Mutational survivorship bias: The case of PNKP
Por um escritor misterioso
Descrição
The molecular function of a protein relies on its structure. Understanding how variants alter structure and function in multidomain proteins is key to elucidate the generation of a pathological phenotype. However, one may fall into the logical bias of assessing protein damage only based on the variants that are visible (survivorship bias), which can lead to partial conclusions. This is the case of PNKP, an important nuclear and mitochondrial DNA repair enzyme with both kinase and phosphatase function. Most variants in PNKP are confined to the kinase domain, leading to a pathological spectrum of three apparently distinct clinical entities. Since proteins and domains may have a different tolerability to variation, we evaluated whether variants in PNKP are under survivorship bias. Here, we provide the evidence that supports a higher tolerance in the kinase domain even when all variants reported are deleterious. Instead, the phosphatase domain is less tolerant due to its lower variant rates, a higher degree of sequence conservation, lower dN/dS ratios, and the presence of more disease-propensity hotspots. Together, our results support previous experimental evidence that demonstrated that the phosphatase domain is functionally more necessary and relevant for DNA repair, especially in the context of the development of the central nervous system. Finally, we propose the term "Wald’s domain" for future studies analyzing the possible survivorship bias in multidomain proteins.
Browse Preprints - Authorea
Xrcc4 protein (mouse) - STRING interaction network
PDF) Mutational survivorship bias: The case of PNKP
Mutational survivorship bias: The case of PNKP
PDF) Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor
Mutations of the DNA repair gene PNKP in a patient with microcephaly, seizures, and developmental delay (MCSZ) presenting with a high-grade brain tumor
Mutational Survivorship Bias: The case of PNKP
Browse Preprints - Authorea
Mutational Survivorship Bias: The case of PNKP
LPAR2 correlated with different prognosis and immune cell infiltration in head and neck squamous cell carcinoma and kidney renal clear cell carcinoma, Hereditas
Prenatal phenotype of PNKP-related primary microcephaly associated with variants affecting both the FHA and phosphatase domain
Mutational survivorship bias: The case of PNKP
Molecular Radiation Biology
PDF) Mutational survivorship bias: The case of PNKP
Frontiers Base Excision Repair in the Immune System: Small DNA Lesions With Big Consequences
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