The non-human primate reference transcriptome resource (NHPRTR) for comparative functional genomics

Pipes, Lenore; Li, Sheng; Bozinoski, Marjan; Palermo, Robert E.; Peng, Xinxia; Blood, Philip D.; Kelly, Sara; Weiss, Jeffrey M.; Thierry‐Mieg, Jean; Thierry-Mieg, Danielle; Zumbo, Paul; Chen, Ronghua; Schroth, Gary P.; Mason, Christopher E.; Katze, Michael G.

doi:10.1093/nar/gks1268

Cited by 74 publications

(76 citation statements)

References 26 publications

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“…To calculate the editing levels of the conserved sites, we used the RNA-seq data for human, chimpanzee, baboon, rhesus and marmoset from NHPRTR 34,51 and computed the ratio of G reads divided by the sum of A and G reads for each site and kept only the sites with the sum of A and G reads higher than 20. We further required that each site should be edited ≥5% in at least one sample of each tissue.…”

Section: Methodsmentioning

confidence: 99%

Dynamic landscape and regulation of RNA editing in mammals

Tan

Shanmugam

et al. 2017

Nature

505

628

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Adenosine-to-inosine (A-to-I) RNA editing is a conserved post-transcriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules1. Although many editing sites have recently been discovered2–7, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood8–10. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. Globally, ADAR1 is the primary editor of repetitive sites and ADAR2 is the primary editor of non-repetitive coding sites, whereas the catalytically inactive ADAR3 predominantly acts as an inhibitor of editing. Cross-species analysis of RNA editing in several tissues revealed that species, rather than tissue type, is the primary determinant of editing levels, suggesting stronger cis-directed regulation of RNA editing for most sites, although the small set of conserved coding sites is under stronger trans-regulation. In addition, we curated an extensive set of ADAR1 and ADAR2 targets and showed that many editing sites display distinct tissue-specific regulation by the ADAR enzymes in vivo. Further analysis of the GTEx data revealed several potential regulators of editing, such as AIMP2, which reduces editing in muscles by enhancing the degradation of the ADAR proteins. Collectively, our work provides insights into the complex cis- and trans-regulation of A-to-I editing.

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Section: Methodsmentioning

confidence: 99%

Dynamic landscape and regulation of RNA editing in mammals

Tan

Shanmugam

et al. 2017

Nature

505

628

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“…The second annotation consisted of sequences orthologous to human large noncoding intergenic RNA (26), which we term "lincRNA." The third annotation consisted of transcripts from the nonhuman primate reference transcriptome resource (27) that did not correspond to any characterized transcript in Ensembl and that showed low protein-coding potential. This was the most comprehensive annotation, containing 6,027 transcripts in total.…”

Section: Resultsmentioning

confidence: 99%

“…Annotations for human large intergenic noncoding RNA (lincRNA) were obtained from a previously published catalogue (26). Annotations for novel macaque ncRNA were obtained from the Nonhuman Primate Reference Transcriptome Resource (27,28).…”

Section: Methodsmentioning

confidence: 99%

Deep Transcriptional Sequencing of Mucosal Challenge Compartment from Rhesus Macaques Acutely Infected with Simian Immunodeficiency Virus Implicates Loss of Cell Adhesion Preceding Immune Activation

