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Identification of brain transcriptional variation reproduced in peripheral blood: an approach for mapping brain expression traits.

ABSTRACT: Genome-wide gene expression studies may provide substantial insight into gene activities and biological pathways differing between tissues and individuals. We investigated such gene expression variation by analyzing expression profiles in brain tissues derived from eight different brain regions and from blood in 12 monkeys from a biomedically important non-human primate model, the vervet (Chlorocebus aethiops sabaeus). We characterized brain regional differences in gene expression, focusing on transcripts for which inter-individual variation of expression in brain correlates well with variation in blood from the same individuals. Using stringent criteria, we identified 29 transcripts whose expression is measurable, stable, replicable, variable between individuals, relevant to brain function and heritable. Polymorphisms identified in probe regions could, in a minority of transcripts, confound the interpretation of the observed inter-individual variation. The high heritability of levels of these transcripts in a large vervet pedigree validated our approach of focusing on transcripts that showed higher inter-individual compared with intra-individual variation. These selected transcripts are candidate expression Quantitative Trait Loci, differentially regulating transcript levels in the brain among individuals. Given the high degree of conservation of tissue expression profiles between vervets and humans, our findings may facilitate the understanding of regional and individual transcriptional variation and its genetic mechanisms in humans. The approach employed here-utilizing higher quality tissue and more precise dissection of brain regions than is usually possible in humans-may therefore provide a powerful means to investigate variation in gene expression relevant to complex brain related traits, including human neuropsychiatric diseases.

SUBMITTER: Jasinska AJ

PROVIDER: S-EPMC2766297 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Identification of brain transcriptional variation reproduced in peripheral blood: an approach for mapping brain expression traits.

Jasinska Anna J AJ Service Susan S Choi Oi-wa OW DeYoung Joseph J Grujic Olivera O Kong Sit-yee SY Jorgensen Matthew J MJ Bailey Julia J Breidenthal Sherry S Fairbanks Lynn A LA Woods Roger P RP Jentsch J David JD Freimer Nelson B NB

Human molecular genetics 20090819 22

Genome-wide gene expression studies may provide substantial insight into gene activities and biological pathways differing between tissues and individuals. We investigated such gene expression variation by analyzing expression profiles in brain tissues derived from eight different brain regions and from blood in 12 monkeys from a biomedically important non-human primate model, the vervet (Chlorocebus aethiops sabaeus). We characterized brain regional differences in gene expression, focusing on t ...[more]

PMID: 19692348

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Project description:Immune traits (ITs) are potentially relevant criteria to characterize individualM-bM-^@M-^Ys immunocompetence. Thus, porcine ITs related to innate and adaptive immunity were studied by functional genomics approaches, with no initial focus on resistance to specific pathogens. Peripheral blood transcriptome was analysed in 60 days old Large White pigs (N=445) 3 weeks after vaccination against Mycoplasma hyopneumoniae. Groups of 4 to 10 animals classified in the extreme tails of CD4-/CD8+and TCRM-NM-3M-NM-4+ cell counts, phagocytosis, in vitro production of IL2, IL10, TNF and IFNG, and anti-Mycoplasma antibodies distributions were selected for transcriptome studies with a porcine generic array enriched with immunity-related genes (SLA-RI/NRSP8-13K). Among the ITs studied, transcriptome analysis revealed differentially expressed genes for CD4-/CD8+cell counts, phagocytosis, and in vitro production of IL2 and IL10. A subset of these genes was confirmed by real time qPCR. Gene set enrichment analysis showed a significant over-representation of immune response functions. An independent set of 74 no overlapping animals was employed for validation and a total of 5 potential gene biomarkers were found for prediction of immunocompetence. These biomarkers performed with 79% sensitivity (95% CI 61% to 97%) and 86% specificity (95% CI 72% to 100%). Considering the observed transcriptome differences in animals with extreme ITs levels, we conclude that gene expression profiling appears promising as a tool for biological monitoring of genetic variance in pigs. Test set: Two-condition experiment (High vs Low) for a total of 8 ITS. Three ITs were measured from total blood and referred to as in vivo ITs. They included the seric levels of IgG directed against Mycoplasma hyopneumoniae (IgG-Mh), and the cell counts for M-NM-1M-NM-2 T lymphocytes CD4- CD8+ (CD4- CD8+, or M-NM-3M-NM-4 T lymphocytes (TCRM-NM-3M-NM-4+)) . Additionally, five ITs were measured after in vitro tests, and were further referred to as in vitro ITs. They include the phagocytosis capacity (PHAG), and the in vitro production of TNFM-NM-1, IFNM-NM-3, IL2 and IL10 after in vitro stimulation of total blood diluted five times. For each IT included in the present report, pigs were selected at the higher and lower 10% of the Gaussian distribution in order to generate two extreme groups defined as High (H) and Low (L). Groups of 4 to 10 animals classified in the extreme tails of different ITs were selected. A two-channel microarray experiments were carried out using a common reference hybridization design. The standard reference RNA sample was prepared by pooling of total RNAs from different porcine tissues. As the reference is common to all the arrays, this design allowed an indirect comparison between the conditions of interest (H vs L groups). Additionally, in order to provide potential gene biomarkers to produce new insight into pig immunocompetence, the top 50 genes most differentially expressed genes when comparing H vs L groups in CD4-/CD8+ cell counts, phagocytosis, and in vitro production of IL2 and IL10 phenotypes were assessed across 74 animals (experimental animals non included) that were analyzed with the same SLA-RI/NRSP8-13K microarray. Validation set: A total of 74 animals were analyzed in order to validate potential gene biomarkers found in the following immune traits: CD4- CD8+ lymphocyte counts, phagocytosis capacity, IL2 and IL10 production. As no differentially gene expressions were detected between animals with High and Low levels of gamma delta T lymphocyte counts, IgG-Mh, and in vitro production of TNF-alpha or IFN-gamma immune traits, some of them were used in the validation set (n=50). None of experimental animals with extreme CD4- CD8+ lymphocyte counts, phagocytosis capacity, IL2 and IL10 production levels were included were included in the validation set.

Dataset Information

Identification of brain transcriptional variation reproduced in peripheral blood: an approach for mapping brain expression traits.

Publications

Identification of brain transcriptional variation reproduced in peripheral blood: an approach for mapping brain expression traits.

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