Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders

Many neuropsychiatric disorders exhibit differences in prevalence, age of onset, symptoms or course of illness between males and females. For the most part, the origins of these differences are not well understood. In this article, we provide an overview of sex differences in psychiatric disorders including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), anxiety, depression, alcohol and substance abuse, schizophrenia, eating disorders and risk of suicide. We discuss both genetic and nongenetic mechanisms that have been hypothesized to underlie these differences, including ascertainment bias, environmental stressors, X‐ or Y‐linked risk loci, and differential liability thresholds in males and females. We then review the use of twin, family and genome‐wide association approaches to study potential genetic mechanisms of sex differences and the extent to which these designs have been employed in studies of psychiatric disorders. We describe the utility of genetic epidemiologic study designs, including classical twin and family studies, large‐scale studies of population registries, derived recurrence risks, and molecular genetic analyses of genome‐wide variation that may enhance our understanding sex differences in neuropsychiatric disorders.     

On the reporting and review requirements of ISO 14044

The International Journal of Life Cycle Assessment -     

Signature of sexual conflict is actually conflict resolved

There has been substantial interest of late in using population genetic methods to study sexual conflict, where an allele increases the fitness of one sex at some cost to the other (Mank, 2017). Population genomic scans for sexual conflict offer an important advance given the difficulties of identifying antagonistic alleles from more traditional methods, and could greatly increase our understanding of the extent and loci of sexual conflict. This is particularly true for studies in natural populations, for which obtaining accurate fitness measurements for each sex can be challenging. In this issue of Molecular Ecology, Bissegger, Laurentino, Roesti, and Berner (2019) present a cautionary tale about how to interpret these population genomic data.     

Population modelling and genetics of a critically endangered Madagascan palm Tahina spectabilis

Madagascar is home to 208 indigenous palm species, almost all of them endemic and >80% of which are endangered. We undertook complete population census and sampling for genetic analysis of a relatively recently discovered giant fan palm, the Critically Endangered Tahina spectablis in 2008 and 2016. Our 2016 study included newly discovered populations and added to our genetic study. We incorporated these new populations into species distribution niche model (SDM) and projected these onto maps of the region. We developed population matrix models based on observed demographic data to model population change and predict the species vulnerability to extinction by undertaking population viability analysis (PVA). We investigated the potential conservation value of reintroduced planted populations within the species potential suitable habitat. We found that the population studied in 2008 had grown in size due to seedling regeneration but had declined in the number of reproductively mature plants, and we were able to estimate that the species reproduces and dies after approximately 70 years. Our models suggest that if the habitat where it resides continues to be protected the species is unlikely to go extinct due to inherent population decline and that it will likely experience significant population growth after approximately 80 years due to the reproductive and life cycle attributes of the species. The newly discovered populations contain more genetic diversity than the first discovered southern population which is genetically depauperate. The species appears to demonstrate a pattern of dispersal leading to isolated founder plants which may eventually lead to population development depending on local establishment opportunities. The conservation efforts currently put in place including the reintroduction of plants within the species potential suitable habitat if maintained are thought likely to enable the species to sustain itself but it remains vulnerable to anthropogenic impacts.     

In vitro induction of neoantigen-specific T cells in myelodysplastic syndrome,a disease with low mutational burden

Therapies that utilize immune checkpoint inhibition work by leveraging mutation-derived neoantigens and have shown greater clinical efficacy in tumors with higher mutational burden. Whether tumors with a low mutational burden are susceptible to neoantigen-targeted therapy has not been fully addressed. To examine the feasibility of neoantigen-specific adoptive T-cell therapy, the authors studied the T-cell response against somatic variants in five patients with myelodysplastic syndrome (MDS), a malignancy with a very low tumor mutational burden. DNA and RNA from tumor (CD34⁺) and normal (CD3⁺) cells isolated from the patients’ blood were sequenced to predict patient-specific MDS neopeptides. Neopeptides representing the somatic variants were used to induce and expand autologous T cells ex vivo, and these were systematically tested in killing assays to determine the proportion of neopeptides yielding neoantigen-specific T cells. The authors identified a total of 32 somatic variants (four to eight per patient) and found that 21 (66%) induced a peptide-specific T-cell response and 19 (59%) induced a T-cell response capable of killing autologous tumor cells. Of the 32 somatic variants, 11 (34%) induced a CD4⁺ response and 11 (34%) induced a CD8⁺ response that killed the tumor. These results indicate that in vitro induction of neoantigen-specific T cells is feasible for tumors with very low mutational burden and that this approach warrants investigation as a therapeutic option for such patients.     

