The GASPACHO tool (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity) has been implemented by researchers to elucidate a genetic variation mechanism linked to COVID-19 susceptibility. This remarkable tool allows scientists to monitor gene expression alterations in the innate immune response, illuminating previously elusive factors contributing to disease risk.
GASPACHO, a novel tool devised by researchers, has facilitated the discovery of a gene variant tied to heightened susceptibility to COVID-19. This tool enables tracking of gene expression fluctuations in the innate immune response, thereby aiding in pinpointing potential therapeutic targets.
By employing the recently developed GASPACHO tool, researchers have unearthed a COVID-19 susceptibility mechanism. GASPACHO records dynamic shifts in gene expression along the innate immune response, granting researchers the ability to identify genes and molecular pathways associated with disease risk that were formerly too intricate to detect or interpret.
Scientists at the Wellcome Sanger Institute, the National Center for Child Health and Development in Japan, Tel Aviv University, and their collaborative partners have identified a gene variant affecting COVID-19 susceptibility using GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity). Unraveling the genetic factors contributing to COVID-19 infection and severity can lead to new biological insights into disease pathogenesis and the identification of therapeutic targets. The tool’s potential to uncover additional susceptibility mechanisms across other human disorders is highly anticipated.
The study, released in Nature Genetics on June 12, contributes to understanding the link between specific genes, their expression levels, and their potential involvement in disease susceptibility. The team’s COVID-19 case study demonstrates the tool’s utility.
Responses to COVID-19 vary significantly among individuals. Approximately 80 percent of infected individuals experience a mild-to-moderate course of illness, while others suffer predominantly from severe respiratory symptoms necessitating hospitalization or even intensive care. This variation may be attributable, in part, to genetic differences, particularly those concerning the genetic regulation of gene expression.
Expression quantitative trait loci (eQTLs), regions that influence gene expression, function as genetic signposts, indicating which genetic variations are associated with changes in specific gene expression. These variations may alter the degree to which a gene is turned up or down, thereby leading to differences in protein levels produced by that gene.
While genome-wide association studies (GWAS) have pinpointed numerous disease-related variants involved in gene expression, suggesting eQTL involvement, they fall short in demonstrating causal relationships. However, genome-wide eQTL mapping shows promise in revealing the genetic mechanisms underlying disease outcome variations.
In this groundbreaking study, scientists aimed to investigate patient-specific immune responses by mapping eQTLs, using a unique approach to demonstrate how genetic variation within cells impacts overall immune response across individuals.
Researchers from the Wellcome Sanger Institute, alongside collaborators in Japan and at Tel Aviv University, induced an antiviral response in human fibroblast cells from 68 healthy donors, then profiled them using single-cell transcriptomics to test GASPACHO.
GASPACHO employs non-linear regression modeling to capture dynamic eQTL changes during various stages of the immune response. Unlike previous eQTL mapping efforts that aggregate single-cell data—measuring average gene expression across numerous cells—GASPACHO provides cell-specific resolution to track changes over time and across individual cells.
The researchers identified 1,275 eQTLs within the genome that modify gene expression along the innate immune response across individuals. These are relevant to 40 immune-related diseases, including Crohn’s disease and diabetes.
Applying GASPACHO to explore variation in COVID-19 outcomes, researchers found a lower expression of the OAS1 gene variant in individuals more likely to contract COVID-19. The OAS1 gene produces a protein that aids in eliminating viral RNA from the cell.
In COVID-19 patients, researchers discovered reduced OAS1 expression in nasal epithelial cells and monocytes in the blood—both types of cells targeted by the virus—compared to a reference genotype group. These findings suggest that a common splicing variant, the OAS1 splicing QTL, can modulate OAS1 expression in these target cell types. This genetic alteration, located at the boundary of an exon and intron, may directly influence the efficiency of viral RNA clearance in individuals, explaining the poor clinical outcome in the COVID-19 patient group.
