{
  "abstract": "The X chromosome carries an unusually high density of immune genes and is a major contributor to sex differences in immune function and autoimmune diseases. In females, X-chromosome inactivation (XCI) has two major functional consequences: it shapes X-linked gene dosage through XCI escape and determines the cellular exposure of heterozygous X-linked variants through XCI skew. Yet because XCI creates a mosaic of cells expressing different parental X chromosomes, these properties have remained largely inaccessible in individual women, becoming measurable only where XCI is non-random or after aggregation across large cohorts. Consequently, how X-linked variation contributes to sex-biased immunity and differs between individual women has remained unresolved. Here we present scDaisyChain, a graph-based framework that reconstructs chromosome-scale X haplotypes directly from heterozygous SNPs and single-cell long-read transcriptomes. scDaisyChain achieves near-ground-truth accuracy in highly polymorphic mouse hybrids and shows strong concordance with orthogonal long-read whole-genome phasing in human samples. Applied to peripheral blood immune cells from healthy women, it reveals a lineage-specific escape program in which lymphoid cells escape XCI more broadly than monocytes, with corresponding gains in the inactive X chromatin accessibility and female-biased expression. Lineage-specific skew further alters the proportion of cells expressing each heterozygous X-linked variant, a property we term variant exposure. Predicted deleterious variants are preferentially found in low-exposure states, exemplified by a splice-altering TLR8 variant expressed in few cytotoxic T cells. In rheumatoid arthritis (RA), the monocyte compartment - which has the lowest escape in health - shows reproducible inactive X dysregulation converging on a trained-immunity programme linked to disease flare and synovial macrophage activation, with elevated escape of IL13RA1 and HDAC8. These findings establish lineage-specific escape, skew and variant exposure as quantifiable, patient-resolved determinants of sex-biased immune gene dosage and X-linked variant penetrance in health and autoimmune disease, resolving a dimension of female biology that has been previously inaccessible in individual donors.",
  "abstract_shown": true,
  "affiliations": [
    "Garvan Institute of Medical Research, Sydney, Australia; School of Biotechnology and Biomedical Sciences, UNSW, Sydney, Australia"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "name": "D. Kavanagh"
    },
    {
      "name": "A. Steel"
    },
    {
      "name": "H. E. King"
    },
    {
      "name": "H. G. S. Vieira"
    },
    {
      "name": "K. R. Kumar"
    },
    {
      "name": "E. Masle-Farquhar"
    },
    {
      "name": "C. King"
    },
    {
      "name": "K. Skvortsova"
    },
    {
      "affs": [
        0
      ],
      "name": "R. J. Weatheritt"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/948x61dysrg1n.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.08.26.739472",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.08.26.739472v1.full",
  "id": "948x61dysrg1n",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.08.26.739472v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "bioinformatics"
    ],
    [
      "openalex",
      "1311|Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities"
    ]
  ],
  "openalex": "W7204798403",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.08.26.739472v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-26",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/948x61dysrg1n.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:17Z",
      "native_id": "10.64898/2026.08.26.739472",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.08.26.739472v2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioinformatics",
      "subfield": "bioinformatics"
    }
  ],
  "title": "Lineage-specific X chromosome inactivation escape and skew underlie sex-biased immune gene dosage and deleterious variant exposure",
  "title_text": "Lineage-specific X chromosome inactivation escape and skew underlie sex-biased immune gene dosage and deleterious variant exposure",
  "type": "preprint",
  "updated_at": "2026-10-30T12:28:51Z",
  "url": "https://research.draconitic.com/paper/948x61dysrg1n",
  "venue": "bioRxiv",
  "versions": []
}