TY - JOUR
T1 - Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways
AU - Miller, Jeremy A.
AU - Horvath, Steve
AU - Geschwind, Daniel H.
PY - 2010/7/13
Y1 - 2010/7/13
N2 - Because mouse models play a crucial role in biomedical research related to the human nervous system, understanding the similarities and differences between mouse and human brain is of fundamental importance. Studies comparing transcription in human and mouse have come to varied conclusions, in part because of their relatively small sample sizes or underpowered methodologies. To better characterize gene expression differences between mouse and human,wetook a systems-biology approach by using weighted gene coexpression network analysis on more than 1,000 microarrays from brain. We find that global network properties of the brain transcriptome are highly preserved between species. Furthermore, all modules of highly coexpressed genes identified in mouse were identified in human, with those related to conserved cellular functions showing the strongest between-species preservation. Modules corresponding to glial and neuronal cells were sufficiently preserved between mouse and human to permit identification of cross species cell-class marker genes. We also identify several robust human-specific modules, including one strongly correlated with measures of Alzheimer disease progression acrossmultiple data sets, whose hubs are poorly-characterized genes likely involved in Alzheimer disease. We present multiple lines of evidence suggesting links between neurodegenerative disease and glial cell types in human, including human-specific correlation of presenilin-1 with oligodendrocyte markers, and significant enrichment for known neurodegenerative disease genes in microglial modules. Together, this work identifies convergent and divergent pathways in mouse and human, and provides a systematic framework that will be useful for understanding the applicability of mouse models for human brain disorders.
AB - Because mouse models play a crucial role in biomedical research related to the human nervous system, understanding the similarities and differences between mouse and human brain is of fundamental importance. Studies comparing transcription in human and mouse have come to varied conclusions, in part because of their relatively small sample sizes or underpowered methodologies. To better characterize gene expression differences between mouse and human,wetook a systems-biology approach by using weighted gene coexpression network analysis on more than 1,000 microarrays from brain. We find that global network properties of the brain transcriptome are highly preserved between species. Furthermore, all modules of highly coexpressed genes identified in mouse were identified in human, with those related to conserved cellular functions showing the strongest between-species preservation. Modules corresponding to glial and neuronal cells were sufficiently preserved between mouse and human to permit identification of cross species cell-class marker genes. We also identify several robust human-specific modules, including one strongly correlated with measures of Alzheimer disease progression acrossmultiple data sets, whose hubs are poorly-characterized genes likely involved in Alzheimer disease. We present multiple lines of evidence suggesting links between neurodegenerative disease and glial cell types in human, including human-specific correlation of presenilin-1 with oligodendrocyte markers, and significant enrichment for known neurodegenerative disease genes in microglial modules. Together, this work identifies convergent and divergent pathways in mouse and human, and provides a systematic framework that will be useful for understanding the applicability of mouse models for human brain disorders.
KW - Evolution
KW - Gene expression
KW - Metaanalysis
KW - Neurodegenerative disease
KW - Systems biology
UR - http://www.scopus.com/inward/record.url?scp=77955454185&partnerID=8YFLogxK
U2 - 10.1073/pnas.0914257107
DO - 10.1073/pnas.0914257107
M3 - Article
C2 - 20616000
AN - SCOPUS:77955454185
SN - 0027-8424
VL - 107
SP - 12698
EP - 12703
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 28
ER -