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Competition for Cellular Resources and Complex Trait Heritability

Core Concepts
Resource competition among genes for cellular resources has a minor effect on gene expression variation and is unlikely to explain the majority of complex trait heritability.
The content explores the impact of resource competition on gene expression and complex trait variance. While resource competition can affect gene expression, it only explains a small fraction of trans-regulation and trait variance. The model suggests that most traits are not significantly influenced by resource competition. The study introduces a theoretical model of resource competition for polymerases during transcription. It shows that competition among genes for shared intracellular resources has a negligible effect on gene expression variation unless a large fraction of polymerases is bound to core genes. This implies that resource competition is not a major driver of complex trait heritability. Furthermore, the analysis indicates that while many genes contribute to trait variance, most of the heritability comes from common variants with small effects spread across the genome. The study highlights the importance of considering both cis- and trans-regulatory effects in understanding complex traits. Overall, the research suggests that resource competition plays a limited role in explaining complex trait heritability and emphasizes the need to consider other factors contributing to genetic variation.
Most human complex traits are polygenic with thousands of contributing variants. Roughly 70% of gene expression heritability is due to trans-regulation. An estimated 10,000 variants across the genome affect trait variance. For some traits, up to 80,000 causal variants contribute to heritability.
"Resource competition provides a possible mechanism for trans regulation since every cis-eQTL is also a weak trans-eQTL for all other genes." "Competition between genes for shared cellular resources may have an appreciable effect under specific conditions." "The vast majority of traits are unlikely to be significantly impacted by resource competition."

Deeper Inquiries

What other factors besides resource competition could explain missing heritability in complex traits?

One factor that could explain missing heritability in complex traits is the hierarchical nature of traits impacted by multiple intermediate processes, each with a polygenic basis. This hierarchical structure can lead to variants affecting these intermediate processes being detected in genome-wide association studies (GWAS) of the endpoint trait. Additionally, selective constraint can play a role by lowering the allele frequencies of large-effect variants, thereby contributing to the modest contributions of core genes. Furthermore, non-biochemical mechanisms such as spatial correlations arising from 3D genome organization can also influence gene expression and contribute to missing heritability.

Could extreme polygenicity be attributed to factors beyond genetic constraints?

Yes, extreme polygenicity may be attributed to factors beyond genetic constraints. For example, environmental influences and epigenetic modifications can also play a significant role in shaping complex traits with thousands of contributing variants. Environmental factors such as diet, lifestyle choices, exposure to toxins or pathogens, and social determinants can interact with genetic predispositions to influence trait variability. Epigenetic mechanisms like DNA methylation and histone modifications can regulate gene expression without altering the underlying DNA sequence, adding another layer of complexity to the genetic architecture of complex traits.

How might spatial correlations in 3D genome organization influence stochastic transcription processes?

Spatial correlations in 3D genome organization can have a profound impact on stochastic transcription processes by influencing how genes are physically positioned within the nucleus and how they interact with regulatory elements. These spatial arrangements can create microenvironments where certain genes are more likely to be transcribed due to their proximity to enhancers or other regulatory elements. As a result, genes located close together may exhibit coordinated expression patterns through long-range chromatin interactions. Additionally, spatial correlations can lead to bursty transcription dynamics where genes are transcribed intermittently in short bursts rather than continuously. This bursty behavior is influenced by the physical proximity of genes within specific nuclear compartments or substructures. Overall, spatial correlations in 3D genome organization create intricate regulatory networks that govern stochastic transcription processes and ultimately shape gene expression profiles across different cell types and conditions.