Newswise — Scientists have unearthed a COVID-19 vulnerability mechanism through a recently devised instrument. The instrument, BURRITO, records live alterations in gene expression during the innate immune reaction, enabling scientists to pinpoint genes and molecular pathways linked to the risk of the illness that were formerly excessively intricate to detect or comprehend.
Employing GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity), scientists from the Wellcome Sanger Institute, the National Center for Child Health and Development in Japan, Tel Aviv University, and their partners have detected a gene alteration impacting susceptibility to COVID-19. Gaining comprehension of genetic elements that contribute to COVID-19 contraction and seriousness could furnish novel biological understandings concerning the development of the disease and ascertain potential therapeutic focal points. The application of this tool in uncovering additional vulnerability mechanisms for diverse human disorders holds promising prospects.
The research, featured in Nature Genetics (12 June), aids in unraveling the correlation between distinct genes, their levels of expression, and their potential association with susceptibility to diseases. The team emphasizes the effectiveness of the tool through a case study focused on COVID-19.
Diverse responses to COVID-19 are observed among individuals. Approximately 80 percent of infected individuals encounter a mild-to-moderate form of illness, whereas others suffer predominantly from severe respiratory symptoms necessitating hospitalization, and in some cases, intensive care. This variability can, in part, be attributed to disparities in our genetic makeup, particularly variations in the regulation of gene expression.
The regions within our DNA that influence gene expression are referred to as expression quantitative trait loci (eQTLs). These eQTLs can be likened to signposts that highlight genetic variations associated with alterations in the expression of specific genes. They have the capacity to regulate the extent to which a gene is activated or suppressed, consequently influencing the levels of proteins produced by that gene.
Although genome-wide association studies (GWAS) have successfully identified many disease-related variants associated with gene expression, they are limited in establishing causal relationships. On the other hand, genome-wide eQTL mapping has emerged as a promising approach for uncovering the fundamental genetic mechanisms underlying variations in disease outcomes. By analyzing the entire genome for eQTLs, this method has the potential to provide valuable insights into the intricate genetic factors contributing to variations in disease outcomes.
In this recent study, researchers aimed to investigate immune responses specific to individual patients by mapping eQTLs. To achieve this, they utilized a novel approach that highlighted the impact of genetic variations within cells on the overall immune response observed among different individuals. By mapping eQTLs, the study shed light on the intricate relationship between genetic diversity and variations in immune responses among patients.
To evaluate the effectiveness of GASPACHO, a team of researchers from the Wellcome Sanger Institute, along with their collaborators from Japan and Tel Aviv University, stimulated an antiviral response in human fibroblast cells derived from 68 healthy donors. They then examined and analyzed the cells using single-cell transcriptomics, utilizing GASPACHO as part of their investigation. This experimental setup allowed them to assess the performance and capabilities of GASPACHO in studying the gene expression patterns and responses to viral infection at the single-cell level.
GASPACHO employs non-linear regression modeling to effectively capture the dynamic fluctuations of eQTLs during various stages of the immune response. Unlike previous approaches in eQTL mapping that aggregated single-cell data by measuring average gene expression across multiple cells, GASPACHO offers a more refined and cell-specific resolution. This capability enables the tracking of changes over time and across individual cells, providing a deeper understanding of how eQTLs evolve throughout the immune response.
In their study, the research team successfully identified 1,275 eQTLs distributed across the genome. These eQTLs were found to modify gene expression patterns along the innate immune response, displaying variations among different individuals. The findings hold relevance for 40 immune-related diseases, including conditions such as Crohn's disease and diabetes. The identification of these eQTLs provides valuable insights into the genetic mechanisms underlying immune-related disorders and offers potential avenues for further research and understanding.
During the application of the tool to examine variations in COVID-19 outcomes, the researchers made an intriguing discovery. They observed that individuals who were more susceptible to contracting COVID-19 exhibited lower expression of the OAS1 gene variant. The OAS1 gene is responsible for encoding a protein that plays a crucial role in eliminating viral RNA from within the cell. This finding suggests a potential connection between the expression levels of the OAS1 gene and the likelihood of COVID-19 infection, providing valuable insights into the genetic factors that may contribute to disease susceptibility.
In COVID-19 patients, the research team made the noteworthy observation that nasal epithelial cells, as well as monocytes present in the blood (both cell types targeted by the virus), displayed lower levels of OAS1 expression compared to a reference genotype group. Their findings indicate that the expression of OAS1 can be influenced by a common splicing variant known as OAS1 splicing QTL. This variant involves a genetic alteration at the boundary of an exon and intron within the DNA sequence. In these specific cells, the splicing variant is likely to directly impact the effectiveness of viral RNA clearance in individuals, thereby providing a potential explanation for the compromised clinical outcomes observed in the COVID-19 patient group.
Indeed, further exploration of this genetic alteration and its implications is necessary to gain a comprehensive understanding of its role in disease susceptibility. However, the insights gained from this study shed light on the molecular mechanisms involved in susceptibility to COVID-19 and other immune-related disorders. This knowledge serves as a foundation for potential therapeutic developments that leverage these genetic mechanisms. By targeting and modulating these molecular pathways, it may be possible to develop novel therapeutic approaches to mitigate the risk and severity of COVID-19 and other immune-related diseases in the future.
Dr. Natsuhiko Kumasaka, the study's first author from the National Center for Child Health and Development in Japan, emphasized the potential utility of OAS1 and other genes within the same cascade as potential drug targets or in drug discovery for combating COVID-19. However, Dr. Kumasaka also highlighted the importance of further research to gain a deeper understanding of the specific mechanisms by which OAS1 or related genes contribute to the development and progression of COVID-19. Additional investigations are necessary to unravel the intricate details of these mechanisms before their potential therapeutic applications can be fully realized.
Dr. Tzachi Hagai, co-lead author of the study from Tel Aviv University, emphasized the significance of the study's findings in highlighting how even small genetic variations can have a profound impact on our health and susceptibility to diseases. These genetic variations influence the activity levels of our genes, thereby influencing various traits, diseases, and even responses to drugs. Dr. Hagai noted that while genetic factors are only part of a larger puzzle that includes environmental, clinical, and social factors, their research provides insights into the molecular mechanisms underlying these interactions. This emphasizes the importance of ongoing scientific investigations to better understand the complex interplay between human genetics and the outcomes of pathogen infections, including emerging viruses such as SARS-CoV-2.
Dr. Sarah Teichmann, co-lead author of the study from the Wellcome Sanger Institute and co-chair of the Human Cell Atlas organizing committee, highlighted the significance of the newly developed tool in harnessing the vast amount of data generated by the Human Cell Atlas project, which aims to map every cell type in the human body. Dr. Teichmann expressed optimism that the tool, by facilitating in-depth analysis of cellular data, will enable the discovery of numerous underlying genetic mechanisms. Ultimately, this knowledge can lead to the identification of potential drug targets, thereby facilitating the development of novel treatments for various diseases. The tool has the potential to contribute significantly to advancing our understanding of human biology and improving healthcare outcomes.
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