Congenic Strain Analysis Reveals Genes That Are Rapidly Evolving Components of a Prezygotic Isolation Mechanism Mediating Incipient Reinforcement

Two decades ago, we developed a congenic strain of Mus musculus, called b-congenic, by replacing the androgen-binding protein Abpa27a allele in the C3H/HeJ genome with the Abpa27b allele from DBA/2J. We and other researchers used this b-congenic strain and its C3H counterpart, the a-congenic strain, to test the hypothesis that, given the choice between signals from two strains with different a27 alleles on the same genetic background, test subjects would prefer the homosubspecific one. It was our purpose in undertaking this study to characterize the segment transferred from DBA to the C3H background in producing the b-congenic strain on which a role for ABPA27 in behavior has been predicated. We determined the size of the chromosome 7 segment transferred from DBA and the genes it contains that might influence preference. We found that the “functional" DBA segment is about 1% the size of the mouse haploid genome and contains at least 29 genes expressed in salivary glands, however, only three of these encode proteins identified in the mouse salivary proteome. At least two of the three genes Abpa27, Abpbg26 and Abpbg27 encoding the subunits of androgen-binding protein ABP dimers evolved under positive selection and the third one may have also. In the sense that they are subunits of the same two functional entities, the ABP dimers, we propose that their evolutionary histories might not be independent of each other

Positive Selection Shaped the Convergent Evolution of Independently Expanded Kallikrein Subfamilies Expressed in Mouse and Rat Saliva Proteomes

We performed proteomics studies of salivas from the genome mouse (C57BL/6 strain) and the genome rat (BN/SsNHsd/Mcwi strain). Our goal was to identify salivary proteins with one or more of three characteristics that may indicate that they have been involved in adaptation: 1) rapid expansion of their gene families; 2) footprints of positive selection; and/or 3) sex-limited expression. The results of our proteomics studies allow direct comparison of the proteins expressed and their levels between the sexes of the two rodent species. Twelve members of the Mus musculus species-specific kallikrein subfamily Klk1b showed sex-limited expression in the mouse saliva proteomes. By contrast, we did not find any of the Rattus norvegicus species-specific kallikrein subfamily Klk1c proteins in male or female genome rat, nor transcripts in their submandibular glands. On the other hand, we detected expression of this family as transcripts in the submandibular glands of both sexes of Sprague-Dawley rats. Using the CODEML program in the PAML package, we demonstrate that the two rodent kallikrein subfamilies have apparently evolved rapidly under the influence of positive selection that continually remodeled the amino acid sites on the same face in the members of the subfamilies. Thus, although their kallikrein subfamily expansions were independent, this evolutionary pattern has occurred in parallel in the two rodent species, suggesting a form of convergent evolution at the molecular level. On the basis of this new data, we suggest that the previous speculative function of the species-specific rodent kallikreins as important solely in wound healing in males be investigated further. In addition to or instead of that function, we propose that their sex-limited expression, coupled with their rapid evolution may be clues to an as-yet-undetermined interaction between the sexes

A Candidate Subspecies Discrimination System Involving a Vomeronasal Receptor Gene with Different Alleles Fixed in M. m. domesticus and M. m. musculus

Assortative mating, a potentially efficient prezygotic reproductive barrier, may prevent loss of genetic potential by avoiding the production of unfit hybrids (i.e., because of hybrid infertility or hybrid breakdown) that occur at regions of secondary contact between incipient species. In the case of the mouse hybrid zone, where two subspecies of Mus musculus (M. m. domesticus and M. m. musculus) meet and exchange genes to a limited extent, assortative mating requires a means of subspecies recognition. We based the work reported here on the hypothesis that, if there is a pheromone sufficiently diverged between M. m. domesticus and M. m. musculus to mediate subspecies recognition, then that process must also require a specific receptor(s), also sufficiently diverged between the subspecies, to receive the signal and elicit an assortative mating response. We studied the mouse V1R genes, which encode a large family of receptors in the vomeronasal organ (VNO), by screening Perlegen SNP data and identified one, Vmn1r67, with 24 fixed SNP differences most of which (15/24) are nonsynonymous nucleotide substitutions between M. m. domesticus and M. m. musculus. We observed substantial linkage disequilibrium (LD) between Vmn1r67 and Abpa27, a mouse salivary androgen-binding protein gene that encodes a proteinaceous pheromone (ABP) capable of mediating assortative mating, perhaps in conjunction with its bound small lipophilic ligand. The LD we observed is likely a case of association rather than residual physical linkage from a very recent selective sweep, because an intervening gene, Vmn1r71, shows significant intra(sub)specific polymorphism but no inter(sub)specific divergence in its nucleotide sequence. We discuss alternative explanations of these observations, for example that Abpa27 and Vmn1r67 are coevolving as signal and receptor to reinforce subspecies hybridization barriers or that the unusually divergent Vmn1r67 allele was not a product of fast positive selection, but was derived from an introgressed allele, possibly from Mus spretus