Staphylococcus aureus cell wall structure and dynamics during host-pathogen interaction

Peptidoglycan is the major structural component of the Staphylococcus aureus cell wall, in which it maintains cellular integrity, is the interface with the host, and its synthesis is targeted by some of the most crucial antibiotics developed. Despite this importance, and the wealth of data from in vitro studies, we do not understand the structure and dynamics of peptidoglycan during infection. In this study we have developed methods to harvest bacteria from an active infection in order to purify cell walls for biochemical analysis ex vivo. Isolated ex vivo bacterial cells are smaller than those actively growing in vitro, with thickened cell walls and reduced peptidoglycan crosslinking, similar to that of stationary phase cells. These features suggested a role for specific peptidoglycan homeostatic mechanisms in disease. As S. aureus missing penicillin binding protein 4 (PBP4) has reduced peptidoglycan crosslinking in vitro its role during infection was established. Loss of PBP4 resulted in an increased recovery of S. aureus from the livers of infected mice, which coincided with enhanced fitness within murine and human macrophages. Thicker cell walls correlate with reduced activity of peptidoglycan hydrolases. S. aureus has a family of 4 putative glucosaminidases, that are collectively crucial for growth. Loss of the major enzyme SagB, led to attenuation during murine infection and reduced survival in human macrophages. However, loss of the other three enzymes Atl, SagA and ScaH resulted in clustering dependent attenuation, in a zebrafish embryo, but not a murine, model of infection. A combination of pbp4 and sagB deficiencies resulted in a restoration of parental virulence. Our results, demonstrate the importance of appropriate cell wall structure and dynamics during pathogenesis, providing new insight to the mechanisms of disease.     

Moths in fragments: insights into the biology and ecology of the Australian endangered golden sun moth Synemon plana (Lepidoptera: Castniidae) in natural temperate and exotic grassland remnants

The conservation and management of endangered species requires an adequate understanding of their biology and ecology. Although there has been an increasing appreciation in Australia of the need for greater efforts to conserve insects, there is only limited information available that can be used to underpin conservation efforts. The endangered golden sun moth, Synemon plana (Lepidoptera: Castniidae) is a flagship species endemic to natural temperate grassland in south-eastern Australia. Most populations of this species are at considerable risk from habitat loss, weed invasion and inadequate management. Despite the considerable knowledge that exists about the species biology and ecology, efforts to improve the species conservation status are hampered because there are still critical gaps in our understanding of the species’ natural history. In particular, the ecology of the larvae is not known. Our study examined the abundance, population structure and reproductive biology of the moths in a broad sample of both natural temperate and exotic grassland remnants in and near Canberra in the Australian Capital Territory (ACT) in south-eastern Australia. The results fill critical gaps in the knowledge needed to achieve effective conservation management. From our findings, it is clear that the species inhabits grasslands dominated by a mixture of native wallaby grasses (Rytidosperma spp. (formerly Austrodanthonia)) and spear grasses (Austrostipa spp.). In contrast to earlier suggestions that S. plana is entirely confined to natural temperate grassland, mature and immature life stages of the species were also present in grasslands comprised entirely of the exotic Chilean needlegrass (Nassella neesiana). Most of the S. plana populations surveyed in the ACT were characterised by low relative abundance with only very few large populations being recorded. The conservation of exotic grasslands as substitute habitat for S. plana is discussed and suggestions regarding future monitoring and research of the species are provided.