Searching for Dark Matter Annihilation in the Smith High-Velocity Cloud

Recent observations suggest that some high-velocity clouds may be confined by massive dark matter halos. In particular, the proximity and proposed dark matter content of the Smith Cloud make it a tempting target for the indirect detection of dark matter annihilation. We argue that the Smith Cloud may be a better target than some Milky Way dwarf spheroidal satellite galaxies and use gamma-ray observations from the Fermi Large Area Telescope to search for a dark matter annihilation signal. No significant gamma-ray excess is found coincident with the Smith Cloud, and we set strong limits on the dark matter annihilation cross section assuming a spatially-extended dark matter profile consistent with dynamical modeling of the Smith Cloud. Notably, these limits exclude the canonical thermal relic cross section ($\sim 3\times10^{-26}{\rm cm}^{3}{\rm s}^{-1}$) for dark matter masses $\lesssim 30$ GeV annihilating via the $b \bar b$ or $\tau^{+}\tau^{-}$ channels for certain assumptions of the dark matter density profile; however, uncertainties in the dark matter content of the Smith Cloud may significantly weaken these constraints.Comment: 7 pages, 5 figures. Published in Ap

Ethical Considerations for the Return of Incidental Findings in Ophthalmic Genomic Research

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Available from PubMed Central (PMC).http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757467/Whole genome and whole exome sequencing technologies are being increasingly used in research. However, they have the potential to identify incidental findings (IF), findings not related to the indication of the test, raising questions regarding researchers' responsibilities toward the return of this information to participants. In this study we discuss the ethical considerations related to the return of IF to research participants, emphasizing that the type of the study matters and describing the current practice standards. There are currently no legal obligations for researchers to return IF to participants, but some viewpoints consider that researchers might have an ethical one to return IF of clinical validity and clinical utility and that are actionable. The reality is that most IF are complex to interpret, especially since they were not the indication of the test. The clinical utility often depends on the participants' preferences, which can be challenging to conciliate and relies on participants' understanding. In summary, in the context of a lack of clear guidance, researchers need to have a clear plan for the disclosure or nondisclosure of IF from genomic research, balancing their research goals and resources with the participants' rights and their duty not to harm

Developing an e-infrastructure for social science

We outline the aims and progress to date of the National Centre for e-Social Science e-Infrastructure project. We examine the challenges faced by the project, namely in ensuring outputs are appropriate to social scientists, managing the transition from research projects to service and embedding software and data within a wider infrastructural framework. We also provide pointers to related work where issues which have ramifications for this and similar initiatives are being addressed

Role of the TCF4 gene intronic variant in normal variation of corneal endothelium

PURPOSE: To identify early features of Fuchs endothelial dystrophy (FED) in carriers of the rs613872(G) transcription factor 4 gene (TCF4) aged 20 to 21 years. METHODS: Prospective cohort study of people aged 20 to 21 years previously enrolled in the Western Australia Pregnancy (Raine) Cohort. Specular microscopy was performed using a noncontact specular microscopy (EM-3000; Tomey, Nagoya, Japan). Individual genotype data were extracted from the genome-wide Illumina 660 Quad Array. Analysis of the association between the rs613872 risk allele in TCF4 and specular microscopic measurements was conducted. RESULTS: Association between the rs613872 risk allele and corneal endothelial cell density (CD) as well as the coefficient of variation in cell shape was the main outcome measure. Genotype and specular microscopic data were available for a total of 445 participants (46% women). The median CD was 2851 and 2850 cells per square millimeter in the right and left eyes, respectively. No significant differences between intereye variability in endothelial CD were seen (right eye to left eye correlation = 0.64); however, a significant difference in variability of endothelial CD between men and women was observed (male: OD, 2839 ± 124 cells/mm and OS, 2845 ± 124 cells/mm vs. female: OD, 2838 ± 134 cells/mm and OS, 2842 ± 132 cells/mm; OD, P = 0.0013 and OS, P = 0.0016). Eleven individuals were homozygous for the rs613872 risk allele. We found no association between rs613872 genotype and CD or coefficient of variation. One of 11 homozygous GG individuals was found to have a gutta in 1 sample field on specular microscopy, whereas 2 of 297 TT individuals also had a gutta each in 1 sample field. CONCLUSIONS: We were unable to detect an association between TCF4 rs613872 genotype and the variation in corneal endothelial CD or variation in cell morphology in a healthy young adult population. Copyrigh

The telomere of human chromosome 1p contains at least two independent autosomal dominant congenital cataract genes.

