Unfavorable switching of skewed X chromosome inactivation leads to Menkes disease in a female infant.

Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene, and female carriers are usually asymptomatic. We describe a 7-month-old female patient with severe intellectual disability, epilepsy, and low levels of serum copper and ceruloplasmin. While heterozygous deletion of exons 16 and 17 of the ATP7A gene was detected in the proband, her mother, and her grandmother, only the proband suffered from Menkes disease clinically. Intriguingly, X chromosome inactivation (XCI) analysis demonstrated that the grandmother and the mother showed skewing of XCI toward the allele with the ATP7A deletion and that the proband had extremely skewed XCI toward the normal allele, resulting in exclusive expression of the pathogenic ATP7A mRNA transcripts. Expression bias analysis and recombination mapping of the X chromosome by the combination of whole genome and RNA sequencing demonstrated that meiotic recombination occurred at Xp21-p22 and Xq26-q28. Assuming that a genetic factor on the X chromosome enhanced or suppressed XCI of its allele, the factor must be on either of the two distal regions derived from her grandfather. Although we were unable to fully uncover the molecular mechanism, we concluded that unfavorable switching of skewed XCI caused Menkes disease in the proband.

Estimation of multiple male mating frequency using paternity skew: An example from a grey-sided vole (Myodes rufocanus) population.

Multiple male mating (MMM) causes sperm competition, which may play an important role in the evolution of reproductive traits. The frequency of multiple paternity (MP), where multiple males sire offspring within a single litter, has been used as an index of MMM frequency. However, MP frequency is necessarily lower than MMM frequency. The magnitude of the difference between MMM and MP frequency depends on litter size (LS) and fertilization probability skew (FPS), and this difference may be meaningfully large in animals with small LSs. In this study, we propose a method to estimate MMM frequency using an individual-based model with three variables (MP frequency, LS and FPS). We incorporated observed paternity skew data to infer a possible range of FPS that cannot be measured in free-living populations and tested the validity of our method using a data set from a grey-sided vole (Myodes rufocanus) population and from hypothetical populations. MP was found in 50 out of 215 litters (23.3%) in the grey-sided vole population, while MMM frequency was estimated in 67 of 215 litters (31.2%), with a certainty range of 59-88 (27.4%-40.9%). The point estimation of MMM frequency was realized, and the certainty range was limited within the practical range. The use of observed paternity skew was very effective at narrowing the certainty range of the estimate. Our method could contribute to a deeper understanding of the ecology of MMM in free-living populations.

Do Native Rodents Prey on Land Snails? An Experimental and Quantitative Study in Hokkaido, Japan.

Predator-prey interaction is one of the most important and pervasive pressures in the ecology and evolution of prey species. However, accurate description of the food web is sometimes extremely difficult as there are many predator-prey interactions in the wild are obscure. Recent studies have reported that two closely related land snails, Karaftohelix editha and K. gainesi, on Hokkaido Island, Japan, were diversified due to predation, probably by carabid beetles. However, it is unclear 1) whether native rodents prey upon land snails on Hokkaido Island, and 2) how frequently land snails are preyed upon by rodents in this region, although it has been reported that several species of rodents are predators of land snails in many regions. Thus, we investigated these issues in this study by captive feeding trials and field observations. No rodent species other than the Siberian chipmunk, Tamias sibiricus, were found to prey upon land snails around the research site on Hokkaido Island. In addition, the population density of T. sibiricus was lower than those of other rodent species, and it has been reported that T. sibiricus is omnivorous and preys upon snails considerably less than on other food sources. Overall, these findings suggest that T. sibiricus is not an important predator of Karaftohelix land snails in Hokkaido.

Crystal structures of the UDP-diacylglucosamine pyrophosphohydrase LpxH from Pseudomonas aeruginosa.

Lipid A (also known as endotoxin) is the hydrophobic portion of lipopolysaccharides. It is an essential membrane component required for the viability of gram-negative bacteria. The enzymes involved in its biosynthesis are attractive targets for the development of novel antibiotics. LpxH catalyzes the fourth step of the lipid A biosynthesis pathway and cleaves the pyrophosphate bond of UDP-2,3-diacylglucosamine to yield 2,3-diacylglucosamine 1-phosphate (lipid X) and UMP. Here we present the structures of LpxH from Pseudomonas aeruginosa (PaLpxH). PaLpxH consists of two domains: a catalytic domain that is homologous to the metallophosphoesterases and a helical insertion domain. Lipid X was captured in the crevice between these two domains, with its phosphate group facing the dinuclear metal (Mn(2+)) center and two acyl chains buried in the hydrophobic cavity. The structures reveal that a large conformational change occurs at the lipid X binding site surface upon the binding/release of the product molecule. Based on these observations, we propose a novel model for lipid X embedding, which involves the scissor-like movement of helix α6, resulting in the release of lipid X into the lipid bilayer.