Although further exploration is required to fully comprehend the role of this genetic alteration, it provides insights into the molecular mechanisms underlying susceptibility to COVID-19 and other immune-related diseases, laying the groundwork for the development of potential therapies based on these genetic mechanisms.
Dr. Natsuhiko Kumasaka, the study’s first author from the National Center for Child Health and Development in Japan, said: “Future work may enable us to leverage OAS1 and other genes within the same cascade in drug discovery or as therapeutic targets, but more research is required to understand the specific mechanisms by which OAS1 or related genes may contribute to COVID-19.”
Dr. Tzachi Hagai, co-lead author of the study from Tel Aviv University, remarked: “It’s astonishing how small differences in our genetic composition can impact our health and disease susceptibility by influencing our genes’ activity. While host-specific genetic factors form just one piece of the puzzle, our work illuminates the molecular mechanisms underpinning various traits, diseases, and drug responses and how these might interact with broader environmental, clinical, and social factors. The discoveries here highlight the importance of ongoing scientific endeavors to unravel the intricate interactions between human genetics and the outcome of pathogen infection, including by 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, said: “This innovative tool will be crucial for extracting meaningful insights from the vast amount of data being generated by the Human Cell Atlas, which aims to map every cell type in the human body. By using the tool, we hope to uncover many underlying genetic mechanisms, and ultimately drug targets to aid in the development of new treatments for a variety of diseases.”
Notes
Non-linear regression modeling is a statistical method used to analyze and describe relationships between variables that do not follow a straight line. It allows for more flexible representations of complex patterns and trends in the data.
Reference: “Mapping interindividual dynamics of innate immune response at single-cell resolution” by Natsuhiko Kumasaka, et al., 12 June 2023, Nature Genetics.
DOI: 10.1038/s41588-023-01421-y
Table of Contents
Frequently Asked Questions (FAQs) about GASPACHO tool
What is the GASPACHO tool?
GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity) is a novel research tool developed to uncover genetic variation mechanisms related to susceptibility to diseases, including COVID-19. It allows scientists to track changes in gene expression during the innate immune response.
What has the GASPACHO tool been used for in this study?
In this study, researchers used the GASPACHO tool to identify a gene variant that contributes to increased susceptibility to COVID-19. The tool has also allowed researchers to monitor dynamic changes in gene expression associated with the innate immune response.
How does the GASPACHO tool work?
The GASPACHO tool uses non-linear regression modeling to capture dynamic changes in gene expression along the innate immune response, providing cell-specific resolution to track changes over time and across individual cells.
What did the researchers discover about the OAS1 gene?
Researchers found that individuals more susceptible to COVID-19 demonstrated lower expression of the OAS1 gene variant. The OAS1 gene encodes a protein that helps remove viral RNA from the cell, which is critical in controlling infection.
What are the potential implications of this research?
The insights provided by the GASPACHO tool could lead to a better understanding of genetic factors contributing to COVID-19 and other diseases, potentially leading to new therapeutic targets. Additionally, it may help scientists identify similar genetic susceptibility mechanisms for other human disorders.
More about GASPACHO tool
- Nature Genetics
- Wellcome Sanger Institute
- National Center for Child Health and Development, Japan
- Tel Aviv University
- Human Cell Atlas
- Information about the OAS1 gene
5 comments
So we’re saying it’s all in the genes now? Seems a bit of a stretch to me, no? Still, if it leads to new treatments, I won’t complain.
im amazed at how much we’re learning about the virus. Genetics is so complex. This GASPACHO tool sounds promising for future research! 🙂
Genetics and health are so interconnected. Never heard of this OAS1 gene before, but now I’m curious! Hope this leads to some real solutions soon.
Wow, science keeps moving forward, eh? Cool to see how they are using these fancy tools to understand this covid thing better. keep up the good work, scientists!
Impressive work by the research team, GASPACHO appears to be a significant step forward in the field. Look forward to seeing how this can be applied to other diseases as well.