Genetic regulation of genes on active and inactive X chromosome and their contribution to sex-biased diseases

活性和非活性 X 染色体上基因的遗传调控及其对性别偏见疾病的贡献

• 批准号: 10751331
• 负责人: Havell Markus
• 金额: $ 3.46万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751331
• 关键词: Address; Alleles; Allelic Imbalance; Autoimmune Diseases; Biological Assay; Biology; Cell Fraction; Cell Line; Cells; Clinical; Complex; Data; Data Set; Development; Diabetes Mellitus; Disease; Dosage Compensation (Genetics); Etiology; Female; Gene Dosage; Gene Expression Regulation; Gene Silencing; Genes; Genetic; Genetic Transcription; Genomics; Genotype; Haplotypes; Health; Heritability; Heterozygote; Human; Human X Chromosome; Individual; Knowledge; Link; Lupus; Maps; Mendelian randomization; Methods; Modeling; Mosaicism; Non-Insulin-Dependent Diabetes Mellitus; Phase; Phenotype; Play; Population; Quantitative Trait Loci; Regulation; Research; Role; Sampling; Series; Sex Bias; Shapes; Statistical Methods; Time; Tissue-Specific Gene Expression; Tissues; Variant; Work; X Chromosome; X Inactivation; addiction; cell type; clinically relevant; computational suite; functional genomics; genetic architecture; genetic association; genetic variant; genome wide association study; human tissue; improved; individual variation; lymphoblast; male; novel; sex; tool; trait; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT The human X chromosome has long been hypothesized to play a significant role in the etiology of sex-biased diseases and traits, particularly autoimmune diseases like lupus. Despite its importance, the X chromosome is largely understudied in genetic association and functional genomics studies. Such an omission is largely due to its unique biology. The hemizygosity of XY males necessitates XX females to achieve dosage compensation of X-linked genes by the means of X-chromosome inactivation (XCI). Thus, in females most genes are expressed only from the active X (Xa) and remain silent on the inactive X (Xi). However, up to 10% of genes consistently escape XCI in healthy females and are transcribed from both Xa and Xi. And 15-30% of genes variably escape XCI in a subset of females or tissues. We hypothesize such inter- and intra- individual heterogeneity is genetically influenced and disease relevant. However, the genetic architecture of X-linked genes and XCI escape remains poorly understood. We recently showed, for the first time, that XCI escape has significant heritability and variable XCI escape genes have a significantly increased enrichment of heritability in female-biased traits when compared to sex-balanced traits. Although promising, the annotations for XCI states were inferred only from lymphoblast cell lines, which could differ across human tissue/cell types. Recent works have shown disease heritability is enriched in regions surrounding genes specific to disease relevant tissues. Thus, matching each trait to relevant tissue/cell type specific XCI states in heritability analysis could pinpoint the disease and trait relevant tissue/cell types in which escape from XCI plays a significant role (Aim 1). To do so, we first propose an empirical bayes method to infer XCI escape states in an individual sample invariant of XCI mosaicism or presence of transcribed heterozygous SNPs in population scale bulk RNA-seq data. Unlike previous efforts, our method maximizes the samples and X-linked genes assayed to construct the most comprehensive XCI escape landscape across human tissue/cell types to date. Such a complete map will enable robust heritability estimation. Next, to understand the genetic influence on variable XCI escape, we propose a two-step method that accurately models XCI mosaicism and genetic regulation of Xa/Xi by jointly modeling male and female samples to detect associations with Xa and Xi expression levels (Xa-/Xi- QTL) (Aim 2). Our method offers substantial advancement and improves power to detect Xa-/Xi- QTLs compared to other approaches that 1) assume genetic regulation on Xa and Xi are largely similar or 2) attribute total expression of X-linked genes to expression from Xa and Xi. We will apply our approach across tissue/cell types and integrate the identified Xa-/Xi- QTL with existence genome wide association studies to identify tissue/cell type specific Xa and Xi gene and trait associations. We will apply our methods to some of the largest datasets for a variety of traits including lupus, diabetes, and addiction. Overall, our proposed methods will allow comprehensive assessment of the role the X chromosome and XCI escape plays in the etiology of diseases and traits, particularly those that are sex-biased like autoimmune diseases.

项目摘要/摘要 长期以来，人类X染色体长期以来一直在性别偏见的病因中发挥重要作用 疾病和特征，尤其是狼疮等自身免疫性疾病。尽管它很重要，但X染色体是 在遗传关联和功能基因组学研究中大部分研究。这样的遗漏主要是由于 它独特的生物学。 XY雄性的半合性需要XX女性获得剂量补偿 X连锁基因通过X染色体灭活（XCI）的平均值。因此，在女性中，大多数基因表达 仅从活动X（XA）中，并在非活动X（XI）上保持沉默。但是，多达10％的基因始终如一 在健康的女性中逃脱XCI，并从XA和XI转录。和15-30％的基因可变逃脱 XCI在女性或组织的子集中。我们假设这种间和内部异质性在遗传上是 影响和疾病相关。但是，X连锁基因和XCI逃生的遗传结构仍然存在 理解不佳。我们最近首次表明XCI逃脱具有明显的遗传力和可变性 XCI逃生基因在女性偏见特征中的遗传力富集显着增加 与性别平衡的特征相比。尽管很有希望，但XCI国家的注释仅是从中推断出的 淋巴细胞细胞系在人体组织/细胞类型中可能有所不同。最近的作品表明疾病 遗传力富含在针对疾病相关组织的基因周围的区域。因此，匹配每个 在遗传性分析中，特征与相关的组织/细胞类型特异性XCI状态可以确定疾病和性状 从XCI中逃脱的相关组织/细胞类型起着重要作用（AIM 1）。为此，我们首先提出 在单个样本中推断XCI逃脱状态的经验贝叶斯方法不变的XCI镶嵌或 在人口尺度大量RNA-seq数据中存在转录的杂合SNP。与以前的努力不同，我们的 方法最大化样品和X连锁基因分析以构建最全面的XCI逃生 迄今为止，人类组织/细胞类型的景观。这样的完整地图将实现强大的遗传力估计。 接下来，要了解对可变XCI逃脱的遗传影响，我们提出了一种两步方法，可以准确地 通过共同建模男性和雌性样品来检测XCI镶嵌和XA/XI的遗传调节 与XA和XI表达水平（XA-/XI-QTL）（AIM 2）的关联。我们的方法提供了可观的进步 与其他方法相比，提高检测XA-/XI-QTL的功率1） Xa和XI在很大程度上相似，或者2）将X连锁基​​因的总表达归因于Xa和Xi的表达。我们 将在组织/细胞类型中应用我们的方法，并将鉴定的XA-/XI-QTL与存在的基因组相结合 广泛的关联研究，以鉴定组织/细胞类型特异性XA和XI基因和性状关联。我们将申请 我们针对一些最大的数据集的方法，用于各种特征，包括狼疮，糖尿病和成瘾。全面的， 我们提出的方法将允许全面评估X染色体和XCI逃生的角色 在疾病和特征的病因中发挥作用，尤其是那些像自身免疫性疾病一样偏见的性行为。