ArticlePLoS genetics2018
Role of duplicate genes in determining the tissue-selectivity of hereditary diseases.
Article in PLoS genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 41 citations in OpenAlex.
- Review
- Tissue-aware interpretation of genetic variants advances the etiology of rare diseases.Molecular systems biology · 2024Article
- Machine-learning analysis reveals an important role for negative selection in shaping cancer aneuploidy landscapes.Genome biology · 2024Article
- Article
- Predicting molecular mechanisms of hereditary diseases by using their tissue-selective manifestation.Molecular systems biology · 2023Article
- Predicting gene knockout effects from expression data.BMC medical genomics · 2023Article
- Identification of genetic mechanisms for tissue-specific genetic effects based on CRISPR screens.Genetics · 2022Article
- Paralog Explorer: A resource for mining information about paralogs in common research organisms.Computational and structural biotechnology journal · 2022Article
- SEC23A rescues SEC23B-deficient congenital dyserythropoietic anemia type II.Science advances · 2021Article
- The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones.Nature communications · 2021Article
- Article
- Mechanisms of tissue and cell-type specificity in heritable traits and diseases.Nature reviews. Genetics · 2020Review
- Dosage-sensitive molecular mechanisms are associated with the tissue-specificity of traits and diseases.Computational and structural biotechnology journal · 2020Article
- Identification of pathogenic variant enriched regions across genes and gene families.Genome research · 2020Article
- Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature.American journal of human genetics · 2019Article
- Looking to the future of zebrafish as a model to understand the genetic basis of eye disease.Human genetics · 2019Review
- Paralog dependency indirectly affects the robustness of human cells.Molecular systems biology · 2019Article
- Paralog Studies Augment Gene Discovery: DDX and DHX Genes.American journal of human genetics · 2019Article
- ResponseNet v.3: revealing signaling and regulatory pathways connecting your proteins and genes across human tissues.Nucleic acids research · 2019Article
- The first Autumn School on Proteostasis: from molecular mechanisms to organismal consequences.Cell stress & chaperones · 2019Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A longstanding puzzle in human genetics is what limits the clinical manifestation of hundreds of hereditary diseases to certain tissues, while their causal genes are expressed throughout the human body. A general conception is that tissue-selective disease phenotypes emerge when masking factors operate in unaffected tissues, but are specifically absent or insufficient in disease-manifesting tissues. Although this conception has critical impact on the understanding of disease manifestation, it was never challenged in a systematic manner across a variety of hereditary diseases and affected tissues. Here, we address this gap in our understanding via rigorous analysis of the susceptibility of over 30 tissues to 112 tissue-selective hereditary diseases. We focused on the roles of paralogs of causal genes, which are presumably capable of compensating for their aberration. We show for the first time at large-scale via quantitative analysis of omics datasets that, preferentially in the disease-manifesting tissues, paralogs are under-expressed relative to causal genes in more than half of the diseases. This was observed for several susceptible tissues and for causal genes with varying number of paralogs, suggesting that imbalanced expression of paralogs increases tissue susceptibility. While for many diseases this imbalance stemmed from up-regulation of the causal gene in the disease-manifesting tissue relative to other tissues, it was often combined with down-regulation of its paralog. Notably in roughly 20% of the cases, this imbalance stemmed only from significant down-regulation of the paralog. Thus, dosage relationships between paralogs appear as important, yet currently under-appreciated, modifiers of disease manifestation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.