AIMS: Multiple genetic causes of congenital cataract have been identified, both as a component of syndromes and in families that present with isolated congenital cataract. Linkage analysis was used to map the genetic locus in a six generation Australian family presenting with total congenital cataract. METHODS: Microsatellite markers located across all known autosomal dominant congenital cataract loci were genotyped in all recruited family members of the Tasmanian family. Both two point and multipoint linkage analysis were used to assess each locus under an autosomal dominant model. RESULTS: Significant linkage was detected at the telomere of the p arm of chromosome 1, with a maximum two point LOD of 4.21 at marker D1S507, a maximum multipoint exact LOD of 5.44, and an estimated location score of 5.61 at marker D1S507. Haplotype analysis places the gene inside a critical region between D1S228 and D1S199, a distance of approximately 6 megabases. The candidate gene PAX7 residing within the critical interval was excluded by direct sequencing in affected individuals. CONCLUSION: This is the third report of congenital cataract linkage to 1ptel. The critical region as defined by the shared haplotype in this family is clearly centromeric from the Volkmann cataract locus identified through study of a Danish family, indicating that two genes causing autosomal dominant congenital cataract map to the telomeric region of chromosome 1p

Investigation of Founder Effects for the Thr377Met Myocilin Mutation in Glaucoma Families from Differing Ethnic Backgrounds

Purpose: The aim of this study was to determine if there is a common founder for the Thr377Met myocilin mutation in primary open angle glaucoma (POAG) families with various ethnic backgrounds. Methods: Genomic DNA of 24 POAG-affected individuals from nine pedigrees with the Thr377Met mutation and 104 unaffected family members was genotyped with six microsatellite markers and four single nucleotide polymorphisms. The families were from Greece, India, Finland, the USA, and Australia. To assess the degree of linkage disequilibrium across MYOC in the general population we also investigated data generated from the HapMap consortium. Results: Three distinct haplotypes associated with the Thr377Met myocilin mutation were identified. The families from the USA and Greece, as well as the three Australian families originating from Greece and the former Yugoslavian Republic of Macedonia had one common haplotype. Interestingly, however, HapMap data suggest that linkage disequilibrium across MYOC was not strong. Conclusions: The Thr377Met myocilin mutation has arisen at least three separate times. Evidence for genetic founder effects in this prevalent age-related, yet heterogeneous, disease has important implications for future gene identification strategies

Assessment of polygenic effects links primary open-angle glaucoma and age-related macular degeneration

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD) are leading causes of irreversible blindness. Several loci have been mapped using genome-wide association studies. Until very recently, there was no recognized overlap in the genetic contribution to AMD and POAG. At genome-wide significance level, only ABCA1 harbors associations to both diseases. Here, we investigated the genetic architecture of POAG and AMD using genome-wide array data. We estimated the heritability for POAG (h2 g = 0.42 ± 0.09) and AMD (h2 g = 0.71 ± 0.08). Removing known loci for POAG and AMD decreased the h2 g estimates to 0.36 and 0.24, respectively. There was evidence for a positive genetic correlation between POAG and AMD (rg = 0.47 ± 0.25) which remained after removing known loci (rg = 0.64 ± 0.31). We also found that the genetic correlation between sexes for POAG was likely to be less than 1 (rg = 0.33 ± 0.24), suggesting that differences of prevalence among genders may be partly due to heritable factors

The p53 codon 72 PRO/PRO genotype may be associated with initial central visual field defects in Caucasians with primary open angle glaucoma

Background: Loss of vision in glaucoma is due to apoptotic retinal ganglion cell loss. While p53 modulates apoptosis, gene association studies between p53 variants and glaucoma have been inconsistent. In this study we evaluate the association between a p53 variant functionally known to influence apoptosis (codon 72 Pro/Arg) and the subset of primary open angle glaucoma (POAG) patients with early loss of central visual field. Methods: Genotypes for the p53 codon 72 polymorphism (Pro/Arg) were obtained for 264 POAG patients and 400 controls from the U.S. and in replication studies for 308 POAG patients and 178 controls from Australia (GIST). The glaucoma patients were divided into two groups according to location of initial visual field defect (either paracentral or peripheral). All cases and controls were Caucasian with European ancestry. Results: The p53-PRO/PRO genotype was more frequent in the U.S. POAG patients with early visual field defects in the paracentral regions compared with those in the peripheral regions or control group (p = 2.761025). We replicated this finding in the GIST cohort (p = 7.361023, and in the pooled sample (p = 6.661027) and in a meta-analysis of both the US and GIST datasets (1.361026, OR 2.17 (1.58–2.98 for the PRO allele). Conclusions: These results suggest that the p53 codon 72 PRO/PRO genotype is potentially associated with early paracentral visual field defects in primary open-angle glaucoma patients.NHMRC: This study was supported by National Institutes of Health/National Eye Institute grants: R01EY015872 (Wiggs), R01EY015473 (Pasquale), P30EY014104 (Wiggs), Research to Prevent Blindness (Wiggs, Pasquale, Realini), the Harvard Glaucoma Center of Excellence (Wiggs, Pasquale), The Massachusetts Lions Eye Research Fund (Wiggs, Pasquale), National Health & Medical Research Council Project grant 229960, the Ophthalmic Research Institute of Australia, and Glaucoma Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD