Mouse model of human disease still good, but significant differences exist

Scientists at Penn State College of Medicine, working alongside an international team of researchers, have produced the most complete encyclopedia of functional elements in the mouse genome to date and compared it to the human genome. The findings, published recently in Nature, uphold the mouse model of human disease, but pinpoint important differences in gene expression that will guide future health research.

Mice are the premier model organism for research into human health and disease because they share most of their protein-coding DNA with us. However, only a small fraction—less than 2 percent—of human and mouse DNA is used to code the building blocks of life. The regulatory elements in our DNA that control the expression of these genes are equally important, if not more so, to disease development and progression, and our understanding of it.

Using high-throughput DNA sequencing techniques, the research team looked at these functional elements in more than 1,000 data sets produced from over 100 mouse cell types and tissues. They were able to assign potential regulatory functions to 12.6 percent of the mouse genome. They then compared these elements and their functions to those of humans.

“This is the most comprehensive effort to do a genomic comparison between humans and mice at this level, including the regulatory elements and gene expression,” said Feng Yue, an assistant professor in the department of biochemistry and molecular biology at Penn State College of Medicine. “We looked at regulations of genes, rather than genes themselves, and whether the gene is expressed in certain tissues or how much the gene is expressed there. We wanted to learn which gene expression patterns were conserved between humans and mice during mammalian evolution, and which gene expression patterns diverged.”

Major similarities, but also important differences, emerged.

Although much similarity exists, mouse and human gene expression differs significantly in specific biological pathways.

“What we found is that the majority of the gene expression patterns are very similar in human and mouse,” Yue said. “That shows that, indeed, the mouse is a good system to use in the study of human disease.

“But there are some genes whose patterns are not quite conserved between human and mouse,” he continued. This divergence was most profound for areas of the mouse genome involved in the immune system and metabolic processes. “These genes may function in a different way between human and mouse.”

The functions of these similar genes likely diverged as mice and humans adapted to their unique environments.

Despite the differences, mice can still be used to study the immune system and metabolic processes in humans.

“In studying these systems in mice, we’ll just need to be more careful and conduct more experiments,” Yue said.

Yue and his team are part of the Mouse ENCODE Consortium, a complement to the ENCODE (Encyclopedia of DNA Elements) Consortium, an international collaboration of research groups funded by the National Human Genome Research Institute (NHGRI).

Also involved in this research from Penn State Hershey is M.D./Ph.D. student Yanli Wang.

The  National Institutes of Health, the Spanish Plan Nacional, the National Science Foundation Graduate Research Fellowship, the Wellcome Trust, the National Human Genome Research Institute and the European Molecular Biology Laboratory funded this research. (R01HG003991, 1U54HG007004, 3RC2HG005602, GM083337, GM085354, F31CA165863, RC2HG005573, R01DK065806 and R01HD043997-09)

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