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What Signatures Dominantly Associate with Gene Age?

ABSTRACT: As genes originate at different evolutionary times, they harbor distinctive genomic signatures of evolutionary ages. Although previous studies have investigated different gene age-related signatures, what signatures dominantly associate with gene age remains unresolved. Here we address this question via a combined approach of comprehensive assignment of gene ages, gene family identification, and multivariate analyses. We first provide a comprehensive and improved gene age assignment by combining homolog clustering with phylogeny inference and categorize human genes into 26 age classes spanning the whole tree of life. We then explore the dominant age-related signatures based on a collection of 10 potential signatures (including gene composition, gene length, selection pressure, expression level, connectivity in protein-protein interaction network and DNA methylation). Our results show that GC content and connectivity in protein-protein interaction network (PPIN) associate dominantly with gene age. Furthermore, we investigate the heterogeneity of dominant signatures in duplicates and singletons. We find that GC content is a consistent primary factor of gene age in duplicates and singletons, whereas PPIN is more strongly associated with gene age in singletons than in duplicates. Taken together, GC content and PPIN are two dominant signatures in close association with gene age, exhibiting heterogeneity in duplicates and singletons and presumably reflecting complex differential interplays between natural selection and mutation.

SUBMITTER: Yin H

PROVIDER: S-EPMC5174733 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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What Signatures Dominantly Associate with Gene Age?

Yin Hongyan H Wang Guangyu G Ma Lina L Yi Soojin V SV Zhang Zhang Z

Genome biology and evolution 20161013 10

As genes originate at different evolutionary times, they harbor distinctive genomic signatures of evolutionary ages. Although previous studies have investigated different gene age-related signatures, what signatures dominantly associate with gene age remains unresolved. Here we address this question via a combined approach of comprehensive assignment of gene ages, gene family identification, and multivariate analyses. We first provide a comprehensive and improved gene age assignment by combining ...[more]

PMID: 27609935

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Project description:BACKGROUND:Clinical variables may correlate with lack of response to treatment (primary resistance) or clinical benefit in patients with clear cell renal cell carcinoma (ccRCC) treated with anti-programmed death 1/ligand one antibodies. METHODS:In this multi-institutional collaboration, clinical characteristics of patients with primary resistance (defined as progression on initial computed tomography scan) were compared to patients with clinical benefit using Two sample t-test and Chi-square test (or Fisher's Exact test). The Kaplan-Meier method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS) in all patients and the subsets of patients with clinical benefit or primary resistance. Cox's regression model was used to evaluate the correlation between survival endpoints and variables of interest. To explore clinical factors in a larger, independent patient sample, The Cancer Genome Atlas (TCGA) was analyzed. RNAseq gene expression data as well as demographic and clinical information were downloaded for primary tumors of 517 patients included within TCGA-ccRCC. RESULTS:Of 90 patients, 38 (42.2%) had primary resistance and 52 (57.8%) had clinical benefit. Compared with the cohort of patients with initial benefit, primary resistance was more likely to occur in patients with worse ECOG performance status (p?=?0.03), earlier stage at diagnosis (p?=?0.04), had no prior nephrectomy (p?=?0.04) and no immune-related adverse events (irAE) (p?=?0.02). In patients with primary resistance, improved OS was significantly correlated with lower International Metastatic RCC Database Consortium risk score (p?=?0.02) and lower neutrophil:lymphocyte ratio (p?=?0.04). In patients with clinical benefit, improved PFS was significantly associated with increased BMI (p?=?0.007) and irAE occurrence (p?=?0.02) while improved OS was significantly correlated with overweight BMI (BMI 25-30; p?=?0.03) and no brain metastasis (p?=?0.005). The cohort TCGA-ccRCC was examined for the correlations between gene expression patterns, clinical factors, and survival outcomes observing associations of T-cell inflammation and angiogenesis signatures with histologic grade, pathologic stage and OS. CONCLUSIONS:Clinical characteristics including performance status, BMI and occurrence of an irAE associate with outcomes in patients with ccRCC treated with immunotherapy. The inverse association of angiogenesis gene signature with ccRCC histologic grade highlight opportunities for adjuvant combination VEGFR2 tyrosine kinase inhibitor and immune-checkpoint inhibition.

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What Signatures Dominantly Associate with Gene Age?

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What Signatures Dominantly Associate with Gene Age?

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