05:27am Saturday 04 April 2020

International team including Jackson Laboratory researchers develop mouse genetic blueprint

The team, led by researchers at the Wellcome Trust Sanger Institute and the University of Oxford, published two reports in the journal Nature about how they decoded and compared the genome sequence of 17 mouse strains.

Since the first mouse genome was sequenced by public and private teams in 2002—that of a female C57B6/J or “Black 6” Jackson mouse—the scientific world has amassed vast quantities of physiological data about the Black 6 strain and many other inbred strains. Researchers measure physical characteristics, known as phenotypes, such as blood pressure, heart rate, weight, cholesterol levels, and even some behaviors.

According to Laura Reinholdt, Ph.D., research scientist for The Jackson Laboratory’s Genetic Resource Science Technology Development unit, “We now have the potential to quickly attach much of that phenotyping information with genotypes, which is a powerful tool for discovering the genetic basis for biomedically important physical characteristics.” Reinholdt, Genetic Resource Science Director Leah Rae Donahue, Ph.D., and Genetic Resource Science research assistant Anne Czechanski were co-authors of one of the papers.

In creating this unique resource, the biggest catalogue for any vertebrate model organism, the team found an astonishing 56.6 million unique sites of variation (known as SNPs) among the strains, in addition to other more complex differences. Among these they identified sequence differences associated with over 700 biological differences, including markers for diseases such as diabetes and heart disease, so linking genes with medically important individual differences.

The catalogue, funded by the Medical Research Council and the Wellcome Trust, with mouse materials provided by The Jackson Laboratory, can be used by researchers to understand the genetic basis of individual variation, and to ask fundamental questions about how genes function and make us more or less likely to have particular diseases.

Inbred strains of mice are invaluable sources of genetic information. Every animal within each inbred strain is essentially genetically identical, but each strain is different from the others both in their genes and across a huge range of medically and biologically important characteristics.

“We are living in an era where we have thousands of human genomes at our fingertips,” says David Adams, Ph.D., of the Wellcome Trust Sanger Institute, who led the project. “The mouse, and the genome sequences we have generated, will play a critical role in understanding how genetic variation contributes to disease and will lead us towards new therapies.”

Reinholdt says the new resource will fast-track research by giving scientists a place to start when looking for genes associated with a given trait. “If you have one inbred strain of mouse that’s prone to glaucoma and one that’s not,” she explains, you can now very quickly get to the potential underlying genetic differences.”

She notes that when she started her postdoctoral training in 2001, before the release of the first public mouse genome sequencing data, the process of identifying genes associated with a particular phenotype was long and laborious. “You had to slowly walk your way down the chromosome to find the mutation underlying a trait of interest. You might spend your whole two-year postdoc tracking down a single gene.” Coauthor Thomas Keane, Ph.D., of the Wellcome Trust Sanger Institute, adds, “Now with our catalogue of variants the analysis of these mice is breathtakingly fast and can be completed in the time it takes to make a cup of coffee.”

Using the sequence of the 17 mouse genomes, the team looked for variants associated with quantitative trait loci (QTLs) implicating differences in the sequence between strains as being associated with the phenotypes that distinguish them.

The Jackson Laboratory scientists provided the DNA and tissue samples from pedigreed mice representing 15 of the 17 inbred strains of mice, some available only from Jackson repositories—a vital component in a project that establishes the official sequence of those strains. “We collected samples from not only a female representative of each strain,” Reinholdt adds, “but also from both her parents and a female sibling. Down the road this will be a valuable source of information about mutations that might be unique to the sequenced mouse.” The Jackson team also conducted other genetic tests for the project.

“This study is a first step in a long path that moves from understanding what the genome is, to what it does,” says study co-leader Jonathan Flint, Ph.D., of the Wellcome Trust Centre for Human Genetics.

The project will be extended by sequencing further mouse strains, defining the genetic changes in mouse cancers and investigating the effect of variants on gene function.

The Wellcome Trust Sanger Institute is one of the world’s leading genome centers. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.

The Jackson Laboratory is an independent, nonprofit biomedical research institution and National Cancer Institute-designated Cancer Center based in Bar Harbor, Maine, with a facility in Sacramento, California. Its mission is to discover the genetic basis for preventing, treating and curing human diseases, and to enable research and education for the global biomedical community. The Laboratory is the world’s source for more than 5,000 strains of genetically defined mice, is home of the mouse genome database and is an international hub for scientific courses, conferences, training and education.

Mouse genomic variation and its effect on phenotypes and gene regulation. Nature: doi:10.1038/nature10413, available online


Joyce Peterson, 207-288-6058, The Jackson Laboratory
Don Powell, 44-1223-496-928, Wellcome Trust Sanger Institute

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