On Sept. 27, 2022, the National Institutes of Health (NIH) announced it had launched 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 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.

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.

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.

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.