Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathway.

Interdepartmental Program for Neuroscience, Department of Human Genetics and Biostatistics, University of California, Los Angeles, CA 90095-1769, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2010; 107(28):12698-703. DOI: 10.1073/pnas.0914257107
Source: PubMed


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, we took 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 across multiple 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.

Download full-text


Available from: Jeremy A Miller, Jan 08, 2014
    • "A transcriptome analysis across human and mouse brains was developed by analyzing more than 1000 gene microarrays in both species. Among them,thespecies-specificgenemodulesdescribedsome highly conserved transcriptomes with an overlap of genetic networks between the two species [159]. When AD and other neurodegenerative disorders were specifically examined, the transcriptome revealed that the recruitment of microglial cells appeared to play a significant role in the development of AD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.
    Journal of Alzheimer's disease: JAD 09/2015; 47(4):815-843. DOI:10.3233/JAD-150136 · 4.15 Impact Factor
  • Source
    • "However, the functional and phenotypic consequences of these changes largely remain unclear. Changes in gene expression, which has been considered to be the major driving force of phenotypic evolution, have been systematically studied for the evolution of different regions of the brain (Oldham et al., 2008; Johnson et al., 2009; Miller et al., 2010; Kang et al., 2011; Hawrylycz et al., 2012; Konopka et al., 2012). The conclusions of many of these studies, however, are affected by some technological limitations. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Next-generation RNA-sequencing has been successfully used for identification of transcript assembly, evaluation of gene expression levels, and detection of post-transcriptional modifications. Despite these large-scale studies, additional comprehensive RNA-seq data from different subregions of the human brain are required to fully evaluate the evolutionary patterns experienced by the human brain transcriptome. Here, we provide a total of 6.5 billion RNA-seq reads from different subregions of the human brain. A significant correlation was observed between the levels of alternative splicing and RNA-editing, which might be explained by a competition between the molecular machineries responsible for the splicing and editing of RNA. Young human protein-coding genes demonstrate biased expression to the neocortical and non-neocortical regions during evolution on the lineage leading to humans. We also found that a significantly greater number of young human protein-coding genes are expressed in the putamen, a tissue that was also observed to have the highest level of RNA-editing activity. The putamen, which previously received little attention, plays an important role in cognitive ability, and our data suggest a potential contribution of the putamen to human evolution. © The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.
    Journal of Molecular Cell Biology 07/2015; 7(4). DOI:10.1093/jmcb/mjv043 · 6.77 Impact Factor
  • Source
    • "This study also carried out Gene Ontology analysis that organized the data for AD affected genes into several categories, such as mitochondrial, synaptic disruption, and apoptosis , thus elucidating molecular pathways that are relevant to the pathophysiology of AD [8]. Similarly, by comparing the transcriptional gene networks of the human and mouse hippocampus, a recent study was able to demonstrate conserved gene coexpression between species [9]. Moreover, this study successfully identified a human-specific expression pattern that strongly correlated with AD progression and found several poorly characterized genes that are correlated with AD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The hippocampus is one of the most essential components of the human brain and plays an important role in learning and memory. The hippocampus has drawn great attention from scientists and clinicians due to its clinical importance in diseases such as Alzheimer's disease (AD), non-AD dementia, and epilepsy.. Understanding the function of the hippocampus and related disease mechanisms requires comprehensive knowledge of the orchestration of the genome, epigenome, transcriptome, proteome, and post-translational modifications (PTMs) of proteins. The past decade has seen remarkable advances in the high-throughput sequencing techniques that are collectively called next generation sequencing (NGS). NGS enables the precise analysis of gene expression profiles in cells and tissues, allowing powerful and more feasible integration of expression data from the gene level to the protein level, even allowing "-omic" level assessment of PTMs. In addition, improved bioinformatics algorithms coupled with NGS technology are finally opening a new era for scientists to discover previously unidentified and elusive proteins. In the present review, we will focus mainly on the proteomics of the human hippocampus with an emphasis on the integrated analysis of genomics, epigenomics, transcriptomics, and proteomics. Finally, we will discuss our perspectives on the potential and future of proteomics in the field of hippocampal biology. This article is part of a Special Issue entitled: Neuroproteomics: Applications in Neuroscience and Neurology. Copyright © 2015 Elsevier B.V. All rights reserved.
    Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics 03/2015; 1854(7). DOI:10.1016/j.bbapap.2015.02.010 · 2.75 Impact Factor
Show more