Divergent and nonuniform gene expression patterns in mouse brain.
Considerable progress has been made in understanding variations in gene sequence and expression level associated with phenotype, yet how genetic diversity translates into complex phenotypic differences remains poorly understood. Here, we examine the relationship between genetic background and spatial patterns of gene expression across seven strains of mice, providing the most extensive cellular-resolution comparative analysis of gene expression in the mammalian brain to date. Using comprehensive brainwide anatomic coverage (more than 200 brain regions), we applied in situ hybridization to analyze the spatial expression patterns of 49 genes encoding well-known pharmaceutical drug targets. Remarkably, over 50% of the genes examined showed interstrain expression variation. In addition, the variability was nonuniformly distributed across strain and neuroanatomic region, suggesting certain organizing principles. First, the degree of expression variance among strains mirrors genealogic relationships. Second, expression pattern differences were concentrated in higher-order brain regions such as the cortex and hippocampus. Divergence in gene expression patterns across the brain could contribute significantly to variations in behavior and responses to neuroactive drugs in laboratory mouse strains and may help to explain individual differences in human responsiveness to neuroactive drugs.
Morris
John A
JA
Allen Institute for Brain Science, Seattle, WA 98103, USA.
Royall
Joshua J
JJ
Bertagnolli
Darren
D
Boe
Andrew F
AF
Burnell
Josh J
JJ
Byrnes
Emi J
EJ
Copeland
Cathy
C
Desta
Tsega
T
Fischer
Shanna R
SR
Goldy
Jeff
J
Glattfelder
Katie J
KJ
Kidney
Jolene M
JM
Lemon
Tracy
T
Orta
Geralyn J
GJ
Parry
Sheana E
SE
Pathak
Sayan D
SD
Pearson
Owen C
OC
Reding
Melissa
M
Shapouri
Sheila
S
Smith
Kimberly A
KA
Soden
Chad
C
Solan
Beth M
BM
Weller
John
J
Takahashi
Joseph S
JS
Overly
Caroline C
CC
Lein
Ed S
ES
Hawrylycz
Michael J
MJ
Hohmann
John G
JG
Jones
Allan R
AR
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D013045:Species Specificity