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Bayesian estimation of gene constraint from an evolutionary model with gene features.

ABSTRACT: Measures of selective constraint on genes have been used for many applications including clinical interpretation of rare coding variants, disease gene discovery, and studies of genome evolution. However, widely-used metrics are severely underpowered at detecting constraint for the shortest ~25% of genes, potentially causing important pathogenic mutations to be overlooked. We developed a framework combining a population genetics model with machine learning on gene features to enable accurate inference of an interpretable constraint metric, shet. Our estimates outperform existing metrics for prioritizing genes important for cell essentiality, human disease, and other phenotypes, especially for short genes. Our new estimates of selective constraint should have wide utility for characterizing genes relevant to human disease. Finally, our inference framework, GeneBayes, provides a flexible platform that can improve estimation of many gene-level properties, such as rare variant burden or gene expression differences.

SUBMITTER: Zeng T

PROVIDER: S-EPMC10245655 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Bayesian estimation of gene constraint from an evolutionary model with gene features.

Zeng Tony T Spence Jeffrey P JP Mostafavi Hakhamanesh H Pritchard Jonathan K JK

bioRxiv : the preprint server for biology 20240410

Measures of selective constraint on genes have been used for many applications including clinical interpretation of rare coding variants, disease gene discovery, and studies of genome evolution. However, widely-used metrics are severely underpowered at detecting constraint for the shortest ∼25% of genes, potentially causing important pathogenic mutations to be overlooked. We developed a framework combining a population genetics model with machine learning on gene features to enable accurate infe ...[more]

PMID: 37292653

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Project description:BackgroundUncovering the evolutionary principles of gene coexpression network is important for our understanding of the network topological property of new genes. However, most existing evolutionary models only considered the evolution of duplication genes and only based on the degree of genes, ignoring the other key topological properties. The evolutionary mechanism by which how are new genes integrated into the ancestral networks are not yet to be comprehensively characterized. Herein, based on the human ribonucleic acid-sequencing (RNA-seq) data, we develop a new evolutionary model of gene coexpression network which considers the evolutionary process of both duplication genes and de novo genes.ResultsBased on the human RNA-seq data, we construct a gene coexpression network consisting of 8061 genes and 638624 links. We find that there are 1394 duplication genes and 126 de novo genes in the network. Then based on human gene age data, we reproduce the evolutionary process of this gene coexpression network and develop a new evolutionary model. We find that the generation rates of duplication genes and de novo genes are approximately 3.58/Myr (Myr=Million year) and 0.31/Myr, respectively. Based on the average degree and coreness of parent genes, we find that the gene duplication is a random process. Eventually duplication genes only inherit 12.89% connections from their parent genes and the retained connections have a smaller edge betweenness. Moreover, we find that both duplication genes and de novo genes prefer to develop new interactions with genes which have a large degree and a large coreness. Our proposed model can generate an evolutionary network when the number of newly added genes or the length of evolutionary time is known.ConclusionsGene duplication and de novo genes are two dominant evolutionary forces in shaping the coexpression network. Both duplication genes and de novo genes develop new interactions through a "rich-gets-richer" mechanism in terms of degree and coreness. This mechanism leads to the scale-free property and hierarchical architecture of biomolecular network. The proposed model is able to construct a gene coexpression network with comprehensive biological characteristics.

Dataset Information

Bayesian estimation of gene constraint from an evolutionary model with gene features.

Publications

Bayesian estimation of gene constraint from an evolutionary model with gene features.

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