The Genetic Basis of Individual-Recognition Signals in the Mouse

SummaryThe major histocompatibility complex (MHC) is widely assumed to be a primary determinant of individual-recognition scents in many vertebrates [1–6], but there has been no functional test of this in animals with normal levels of genetic variation. Mice have evolved another polygenic and highly polymorphic set of proteins for scent communication, the major urinary proteins (MUPs) [7–12], which may provide a more reliable identity signature ([13, 14] and A.L. Sherborne, M.D.T., S. Paterson, F.J., W.E.R.O., P. Stockley, R.J.B., and J.L.H., unpublished data). We used female preference for males that countermark competitor male scents [15–17] to test the ability of wild-derived mice to recognize individual males differing in MHC or MUP type on a variable genetic background. Differences in MHC type were not used for individual recognition. Instead, recognition depended on a difference in MUP type, regardless of other genetic differences between individuals. Recognition also required scent contact, consistent with detection of involatile components through the vomeronasal system [6, 18]. Other differences in individual scent stimulated investigation but did not result in individual recognition. Contrary to untested assumptions of a vertebrate-wide mechanism based largely on MHC variation, mice use a species-specific [12] individual identity signature that can be recognized reliably despite the complex internal and external factors that influence scents [2]. Specific signals for genetic identity recognition in other species now need to be investigated

Darcin: a male pheromone that stimulates female memory and sexual attraction to an individual male's odour

<p>Abstract</p> <p>Background</p> <p>Among invertebrates, specific pheromones elicit inherent (fixed) behavioural responses to coordinate social behaviours such as sexual recognition and attraction. By contrast, the much more complex social odours of mammals provide a broad range of information about the individual owner and stimulate individual-specific responses that are modulated by learning. How do mammals use such odours to coordinate important social interactions such as sexual attraction while allowing for individual-specific choice? We hypothesized that male mouse urine contains a specific pheromonal component that invokes inherent sexual attraction to the scent and which also stimulates female memory and conditions sexual attraction to the airborne odours of an individual scent owner associated with this pheromone.</p> <p>Results</p> <p>Using wild-stock house mice to ensure natural responses that generalize across individual genomes, we identify a single atypical male-specific major urinary protein (MUP) of mass 18893Da that invokes a female's inherent sexual attraction to male compared to female urinary scent. Attraction to this protein pheromone, which we named darcin, was as strong as the attraction to intact male urine. Importantly, contact with darcin also stimulated a strong learned attraction to the associated airborne urinary odour of an individual male, such that, subsequently, females were attracted to the airborne scent of that specific individual but not to that of other males.</p> <p>Conclusions</p> <p>This involatile protein is a mammalian male sex pheromone that stimulates a flexible response to individual-specific odours through associative learning and memory, allowing female sexual attraction to be inherent but selective towards particular males. This 'darcin effect' offers a new system to investigate the neural basis of individual-specific memories in the brain and give new insights into the regulation of behaviour in complex social mammals.</p> <p>See associated Commentary <url>http://www.biomedcentral.com/1741-7007/8/71</url></p

The contribution of diet and genotype to iron status in women:a classical twin study

This is the first published report examining the combined effect of diet and genotype on body iron content using a classical twin study design. The aim of this study was to determine the relative contribution of genetic and environmental factors in determining iron status. The population was comprised of 200 BMI- and age-matched pairs of MZ and DZ healthy twins, characterised for habitual diet and 15 iron-related candidate genetic markers. Variance components analysis demonstrated that the heritability of serum ferritin (SF) and soluble transferrin receptor was 44% and 54% respectively. Measured single nucleotide polymorphisms explained 5% and selected dietary factors 6% of the variance in iron status; there was a negative association between calcium intake and body iron (p = 0.02) and SF (p = 0.04)

Health Systems and Sustainability: Doctors and Consumers Differ on Threats and Solutions

