Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Diversity of Human Copy Number Variation and Multicopy Genes

ABSTRACT: Copy number variants (CNVs) affect both disease and normal phenotypic variation but those lying within heavily duplicated, highly identical sequence have been difficult to assay. By analyzing short-read mapping depth for 159 human genomes, we demonstrate accurate estimation of absolute copy number for duplications as small as 1.9 kbp, ranging from 0-48 copies. We identified 4.1 million ‘singly unique nucleotide’ (SUN) positions informative in distinguishing specific copies, and use them to genotype the copy and content of specific paralogs within highly duplicated gene families. These data identify human-specific expansions in genes associated with brain development, reveal extensive population genetic diversity, and detect signatures consistent with gene conversion in the human species. Our approach makes ~1000 genes accessible to genetic studies of disease association. This dataset complements the results from short read sequencing by performing validation on five individuals. We analyzed the 17q21.1 locus in 5 HapMap individuals by array CGH on a custom Agilent 4-plex 310k array performing 1 experiment for each sample. This array was targeted at high density (1 probe/105bp) to 7 genomic loci, including 17q21. The reference individual used was NA19240.

ORGANISM(S): Homo sapiens

SUBMITTER: Peter Sudmant

PROVIDER: E-GEOD-24334 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background Primitive brain tumors are the first cause of cancer-related death in children. Tumor cells with stem-like properties (TSCs), thought to account for tumorigenesis and therapeutic resistance, have been isolated from high-grade gliomas in adults. Whether TSCs are a common component of pediatric brain tumors and are of clinical relevance remains to be determined. Methodology/Principal findings Tumor cells with self-renewal properties were isolated with cell biology techniques from a majority of 55 pediatric brain tumors samples, regardless of their histopathologies and grades of malignancy (57% of embryonal tumors, 57% of low-grade gliomas and neuro-glial tumors, 70% of ependymomas, 91% of high-grade gliomas). The vast majority (10/12) of high-grade glioma-derived oncospheres sustained long-term self-renewal numbers akin to neural stem cells (>7 self-renewals), whereas cells with limited renewing abilities akin to neural progenitors dominated in all other tumor types. Regardless of tumor entities, the young age group was associated with self-renewal properties akin to neural stem cells (P=0.05, chi-square test). TSCs shared a complex molecular profile combining embryonic stem cell markers with elements controlling neural stem cell properties and epithelio-mesenchymal transitions. They were radio- and chemoresistant and formed aggressive tumors after intracerebral grafting. Survival analysis of the cohort showed an association between isolation of TSCs with long-term self-renewal abilities and a patients higher mortality rate (P = 0.022, log-rank test). Patients bearing cells with limited self-renewal properties constituted an intermediate group of survival but which did not reach statistical significance. Conclusions/Significance In brain tumors affecting adult patients, TSC have been isolated only from high-grade gliomas. In contrast, our data show that tumor cells with stem cell-like or progenitor-like properties can be isolated from a wide range of histological sub-types and grades of pediatric brain tumors. They suggest that cellular mechanisms fueling tumor development differ between adult and pediatric brain tumors.

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Diversity of Human Copy Number Variation and Multicopy Genes

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