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Aneuploidy effects on human gene expression across three cell types.
Liu, Siyuan; Akula, Nirmala; Reardon, Paul K; Russ, Jill; Torres, Erin; Clasen, Liv S; Blumenthal, Jonathan; Lalonde, Francois; McMahon, Francis J; Szele, Francis; Disteche, Christine M; Cader, M Zameel; Raznahan, Armin.
Afiliação
  • Liu S; Section on Developmental Neurogenomics, Human Genetics Branch, National Institute of Mental Health, Bethesda, MD 20892.
  • Akula N; Section on the Genetic Basis of Mood and Anxiety Disorders Section, Human Genetics Branch, National Institute of Mental Health, Bethesda, MD 20892.
  • Reardon PK; Section on Developmental Neurogenomics, Human Genetics Branch, National Institute of Mental Health, Bethesda, MD 20892.
  • Russ J; Section on Developmental Neurogenomics, Human Genetics Branch, National Institute of Mental Health, Bethesda, MD 20892.
  • Torres E; Section on the Genetic Basis of Mood and Anxiety Disorders Section, Human Genetics Branch, National Institute of Mental Health, Bethesda, MD 20892.
  • Clasen LS; Section on Developmental Neurogenomics, Human Genetics Branch, National Institute of Mental Health, Bethesda, MD 20892.
  • Blumenthal J; Section on Developmental Neurogenomics, Human Genetics Branch, National Institute of Mental Health, Bethesda, MD 20892.
  • Lalonde F; Section on Developmental Neurogenomics, Human Genetics Branch, National Institute of Mental Health, Bethesda, MD 20892.
  • McMahon FJ; Section on Developmental Neurogenomics, Human Genetics Branch, National Institute of Mental Health, Bethesda, MD 20892.
  • Szele F; Section on the Genetic Basis of Mood and Anxiety Disorders Section, Human Genetics Branch, National Institute of Mental Health, Bethesda, MD 20892.
  • Disteche CM; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom.
  • Cader MZ; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195.
  • Raznahan A; Department of Medicine, University of Washington, Seattle, WA 98195.
Proc Natl Acad Sci U S A ; 120(21): e2218478120, 2023 05 23.
Article em En | MEDLINE | ID: mdl-37192167
Aneuploidy syndromes impact multiple organ systems but understanding of tissue-specific aneuploidy effects remains limited-especially for the comparison between peripheral tissues and relatively inaccessible tissues like brain. Here, we address this gap in knowledge by studying the transcriptomic effects of chromosome X, Y, and 21 aneuploidies in lymphoblastoid cell lines, fibroblasts and iPSC-derived neuronal cells (LCLs, FCL, and iNs, respectively). We root our analyses in sex chromosome aneuploidies, which offer a uniquely wide karyotype range for dosage effect analysis. We first harness a large LCL RNA-seq dataset from 197 individuals with one of 6 sex chromosome dosages (SCDs: XX, XXX, XY, XXY, XYY, and XXYY) to i) validate theoretical models of SCD sensitivity and ii) define an expanded set of 41 genes that show obligate dosage sensitivity to SCD and are all in cis (i.e., reside on the X or Y chromosome). We then use multiple complementary analyses to show that cis effects of SCD in LCLs are preserved in both FCLs (n = 32) and iNs (n = 24), whereas trans effects (i.e., those on autosomal gene expression) are mostly not preserved. Analysis of additional datasets confirms that the greater cross-cell type reproducibility of cis vs. trans effects is also seen in trisomy 21 cell lines. These findings i) expand our understanding of X, Y, and 21 chromosome dosage effects on human gene expression and ii) suggest that LCLs may provide a good model system for understanding cis effects of aneuploidy in harder-to-access cell types.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Síndrome de Down / Aneuploidia Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Síndrome de Down / Aneuploidia Idioma: En Ano de publicação: 2023 Tipo de documento: Article