X-inactivation mosaicism and the effects of X-linked mutations in the human brain
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Burger, Steven
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Burger, Steven. 2023. X-inactivation mosaicism and the effects of X-linked mutations in the human brain. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences.Abstract
Cells in every human female have inactivated one or the other X chromosome (X1 or X2). To enable analysis of this epigenetic mosaicism – and its biological effects – we developed a computational approach that uses single-cell RNA-seq data and transcribed SNPs to infer the X-inactivation choice of individual cells.Within the dorsolateral prefrontal cortex of human female brain donors, active-X proportions varied by cell type, and, across 68 females, quantitative patterns in this variation reflected shared and distinct features of these cell types’ developmental histories.
In most females, differences in global gene expression between X1 and X2 cells of a given cell type were modest and largely involved X-chromosome genes. In contrast, we found profound gene-expression differences between X1 and X2 cells of the same cell type when we analyzed brain tissue from donors with two X-linked neurodevelopmental disorders – Rett syndrome (caused by mutations in MECP2) and CDKL5 Deficiency Disorder (CDD, caused by mutations in CDKL5) – reflecting the functional mosaicism resulting from heterozygous X-linked mutations of large effect. Though CDD has been considered a variant of Rett syndrome due to the similarity in the disorders’ clinical symptoms, our analyses revealed that the cell-autonomous transcriptional effects of MECP2 and CDKL5 mutations were largely distinct, suggesting that clinical overlap between these disorders arises primarily from convergent, cell non-autonomous effects.
We hypothesized that this same approach could also identify, among females not known to have X-linked mutations, individuals with unusual levels of X-inactivation-associated gene expression mosaicism. We discovered two such individuals, with distinct gene-expression-mosaicism signatures, among 38 females diagnosed with schizophrenia. One of these individuals had a gene-expression-mosaicism signature strongly resembling that of MECP2 mutations; genome sequencing revealed a previously unrecognized MECP2 missense mutation (R167W), which likely contributed to this individual’s lifelong struggles with learning disabilities preceding schizophrenia.
Our approach can be used to characterize X-inactivation mosaicism in any female (XX) tissue, offering insight into cell types’ developmental histories and the cell-autonomous effects of X-linked genetic variation.
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