Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease

Editing Embryos: Considering Restrictions on Genetically Engineering Humans

In April 2015, scientists used a new genetic engineering tool known as CRISPR to edit the genes of a human embryo for the first time. CRISPR has made gene editing cheaper, more efficient, and more accurate than ever before. These advances in technology indicate that in the near future, technology will enable the genes of embryos to be edited, leading to the birth of the first “genetically modified human.” This Note explores the potential benefits and risks of editing embryos for reproductive purposes, and problematizes the lack of meaningful public regulation or deliberation in the United States on editing embryos. Given this risk of misuse, the United States needs to democratically develop regulations that ensure that the free market is not the only constraint on the practice of genetically modifying embryos. In order to demonstrate these points, this Note evaluates the potential beneficial uses for editing embryos, and weighs those benefits against the potential dangers of editing embryos. In discussing the dangers, it discusses individual health and safety risks, as well as societal risks, including the possibility that embryo editing facilitates a new type of eugenics. After evaluating the promises and perils of edited embryos, it discusses the lack of regulatory oversight of editing embryos in the United States, as compared to other technologically advanced countries. Given the lack of limits on genetically modifying embryos in the United States, and the dangers that editing embryos pose to individuals and society, thoughtful public policy discussion on how to regulate this technology is needed. This Note proposes several recommendations for how the law can help facilitate democratic discussion about whether, or under what circumstances, editing embryos should be permitted. Finally, this Note addresses two arguments that may be raised against regulation, and analyzes why neither of these arguments provide a strong reason to reject regulatio

The role of human rights litigation in improving access to reproductive health care and achieving reductions in maternal mortality

Abstract Background Improving maternal health, reducing global maternal mortality, and working toward universal access to reproductive health care are global priorities for United Nations agencies, national governments, and civil society organizations. Human rights lawyers have joined this global movement, using international law and domestic constitutions to hold nations accountable for preventable maternal death and for failing to provide access to reproductive health care services. Case presentation This article discusses three decisions in which international treaty bodies find the nations of Brazil and Peru responsible for violations of the Convention on the Elimination of All Forms of Discrimination Against Women and the International Covenant on Civil and Political Rights and also two domestic decisions alleging constitutional violations in India and Uganda. Conclusions The authors analyze the impact of these decisions on access to maternal and other reproductive health services in Brazil, Peru, India, and Uganda and conclude that litigation is most effective when aligned with ongoing efforts by the public health community and civil society organizations. In filing these complaints and cases on behalf of individual women and their families, legal advocates highlight health system failures and challenge the historical structures and hierarchies that discriminate against and devalue women. These international and domestic decisions empower women and their communities and inspire nations and other stakeholders to commit to broader social, economic, and political change. Human rights litigation brings attention to existing public health campaigns and supports the development of local and global movements and coalitions to improve women’s health

Additional file 1: of The role of human rights litigation in improving access to reproductive health care and achieving reductions in maternal mortality

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Integrase-Specific Enhancement and Suppression of Retroviral DNA Integration by Compacted Chromatin Structure In Vitro

Integration of viral DNA into the host chromosome is an obligatory step in retroviral replication and is dependent on the activity of the viral enzyme integrase. To examine the influence of chromatin structure on retroviral DNA integration in vitro, we used a model target comprising a 13-nucleosome extended array that includes binding sites for specific transcription factors and can be compacted into a higher-ordered structure. We found that the efficiency of in vitro integration catalyzed by human immunodeficiency virus type 1 (HIV-1) integrase was decreased after compaction of this target with histone H1. In contrast, integration by avian sarcoma virus (ASV) integrase was more efficient after compaction by either histone H1 or a high salt concentration, suggesting that the compacted structure enhances this reaction. Furthermore, although site-specific binding of transcription factors HNF3 and GATA4 blocked ASV DNA integration in extended nucleosome arrays, local opening of H1-compacted chromatin by HNF3 had no detectable effect on integration, underscoring the preference of ASV for compacted chromatin. Our results indicate that chromatin structure affects integration site selection of the HIV-1 and ASV integrases in opposite ways. These distinct properties of integrases may also affect target site selection in vivo, resulting in an important bias against or in favor of integration into actively transcribed host DNA

Gene network transitions in embryos depend upon interactions between a pioneer transcription factor and core histones

Gene network transitions in embryos and other fate-changing contexts involve combinations of transcription factors. A subset of fate-changing transcription factors act as pioneers; they scan and target nucleosomal DNA and initiate cooperative events that can open the local chromatin. However, a gap has remained in understanding how molecular interactions with the nucleosome contribute to the chromatin-opening phenomenon. Here we identified a short α-helical region, conserved among FOXA pioneer factors, that interacts with core histones and contributes to chromatin opening in vitro. The same domain is involved in chromatin opening in early mouse embryos for normal development. Thus, local opening of chromatin by interactions between pioneer factors and core histones promotes genetic programming.M.I. was supported by postdoctoral fellowships from Japan Society for the Promotion of Science Foundation (H26-683), Naito Foundation (RYU10000032), Astellas Foundation for Research on Metabolic Disorders (K0076) and Uehara Memorial Foundation (H24-20124). P.S. was supported by grant nos. SAF2016-75531-R (MICINN/FEDER, UE) and B2017/BMD-3724 (Comunidad de Madrid). The research was supported by NIH grant no. GM36477 to K.S.Z.Peer reviewe