ORCID Profile
0000-0002-4411-1330
Current Organisation
Princeton University
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Publisher: Springer Science and Business Media LLC
Date: 11-10-2017
DOI: 10.1038/NG.3969
Publisher: Elsevier BV
Date: 10-2020
Publisher: Springer Science and Business Media LLC
Date: 09-2012
DOI: 10.1038/NATURE11247
Publisher: Springer Science and Business Media LLC
Date: 12-10-2017
DOI: 10.1038/NATURE24277
Abstract: Characterization of the molecular function of the human genome and its variation across in iduals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across in iduals and erse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-in idual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2017
DOI: 10.1038/NATURE24265
Abstract: X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of ‘escape’ from inactivation varying between genes and in iduals 1,2 . The extent to which XCI is shared between cells and tissues remains poorly characterized 3,4 , as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression 5 and phenotypic traits 6 . Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 in iduals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify ex les of heterogeneity between tissues, in iduals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic ersity 6,7 . Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2017
DOI: 10.1038/NATURE24267
Abstract: Rare genetic variants are abundant in humans and are expected to contribute to in idual disease risk 1,2,3,4 . While genetic association studies have successfully identified common genetic variants associated with susceptibility, these studies are not practical for identifying rare variants 1,5 . Efforts to distinguish pathogenic variants from benign rare variants have leveraged the genetic code to identify deleterious protein-coding alleles 1,6,7 , but no analogous code exists for non-coding variants. Therefore, ascertaining which rare variants have phenotypic effects remains a major challenge. Rare non-coding variants have been associated with extreme gene expression in studies using single tissues 8,9,10,11 , but their effects across tissues are unknown. Here we identify gene expression outliers, or in iduals showing extreme expression levels for a particular gene, across 44 human tissues by using combined analyses of whole genomes and multi-tissue RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project v6p release 12 . We find that 58% of underexpression and 28% of overexpression outliers have nearby conserved rare variants compared to 8% of non-outliers. Additionally, we developed RIVER (RNA-informed variant effect on regulation), a Bayesian statistical model that incorporates expression data to predict a regulatory effect for rare variants with higher accuracy than models using genomic annotations alone. Overall, we demonstrate that rare variants contribute to large gene expression changes across tissues and provide an integrative method for interpretation of rare variants in in idual genomes.
Publisher: Springer Science and Business Media LLC
Date: 12-10-2017
DOI: 10.1038/NATURE24041
Publisher: Springer Science and Business Media LLC
Date: 11-09-2020
DOI: 10.1186/S13059-020-02122-Z
Abstract: Allele expression (AE) analysis robustly measures cis -regulatory effects. Here, we present and demonstrate the utility of a vast AE resource generated from the GTEx v8 release, containing 15,253 s les spanning 54 human tissues for a total of 431 million measurements of AE at the SNP level and 153 million measurements at the haplotype level. In addition, we develop an extension of our tool phASER that allows effect sizes of cis -regulatory variants to be estimated using haplotype-level AE data. This AE resource is the largest to date, and we are able to make haplotype-level data publicly available. We anticipate that the availability of this resource will enable future studies of regulatory variation across human tissues.
Publisher: Cold Spring Harbor Laboratory
Date: 11-10-2017
Abstract: The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes ( cis -eQTLs). More research is needed to identify effects of genetic variation on distant genes ( trans -eQTLs) and understand their biological mechanisms. One common trans -eQTLs mechanism is “mediation” by a local ( cis ) transcript. Thus, mediation analysis can be applied to genome-wide SNP and expression data in order to identify transcripts that are “ cis -mediators” of trans -eQTLs, including those “ cis -hubs” involved in regulation of many trans -genes. Identifying such mediators helps us understand regulatory networks and suggests biological mechanisms underlying trans -eQTLs, both of which are relevant for understanding susceptibility to complex diseases. The multitissue expression data from the Genotype-Tissue Expression (GTEx) program provides a unique opportunity to study cis -mediation across human tissue types. However, the presence of complex hidden confounding effects in biological systems can make mediation analyses challenging and prone to confounding bias, particularly when conducted among erse s les. To address this problem, we propose a new method: Genomic Mediation analysis with Adaptive Confounding adjustment (GMAC). It enables the search of a very large pool of variables, and adaptively selects potential confounding variables for each mediation test. Analyses of simulated data and GTEx data demonstrate that the adaptive selection of confounders by GMAC improves the power and precision of mediation analysis. Application of GMAC to GTEx data provides new insights into the observed patterns of cis -hubs and trans -eQTL regulation across tissue types.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-09-2020
Abstract: Cell type composition, estimated from bulk tissue, maps the cellular specificity of genetic variants.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-09-2020
Abstract: The Genotype-Tissue Expression (GTEx) project dissects how genetic variation affects gene expression and splicing.
Publisher: Cold Spring Harbor Laboratory
Date: 11-10-2017
Abstract: Gene co-expression networks capture biologically important patterns in gene expression data, enabling functional analyses of genes, discovery of biomarkers, and interpretation of genetic variants. Most network analyses to date have been limited to assessing correlation between total gene expression levels in a single tissue or small sets of tissues. Here, we built networks that additionally capture the regulation of relative isoform abundance and splicing, along with tissue-specific connections unique to each of a erse set of tissues. We used the Genotype-Tissue Expression (GTEx) project v6 RNA sequencing data across 50 tissues and 449 in iduals. First, we developed a framework called Transcriptome-Wide Networks (TWNs) for combining total expression and relative isoform levels into a single sparse network, capturing the interplay between the regulation of splicing and transcription. We built TWNs for 16 tissues and found that hubs in these networks were strongly enriched for splicing and RNA binding genes, demonstrating their utility in unraveling regulation of splicing in the human transcriptome. Next, we used a Bayesian biclustering model that identifies network edges unique to a single tissue to reconstruct Tissue-Specific Networks (TSNs) for 26 distinct tissues and 10 groups of related tissues. Finally, we found genetic variants associated with pairs of adjacent nodes in our networks, supporting the estimated network structures and identifying 20 genetic variants with distant regulatory impact on transcription and splicing. Our networks provide an improved understanding of the complex relationships of the human transcriptome across tissues.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-08-2018
Abstract: Flores Island in Indonesia has a long history of hominin occupation, including by the extinct Homo floresiensis and a more recent settlement by modern humans. Furthermore, Flores has an extant population of pygmy humans, and H. floresiensis exhibited a diminutive adult size relative to other hominins. Tucci et al. examined genetic variation among 32 in iduals, including 10 sequenced genomes, from a population of pygmies living close to the cave where H. floresiensis remains were discovered. These in iduals exhibit signatures of polygenic selection explaining the short stature and have genomic content from both Neanderthals and Denisovans, but no additional archaic lineages. Thus, restricted height is under selection at this location and has evolved independently at least twice in hominins. Science , this issue p. 511
Location: United States of America
No related grants have been discovered for Joshua Akey.