March 15, 2016

 

 Searching beyond the lamplight

​Posted March 2, 2016

Even after the human genome was mapped, genetic researchers continued to focus on known kinases.

Colin Fletcher, PhD, program director for the Knockout Mouse Project of the National Human Genome Research Institute, said researchers had trouble getting funding for studies on the “dark” areas of the genome about which little was known because of the uncertainty of research results. The National Institute of Health–funded Knockout Mouse Project is part of an international effort to create and phenotype mice with individual genes turned off to identify how similar genes in humans may contribute to disease. 

He said the project can show that a particular gene is connected with, say, T-cell development, and provide enough information for someone to develop hypotheses and seek funding for more extensive study. 

The NIH is participating in the International Mouse Phenotyping Consortium, which was started in 2011 with plans to create and phenotype about 20,000 “knockout” mouse strains to discover the biological function of every known or predicted protein-coding gene in mice and build “the first truly comprehensive, functional catalogue of a mammalian genome.” 

While laboratories had developed knockout mice before the project, Dr. Fletcher said many researchers were specialized and “looking under the lamppost,” missing phenotypic information because they were looking in a narrow area. The NIH project instead gathers data through robust and sensitive assays, providing a broad array of data, he said. 

The project participants are expected to surpass 5,000 phenotyped mouse models this fall, and Dr. Fletcher hopes that at least 5,000 more will be created through a five-year extension running through 2021, especially with a shift toward CRISPR-Cas9 gene editing and increased program efficiency. He described the CRISPR-Cas 9 technology as an astonishing, powerful breakthrough, and he likened the improvements in gene editing technology to “a snowball going downhill.”

While the Knockout Mouse Project calls for phenotypes for about 20,000 mouse genes, Dr. Fletcher places his target between 16,000 and 20,000, short of a full genomic catalogue that he said would include genes without counterparts in humans—such as some mouse olfactory receptor–coding genes—or that may lack function. 

About 30 percent of null alleles induced in the project have been lethal in embryos or have been sources of reduced viability, information Dr. Fletcher expects could be useful in related fields of human medicine.