng for helpful comments.

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Neurological and neuropsychiatric disorders affect men and women differently. Multiple sclerosis, Alzheimer’s disease, anxiety disorders, depression, meningiomas and late-onset schizophrenia affect women more frequently than men. By contrast, Parkinson’s disease, autism spectrum condition, attention-deficit hyperactivity disorder, Tourette’s syndrome, amyotrophic lateral sclerosis and early-onset schizophrenia are more prevalent in men. Women have been historically under-recruited or excluded from clinical trials, and most basic research uses male rodent cells or animals as disease models, rarely studying both sexes and factoring sex as a potential source of variation, resulting in a poor understanding of the underlying biological reasons for sex and gender differences in the development of such diseases. Putative pathophysiological contributors include hormones and epigenetics regulators but additional biological and non-biological influences may be at play. We review here the evidence for the underpinning role of the sex chromosome complement, X chromosome inactivation, and environmental and epigenetic regulators in sex differences in the vulnerability to brain disease. We conclude that there is a pressing need for a better understanding of the genetic, epigenetic and environmental mechanisms sustaining sex differences in such diseases, which is critical for developing a precision medicine approach based on sex-tailored prevention and treatment.
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According to our case series most successful drugs were VPA and LEV. Long term prognosis of epilepsy in our case series was good. Our experience suggests that all triple X patients achieve good seizure control and in 69% of cases normalization of the EEG.
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Citation Excerpt :
Considering intellectual disability, the incidence of mutations in human X-linked genes, which lead to XLID, is about 3.5 fold higher than that in autosomal genes (Neri et al., 2018). In addition, RNA measurements show that a greater number of genes are expressed in the brain and that X-linked genes are more highly expressed in the brain versus other tissues (Deng et al., 2011; Nguyen and Disteche, 2006a). This is apparent in both mouse and human, although possibly more pronounced in the latter (Nguyen and Disteche, 2006a;Nguyen and Disteche, 2006b).
Humans show reproducible sex-differences in cognition and psychopathology that may be contributed to by influences of gonadal sex-steroids and/or sex-chromosomes on regional brain development. Gonadal sex-steroids are well known to play a major role in sexual differentiation of the vertebrate brain, but far less is known regarding the role of sex-chromosomes. Our review focuses on this latter issue by bridging together two literatures that have to date been largely disconnected. We first consider “bottom-up” genetic and molecular studies focused on sex-chromosome gene content and regulation. This literature nominates specific sex-chromosome genes that could drive developmental sex-differences by virtue of their sex-biased expression and their functions within the brain. We then consider the complementary “top down” view, from magnetic resonance imaging studies that map sex- and sex chromosome effects on regional brain anatomy, and link these maps to regional gene-expression within the brain. By connecting these top-down and bottom-up approaches, we emphasize the potential role of X-linked genes in driving sex-biased brain development and outline key goals for future work in this field.
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The aim was to analyze emotional state, cognitive functioning and quality of life (QoL) of adult women with Turner syndrome (TS) in Lithuania.
Of all invited adult TS patients from Lithuanian TS database (n = 150), 68 (age 18–60, average 30.2 ± 9.0 years) agreed and were recruited for the study, as well as 68 age-matched healthy control women. Emotional state was evaluated by Profile of Mood States (POMS) questionnaire, cognitive functioning by Trail Making Test and Digit Span Test (DST) of Wechsler Adult Intelligence Scale, and QoL by WHO Brief Quality of Life Questionnaire (WHO QoL).
Patients with TS were of a significantly shorter stature (p < .001) than age-matched control women and than the 3rd percentile of the National Standards of Lithuania.
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In conclusion, after the adjustment for height, weight and BMI, adult women with Turner syndrome in Lithuania have impaired cognitive functioning and worse psychological and social aspects of QoL, but not emotional state and physical and environmental aspects of QoL in comparison to age-matched healthy women.

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Short CommunicationHigh expression of the mammalian X chromosome in brain

Abstract

Section snippets

Acknowledgments

Curr. Opin. Genet. Dev.

Trends Genet.

Curr. Opin. Genet. Dev.

Trends Genet.

Evidence of evolutionary up-regulation of the single active X chromosome in mammals based on Clc4 expression levels in Mus spretus and Mus musculus

Proc. Natl. Acad. Sci. U. S. A.

Dosage-dependent over-expression of genes in the trisomic region of Ts1Cje mouse model for Down syndrome

Hum. Mol. Genet.

X-inactivation profile reveals extensive variability in X-linked gene expression in females

Nature

Steps in the evolution of heteromorphic sex chromosomes

Heredity

Escape from X inactivation

Cytogenet. Genome Res.

Nuclear compartmentalization and gene activity

Nat. Rev., Mol. Cell Biol.