Comparing the Mouse and Human Genomes (2014-12-10)

Researchers often turn to model organisms to understand the complex molecular mechanisms of the human body. The mouse has long been used to gain insights into gene function, disease, and drug development. But not all aspects of mouse biology reflect human biology. Understanding which aspects are similar will allow scientists to identify when mice can best serve as a useful model organism.

The mouse ENCODE project—part of the ENCODE, or ENCyclopedia Of DNA Elements, program—aims to examine the genetic and biochemical processes involved in regulating the mouse and human genomes. Launched by NIH’s National Human Genome Research Institute (NHGRI), ENCODE has been building a comprehensive catalog of functional elements in the human and mouse genomes. These elements include the genes that provide instructions to build proteins, non-protein-coding genes, and regulatory elements that control when genes are expressed (turned on and off) in different cells and tissues.

ENCODE scientists applied several genomic approaches to 123 different mouse cell types and tissues, and then compared them with the human genome. The results appeared in 4 papers in Nature on November 20, 2014, and several related papers in Science, Proceedings of the National Academy of Sciences, and other journals.

The researchers found that, at a general level, gene regulation and other systems important to mammalian biology have many similarities between mice and humans. Specific DNA sequence differences linked to diseases in humans often have counterparts in the mouse genome. Genes whose expression patterns are related in one species also tend to be similarly related in the other species. These findings validate the importance of using mouse models to study certain human diseases.

Mice and humans share approximately 70 percent of the same protein-coding gene sequences, which is just 1.5 percent of these genomes.

For example, investigators found that for the mouse immune system, metabolic processes and stress response, the activity of some genes varied between mice and humans, which echoes earlier research. The researchers subsequently identified genes and other elements potentially involved in regulating these mouse genes, some of which lacked counterparts in humans.

In general, the gene regulation machinery and networks are conserved in mouse and human, but the details differ quite a bit,” noted co-senior author Michael Snyder, Ph.D., director, Stanford Center for Genomics and Personalized Medicine, Stanford University, Stanford, California.

“We didn’t know before these results came out that there are a large number of genes with expression levels systematically different between mouse and human,” said Ross Hardison, Ph.D., director, Huck Institute for Comparative Genomics and Bioinformatics at Pennsylvania State University, University Park, and a co-senior author on the main Nature study and other publications. “Now we know which genes have expression patterns conserved between mouse and humans.

Two companion studies further illustrate differences between mouse and human. Co-senior Nature author John Stamatoyannopoulos, M.D., associate professor of genome sciences and medicine at the University of Washington, Seattle, and his colleagues compared more than 1.3 million genome locations called DNase 1 hypersensitivity sites (which identify regulatory DNA) in 45 mouse cell and tissue types to those in humans.
They reported in Science that about 35 percent of these elements were shared by mouse and human and were active in different types of cells. “We looked inside the shared regulatory sequences and found mouse and human genomes to have a common language in regulation, but that there is a tremendous amount of flexibility in evolution. For example, an element active in the mouse liver might be repurposed to be active in the brain in the human,” he said. “Such repurposing represents a tremendously facile switch that nature can use to achieve regulatory control.”

In a study in Proceedings of the National Academy of Sciences, Dr. Snyder and his colleagues compared gene expression in 15 different tissue types in mice and humans. Contrary to previous evidence, they found that some aspects of the gene readouts were more similar between different tissues in the same species than they were between the same tissues in both species.

More than a dozen related studies also appear or will appear in journals such as Genome Research, Genome Biology, Blood, and Nature Communications.

ENCODE data are freely shared with the biomedical community, and the mouse resource has been used by outside researchers in about 50 publications to date.

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Comparing the Mouse and Human Genomes

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