Chelators in Iron and Copper Toxicity

Purpose of Review Chelation therapy is used for diseases causing an imbalance of iron levels (for example haemochromatosis and thalassaemia) or copper levels (for example Menkes’ and Wilson’s diseases). Currently, most pharmaceutical chelators are relatively simple but often have side effects. Some have been taken off the market. This review attempts to find theory and knowledge required to design or find better chelators. Recent Findings Recent research attempting to understand the biological mechanisms of protection against iron and copper toxicity is reviewed. Understanding of molecular mechanisms behind normal iron/copper regulation may lead to the design of more sophisticated chelators. The theory of metal ion toxicity explains why some chelators, such as EDTA, which chelate metal ions in a way which exposes the ion to the surrounding environment are shown to be unsuitable except as a means of killing cancer cells. The Lewis theory of acids and bases suggests which amino acids favour the attachment of the hard/intermediate ions Fe2+, Fe3+, Cu2+ and soft ion Cu+. Non-polar amino acids will chelate the ion in a position not in contact with the surrounding cellular environment. The conclusion is that only the soft ion binding cysteine and methionine appear as suitable chelators. Clearly, nature has developed proteins which are less restricted. Recent research on naturally produced chelators such as siderophores and phytochemicals show some promise as pharmaceuticals. Summary Although an understanding of natural mechanisms of Fe/Cu regulation continues to increase, the pharmaceutical chelators for metal overload diseases remain simple non-protein molecules. Natural and synthetic alternatives have been studied but require further research before being accepted

ICAR: endoscopic skull‐base surgery

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Phenotypic heterogeneity and genetic modifiers in prion disease caused by a Pro102Leu mutation in the PRNP gene

This Practice Point commentary describes the findings of a study by Webb et al. in which the researchers investigated phenotypic heterogeneity and disease-modifying factors in a large series of patients with inherited prion disease caused by a mutation in the PRNP gene that results in a Pro102Leu amino acid substitution. This mutation is traditionally associated with Gerstmann-Sträussler-Scheinker syndrome (GSS), and the clinical presentation in most patients in the study fitted into the GSS spectrum, but a subset presented with prominent cognitive impairment. In addition, the authors noted remarkable interfamilial and intrafamilial variability with respect to age at disease onset (range 27-66 years) and disease duration (range 7-132 months). Importantly, a polymorphism at PRNP codon 129 and the apolipoprotein E genotype were both identified as factors that modified the age at onset. These findings could have important implications for genetic counseling of individuals at risk from prion disease

Phenotypic variability of Gerstmann-Str\ue4ussler-Scheinker disease is associated with prion protein heterogeneity.

Gerstmann-Str\ue4ussler-Scheinker disease (GSS), a cerebello-pyramidal syndrome associated with dementia and caused by mutations in the prion protein gene (PRNP), is phenotypically heterogeneous. The molecular mechanisms responsible for such heterogeneity are unknown. Since we hypothesize that prion protein (PrP) heterogeneity may be associated with clinico-pathologic heterogeneity, the aim of this study was to analyze PrP in several GSS variants. Among the pathologic phenotypes of GSS, we recognize those without and with marked spongiform degeneration. In the latter (i.e. a subset of GSS P102L patients) we observed 3 major proteinase-K resistant PrP (PrPres) isoforms of ca. 21-30 kDa, similar to those seen in Creutzfeldt-Jakob disease. In contrast, the 21-30 kDa isoforms were not prominent in GSS variants without spongiform changes, including GSS A117V, GSS D202N, GSS Q212P, GSS Q217R, and 2 cases of GSS P102L. This suggests that spongiform changes in GSS are related to the presence of high levels of these distinct 21-30 kDa isoforms. Variable amounts of smaller, distinct PrPres isoforms of ca. 7-15 kDa were seen in all GSS variants. This suggests that GSS is characterized by the presence PrP isoforms that can be partially cleaved to low molecular weight PrPres peptides