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
基本信息
- 批准号:10751331
- 负责人:
- 金额:$ 3.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAllelesAllelic ImbalanceAutoimmune DiseasesBiological AssayBiologyCell FractionCell LineCellsClinicalComplexDataData SetDevelopmentDiabetes MellitusDiseaseDosage Compensation (Genetics)EtiologyFemaleGene DosageGene Expression RegulationGene SilencingGenesGeneticGenetic TranscriptionGenomicsGenotypeHaplotypesHealthHeritabilityHeterozygoteHumanHuman X ChromosomeIndividualKnowledgeLinkLupusMapsMendelian randomizationMethodsModelingMosaicismNon-Insulin-Dependent Diabetes MellitusPhasePhenotypePlayPopulationQuantitative Trait LociRegulationResearchRoleSamplingSeriesSex BiasShapesStatistical MethodsTimeTissue-Specific Gene ExpressionTissuesVariantWorkX ChromosomeX Inactivationaddictioncell typeclinically relevantcomputational suitefunctional genomicsgenetic architecturegenetic associationgenetic variantgenome wide association studyhuman tissueimprovedindividual variationlymphoblastmalenovelsextooltraittranscriptome sequencing
项目摘要
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.
项目概要/摘要
长期以来,人们一直假设人类 X 染色体在性别偏见的病因学中发挥着重要作用
疾病和特征,特别是狼疮等自身免疫性疾病。尽管 X 染色体很重要,但
在遗传关联和功能基因组学研究中很大程度上没有得到充分研究。这种遗漏很大程度上是由于
其独特的生物学特性。 XY 雄性的半合性需要 XX 雌性来实现
通过 X 染色体失活 (XCI) 实现 X 连锁基因。因此,在女性中,大多数基因都表达
仅来自活动 X (Xa),并对非活动 X (Xi) 保持沉默。然而,高达 10% 的基因一致
在健康女性体内逃脱 XCI,并由 Xa 和 Xi 转录。 15-30% 的基因不同程度地逃脱
XCI 在女性或组织的子集中。我们假设这种个体间和个体内的异质性是遗传性的
影响与疾病有关。然而,X连锁基因和XCI逃逸的遗传结构仍然存在
不太了解。我们最近首次证明 XCI 逃逸具有显着的遗传性和可变性
当 XCI 逃逸基因显着增加雌性偏向性状的遗传力丰富度时
与性别平衡特征相比。尽管很有希望,但 XCI 状态的注释只能从
淋巴母细胞系,在不同的人体组织/细胞类型中可能有所不同。最近的作品显示了疾病
遗传力在疾病相关组织特异基因周围的区域丰富。因此,匹配每个
遗传力分析中相关组织/细胞类型特定 XCI 状态的特征可以查明疾病和特征
相关组织/细胞类型,其中逃离 XCI 起着重要作用(目标 1)。为此,我们首先提出
用于推断 XCI 镶嵌现象的单个样本不变量中的 XCI 逃逸态的经验贝叶斯方法或
群体规模的批量 RNA-seq 数据中是否存在转录的杂合 SNP。与之前的努力不同,我们
方法最大化检测的样本和 X 连锁基因,构建最全面的 XCI 逃逸
迄今为止人类组织/细胞类型的景观。这样一个完整的图谱将能够实现稳健的遗传力估计。
接下来,为了了解遗传对变量 XCI 逃逸的影响,我们提出了一种两步方法,可以准确地
通过联合建模男性和女性样本来检测 XCI 嵌合体和 Xa/Xi 的遗传调控
与 Xa 和 Xi 表达水平 (Xa-/Xi- QTL) 的关联(目标 2)。我们的方法取得了显着的进步
与其他方法相比,提高了检测 Xa-/Xi- QTL 的能力,这些方法 1) 假定基因调控
Xa 和 Xi 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,并将识别的 Xa-/Xi- QTL 与现有基因组整合
广泛关联研究,以确定组织/细胞类型特异性 Xa 和 Xi 基因与性状关联。我们将申请
我们的方法针对各种特征(包括狼疮、糖尿病和成瘾)的一些最大的数据集。全面的,
我们提出的方法将允许全面评估 X 染色体和 XCI 逃逸的作用
在疾病和性状的病因学中发挥着作用,特别是那些具有性别偏见的疾病和特征,如自身免疫性疾病。
项目成果
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