Dataset Information

Collapse of germline piRNAs in the absence of Argonaute3 reveals somatic piRNAs in flies.

ABSTRACT: Piwi-interacting RNAs (piRNAs) silence transposons in animal germ cells. piRNAs are thought to derive from long transcripts spanning transposon-rich genomic loci and to direct an autoamplification loop in which an antisense piRNA, bound to Aubergine or Piwi protein, triggers production of a sense piRNA bound to the PIWI protein Argonaute3 (Ago3). In turn, the new piRNA is envisioned to produce a second antisense piRNA. Here, we describe strong loss-of-function mutations in ago3, allowing a direct genetic test of this model. We find that Ago3 acts to amplify piRNA pools and to enforce on them an antisense bias, increasing the number of piRNAs that can act to silence transposons. We also detect a second, Ago3-independent piRNA pathway centered on Piwi. Transposons targeted by this second pathway often reside in the flamenco locus, which is expressed in somatic ovarian follicle cells, suggesting a role for piRNAs beyond the germline.

SUBMITTER: Li C

PROVIDER: S-EPMC2768572 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Publications

Collapse of germline piRNAs in the absence of Argonaute3 reveals somatic piRNAs in flies.

Li Chengjian C Vagin Vasily V VV Lee Soohyun S Xu Jia J Ma Shengmei S Xi Hualin H Seitz Hervé H Horwich Michael D MD Syrzycka Monika M Honda Barry M BM Kittler Ellen L W EL Zapp Maria L ML Klattenhoff Carla C Schulz Nadine N Theurkauf William E WE Weng Zhiping Z Zamore Phillip D PD

Cell 20090423 3

Piwi-interacting RNAs (piRNAs) silence transposons in animal germ cells. piRNAs are thought to derive from long transcripts spanning transposon-rich genomic loci and to direct an autoamplification loop in which an antisense piRNA, bound to Aubergine or Piwi protein, triggers production of a sense piRNA bound to the PIWI protein Argonaute3 (Ago3). In turn, the new piRNA is envisioned to produce a second antisense piRNA. Here, we describe strong loss-of-function mutations in ago3, allowing a direc ...[more]

PMID: 19395009

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Project description:Somatic variants play a crucial role in the occurrence and progression of cancer. However, in the absence of matched normal controls, distinguishing between germline and somatic variants becomes challenging in tumor samples. The existing tumor-only genomic analysis methods either suffer from limited performance or insufficient interpretability due to an excess of features. Therefore, there is an urgent need for an alternative approach that can address these issues and have practical implications. Here, we presented OncoTOP, a computational method for genomic analysis without matched normal samples, which can accurately distinguish somatic mutations from germline variants. Reference sample analysis revealed a 0% false positive rate and 99.7% reproducibility for variant calling. Assessing 2864 tumor samples across 18 cancer types yielded a 99.8% overall positive percent agreement and a 99.9% positive predictive value. OncoTOP can also accurately detect clinically actionable variants and subclonal mutations associated with drug resistance. For the prediction of mutation origins, the positive percent agreement stood at 97.4% for predicting somatic mutations and 95.7% for germline mutations. High consistency of tumor mutational burden (TMB) was observed between the results generated by OncoTOP and tumor-normal paired analysis. In a cohort of 97 lung cancer patients treated with immunotherapy, TMB-high patients had prolonged PFS (P = .02), proving the reliability of our approach in estimating TMB to predict therapy response. Furthermore, microsatellite instability status showed a strong concordance (97%) with polymerase chain reaction results, and leukocyte antigens class I subtypes and homozygosity achieved an impressive concordance rate of 99.3% and 99.9% respectively, compared to its tumor-normal paired analysis. Thus, OncoTOP exhibited high reliability in variant calling, mutation origin prediction, and biomarker estimation. Its application will promise substantial advantages for clinical genomic testing.

Dataset Information

Collapse of germline piRNAs in the absence of Argonaute3 reveals somatic piRNAs in flies.

Publications

Collapse of germline piRNAs in the absence of Argonaute3 reveals somatic piRNAs in flies.

Similar Datasets

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