Consequences of gaining an extra chromosome

Abstract

Mistakes in chromosome segregation leading to aneuploidy are the primary cause of miscarriages in humans. Excluding sex chromosomes, viable aneuploidies in humans include trisomies of chromosomes 21, 18, or 13, which cause Down, Edwards, or Patau syndromes, respectively. While individuals with trisomy 18 or 13 die soon after birth, people with Down syndrome live to adulthood but have intellectual disabilities and are prone to multiple diseases. At the cellular level, mistakes in the segregation of a single chromosome leading to a cell losing a chromosome are lethal. In contrast, the cell that gains a chromosome can survive. Several studies support the hypothesis that gaining an extra copy of a chromosome causes gene-specific phenotypes and phenotypes independent of the identity of the genes encoded within that chromosome. The latter, referred to as aneuploidy-associated phenotypes, are the focus of this review. Among the conserved aneuploidy-associated phenotypes observed in yeast and human cells are lower viability, increased gene expression, increased protein synthesis and turnover, abnormal nuclear morphology, and altered metabolism. Notably, abnormal nuclear morphology of aneuploid cells is associated with increased metabolic demand for de novo synthesis of sphingolipids. These findings reveal important insights into the possible pathological role of aneuploidy in Down syndrome. Despite the adverse effects on cell physiology, aneuploidy is a hallmark of cancer cells. Understanding how aneuploidy affects cell physiology can reveal insights into the selective pressure that aneuploid cancer cells must overcome to support unlimited proliferation.

Keywords: Aneuploidy; Down syndrome; Human trisomy; Nuclear morphology; Serine synthesis; Sphingolipids; Yeast.

Fig. 1

The number of protein-coding genes increases the deleterious effects on cell physiology. a Human chromosomes are arranged by DNA content. Data were obtained from Genome Reference Consortium (GRCh38.p14). a–g To highlight the data of autosomes 13, 18, and 21 are colored in light blue, and sex chromosomes X and Y in red and green, respectively. b Human chromosomes are arranged by the number of protein-coding genes. Autosomes 13, 18, and 21 are not the smallest in size but encode the least number of proteins compared to other autosomes. c Number of transcripts per million counts (TPM) per chromosome does not correlate with chromosome size. RNAseq of a euploid primary human fibroblast from Hwang et al. (Hwang et al. 2021) was used. Prism 9 software was used to calculate linear regression analysis. d Number of transcripts per million counts (TPM) per chromosome correlates with number of protein-coding genes. Prism 9 software was used to calculate linear regression analysis. e Number of peptide counts per chromosome do not correlate with chromosome size. Tandem mass tag (TMT) proteomics of a euploid primary human fibroblast from Hwang et al. (Hwang et al. 2021) was used. Prism 9 software was used to calculate linear regression analysis. No proteins encoded on chromosome Y were detected. f Number of peptide counts per chromosome correlates with the number of protein-coding genes. Prism 9 software was used to calculate linear regression analysis. g Summary of the number of genes expressed and life expectancy in human trisomies. Asterisk (*) = few genes in the extra copy of chromosome X escape transcriptional silencing by Xist (Disteche 1995). RNAseq analysis of human fibroblast from male donors detects only three genes expressed at low levels from chromosome Y. h Summary of the effects of different trisomies on viability, cell cycle, and senescence. Yeast results are from Torres et al. (Torres et al. 2007), human trisomies from Hwang et al. (Hwang et al. 2021), mouse trisomies from Williams et al. (Williams et al. 2008), and human cell lines from Stingele et al. (Stingele et al. 2012). ND, not detected

Fig. 2

Transcript levels increase proportionally to gene copy number in aneuploid cells. a Heat map of the average log₂ ratio of gene expression per chromosome in aneuploid cells relative to controls. Yeast expression data was obtained from Torres et al. (Torres et al. 2007), human trisomies from Hwang et al. (Hwang et al. 2021), mouse trisomies from Williams et al. (Williams et al. 2008), and human cell lines from Stingele et al. (Stingele et al. 2012). b Histograms of the log₂ ratios of gene expression of non-duplicated (left, mean = 0) and duplicated genes (right, mean = 1) with a standard deviation (SD) of 0.3 as measured in aneuploid yeast strains. Plots indicate that only a handful of genes, 1.45%, fall outside 2 * SD from the mean (p < 0.05). If a particular gene shows a log₂ ratio lower than the expected value of 1 but higher than 0.4, it cannot be considered as dosage compensated because it falls within the expected variability of population measurements with a p value higher than 0.05

