Gene-Expression Variation Within and Among Human Populations

Department of Biostatistics, University of Washington, Seattle, WA 98195-7730, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 04/2007; 80(3):502-9. DOI: 10.1086/512017
Source: PubMed


Understanding patterns of gene-expression variation within and among human populations will provide important insights into the molecular basis of phenotypic diversity and the interpretation of patterns of expression variation in disease. However, little is known about how gene-expression variation is apportioned within and among human populations. Here, we characterize patterns of natural gene-expression variation in 16 individuals of European and African ancestry. We find extensive variation in gene-expression levels and estimate that approximately 83% of genes are differentially expressed among individuals and that approximately 17% of genes are differentially expressed among populations. By decomposing total gene-expression variation into within- versus among-population components, we find that most expression variation is due to variation among individuals rather than among populations, which parallels observations of extant patterns of human genetic variation. Finally, we performed allele-specific quantitative polymerase chain reaction to demonstrate that cis-regulatory variation in the lymphocyte adaptor protein (SH2B adapter protein 3) contributes to differential expression between European and African samples. These results provide the first insight into how human population structure manifests itself in gene-expression levels and will help guide the search for regulatory quantitative trait loci.

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Available from: Jeanna Strout, Feb 20, 2015
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    • "We estimated the transcriptome-wide effect of the PRPF8 mutation by using the π0 statistic, which in the context of multiple hypothesis testing, is an estimate of the proportion of tests that conform to the null hypothesis. This approach has previously been applied in transcriptome-wide studies of population differential gene expression between human populations [56] and, more recently, in the study of cis- and trans-expression quantitative loci [22]. The observed value of π0 was the lowest among all permutations of the case-control labels. "
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    ABSTRACT: Background Substantial progress has been made in the identification of sequence elements that control mRNA splicing and the genetic variants in these elements that alter mRNA splicing (referred to as splicing quantitative trait loci – sQTLs). Genetic variants that affect mRNA splicing in trans are harder to identify because their effects can be more subtle and diffuse, and the variants are not co-located with their targets. We carried out a transcriptome-wide analysis of the effects of a mutation in a ubiquitous splicing factor that causes retinitis pigmentosa (RP) on mRNA splicing, using exon microarrays. Results Exon microarray data was generated from whole blood samples obtained from four individuals with a mutation in the splicing factor PRPF8 and four sibling controls. Although the mutation has no known phenotype in blood, there was evidence of widespread differences in splicing between cases and controls (affecting approximately 20% of exons). Most probesets with significantly different inclusion (defined as the expression intensity of the exon divided by the expression of the corresponding transcript) between cases and controls had higher inclusion in cases and corresponded to exons that were shorter than average, AT rich, located towards the 5’ end of the gene and flanked by long introns. Introns flanking affected probesets were particularly depleted for the shortest category of introns, associated with splicing via intron definition. Conclusions Our results show that a mutation in a splicing factor, with a phenotype that is restricted to retinal tissue, acts as a trans-sQTL cluster in whole blood samples. Characteristics of the affected exons suggest that they are spliced co-transcriptionally and via exon definition. However, due to the small sample size available for this study, further studies are required to confirm the widespread impact of this PRPF8 mutation on mRNA splicing outside the retina.
    Full-text · Article · Jun 2014 · BMC Research Notes
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    • "Variations within and among populations are critical for understanding species-range structure and dynamics (Storey et al., 2007; Bertocci et al., 2011; Guo, 2012). Both population size and density are main elements reflecting population structure and dynamics. "
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    ABSTRACT: The species’ range limits and associated central-marginal (C-M; i.e., from species range center to margin) population dynamics continue to draw increasing attention because of their importance for current emerging issues such as biotic invasions and epidemic diseases under global change. Previous studies have mainly focused on species borders and C-M process in natural settings for native species. More recently, growing efforts are devoted to examine the C-M patterns and process for invasive species partly due to their relatively short history, highly dynamic populations, and management implications. Here I examine recent findings and information gaps related to (1) the C-M population dynamics linked to species invasions, and (2) the possible effects of climate change and land use on the C-M patterns and processes. Unlike most native species that are relatively stable (some even having contracting populations or ranges), many invasive species are still spreading fast and form new distribution or abundance centers. Because of the strong nonlinearity of population demographic or vital rates (i.e. birth, death, immigration and emigration) across the C-M gradients and the increased complexity of species ranges due to habitat fragmentation, multiple introductions, range-wide C-M comparisons and simulation involving multiple vital rates are needed in the future.
    Full-text · Article · Jun 2014
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    • "The vast majority of such studies compare group means in expression levels, while much less attention has been given to the occurrence and potential significance of within-population gene expression variation. However, large inter-individual differences in gene expression variation within populations have in fact been observed in organisms as diverse as teleost fish [18] [19], Drosophila melanogaster [20], and humans [21]. Such variation can drive differences in the physiological performance between individuals [19] [22], affect disease susceptibility [23], and therefore may be of functional and biological importance. "
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    ABSTRACT: Variation in gene expression is an important component of the phenotypic differences observed in nature. Gene expression variance across biological groups and environmental conditions has been studied extensively and has revealed specific genes and molecular mechanisms of interest. However, little is known regarding the importance of within-population gene expression variation to environmental adaptation. To address this issue, we quantified the proteomes of individuals of European whitefish (Coregonus lavaretus) from populations that have previously been shown to have adapted during early development to freshwater and brackishwater salinity environments. Using MS-based label-free proteomics, we studied 955 proteins in eight hatch-stage fish embryos from each population that had been reared in either freshwater or brackishwater salinity conditions. By comparing the levels of within-population protein expression variance over individuals and per protein between populations, we found that fish embryos from the population less affected by salinity level had also markedly higher levels of expression variance. Gene Ontologies and molecular pathways associated with osmoregulation showed the most significant difference of within-population proteome variance between populations. Several new candidate genes for salinity adaptation were identified, emphasising the added value of combining assessments of within-population gene expression variation with standard gene expression analysis practices for better understanding the mechanisms of environmental adaptation.
    Full-text · Article · Jan 2014 · Journal of proteomics
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