De novo individualized disease modules reveal the synthetic penetrance of genes and inform personalized treatment regimens.

Current understandings of individual disease etiology and therapeutics are limited despite great need. To fill the gap, we propose a novel computational pipeline that collects potent disease gene cooperative pathways to envision individualized disease etiology and therapies. Our algorithm constructs individualized disease modules de novo, which enables us to elucidate the importance of mutated genes in specific patients and to understand the synthetic penetrance of these genes across patients. We reveal that importance of the notorious cancer drivers TP53 and PIK3CA fluctuate widely across breast cancers and peak in tumors with distinct numbers of mutations and that rarely mutated genes such as XPO1 and PLEKHA1 have high disease module importance in specific individuals. Furthermore, individualized module disruption enables us to devise customized singular and combinatorial target therapies that were highly varied across patients, showing the need for precision therapeutics pipelines. As the first analysis of de novo individualized disease modules, we illustrate the power of individualized disease modules for precision medicine by providing deep novel insights on the activity of diseased genes in individuals.

Gene utility recapitulates chromosomal aberrancies in advanced stage neuroblastoma.

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Although only a few recurrent somatic mutations have been identified, chromosomal abnormalities, including the loss of heterozygosity (LOH) at the chromosome 1p and gains of chromosome 17q, are often seen in the high-risk cases. The biological basis and evolutionary forces that drive such genetic abnormalities remain enigmatic. Here, we conceptualize the Gene Utility Model (GUM) that seeks to identify genes driving biological signaling via their collective gene utilities and apply it to understand the impact of those differentially utilized genes on constraining the evolution of NB karyotypes. By employing a computational process-guided flow algorithm to model gene utility in protein-protein networks that built based on transcriptomic data, we conducted several pairwise comparative analyses to uncover genes with differential utilities in stage 4 NBs with distinct classification. We then constructed a utility karyotype by mapping these differentially utilized genes to their respective chromosomal loci. Intriguingly, hotspots of the utility karyotype, to certain extent, can consistently recapitulate the major chromosomal abnormalities of NBs and also provides clues to yet identified predisposition sites. Hence, our study not only provides a new look, from a gene utility perspective, into the known chromosomal abnormalities detected by integrative genomic sequencing efforts, but also offers new insights into the etiology of NB and provides a framework to facilitate the identification of novel therapeutic targets for this devastating childhood cancer.

Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo.

Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles. Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology.