Investigators have developed an important mouse genetic blueprint that will speed up future research and understanding of human genetics. In two articles published in Nature on 14 September, the international team, led by investigators at the Wellcome Trust Sanger Institute and the University of Oxford, explain how they cracked and assessed the genome sequence of 17 mouse strains.

In creating this blueprint, the biggest resource for any vertebrate model organism, they discovered an amazing 56.7 million unique sites of variation (known as SNPs) between strains, as well as other more complicated differences. Among these they identified sequence differences linked with more than 700 biological differences, including markers for diseases – such as diabetes and heart disease, so connecting genes with medically important individual differences.

Mainly funded by the Medical Research Council and the Wellcome Trust, the blueprint can be used by investigators to understand the genetic basis of individual variation, and ask important questions regarding how genes work and how genes increase or decrease the chances of us having particular diseases.

Inbred strains of mice are a vital source of genetic information. Every inbred mouse is essentially genetically identical, but every mouse is different in both their genes and across a wide range of medically and biologically importance characteristics.

Dr Adams, from the Wellcome Trust Sanger Institute, who led the project, explained:

“We are living in an era where we have thousands of human genomes at our finger tips. The mouse, and the genome sequences we have generated, will play a crucial role in understanding of how genetic variations contributes to disease and will lead us towards new therapies.”

By using this blueprint investigators won’t have to rely as much on breeding mice in order to find mutations, they will be able to find mutations at a much faster rate by searching data on their computer.

These mice are used in all areas of biology to increase our understanding of human disease, and there is significantly more to discover. With the variants to hand, the task moves to understanding the biological consequences.

Dr Thomas Keane who was the first author on one of the reports, said:

“In some cases it has taken 40 years, an entire working life, to pin down a gene in a mouse model that is associated with a human disease, looking for the cause. 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.

Now we know where all the variants are, so the questions today are what do they do, and can we explain the phenotypic differences between different strains of mice?”

Importantly, the amount of mouse breeding and testing required to identify genes and mutations will be reduced thanks to the catalogue, which will reduce the mice needed for each investigation. The first discovery can be made on the computer. This wide-ranging blueprint will be vital for connecting variation in a trait with changes to DNA – the biologist’s journey from phenotype to genotype.

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

Professor Jonathan Flint, from the Wellcome Trust Center for Human Genetics, who co-led the investigation, explained:

“This study is a first step in a long path that moves from understanding what the genome is, to what it does.”

Professor Ian Jackson, joint head of Medical and Development Genetics at the Medical Research Council’s Human Genetics Unit, said:

“The biological differences across the inbred strains of mice model variation between individual humans. This resource, made possible through huge recent advances in sequencing technology, is transforming our understanding of how DNA sequence variation relates to gene function, and ultimately is associated with biology and human health.”

The project will be lengthened by sequencing additional mouse strains, defining the genetic changes in mouse cancers and researching the effect of variants on gene function.

The catalogue, combined with today’s faster sequencing, allows investigators to prove deeper to discover mutations affecting gene function much more faster. In addition to opening the door to the possibility of sequencing significantly large numbers of mice, with plans to extend the project to hundreds of mouse strains, a mission that just a few years ago would have seemed impossible.

Written by Grace Rattue