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.

Despite there is a growing interest in studying the presence and effects of microplastics (MP) in fishes and other aquatic species, knowledge is still limited in tropical areas. In this study, we examined the presence of MP in the gastrointestinal content of 30 filter feeders of thread herring, Opisthonema complex (Clupeiformes: Clupeidae) from the Central Pacific coast of Costa Rica. We detected the presence of MP in 100% of the individuals with an average of 36.7 pieces per fish, of which 79.5% were fibers and 20.5% particles. To our knowledge, this is the first study in Costa Rica that demonstrates the presence of MP in planktivorous fishes. The effects of microplastics ingestion by O. libertate and its transit through aquatic food webs should be studied in greater detail, with greater number of sampling points at different times of the year. However, our work confirms that contamination by microplastics is having direct effects on the marine life of Costa Rica.

Despite there is a growing interest in studying the presence and effects of 18 microplastics (MP) in fishes and other aquatic species, knowledge is still limited in tropical 19 areas. In this study, we examined the presence of MP in the gastrointestinal content of 30 filter 20 feeders of thread herring, Opisthonema complex (Clupeiformes: Clupeidae) from the Central 21 Pacific coast of Costa Rica. We detected the presence of MP in 100% of the individuals with 22 an average of 36.7 pieces per fish, of which 79.5% were fibers and 20.5% particles. To our 23 knowledge, this is the first study in Costa Rica that demonstrates the presence of MP in 24 planktivorous fishes. The effects of microplastics ingestion by O. libertate and its transit 25 through aquatic food webs should be studied in greater detail, with greater number of sampling 26 points at different times of the year. However, our work confirms that contamination by 27 microplastics is having direct effects on the marine life of Costa Rica.28 29

The molecular function of a protein relies on its structure. Understanding how mutations alter structure and function in multi-domain proteins, is key to elucidate how a pathological phenotype is generated. However, one may fall into the logical bias of assessing protein damage only based on the mutations that are viable (survivorship bias), which can lead to partial conclusions. This is the case of PNKP, an important nuclear and mitochondrial DNA repair enzyme with kinase and phosphatase function. Most mutations 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 tolerance to disease causing mutations, we evaluated whether mutations in PNKP are under survivorship bias. Even when all mutations in the kinase domain are deleterious, we found a mayor mutation tolerability landscape in terms of survival. Instead, the phosphatase domain is less tolerant due to its low mutation rates, higher degree of sequence conservation, lower dN/dS ratios, and more disease-propensity hotspots. Thus, in multi-domain proteins, we propose the term "Wald's domain" for those who are not apparently more associated with disease, but that are less resistant to mutations in terms of survival. 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. Thus, this bias should be taken into account when analyzing the mutational landscape in protein structure, function, and finally in disease.