An RNA-informed dosage sensitivity map reflects the intrinsic functional nature of genes.
Am J Hum Genet
; 110(9): 1509-1521, 2023 09 07.
Article
en En
| MEDLINE
| ID: mdl-37619562
ABSTRACT
Understanding dosage sensitivity or why Mendelian diseases have dominant vs. recessive modes of inheritance is crucial for uncovering the etiology of human disease. Previous knowledge of dosage sensitivity is mainly based on observations of rare loss-of-function mutations or copy number changes, which are underpowered due to ultra rareness of such variants. Thus, the functional underpinnings of dosage constraint remain elusive. In this study, we aim to systematically quantify dosage perturbations from cis-regulatory variants in the general population to yield a tissue-specific dosage constraint map of genes and further explore their underlying functional logic. We reveal an inherent divergence of dosage constraints in genes by functional categories with signaling genes (transcription factors, protein kinases, ion channels, and cellular machinery) being dosage sensitive, while effector genes (transporters, metabolic enzymes, cytokines, and receptors) are generally dosage resilient. Instead of being a metric of functional dispensability, we show that dosage constraint reflects underlying homeostatic constraints arising from negative feedback. Finally, we employ machine learning to integrate DNA and RNA metrics to generate a comprehensive, tissue-specific map of dosage sensitivity (MoDs) for autosomal genes.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Citocinas
/
Benchmarking
Tipo de estudio:
Diagnostic_studies
Límite:
Humans
Idioma:
En
Revista:
Am J Hum Genet
Año:
2023
Tipo del documento:
Article
País de afiliación:
China