The best-laid plans of mice and men / Often go awry — Robert Burns

If mouse models of human disease are used incautiously, the best-laid plans of researchers might also, as the poet said, go awry. Researchers, however, may avoid coming to grief if they heed results that have been compiled by the Mouse ENCODE Consortium, which has published a raft of articles that systematically compare (and contrast) the mouse and human genomes. These articles indicate that the systems that are used to control gene activity have many similarities in mice and humans, and have been conserved through evolutionary time.

The Mouse ENCODE Consortium is part of the ENCODE, or ENCyclopedia Of DNA Elements, program. With support from the National Human Genome Research Institute (NHGRI), ENCODE is building a comprehensive catalog of functional elements in the human and mouse genomes. The catalog is meant to provide insights into gene regulation and other systems important to mammalian biology. It may also help researchers determine when the mouse is an appropriate model to study human biology and disease. And finally, it might explain some of the limitations of mouse models.
The Mouse ENCODE Consortium reported its findings November 19 and in four papers that appeared in Nature:

  • “A comparative encyclopedia of DNA elements in the mouse genome”
  • “Principles of regulatory information conservation between mouse and human”
  • “Topologically associating domains are stable units of replication-timing regulation”
  • “Conservation of trans-acting circuitry during mammalian regulatory evolution”

The first of the Nature papers listed above stated that the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications, and replication domains throughout the mouse genome in diverse cell and tissue types.

“By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization,” the paper’s authors explained. “Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.”

In many cases, the Mouse ENCODE Consortium investigators found that some DNA sequence differences linked to diseases in humans appeared to have counterparts in the mouse genome. They also showed that certain genes and elements are similar in both species, providing a basis to use the mouse to study relevant human disease. However, they also uncovered many DNA variations and gene expression patterns that are not shared, potentially limiting the mouse's use as a disease model. 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, the Mouse ENCODE Consortium 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.

Besides publishing in Nature articles, researchers affiliated with the Mouse ENCODE Consortium presented related studies in journals such as Blood, Genome Biology, Genome Research, Nature Communications, the Proceedings of the National Academy of Sciences, and Science.

The Science paper, “Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution,” more than 1.3 million deoxyribonuclease I–hypersensitive sites (DHSs) in 45 mouse cell and tissue types were systematically compared with human DHS maps from orthologous compartments. It was found that about 35% 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,” said the study’s senior author, John Stamatoyannopoulos, M.D., associate professor of genome sciences and medicine at the University of Washington, Seattle. “Such repurposing represents a tremendously facile switch that nature can use to achieve regulatory control.”

In the study in the Proceedings of the National Academy of Sciences, investigators describe how they compared gene expression in 15 different tissue types in mice and humans. Contrary to previous evidence, the investigators 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.

“In general, the gene regulation machinery and networks are conserved in mouse and human, but the details differ quite a bit,” noted one of the study’s authors, Michael Snyder, Ph.D., director, Stanford Center for Genomics and Personalized Medicine, Stanford University, Stanford, California. “By understanding the differences, we can understand how and when the mouse model can best be used.”

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