Dataset Information

Ribosomal DNA copy number loss and sequence variation in cancer.

ABSTRACT: Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number. Despite the importance of rDNA for cellular function, we know virtually nothing about what governs its copy number, stability, and sequence in the mammalian genome due to challenges associated with mapping and analysis. We applied computational and droplet digital PCR approaches to measure rDNA copy number in normal and cancer states in human and mouse genomes. We find that copy number and sequence can change in cancer genomes. Counterintuitively, human cancer genomes show a loss of copies, accompanied by global copy number co-variation. The sequence can also be more variable in the cancer genome. Cancer genomes with lower copies have mutational evidence of mTOR hyperactivity. The PTEN phosphatase is a tumor suppressor that is critical for genome stability and a negative regulator of the mTOR kinase pathway. Surprisingly, but consistent with the human cancer genomes, hematopoietic cancer stem cells from a Pten-/- mouse model for leukemia have lower rDNA copy number than normal tissue, despite increased proliferation, rRNA production, and protein synthesis. Loss of copies occurs early and is associated with hypersensitivity to DNA damage. Therefore, copy loss is a recurrent feature in cancers associated with mTOR activation. Ribosomal DNA copy number may be a simple and useful indicator of whether a cancer will be sensitive to DNA damaging treatments.

SUBMITTER: Xu B

PROVIDER: S-EPMC5480814 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Ribosomal DNA copy number loss and sequence variation in cancer.

Xu Baoshan B Li Hua H Perry John M JM Singh Vijay Pratap VP Unruh Jay J Yu Zulin Z Zakari Musinu M McDowell William W Li Linheng L Gerton Jennifer L JL

PLoS genetics 20170622 6

Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number. Despite the importance of rDNA for cellular function, we know virtually nothing about what governs its copy number, stability, and sequence in the mammalian genome due to challenges associated with mapping and analysis. We applied computational and droplet digital PCR approaches to measure rDNA copy number in normal and cancer states in human and mouse genomes. We find that copy number and sequence ...[more]

PMID: 28640831

Similar Datasets

Project description:BackgroundDespite their ubiquity and high diversity in eukaryotic genomes, DNA transposons are rarely encountered in ribosomal DNA (rDNA). In contrast, R-elements, a diverse group of non-LTR retrotransposons, specifically target rDNA. Pokey is a DNA transposon that targets a specific rDNA site, but also occurs in many other genomic locations, unlike R-elements. However, unlike most DNA transposons, Pokey has been a stable component of Daphnia genomes for over 100 million years. Here we use qPCR to estimate the number of 18S and 28S ribosomal RNA genes and Pokey elements in rDNA (rPokey), as well as other genomic locations (gPokey) in two species of Daphnia. Our goals are to estimate the correlation between (1) the number of 18S and 28S rRNA genes, (2) the number of 28S genes and rPokey, and (3) the number of rPokey and gPokey. In addition, we ask whether Pokey number and distribution in both genomic compartments are affected by differences in life history between D. pulex and D. pulicaria.ResultsWe found differences in 18S and 28S gene number within isolates that are too large to be explained by experimental variation. In general, Pokey number within isolates is modest (< 20), and most are gPokey. There is no correlation between the number of rRNA genes and rPokey, or between rPokey and gPokey. However, we identified three isolates with unusually high numbers of both rPokey and gPokey, which we infer is a consequence of recent transposition. We also detected other rDNA insertions (rInserts) that could be degraded Pokey elements, R- elements or the divergent PokeyB lineage recently detected in the Daphnia genome sequence. Unlike rPokey, rInserts are positively correlated with rRNA genes, suggesting that they are amplified by the same mechanisms that amplify rDNA units even though rPokey is not. Overall, Pokey frequency and distribution are similar in D. pulex and D. pulicaria suggesting that differences in life history have no impact on Pokey.ConclusionsThe possibility that many rDNA units do not contain a copy of both 18S and 28S genes suggests that rDNA is much more complicated than once thought, and warrants further study. In addition, the lack of correlation between rPokey, gPokey and rDNA unit numbers suggests that Pokey transposition rate is generally very low, and that recombination, in combination with natural selection, eliminates rPokey much faster than gPokey. Our results suggest that further research to determine the mechanisms by which Pokey has escaped complete inactivation by its host (the usual fate of DNA transposons), would provide important insights into transposon biology.

Project description:Objectives: Copy number variant (CNV) is believed to be the potential genetic cause of pregnancy loss. However, CNVs less than 3 Mb in euploid products of conceptions (POCs) remain largely unexplored. The aim of this study was to investigate the features of CNVs less than 3 Mb in POCs and their potential clinical significance in pregnancy loss/fetal death. Methods: CNV data were extracted from a cohort in our institution and 19 peer-reviewed publications, and only those CNVs less than 3 Mb detected in euploid pregnancy loss/fetal death were included. We conducted a CNV map to analyze the distribution of CNVs in chromosomes using R packages karyoploteR_1.10.5. Gene names and annotated gene types covered by those CNVs were mined from the human Release 19 reference genome file and GENECODE database. We assessed the expression patterns and the consequences of murine knock-out of those genes using TiGER and Mouse Genome Informatics (MGI) databases. Functional enrichment and pathway analysis for genes in CNVs were performed using clusterProfiler V3.12.0. Result: Breakpoints of 564 CNVs less than 3 Mb were obtained from 442 euploid POCs, with 349 gains and 185 losses. The CNV map showed that CNVs were distributed in all chromosomes, with the highest frequency detected in chromosome 22 and the lowest frequency in chromosome Y, and CNVs showed a higher density in the pericentromeric and sub-telomeric regions. A total of 5,414 genes mined from the CNV regions (CNVRs), Gene Ontology (GO), and pathway analysis showed that the genes were significantly enriched in multiple terms, especially in sensory perception, membrane region, and tight junction. A total of 995 protein-coding genes have been reported to present mammalian phenotypes in MGI, and 276 of them lead to embryonic lethality or abnormal embryo/placenta in knock-out mouse models. CNV located at 19p13.3 was the most common CNV of all POCs. Conclusion: CNVs less than 3 Mb in euploid POCs distribute unevenly in all chromosomes, and a higher density was seen in the pericentromeric and sub-telomeric regions. The genes in those CNVRs are significantly enriched in biological processes and pathways that are important to embryonic/fetal development. CNV in 19p13.3 and the variations of ARID3A and FSTL3 might contribute to pregnancy loss.

Dataset Information

Ribosomal DNA copy number loss and sequence variation in cancer.

Publications

Ribosomal DNA copy number loss and sequence variation in cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets