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December 8, 2014
Comparing the Mouse and Human Genomes
At a Glance
- An international group of researchers gained insights into how similarities and differences between mice and people arise from their genomes.
- The findings will help scientists better understand how and when mouse models can best be used to study human biology and disease.
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.
However, the researchers uncovered many DNA variations and gene expression patterns that are not shared between the species. Understanding these differences enhances the value of the mouse as a model organism. For example, the regulatory elements and activity of many genes of the immune system, metabolic processes, and stress response vary between mice and humans.
“In general, the gene regulation machinery and networks are conserved in mouse and human, but the details differ quite a bit,” notes Dr. Michael Snyder of Stanford University, a co-senior author on the main Nature study. “By understanding the differences, we can understand how and when the mouse model can best be used.”
“These results provide a wealth of information about how the mouse genome works, and a foundation on which scientists can build to further understand both mouse and human biology,” says NHGRI Director Dr. Eric Green.
ENCODE data are freely shared with the biomedical community. The mouse resource has already been used by researchers in about 50 publications to date.
Reference: A comparative encyclopedia of DNA elements in the mouse genome. Yue F, Cheng Y, Breschi A, Vierstra J, Wu W, Ryba T, Sandstrom R, Ma Z, Davis C, Pope BD, Shen Y, Pervouchine DD, Djebali S, Thurman RE, Kaul R, Rynes E, Kirilusha A, Marinov GK, Williams BA, Trout D, Amrhein H, Fisher-Aylor K, Antoshechkin I, DeSalvo G, See LH, Fastuca M, Drenkow J, Zaleski C, Dobin A, Prieto P, Lagarde J, Bussotti G, Tanzer A, Denas O, Li K, Bender MA, Zhang M, Byron R, Groudine MT, McCleary D, Pham L, Ye Z, Kuan S, Edsall L, Wu YC, Rasmussen MD, Bansal MS, Kellis M, Keller CA, Morrissey CS, Mishra T, Jain D, Dogan N, Harris RS, Cayting P, Kawli T, Boyle AP, Euskirchen G, Kundaje A, Lin S, Lin Y, Jansen C, Malladi VS, Cline MS, Erickson DT, Kirkup VM, Learned K, Sloan CA, Rosenbloom KR, Lacerda de Sousa B, Beal K, Pignatelli M, Flicek P, Lian J, Kahveci T, Lee D, Kent WJ, Ramalho Santos M, Herrero J, Notredame C, Johnson A, Vong S, Lee K, Bates D, Neri F, Diegel M, Canfield T, Sabo PJ, Wilken MS, Reh TA, Giste E, Shafer A, Kutyavin T, Haugen E, Dunn D, Reynolds AP, Neph S, Humbert R, Hansen RS, De Bruijn M, Selleri L, Rudensky A, Josefowicz S, Samstein R, Eichler EE, Orkin SH, Levasseur D, Papayannopoulou T, Chang KH, Skoultchi A, Gosh S, Disteche C, Treuting P, Wang Y, Weiss MJ, Blobel GA, Cao X, Zhong S, Wang T, Good PJ, Lowdon RF, Adams LB, Zhou XQ, Pazin MJ, Feingold EA, Wold B, Taylor J, Mortazavi A, Weissman SM, Stamatoyannopoulos JA, Snyder MP, Guigo R, Gingeras TR, Gilbert DM, Hardison RC, Beer MA, Ren B; Mouse ENCODE Consortium. Nature. 2014 Nov 20;515(7527):355-64. doi: 10.1038/nature13992. PMID: 25409824.
Conservation of trans-acting circuitry during mammalian regulatory evolution. Stergachis AB, Neph S, Sandstrom R, Haugen E, Reynolds AP, Zhang M, Byron R, Canfield T, Stelhing-Sun S, Lee K, Thurman RE, Vong S, Bates D, Neri F, Diegel M, Giste E, Dunn D, Vierstra J, Hansen RS, Johnson AK, Sabo PJ, Wilken MS, Reh TA, Treuting PM, Kaul R, Groudine M, Bender MA, Borenstein E, Stamatoyannopoulos JA. Nature. 2014 Nov 20;515(7527):365-70. doi: 10.1038/nature13972. PMID: 25409825.
Principles of regulatory information conservation between mouse and human. Cheng Y, Ma Z, Kim BH, Wu W, Cayting P, Boyle AP, Sundaram V, Xing X, Dogan N, Li J, Euskirchen G, Lin S, Lin Y, Visel A, Kawli T, Yang X, Patacsil D, Keller CA, Giardine B; Mouse ENCODE Consortium, Kundaje A, Wang T, Pennacchio LA, Weng Z, Hardison RC, Snyder MP. Nature. 2014 Nov 20;515(7527):371-5. doi: 10.1038/nature13985. PMID: 25409826.
Topologically associating domains are stable units of replication-timing regulation. Pope BD, Ryba T, Dileep V, Yue F, Wu W, Denas O, Vera DL, Wang Y, Hansen RS, Canfield TK, Thurman RE, Cheng Y, Gülsoy G, Dennis JH, Snyder MP, Stamatoyannopoulos JA, Taylor J, Hardison RC, Kahveci T, Ren B, Gilbert DM. Nature. 2014 Nov 20;515(7527):402-5. doi: 10.1038/nature13986. PMID: 25409831.
Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution. Vierstra J, Rynes E, Sandstrom R, Zhang M, Canfield T, Hansen RS, Stehling-Sun S, Sabo PJ, Byron R, Humbert R, Thurman RE, Johnson AK, Vong S, Lee K, Bates D, Neri F, Diegel M, Giste E, Haugen E, Dunn D, Wilken MS, Josefowicz S, Samstein R, Chang KH, Eichler EE, De Bruijn M, Reh TA, Skoultchi A, Rudensky A, Orkin SH, cPapayannopoulou T, Treuting PM, Selleri L, Kaul R, Groudine M, Bender MA, Stamatoyannopoulos JA. Science. 2014 Nov 21;346(6212):1007-12. doi: 10.1126/science.1246426. PMID: 25411453.
Comparison of the transcriptional landscapes between human and mouse tissues. Lin S, Lin Y, Nery JR, Urich MA, Breschi A, Davis CA, Dobin A, Zaleski C, Beer MA, Chapman WC, Gingeras TR, Ecker JR, Snyder MP. Proc Natl Acad Sci U S A. 2014 Dec 2;111(48):17224-9. doi: 10.1073/pnas.1413624111. Epub 2014 Nov 20. PMID: 25413365.
Funding: NIH’s National Human Genome Research Institute (NHGRI), National Institute of General Medical Sciences (NIGMS), National Cancer Institute (NCI), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Environmental Health Sciences (NIEHS), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), National Institute of Neurological Disorders and Stroke (NINDS), and NIH Common Fund; Spanish Plan Nacional; Wellcome Trust; Howard Hughes Medical Institute; National Science Foundation; and the American Recovery and Reinvestment Act.