NIH initiative to systematically investigate and establish function of every human gene

The National Institutes of Health is launching a program to better understand the function of every human gene and generate a catalog of the molecular and cellular consequences of inactivating each gene. The Molecular Phenotypes of Null Alleles in Cells (MorPhiC) program, managed by the National Human Genome Research Institute, aims to systematically investigate the function of each gene through multiple phases that will each build upon the work of the previous.

The program will be funded initially for five years for a total of $42.5 million, pending the availability of funds. Phase 1 of the program will focus on 1,000 protein-coding genes and serve as a pilot phase and has 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 other researchers can reproduce.

“The function of thousands of genes is still a mystery, and they likely serve vital biological roles," said Colin Fletcher, Ph.D., NHGRI program director in the Division of Genome Sciences. “Understanding fundamental biology can help us figure out why certain diseases occur and how can we develop drugs to target and treat those diseases.”

Projects funded by the program will use versions of genes that do not make functional proteins, called null alleles. In the absence of making its functional protein, a given gene’s function can be more readily deduced by studying the resulting biological characteristics, or phenotype. The researchers expect this process to make it easier to interpret the results.

Currently, over 6,000 out of the estimated 19,000 protein-coding genes have not been well-studied. Among the genes that have been studied, only a subset of their functions is well-characterized.

The function of thousands of genes is still a mystery, and they likely serve vital biological roles. Understanding fundamental biology can help us figure out why certain diseases occur and how can we develop drugs to target and treat those diseases.

Creating a catalog of what all human genes do is no easy feat. Most genes are likely to have more than one function and behave differently depending on the type of cell in which they are expressed. In addition, genes may turn on or off depending on the cell’s relationship to surrounding cells, environment and age.

Research funded by the MorPhiC program will use cell culture models such as organoids, which are miniature, three-dimensional models composed of multiple cell types that mimic the function of real tissues and organs. Research that works with cells in culture has a major advantage: it can more robustly study human cells, and therefore, human genes. All data will be made available to the broader research community. If Phase 1 is successful, NIH will activate a second phase to characterize a larger set of human genes.

“MorPhiC is meant to add another layer of functional information between the gene knock-out at the DNA level and the organism-level effects. We want to catalog the effects of knocking out each gene within cells and — together with information from other studies — use that to understand how genes function to produce an organism,” said Adam Felsenfeld, Ph.D., NHGRI program director in the Division of Genome Sciences.

The MorPhiC program offers a new approach to understanding gene function when compared to other programs at NIH and NHGRI. For example, a well-established NIH effort to probe gene function has been investigating the consequences of knocking out genes in mice at the level of tissues and organs as part of the Knockout Mouse Program. Another effort is applying new technologies, genome-sequencing strategies and analytical approaches to significantly increase the proportion of human genetic diseases with an identified genetic cause, as part of the Genomics Research to Elucidate the Genetics of Rare Diseases Consortium. Research into understanding how genomic variation affects genome function and phenotype is also an area of ongoing NHGRI investment through the Impact of Genomic Variation on Function Consortium.

“MorPhiC complements these other efforts by examining the impact of human gene knock outs at the molecular and cellular level,” said Carolyn Hutter, Ph.D., director in the Division of Genome Science. “Ultimately, catalytic advances will come when we are able to collaborate across these different programs.”

Funding for Phase 1 of the MorPhiC program will be awarded to support the following investigators:

• Mazhar Adli, Ph.D.
  Northwestern University Feinberg School of Medicine, Chicago
  Molecular and cellular characterization of essential human genes
   
• Luke Gilbert, Ph.D.
  University of California, San Francisco 
  Spatial multiomic mapping of gene function with CRISPRoff
   
• Danwei Huangfu, Ph.D.
  Sloan-Kettering Institute for Cancer Research, New York City
  Center for scalable knockout and multimodal phenotyping in genetically diverse human genomes
   
• Paul Robson, Ph.D.
  Jackson Laboratory, Farmington, Connecticut
  JAX MorPhiC data production center
   
• Stephan Schürer, Ph.D.
  University of Miami
  MorPhiC data resource and administrative coordinating center