Fig. 3

Protein levels increase proportionally to gene copy number in aneuploid cells, except for subunits of multiprotein complexes. a Heatmap of the average log₂ ratio of protein levels per chromosome in aneuploid cells relative to controls. Proteomics data for yeast was obtained from Dephoure et al. (Dephoure et al. 2014), human trisomies from Hwang et al. (Hwang et al. 2021), and human cell lines from Stingele et al. (Stingele et al. 2012). b About 30% of duplicated proteins enriched for subunits of multiprotein complexes do not scale up with gene copy numbers in yeast and human aneuploid cells (green bar). Ribosome footprinting in yeast disomes shows that the attenuated proteins are translated proportionally to gene copy number. Inhibition of protein degradation leads to increased levels of the attenuated proteins within 90 s (orange bar). c Heatmaps of mRNA levels and protein levels of duplicated ribosomal subunits in yeast and aneuploid human cell lines are shown. This gene set invariably shows increased transcript levels, but the proteins are degraded—color scale bar of log₂ ratio is the same as in a

Fig. 4

An extra chromosome disrupts the morphology of the nucleus. a Images of yeast cells expressing Heh1-GFP to mark the nuclear envelope shows that an extra chromosome disrupts the morphology of the nucleus. Differential interference contract is shown (DIC). Scale bar, 5 µm. b Immunofluorescence microscopy of lamin B1 in red and DNA in blue of human skin fibroblasts (HSFs). Scale bar, 2.5 µm. Up to 50% of the population of trisomic HSFs show abnormal shapes compared to euploid controls. c Images of primary human astrocytes from 2 euploid donors and 2 donors with Down syndrome. DNA is stained blue. Scale bar, 2.5 µm. d Immunofluorescence microscopy of lamin B1 in red and DNA in blue of RPE1 cells harboring extra chromosomes. Scale bar, 5 µm. e Immunofluorescence microscopy of lamin B1 in red and DNA in blue of HSFs from donors with triple X and XYY syndromes. Scale bar, 5 µm. f Immunofluorescence microscopy of lamin B1 in red and DNA in blue of HSFs from young, old donors, and donor with Hutchinson-Gilford progeria syndrome. Scale bar, 2.5 µm. Images adapted from Hwang et al. (Hwang et al. 2019)

Fig. 5

Aneuploid cells rely on increased serine synthesis to survive. a A gain of an extra chromosome increases the demand for biomass synthesis including nucleic acids, amino acids, and lipid synthesis. The biosynthesis of serine is required for the survival of aneuploid cells because serine is used to make other amino acids and proteins, nucleotides, and lipids. The de novo biosynthesis of serine requires increased utilization of glucose and glutamine. 3-PG, 3-phoshoglycerate; 3-PHP, 3-phosphopyruvate; 3-PSer, 3-phosphoserine; alpha-KG, alpha-ketoglutarate; PHGDH, 3-phosphoglycerate dehydrogenase; PSAT1, phosphoserine transaminase 1; PSPH, phosphoserine phosphatase. b In yeast, deletion of SER2 (PSPH) hampers the proliferation of wild type cells grown in minimal media containing 1 mM serine. Disomic strains harboring the same deletion grow extremely poorly in minimal media containing 1 mM serine. Asterisk (*) indicates loss of SER2 causes is lethal in disomes IV, XIV, XV, and XVI. Data adapted from Hwang et al. (Hwang et al. 2017). HSFs trisomic for chromosomes 13, 18, or 21 are sensitive to serine depletion from the growth media. Dis, disome; Con.1, control 1; T13.1, trisomy 13 donor 1. c Quantitative lipidomics shows that the levels of LCBs and ceramides are increased in aneuploid yeast and human cells. Data obtained from Hwang et al. (Hwang et al. , Hwang et al. 2021)