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Principal Investigator: Havell Markus
Organization: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
Fiscal Year: 2024
Award: $34,800
Funding agency: National Institute of General Medical Sciences
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.
Terms: <Address><Adult-Onset Diabetes Mellitus><Alleles><Allelic Imbalance><Allelomorphs><Assay><Autoimmune Diseases><Bioassay><Biological Assay><Biology><Body Tissues><Causality><Cell Body><Cell Fraction><Cell Line><CellLine><Cells><Clinical><Complex><Data><Data Set><Development><Diabetes Mellitus><Differential Gene Expression><Disease><Disorder><Disproportionate number of females><Disproportionate number of women><Disproportionately affects females><Disproportionately affects women><Disproportionately impacts females><Disproportionately impacts women><Disproportionately in females><Disproportionately in women><Dosage Compensation><Dosage Compensation (Genetics)><Etiology><Female><GWA study><GWAS><Gender Bias><Gene Action Regulation><Gene Copy Number><Gene Dosage><Gene Expression Regulation><Gene Inactivation><Gene Regulation><Gene Regulation Process><Gene Silencing><Gene Transcription><Gene variant><Genes><Genetic><Genetic Transcription><Genomics><Genotype><Haplotypes><Health><Heritability><Heterozygote><Human><Human X Chromosome><Individual><Ketosis-Resistant Diabetes Mellitus><Knowledge><Link><Lupus><Lyonization><Maps><Maturity-Onset Diabetes Mellitus><Mendelian randomization><Methods><Modeling><Modern Man><Mosaicism><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Phase><Phenotype><Play><Population><QTL><Quantitative Trait Loci><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Regulation><Research><Role><Sampling><Series><Sex Bias><Shapes><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Statistical Methods><Strains Cell Lines><T2 DM><T2D><T2DM><Time><Tissue-Specific Differential Gene Expression><Tissue-Specific Gene Expression><Tissues><Transcription><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Variant><Variation><Work><X Chromosome><X Inactivation><X-Chromosome Inactivation><addiction><addictive disorder><adult onset diabetes><allele variant><allelic variant><autoimmune condition><autoimmune disorder><autoimmunity disease><causation><cell type><clinical relevance><clinically relevant><computational suite><cultured cell line><developmental><diabetes><disease causation><female bias><female preponderance><functional genomics><genetic architecture><genetic association><genetic variant><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic variant><heterozygosity><human tissue><improved><individual heterogeneity><individual variability><individual variation><ketosis resistant diabetes><lymphoblast><male><maturity onset diabetes><mosaic diseases><mosaic disorders><novel><sex><social role><statistic methods><tool><trait><transcriptional silencing><transcriptome sequencing><transcriptomic sequencing><type 2 DM><type II DM><type two diabetes><whole genome association analysis><whole genome association studies><whole genome association study><women's preponderance>