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High order chromatin architecture shapes the landscape of chromosomal alterations in cancer.

ABSTRACT: The accumulation of data on structural variation in cancer genomes provides an opportunity to better understand the mechanisms of genomic alterations and the forces of selection that act upon these alterations in cancer. Here we test evidence supporting the influence of two major forces, spatial chromosome structure and purifying (or negative) selection, on the landscape of somatic copy-number alterations (SCNAs) in cancer. Using a maximum likelihood approach, we compare SCNA maps and three-dimensional genome architecture as determined by genome-wide chromosome conformation capture (HiC) and described by the proposed fractal-globule model. This analysis suggests that the distribution of chromosomal alterations in cancer is spatially related to three-dimensional genomic architecture and that purifying selection, as well as positive selection, influences SCNAs during somatic evolution of cancer cells.

SUBMITTER: Fudenberg G

PROVIDER: S-EPMC3268007 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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High order chromatin architecture shapes the landscape of chromosomal alterations in cancer.

Fudenberg Geoff G Getz Gad G Meyerson Matthew M Mirny Leonid A LA

Nature biotechnology 20111120 12

The accumulation of data on structural variation in cancer genomes provides an opportunity to better understand the mechanisms of genomic alterations and the forces of selection that act upon these alterations in cancer. Here we test evidence supporting the influence of two major forces, spatial chromosome structure and purifying (or negative) selection, on the landscape of somatic copy-number alterations (SCNAs) in cancer. Using a maximum likelihood approach, we compare SCNA maps and three-dime ...[more]

PMID: 22101486

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Project description:Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

Dataset Information

High order chromatin architecture shapes the landscape of chromosomal alterations in cancer.

Publications

High order chromatin architecture shapes the landscape of chromosomal alterations in cancer.

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