Department of Health
and Human Services (HHS)
and Human Services (HHS)
EXPIRED
December 3, 2020
PA-18-868 - Novel Approaches for Relating Genetic Variation to Function and Disease (R01 Clinical Trial Not Allowed)
PA-18-867 - Novel Approaches for Relating Genetic Variation to Function and Disease (R21 Clinical Trial Not Allowed)
PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)
National Human Genome Research Institute (NHGRI)
The National Human Genome Research Institute (NHGRI) is issuing this Notice of Special Interest (NOSI) to encourage applications focused on developing novel methods to perform high-throughput molecular and cellular phenotyping in order to elucidate the functional consequences of DNA variation.
Background
Understanding the relationship between genotype and phenotype remains a central problem of biology. In terms of human health, understanding the clinical significance of variation in a patient genome is critical for the application of genetic medicine. While progress has been made in linking alleles to traits and diseases, in most cases the physiological impact or disease mechanism is not understood. Furthermore, continuing advances in DNA sequencing are driving the discovery of millions of sequence variants whose significance are unknown. The scale of the problem has overwhelmed the capacity of traditional low throughput functional assays commonly employed to define the biological mechanisms underlying specific genetic diseases and traits. Methods to perform molecular and cellular phenotyping at scale will be required to elucidate the functional consequences of DNA variation.
Research Objectives
The emerging paradigm in this field is to couple comprehensive saturation mutagenesis with high throughput phenotyping by multiplexing. Thus, rather than post-hoc analyses of candidate variants, the approach prospectively interrogates nearly all possible variants. These strategies, employing methods known variously as “deep mutational scanning”, “multiplexed assays of variant effects” or “massively parallel reporter assays,” have been applied to both protein coding sequences and non-coding regulatory elements. To date readouts have included phenotypes such as cell viability, expression of a fluorescent reporter tag, or gene expression. Significant technological improvements will be required to fully exploit this approach. For example, it is estimated that only about 50% of disease genes have an assay that is compatible with multiplexing. Furthermore, complex cellular phenotypes, such as morphology, differentiation and transcriptional state, or network status have not been deeply interrogated.
The objective of this NOSI is to stimulate the development of novel high-throughput phenotyping assays of high utility, generalizability, and rigor, in order to expand their utility and the range of molecular and cellular phenotypes that can be interrogated. For these purposes we define utility broadly as the improved ability to explore a process of high importance to basic or clinical science. For example, utility may be defined as having the sensitivity and dynamic range required to distinguish disease-relevant alleles from functionally normal genetic elements. Utility could be relative to the ability to increase scale and/or information content relevant to understanding gene and/or non-coding regulatory element function. Utility could be relevant to improved ability to query physiological functions that are poorly accessible to current methods, such as cell-cell signaling, functions specific to differentiated cells or tissues, measuring the impact of genetic background, or detecting the interplay of multiple genetic variants on function.
Applicants should propose assays that are generalizable, in being able to interrogate function in a genome-wide approach across multiple input sources, including cell lines, tissues, organoids, and organisms. Rigor can be addressed by explaining the suitability of quality control metrics to evaluate the replicability and reliability of the assay. Finally, it is important to recognize that aggregation and integration of assay data will be critically important to developing a comprehensive understanding of genome function. Thus, applicants should consider the design and deposition of datasets, and associated metadata and protocols, in a manner that supports the FAIR principles.
Application and Submission Information
This notice applies to due dates on or after February 5, 2021 and subsequent receipt dates of current and reissued FOAs through January 10, 2024.
Applications in response to this NOSI must be submitted using one of the following target opportunities or subsequently reissued equivalents.
PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)
PA-18-868 - Novel Approaches for Relating Genetic Variation to Function and Disease (R01 Clinical Trial Not Allowed)
PA-18-867 - Novel Approaches for Relating Genetic Variation to Function and Disease (R21 Clinical Trial Not Allowed)
All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:
Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.
Scientific/Research Contact(s)
Colin Fletcher, Ph.D.
National Human Genome Research Institute (NHGRI)
Telephone: (301) 496-7531
Email: [email protected]
Peer Review Contact(s)
Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).