TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila

Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities

Parental investment in southern elephant seals, Mirounga leonina

The southern elephant seal is among the most sexually dimorphic and polygynous of all mammals: males may be more than 10 times the weight of reproducing females and only the largest 2–3% of males are likely to breed. Current optimization theories of sexual selection predict that evolution would favor greater parental investment in individual males than in females. Because southern elephant seals represent an extreme of polygyny and sexual dimorphism, they might be expected to show a dramatic difference in parental investment in male and female pups. However, in a study of parental investment in elephant seals at South Georgia, using several different methods, we found no such difference after parturition. Mother-pup pairs were immobilized and weighed early in lactation, recaptured near the end of lactation and reweighed. A further 30 pups were weighed an average of five times during lactation to establish the shape of the growth curve and to serve as partial controls for the previous set of animals. Initial post-partum weight in females ranged from 346 to 803 kg (=506, SD=111, n=26). Pup birth weight was related to mothers' post-partum weight in female pups but small females often gave birth to large male pups. Male pups were significantly heavier at birth than females. However, this size difference did not persist. Male and female pups were suckled for the same period, grew at the same rate and were not significantly different in weight at weaning. Mothers lost weight at the same rate regardless of their pup's sex