Capturing variation impact on molecular interactions in the IMEx Consortium mutations data set

Abstract

The current wealth of genomic variation data identified at nucleotide level presents the challenge of understanding by which mechanisms amino acid variation affects cellular processes. These effects may manifest as distinct phenotypic differences between individuals or result in the development of disease. Physical interactions between molecules are the linking steps underlying most, if not all, cellular processes. Understanding the effects that sequence variation has on a molecule’s interactions is a key step towards connecting mechanistic characterization of nonsynonymous variation to phenotype. We present an open access resource created over 14 years by IMEx database curators, featuring 28,000 annotations describing the effect of small sequence changes on physical protein interactions. We describe how this resource was built, the formats in which the data is provided and offer a descriptive analysis of the data set. The data set is publicly available through the IntAct website and is enhanced with every monthly release.

Structural variation and its potential impact on genome instability: Novel discoveries in the EGFR landscape by long-read sequencing

“…The number of missing reverse complements were 8, 9 and 4 within the landscapes for 4C, 6C, and hg38, respectively. These sequence variations are consistent with the recent findings of hundreds of thousands of indels (<50 bp) and tens of thousands of SVs (>50 bp) within human genomes [1].…”

“…Although short-read technology has been of tremendous benefit in identifying many of the cancer-driver genes, it has significant limitations when it comes to identifying structural variation (SV). Short-read sequencing is often challenging for accurate calling of large structural variants, especially in highly repetitive regions of a genome [1][2][3][4]. SV occurs most commonly in the non-coding regions of the genome [5,6].…”

“…The frequency of structural variants (� 50 bp) and small indel variants (<50 bp) has been shown to exceed 840,000 per diploid human genome. Thus, the average combined indel and structural variant incidence within the human genome is over 100 per megabase, and human structural variants outnumber protein coding genes by a factor of 20 [1,3,11]. Despite the extent of SV in the human genome, it does not appear to occur randomly.…”

TP53 mutations in high grade serous ovarian cancer and impact on clinical outcomes: a comparison of next generation sequencing and bioinformatics analyses

“…This group was less likely to achieve optimal debulking surgery. According to del-Toro et al , among other changes, mutations enriched in cluster 3 disrupt interactions with BCL2L11,25 also potentially explaining poor outcome due to chemotherapy resistance26 27 …”

3D spatial organization and network-guided comparison of mutation profiles in Glioblastoma reveals similarities across patients

“…Several studies have focused on the impact of the disease-associated alterations in the protein-protein interaction networks [5–8]. Very recently, IMEX consortium [9] also started an effort to curate and catalogue the functional impact of mutations in protein interactions [10]. Combining three-dimensional structure data with large scale mutation data might help to elucidate the effect of mutations in cancer [6, 11–14].…”