Background: Healthcare systems face the problem of insufficient resources to meet the needs of ageing populations and increasing demands for access to new treatments. It is unclear whether doctors and consumers agree on the main challenges to health system sustainability. Methodology: We conducted a mail survey of Australian doctors (specialists and general practitioners) and a computer assisted telephone interview (CATI) of consumers to determine their views on contributors to increasing health care costs, rationing of services and involvement in health resource allocation decisions. Differences in responses are reported as odds ratios (OR) and 99% confidence intervals (CI). Results: Of 2948 doctors, 1139 (38.6%) responded; 533 of 826 consumers responded (64.5% response). Doctors were more concerned than consumers with the effects of an ageing population (OR 3.0; 99% CI 1.7, 5.4), and costs of new drugs and technologies (OR 5.1; CI 3.3, 8.0), but less likely to consider pharmaceutical promotional activities as a cost driver (OR 0.29, CI 0.22, 0.39). Doctors were more likely than consumers to view ‘community demand’ for new technologies as a major cost driver, (OR 1.6; 1.2, 2.2), but less likely to attribute increased costs to patients failing to take responsibility for their own health (OR 0.35; 0.24, 0.49). Like doctors, the majority of consumers saw a need for public consultation in decisions about funding for new treatments. Conclusions: Australian doctors and consumers hold different views on the sustainability of the healthcare system, and a number of key issues relating to costs, cost drivers, roles and responsibilities. Doctors recognise their dual responsibility to patients and society, see an important role for physicians in influencing resource allocation, and acknowledge their lack of skills in assessing treatments of marginal value. Consumers recognise cost pressures on the health system, but express willingness to be involved in health care decision making

Molecular complexity of the major urinary protein system of the Norway rat, <i>Rattus norvegicus</i>

ABSTRACTMajor urinary proteins (MUP) are the major component of the urinary protein fraction in house mice (Mus spp.) and rats (Rattus spp.). The structure, polymorphism and functions of these lipocalins have been well described in the western European house mouse (Mus musculus domesticus), clarifying their role in semiochemical communication. The complexity of these roles in the mouse raises the question of similar functions in other rodents, including the Norway rat, Rattus norvegicus. Norway rats express MUPs in urine but information about specific MUP isoform sequences and functions is limited. In this study, we present a detailed molecular characterization of the MUP proteoforms expressed in the urine of two laboratory strains, Wistar Han and Brown Norway, and wild caught animals, using a combination of manual gene annotation, intact protein mass spectrometry and bottom-up mass spectrometry-based proteomic approaches. Detailed sequencing of the proteins reveals a less complex pattern of primary sequence polymorphism than the mouse. However, unlike the mouse, rat MUPs exhibit added complexity in the form of post-translational modifications including phosphorylation and exoproteolytic trimming of specific isoforms. The possibility that urinary MUPs may have different roles in rat chemical communication than those they play in the house mouse is also discussed.</jats:p

Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders.

Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is currently unclear. Here we present 19 de novo mutations in this gene, including five missense mutations, identified by the Deciphering Developmental Disorder study. Protein structural analysis reveals that the missense mutations are either close to the ATP or peptide binding-sites within the kinase domain, or are important for protein stability, suggesting they lead to a loss of the protein's function mechanism. Furthermore, there is some correlation between the magnitude of the change and the severity of the resultant phenotype. A comparison of the distribution of the pathogenic mutations along the length of DYRK1A with that of natural variants, as found in the ExAC database, confirms that mutations in the N-terminal end of the kinase domain are more disruptive of protein function. In particular, pathogenic mutations occur in significantly closer proximity to the ATP and the substrate peptide than the natural variants. Overall, we suggest that de novo dominant mutations in DYRK1A account for nearly 0.5% of severe developmental disorders due to substantially reduced kinase function

Diagnostic value of exome and whole genome sequencing in craniosynostosis

Background Craniosynostosis, the premature fusion of one or more cranial sutures, occurs in ~1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing. Methods We used exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high-priority cases, and in whom prior clinically driven genetic testing had been negative. Results We identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (two families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3). Conclusions This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results

Genotype-phenotype correlation at codon 1740 ofSETD2

The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2

Industry-Informed Workshops to Develop Graduate Skill Sets in the Circular Economy Using Systems Thinking

Increasing demand for chemicals worldwide, depleting resources, consumer pressure, stricter legislation, and the rising cost of waste disposal are placing increasing pressure on chemical and related industries. For any organization to survive in the current arena of growing climate change laws and regulations, and increasing public influence, the issue of sustainability must be fundamental to the way it operates. A sustainable manufacturing approach will enable economic growth to be combined with environmental and social sustainability and will be realized via collaboration between a multidisciplinary community including chemists, biologists, engineers, environmental scientists, economists, experts in management, and policy makers. Hence, employees with new skills, knowledge, and experience are essential. To realize this approach, the design and development of a series of workshops encompassing systems thinking are presented here. After close consultation with industry, an annual program of interactive workshops has been designed for graduate students to go beyond examining the "greening" of chemical reactions, processes, and products, and instead embed a systems thinking approach to learning. The workshops provide a valuable insight into the issues surrounding sustainable manufacturing covering change management, commercialization, environmental impact, circular economy, legislation, and bioresources incorporating the conversion of waste into valuable products. The multidisciplinary course content incorporates industrial case studies, providing access to real business issues, and is delivered by experts from academic departments across campus and industry