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Tissue Specificity of Gene Expression Evolves Across Mammal Species.

ABSTRACT: Tissue specificity of gene expression sheds light on the tissue-selective manifestation of hereditary disease despite the same DNA across all tissues. The evolutionary path of such tissue specificity provides essential information about the tissue-specific function of genes and the validity of disease animal models. With recent improvements of the sequencing technology, more and more large-scale transcriptomics studies have been conducted among different species across multiple tissues. In this study, we exploit existing transcriptomics resources of humans, cynomolgus macaques, rats, mice, and dogs across 13 tissues. We find that although tissue specificity of homologous gene expression is largely well conserved across species, a total of 380 genes shift or are in the process of shifting their tissue specificity. The tissue-specificity-shifting genes are less conserved than those preserving their tissue specificity or housekeeping genes. Interestingly, tissue-specificity-shifting genes tend to be less conserved at the third codon positions, likely due to their relaxed synonymous codon usage bias. Moreover, compared with genes, cassette exons are more likely to shift their tissue specificity of splicing across the five species.

SUBMITTER: Jiang W

PROVIDER: S-EPMC9464367 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Tissue Specificity of Gene Expression Evolves Across Mammal Species.

Jiang Wei W Chen Liang L

Journal of computational biology : a journal of computational molecular cell biology 20220701 8

Tissue specificity of gene expression sheds light on the tissue-selective manifestation of hereditary disease despite the same DNA across all tissues. The evolutionary path of such tissue specificity provides essential information about the tissue-specific function of genes and the validity of disease animal models. With recent improvements of the sequencing technology, more and more large-scale transcriptomics studies have been conducted among different species across multiple tissues. In this ...[more]

PMID: 35776510

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Project description:The genetic alterations that underlie cancer development are highly tissue-specific with the majority of driving alterations occurring in only a few cancer types and with alterations common to multiple cancer types often showing a tissue-specific functional impact. This tissue-specificity means that the biology of normal tissues carries important information regarding the pathophysiology of the associated cancers, information that can be leveraged to improve the power and accuracy of cancer genomic analyses. Research exploring the use of normal tissue data for the analysis of cancer genomics has primarily focused on the paired analysis of tumor and adjacent normal samples. Efforts to leverage the general characteristics of normal tissue for cancer analysis has received less attention with most investigations focusing on understanding the tissue-specific factors that lead to individual genomic alterations or dysregulated pathways within a single cancer type. To address this gap and support scenarios where adjacent normal tissue samples are not available, we explored the genome-wide association between the transcriptomes of 21 solid human cancers and their associated normal tissues as profiled in healthy individuals. While the average gene expression profiles of normal and cancerous tissue may appear distinct, with normal tissues more similar to other normal tissues than to the associated cancer types, when transformed into relative expression values, i.e., the ratio of expression in one tissue or cancer relative to the mean in other tissues or cancers, the close association between gene activity in normal tissues and related cancers is revealed. As we demonstrate through an analysis of tumor data from The Cancer Genome Atlas and normal tissue data from the Human Protein Atlas, this association between tissue-specific and cancer-specific expression values can be leveraged to improve the prognostic modeling of cancer, the comparative analysis of different cancer types, and the analysis of cancer and normal tissue pairs.

Project description:BackgroundAging is a complex process that involves all tissues in an organism and shows sex dimorphism. While transcriptional changes in aging have been well characterized, the majority of studies have focused on a single sex and sex differences in gene expression in aging are poorly understood. In this study, we explore sex dimorphism in gene expression in aging mice across three tissues.MethodsWe collected gastrocnemius muscle, liver and white adipose tissue from young (6 months, n = 14) and old (24 months, n = 14) female and male C57BL/6NIA mice and performed RNA-seq. To investigate sex dimorphism in aging, we considered two levels of comparisons: (a) differentially expressed genes between females and males in the old age group and (b) comparisons between females and males across the aging process. We utilized differential expression analysis and gene feature selection to investigate candidate genes. Gene set enrichment analysis was performed to identify candidate molecular pathways. Furthermore, we performed a co-expression network analysis and chose the gene module(s) associated with aging independent of sex or tissue-type.ResultsWe identified both tissue-specific and tissue-independent genes associated with sex dimorphism in aged mice. Unique differentially expressed genes between old males and females across tissues were mainly enriched for pathways related to specific tissue function. We found similar results when exploring sex differences in the aging process, with the exception that in the liver genes enriched for lipid metabolism and digestive system were identified in both females and males. Combining enriched pathways across analyses, we identified amino acid metabolism, digestive system, and lipid metabolism as the core mechanisms of sex dimorphism in aging. Although the vast majority of age-related genes were sex and tissue specific, we identified 127 hub genes contributing to aging independent of sex and tissue that were enriched for the immune system and signal transduction.ConclusionsThere are clear sex differences in gene expression in aging across liver, muscle and white adipose. Core pathways, including amino acid metabolism, digestive system and lipid metabolism, contribute to sex differences in aging.

Dataset Information

Tissue Specificity of Gene Expression Evolves Across Mammal Species.

Publications

Tissue Specificity of Gene Expression Evolves Across Mammal Species.

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