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The multi-omic landscape of sex chromosome abnormalities: current status and future directions - PubMed

  • ️Sun Jan 01 2023

Review

The multi-omic landscape of sex chromosome abnormalities: current status and future directions

Helene Bandsholm Leere Tallaksen et al. Endocr Connect. 2023.

Abstract

Sex chromosome abnormalities (SCAs) are chromosomal disorders with either a complete or partial loss or gain of sex chromosomes. The most frequent SCAs include Turner syndrome (45,X), Klinefelter syndrome (47,XXY), Trisomy X syndrome (47,XXX), and Double Y syndrome (47,XYY). The phenotype seen in SCAs is highly variable and may not merely be due to the direct genomic imbalance from altered sex chromosome gene dosage but also due to additive alterations in gene networks and regulatory pathways across the genome as well as individual genetic modifiers. This review summarizes the current insight into the genomics of SCAs. In addition, future directions of research that can contribute to decipher the genomics of SCA are discussed such as single-cell omics, spatial transcriptomics, system biology thinking, human-induced pluripotent stem cells, and animal models, and how these data may be combined to bridge the gap between genomics and the clinical phenotype.

Keywords: Klinefelter syndrome; Turner syndrome; genetics; sex chromosome abnormalities.

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Conflict of interest statement

The authors have no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Figures

Figure 1
Figure 1

(A) The most frequent karyotype of Turner syndrome (TS; 45,X), Trisomy X syndrome (47,XXY), Klinefelter syndrome (KS; 47,XXY), and Double Y syndrome (47,XYY) is depicted together with karyotypically normal females (46,XX) and males (46,XY). The X chromosome and Y chromosome are shown in pink and blue color, respectively. (B) The copy number of PAR1 genes (genes located on the pseudoautosomal region 1), X and Y homologs, XCIE (genes that escape from X chromosome inactivation), and XCI (genes that are inactivated) according to karyotype. (C) The X and Y chromosome with depictions of the PAR1 genes and X and Y homologs. This figure was created with BioRender.com.

Figure 2
Figure 2

SCAs are associated with several clinical phenotypic traits that show a huge range of inter-individual variation, even in subjects with the same karyotype. Several genetic modifiers (e.g. mosaicism, copy number variations (CNVs), and single-nucleotide polymorphisms (SNPs)) have been suggested to be implicated in the inter-individual variation seen. Thus, many of the phenotypic traits seen in SCAs may be seen as a spectrum following a normal distribution curve, like that of the general population, only shifted to the left (e.g. intelligence in KS) or right (e.g. height in KS), rather than a binary classification. This figure was created with BioRender.com.

Figure 3
Figure 3

Multi-tissue and multi-omics approach at the single cell level to better deep phenotype SCAs. From SCA individuals, representative tissue biopsies should be obtained from relevant tissues. Biopsies can then either be dissociated to a single-cell suspension, barcoded and sequenced to obtain single cell omics (A) or sectioned, stained, imaged and barcoded prior to sequencing for spatial RNA expression (B). If possible, clinical measurements should be obtained at the same time for the same individuals (C). Multi-omics and clinical measurements can be combined into an integrated dataset, maintaining both the single cell resolution and the spatial information, thus, making it possible to identify specific molecular signatures for each SCA in a tissue and cell-specific phenotypic context (D). This figure was created with BioRender.com.

Figure 4
Figure 4

(A) The table shows the zebrafish orthologs to the human PAR1 genes and X–Y gene pairs and their chromosome location in the zebrafish genome. The data in this table are retrieved from the Alliance of Genome Resources (

https://www.alliancegenome.org

). In the table, – indicates that no ortholog is found, while 1 and 2 indicate that the gene is an ortholog to the X homolog and X–Y gene pair, respectively. (B) An example of how to genetically manipulate zebrafish and establish knockout lines using CRISPR/Cas9. Wildtype embryos are obtained by crossing adult wildtype zebrafish. Subsequently, single guide RNA (sgRNA) and Cas9 mRNA are co-injected into the one-cell stage wildtype embryos to disrupt gene function of the target gene by, for example, introducing a premature termination codon (PTC). When the injected embryos become adult fish, they are screened to identify a founder fish (F0) that can pass on the PTC to the next generations. The F1 and F2 generations are obtained by crossing F0 founders with wildtype zebrafish and crossing F1 zebrafish with wildtype zebrafish, respectively. The F2 zebrafish can be used for phenotype analysis. This figure was created with BioRender.com.

Figure 5
Figure 5

The molecular underpinnings of the phenotype of SCAs are complex and may include mosaicism, genomic variations (e.g. CNVs and SNPs), altered methylome and transcriptome. It has been speculated whether the altered methylation can alleviate the effect of sex chromosome loss or gain and thereby the phenotype. The altered transcription of the protein-coding genes may result in an altered proteome that may also contribute to the phenotype. Moreover, the non-coding RNAs (e.g. microRNAs, circular RNAs, and lncRNAs) have been suggested to contribute to the phenotype. This figure was created with BioRender.com.

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References

    1. Berglund A Stochholm K & Gravholt CH. The epidemiology of sex chromosome abnormalities. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics 2020184202–215. (10.1002/ajmg.c.31805) - DOI - PubMed
    1. Lahn BT & Page DC. Four evolutionary strata on the human X chromosome. Science 1999286964–967. (10.1126/science.286.5441.964) - DOI - PubMed
    1. Bellott DW, Skaletsky H, Pyntikova T, Mardis ER, Graves T, Kremitzki C, Brown LG, Rozen S, Warren WC, Wilson RK, et al.Convergent evolution of chicken Z and human X chromosomes by expansion and gene acquisition. Nature 2010466612–616. (10.1038/nature09172) - DOI - PMC - PubMed
    1. Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, Brown LG, Repping S, Pyntikova T, Ali J, Bieri T, et al.The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature 2003423825–837. (10.1038/nature01722) - DOI - PubMed
    1. Lyon MF. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 1961190372–373. (10.1038/190372a0) - DOI - PubMed

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