X-linked competition - implications for human development and disease

Abstract

During early mammalian female development, X chromosome inactivation leads to random transcriptional silencing of one of the two X chromosomes. This inactivation is maintained through subsequent cell divisions, leading to intra-individual diversity, whereby cells express either the maternal or paternal X chromosome. Differences in X chromosome sequence content can trigger competitive interactions between clones that may alter organismal development and skew the representation of X-linked sequence variants in a cell-type-specific manner - a recently described phenomenon termed X-linked competition in analogy to existing cell competition paradigms. Skewed representation can define the phenotypic impact of X-linked variants, for example, the manifestation of disease in female carriers of X-linked disease alleles. Here, we review what is currently known about X-linked competition, reflect on what remains to be learnt and map out the implications for X-linked human disease.

Figure 1.. X-chromosome inactivation and its clonal propagation.

a, X-chromosome inactivation and its epigenetic propagation mean that XX individuals comprise a mosaic of clones expressing either the maternal or the paternal X chromosome ^–. b, Visualization of X-chromosome usage in mouse tissues . Expression of the two X chromosomes is marked by either red or green fluorescent reporter proteins shows patterns of clonal mixing. These images are from transgenic mice, and X-chromosome activity patterns have not yet been directly visualized in humans. c, Stochastic differences in maternal versus paternal X-chromosome usage between germ layers and cell types of the same XX individual. The ratio of cells expressing the maternal versus the paternal X chromosome in undifferentiated cells of the early embryo is not necessarily 50:50 and can be further skewed by stochastic sampling of small numbers of progenitors to form each of the three germ layers, which can each show different X-chromosome usage. Within each germ layer, small numbers of progenitors give rise to each cell type and tissue, which may skew X-chromosome usage further. This results in considerable variation in X-chromosome usage between cell types and tissues. c, Genetic variation on the X chromosome generates an added layer of intra-individual variation in XX individuals. The human X chromosome exhibits substantial genetic variation, with on average approximately 150 protein-coding variants found between any two human X chromosomes. Individual cells in tissues selectively express the unique sequence content of one or the other X chromosome owing to X-chromosome inactivation followed by clonal propagation, leading to mosaicism at the cellular level. Part b reproduced with permission from Ref. .

Figure 2.. X-linked competition.

a, The tissue-specific skewing of X-chromosome usage in specific cell types and tissues in mouse models of human sequence variation in the X-linked Stag2 gene . STAG2 variant clones are absent from a polyclonal B cell line derived from the blood of a human XX individual. d, The number of heterozygous missense variants (non-synonymous single-nucleotide variants (SNVs)) between the two X chromosomes in 1,271 XX individuals across human populations in phase 3 of the 1000 Genomes Project and SNVs were filtered with bcftools v1.20 (Ref. ) to those with only one alternate allele present per individual. We removed SNVs in genes known to escape X-chromosome inactivation , identified missense variants with the Bioconductor package VariantAnnotation using Gencode v19 (GRCh37.p13), and counted non-synonymous heterozygous X-chromosome variants for each individual. Ethnicities are from ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/technical/working/20130606_sample_info/20130606_sample_info.xlsx. Colours indicate superpopulations. CHS: Southern Han Chinese South; JPT: Japanese in Tokyo, Japan; CHB: Han Chinese in Beijing, China; KHV: Kinh in Ho Chi Minh City, Vietnam; CDX: Dai Chinese in Xishuangbanna, China; TSI: Tuscan in Tuscany, Italy; FIN: Finnish in Finland; GBR: British in England and Scotland; PEL: Peruvian in Lima, Peru; PJL: Punjabi in Lahore, Pakistan; STU: Sri Lankan Tamil in the UK; IBS: Iberian populations in Spain; CEU: Utah residents with Northern and Western European ancestry; ITU: Indian Telugu in the UK; GIH: Gujarati Indian in Houston, TX; BEB: Bengali in Bangladesh; MXL: Mexican Ancestry in Los Angeles, California; CLM: Colombian in Medellin, Colombia; PUR: Puerto Rican in Puerto Rico; GWD: Gambian in Western Division, The Gambia; ESN: Esan in Nigeria; ACB: African-Caribbean in Barbados; YRI: Yoruba in Ibadan, Nigeria; ASW: African-American Ancestry in Southwest US; LWK: Luhya in Webuye, Kenya; MSL: Mende in Sierra Leone.

Figure 3.. Cell competition.

a, Cell competition amplifies minor fitness differences between prospective winner and loser cells. On their own, loser cells are capable of proliferation but fail to expand in the presence of winner cells ^,. b, Cell competition designates winner and loser cells. Loser cells are eliminated by apoptosis only in the presence of winner cells. c, Somatic changes, including changes that drive overexpression of MYC, can turn cells into super-competitors that displace cells without mutations and can eliminate nascent tumours d, Cell competition can be hijacked by super-competitors that eliminate their neighbours. This creates space for the mutant clones and facilitates the emergence of adenomas and potentially adenocarcinomas ^,.

Figure 4.. Variable manifestation of X-linked disease in heterozygous individuals.

The expressivity of X-linked mutations and the manifestation of X-linked disease in heterozygous individuals can be affected by the nature of the mutation and the disease and is often correlated with the fraction of cells that use the X chromosome harbouring the mutant allele in disease-relevant cell types and tissues.