Barrenäs

Palermo

Agricola

et al. 2014

J Virol

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Pathology resulting from human immunodeficiency virus (HIV) infection is driven by protracted inflammation; the primary loss of CD4؉ T cells is caused by activation-driven apoptosis. Recent studies of nonhuman primates (NHPs) have suggested that during the acute phase of infection, antiviral mucosal immunity restricts viral replication in the primary infection compartment. These studies imply that HIV achieves systemic infection as a consequence of a failure in host antiviral immunity. Here, we used high-dose intrarectal inoculation of rhesus macaques with simian immunodeficiency virus (SIV) SIV mac251 to examine how the mucosal immune system is overcome by SIV during acute infection. The host response in rectal mucosa was characterized by deep mRNA sequencing (mRNA-seq) at 3 and 12 days postinoculation (dpi) in 4 animals for each time point. While we observed a strong host transcriptional response at 3 dpi, functions relating to antiviral immunity were absent. Instead, we observed a significant number of differentially expressed genes relating to cell adhesion and reorganization of the cytoskeleton. We also observed downregulation of genes encoding members of the claudin family of cell adhesion molecules, which are coexpressed with genes associated with pathology in the colorectal mucosa, and a large number of noncoding transcripts. In contrast, at 12 dpi the differentially expressed genes were enriched in those involved with immune system functions, in particular, functions relating to T cells, B cells, and NK cells. Our findings indicate that host responses that negatively affect mucosal integrity occur before inflammation. Consequently, when inflammation is activated at peak viremia, mucosal integrity is already compromised, potentially enabling rapid tissue damage, driving further inflammation. IMPORTANCEThe HIV pandemic is one of the major threats to human health, causing over a million deaths per year. Recent studies have suggested that mucosal antiviral immune responses play an important role in preventing systemic infection after exposure to the virus. Yet, despite their potential role in decreasing transmission rates between individuals, these antiviral mechanisms are poorly understood. Here, we carried out the first deep mRNA sequencing analysis of mucosal host responses in the primary infection compartment during acute SIV infection. We found that during acute infection, a significant host response was mounted in the mucosa before inflammation was triggered. Our analysis indicated that the response has a detrimental effect on tissue integrity, causing increased permeability, tissue damage, and recruitment of SIV target cells. These results emphasize the importance of mucosal host responses preceding immune activation in preventing systemic SIV infection.

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“…Useful results were obtained from projects SRP007412 (Brawand et al 2011; gorilla and orangutan), SRP017959 (Necsulea et al 2014;gorilla) and SRP021223 (Pipes et al 2013;gorilla).…”

Section: Expression In Transcriptomic Librariesmentioning

confidence: 99%

Structure and evolution of the gorilla and orangutan growth hormone loci

2016

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In primates, the unigenic growth hormone (GH) locus of prosimians, expressed primarily in the anterior pituitary, evolved by gene duplications, independently in New World Monkeys (NWM) and Old World Monkeys (OWMs)/apes, to give complex clusters of genes expressed in the pituitary and placenta. In human and chimpanzee, the GH locus comprises five genes, GH-N being expressed as pituitary GH, whereas GH-V (placental GH) and CSHs (chorionic somatomammotropins) are expressed (in human and probably chimpanzee) in the placenta; the CSHs comprise CSH-A, CSH-B and the aberrant CSH-L (possibly a pseudogene) in human, and CSH-A1, CSH-A2 and CSH-B in chimpanzee. Here the GH locus in two additional great apes, gorilla (Gorilla gorilla gorilla) and orangutan (Pongo abelii), is shown to contain six and four GH-like genes respectively. The gorilla locus possesses six potentially expressed genes, gGH-N, gGH-V and four gCSHs, whereas the orangutan locus has just three functional genes, oGH-N, oGH-V and oCSH-B, plus a pseudogene, oCSH-L. Analysis of regulatory sequences, including promoter, enhancer and P-elements, shows significant variation; in particular the proximal Pit-1 element of GH-V genes differs markedly from that of other genes in the cluster. Phylogenetic analysis shows that the initial gene duplication led to distinct GH-like and CSH-like genes, and that a second duplication provided separate GH-N and GH-V. However, evolution of the CSHlike genes remains unclear. Rapid adaptive evolution gave rise to the distinct CSHs, after the first duplication, and to GH-V after the second duplication. Analysis of transcriptomic databases derived from gorilla tissues establishes that the gGH-N, gGH-V and several gCSH genes are expressed, but the significance of the many CSH genes in gorilla remains unclear.3

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The non-human primate reference transcriptome resource (NHPRTR) for comparative functional genomics

Cited by 74 publications

References 26 publications

Dynamic landscape and regulation of RNA editing in mammals

Dynamic landscape and regulation of RNA editing in mammals

Deep Transcriptional Sequencing of Mucosal Challenge Compartment from Rhesus Macaques Acutely Infected with Simian Immunodeficiency Virus Implicates Loss of Cell Adhesion Preceding Immune Activation

Structure and evolution of the gorilla and orangutan growth hormone loci

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