News Statement
Tuesday, 27 September 2022
The Molecular Phenotypes of Null Alleles in Cells program will initially examine genes that code for proteins.
The National Institutes of Health are undertaking a study to better comprehend the function of every human gene and compile a record of the molecular and cellular effects of inactivating each gene. The National Human Genome Research Institute’s Molecular Phenotypes of Null Alleles in Cells (MorPhiC) initiative seeks to methodically explore the function of each gene through various phases that will each build on the preceding.
Initially, the program will be funded for a total of $42.5 million over five years, contingent upon the availability of finances. Phase 1 of the program will focus on 1,000 protein-coding genes and serve as a pilot phase, with three goals: exploring multiple methods of inactivating, or “knocking out,” gene function; developing molecular and cellular systems that model multiple human tissues and developmental stages; and developing molecular and cellular approaches to catalog gene function that can be replicated by other researchers.
Colin Fletcher, Ph.D., program director in the Division of Genome Sciences at the National Human Genome Research Institute (NHGRI), stated, “The function of thousands of genes is still unknown, and it is likely that they play critical biological roles.” Understanding basic biology can help us determine why certain diseases occur and how we can design medications to target and treat them.
The program will subsidize the use of null alleles, which are variants of genes that do not produce functional proteins. In the absence of a functional protein, a gene’s function can be more easily deduced by examining the phenotype, or the resulting biological characteristics. The researchers anticipate that this procedure will facilitate interpretation of the results.
Over 6,000 of the approximately 19,000 protein-coding genes have not been thoroughly investigated. Only a portion of the examined genes’ functions have been thoroughly described.
The task of cataloging the functions of all human genes is not simple. It is probable that the majority of genes have several functions and behave differently depending on the cell type in which they are produced. In addition, genes may become active or inactive based on the cell’s connection with neighboring cells, its environment, and its age.
The MorPhiC initiative will fund research utilizing cell culture models, such as organoids, which are small, three-dimensional models made of various cell types that imitate the function of actual tissues and organs. A key advantage of research involving cultured cells is that it allows for a more thorough examination of human cells and, by extension, human genes. All data will be made accessible to the scholarly community at large. NIH will initiate a second phase to define a bigger collection of human genes if Phase 1 is effective.
“MorPhiC is intended to provide further functional information between gene knock-out at the DNA level and organism-level effects. Adam Felsenfeld, Ph.D., program director in the Division of Genome Sciences at the National Human Genome Research Institute (NHGRI), said, “We want to catalog the effects of knocking out each gene within cells and, in conjunction with data from other studies, use that to understand how genes function to produce an organism.”
Compared to other NIH and NHGRI studies, the MorPhiC study provides a novel method to investigating gene function. As part of the Knockout Mouse Program, a well-established NIH effort to investigate gene function has examined the effects of knocking out genes in mice at the level of tissues and organs. As part of the Genomics Research to Elucidate the Genetics of Rare Diseases Consortium, new technology, genome-sequencing methodologies, and analytical approaches are being used to greatly enhance the fraction of human genetic diseases with identifiable genetic causes. Through the Impact of Genomic Variation on Function Consortium, the NHGRI is also investing in ongoing research into how genomic variation influences genome function and phenotype.
“MorPhiC complements these other initiatives by investigating the impact of human gene knockouts at the molecular and cellular levels,” said Carolyn Hutter, Ph.D., director of the Division of Genome Science. Ultimately, catalytic advancements will result from our ability to collaborate across these various programs.
The following investigators will receive funding for the first phase of the MorPhiC program:
Northwestern University Feinberg School of Medicine, Chicago; Dr. Mazhar Adli
Characterization at the molecular and cellular level of key human genes
San Francisco, University of California, Luke Gilbert, Ph.D.
CRISPRoff spatial multiomic mapping of gene function
Sloan-Kettering Institute for Cancer Research, New York City Center for scalable knockout and multimodal phenotyping in genetically varied human genomes, Danwei Huangfu, Ph.D.
Paul Robson, Ph.D., Jackson Laboratory, Farmington, Connecticut, JAX MorPhiC data center
University of Miami MorPhiC data resource and administrative coordinating center directed by Stephan Schürer, Ph.D.
The National Human Genome Research Institute (NHGRI) is one of the 27 institutes and centers that make up the National Institutes of Health (NIH), a branch of the Department of Health and Human Services. The Division of Intramural Research of the National Human Genome Research Institute develops and implements technologies to investigate, diagnose, and cure genomic and genetic illnesses. There is more information on NHGRI available at www.genome.gov.
NIH stands for the National Institutes of Health. The National Institutes of Health (NIH), the nation’s medical research organization, consists of 27 Institutes and Centers and is part of the U.S. Department of Health and Human Services. The NIH is the principal government organization that conducts and supports basic, clinical, and translational medical research and investigates the causes, treatments, and cures for both common and rare diseases. Visit www.nih.gov for more information on the NIH and its initiatives.
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