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An analytical framework for decoding cell type-specific genetic variation of gene regulation.

ABSTRACT: A deeper understanding of genetic regulation and functional mechanisms underlying genetic associations with complex traits and diseases is impeded by cellular heterogeneity and linkage disequilibrium. To address these limits, we introduce Huatuo, a framework to decode genetic variation of gene regulation at cell type and single-nucleotide resolutions by integrating deep-learning-based variant predictions with population-based association analyses. We apply Huatuo to generate a comprehensive cell type-specific genetic variation landscape across human tissues and further evaluate their potential roles in complex diseases and traits. Finally, we show that Huatuo's inferences permit prioritizations of driver cell types associated with complex traits and diseases and allow for systematic insights into the mechanisms of phenotype-causal genetic variation.

SUBMITTER: Xiao Y

PROVIDER: S-EPMC10313894 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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An analytical framework for decoding cell type-specific genetic variation of gene regulation.

Xiao Yanyu Y Wang Jingjing J Li Jiaqi J Zhang Peijing P Li Jingyu J Zhou Yincong Y Zhou Qing Q Chen Ming M Sheng Xin X Liu Zhihong Z Han Xiaoping X Guo Guoji G

Nature communications 20230630 1

A deeper understanding of genetic regulation and functional mechanisms underlying genetic associations with complex traits and diseases is impeded by cellular heterogeneity and linkage disequilibrium. To address these limits, we introduce Huatuo, a framework to decode genetic variation of gene regulation at cell type and single-nucleotide resolutions by integrating deep-learning-based variant predictions with population-based association analyses. We apply Huatuo to generate a comprehensive cell ...[more]

PMID: 37391400

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Project description:BackgroundGenome-wide association studies have identified genetic variants associated with the risk of brain-related diseases, such as neurological and psychiatric disorders, while the causal variants and the specific vulnerable cell types are often needed to be studied. Many disease-associated genes are expressed in multiple cell types of human brains, while the pathologic variants affect primarily specific cell types. We hypothesize a model in which what determines the manifestation of a disease in a cell type is the presence of disease module comprised of disease-associated genes, instead of individual genes. Therefore, it is essential to identify the presence/absence of disease gene modules in cells.MethodsTo characterize the cell type-specificity of brain-related diseases, we construct human brain cell type-specific gene interaction networks integrating human brain nucleus gene expression data with a referenced tissue-specific gene interaction network. Then from the cell type-specific gene interaction networks, we identify significant cell type-specific disease gene modules by performing statistical tests.ResultsBetween neurons and glia cells, the constructed cell type-specific gene networks and their gene functions are distinct. Then we identify cell type-specific disease gene modules associated with autism spectrum disorder and find that different gene modules are formed and distinct gene functions may be dysregulated in different cells. We also study the similarity and dissimilarity in cell type-specific disease gene modules among autism spectrum disorder, schizophrenia and bipolar disorder. The functions of neurons-specific disease gene modules are associated with synapse for all three diseases, while those in glia cells are different. To facilitate the use of our method, we develop an R package, CtsDGM, for the identification of cell type-specific disease gene modules.ConclusionsThe results support our hypothesis that a disease manifests itself in a cell type through forming a statistically significant disease gene module. The identification of cell type-specific disease gene modules can promote the development of more targeted biomarkers and treatments for the disease. Our method can be applied for depicting the cell type heterogeneity of a given disease, and also for studying the similarity and dissimilarity between different disorders, providing new insights into the molecular mechanisms underlying the pathogenesis and progression of diseases.

Project description:Understanding how genetic variation affects distinct cellular phenotypes, such as gene expression levels, alternative splicing and DNA methylation levels, is essential for better understanding of complex diseases and traits. Furthermore, how inter-individual variation of DNA methylation is associated to gene expression is just starting to be studied. In this study, we use the GenCord cohort of 204 newborn Europeans' lymphoblastoid cell lines, T-cells and fibroblasts derived from umbilical cords. The samples were previously genotyped for 2.5 million SNPs, mRNA-sequenced, and assayed for methylation levels in 482,421 CpG sites. We observe that methylation sites associated to expression levels are enriched in enhancers, gene bodies and CpG island shores. We show that while the correlation between DNA methylation and gene expression can be positive or negative, it is very consistent across cell-types. However, this epigenetic association to gene expression appears more tissue-specific than the genetic effects on gene expression or DNA methylation (observed in both sharing estimations based on P-values and effect size correlations between cell-types). This predominance of genetic effects can also be reflected by the observation that allele specific expression differences between individuals dominate over tissue-specific effects. Additionally, we discover genetic effects on alternative splicing and interestingly, a large amount of DNA methylation correlating to alternative splicing, both in a tissue-specific manner. The locations of the SNPs and methylation sites involved in these associations highlight the participation of promoter proximal and distant regulatory regions on alternative splicing. Overall, our results provide high-resolution analyses showing how genome sequence variation has a broad effect on cellular phenotypes across cell-types, whereas epigenetic factors provide a secondary layer of variation that is more tissue-specific. Furthermore, the details of how this tissue-specificity may vary across inter-relations of molecular traits, and where these are occurring, can yield further insights into gene regulation and cellular biology as a whole.

Project description:MotivationRecent advances in sequencing technology provide opportunities to study biological processes at a higher resolution. Cell type annotation is an important step in scRNA-seq analysis, which often relies on established marker genes. However, most of the previous methods divide the identification of cell types into two stages, clustering and assignment, whose performances are susceptible to the clustering algorithm, and the marker information cannot effectively guide the clustering process. Furthermore, their linear heuristic-based cell assignment process is often insufficient to capture potential dependencies between cells and types.ResultsHere, we present Interpretable Cell Type Annotation based on self-training (sICTA), a marker-based cell type annotation method that combines the self-training strategy with pseudo-labeling and the nonlinear association capturing capability of Transformer. In addition, we incorporate biological priori knowledge of genes and pathways into the classifier through an attention mechanism to enhance the transparency of the model. A benchmark analysis on 11 publicly available single-cell datasets demonstrates the superiority of sICTA compared to state-of-the-art methods. The robustness of our method is further validated by evaluating the prediction accuracy of the model on different cell types for each single-cell data. Moreover, ablation studies show that self-training and the ability to capture potential dependencies between cells and cell types, both of which are mutually reinforcing, work together to improve model performance. Finally, we apply sICTA to the pancreatic dataset, exemplifying the interpretable attention matrix captured by sICTA.Availability and implementationThe source code of sICTA is available in public at https://github.com/nbnbhwyy/sICTA. The processed datasets can be found at https://drive.google.com/drive/folders/1jbqSxacL_IDIZ4uPjq220C9Kv024m9eL. The final version of the model will be permanently available at https://doi.org/10.5281/zenodo.13474010.

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An analytical framework for decoding cell type-specific genetic variation of gene regulation.

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An analytical framework for decoding cell type-specific genetic variation of gene regulation.

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