Dnd knockout ablates germ cells and demonstrates germ cell independent sex differentiation in Atlantic salmon

-Introgression of farmed salmon escapees into wild stocks is a major threat to the genetic integrity of wild populations. Using germ cell-free fish in aquaculture may mitigate this problem. Our study investigated whether it is possible to produce germ cell-free salmon in F0 by using CRISPR-Cas9 to knock out dnd, a factor required for germ cell survival in vertebrates. To avoid studying mosaic animals, sgRNA targeting alb was simultaneously used as a visual tracer since the phenotype of alb KO is complete loss of pigmentation. Induced mutations for the tracer (alb) and the target (dnd) genes were highly correlated and produced germ cell-less fish lacking pigmentation, underlining the suitability of alb KO to serve as tracer for targeted double allelic mutations in F0 animals in species with prohibitively long generation times. This is also the first report describing dnd knockout in any fish species. Analyzing gene expression and histology of dnd KO fish revealed that sex differentiation of the somatic compartment does not depend on the presence of germ cells. However, the organization of the ovarian somatic compartment seems compromised in mutant fish

Large Cancer Pedigree Involving Multiple Cancer Genes including Likely Digenic MSH2 and MSH6 Lynch Syndrome (LS) and an Instance of Recombinational Rescue from LS

Funding Information: This research was funded in part by a Cedars-Sinai Medical Center Precision Health Initiative Award to Megan P. Hitchins and Andrew Hendifar. Publisher Copyright: © 2022 by the authors.Lynch syndrome (LS), caused by heterozygous pathogenic variants affecting one of the mismatch repair (MMR) genes (MSH2, MLH1, MSH6, PMS2), confers moderate to high risks for colorectal, endometrial, and other cancers. We describe a four-generation, 13-branched pedigree in which multiple LS branches carry the MSH2 pathogenic variant c.2006G>T (p.Gly669Val), one branch has this and an additional novel MSH6 variant c.3936_4001+8dup (intronic), and other non-LS branches carry variants within other cancer-relevant genes (NBN, MC1R, PTPRJ). Both MSH2 c.2006G>T and MSH6 c.3936_4001+8dup caused aberrant RNA splicing in carriers, including out-of-frame exon-skipping, providing functional evidence of their pathogenicity. MSH2 and MSH6 are co-located on Chr2p21, but the two variants segregated independently (mapped in trans) within the digenic branch, with carriers of either or both variants. Thus, MSH2 c.2006G>T and MSH6 c.3936_4001+8dup independently confer LS with differing cancer risks among family members in the same branch. Carriers of both variants have near 100% risk of transmitting either one to offspring. Nevertheless, a female carrier of both variants did not transmit either to one son, due to a germline recombination within the intervening region. Genetic diagnosis, risk stratification, and counseling for cancer and inheritance were highly individualized in this family. The finding of multiple cancer-associated variants in this pedigree illustrates a need to consider offering multicancer gene panel testing, as opposed to targeted cascade testing, as additional cancer variants may be uncovered in relatives.Peer reviewe

Limit sets of Teichmüller geodesics with minimal non-uniquely ergodic vertical foliation

v1: 28 pages, 4 figures. v2: Fixed figures and minor typos, added referencesInternational audienceWe describe a method for constructing Teichmüller geodesics where the vertical measured foliation $\nu$ is minimal but is not uniquely ergodic and where we have a good understanding of the behavior of the Teichmüller geodesic. The construction depends on various parameters, and we show that one can adjust the parameters to ensure that the set of accumulation points of such a geodesic in the Thurston boundary is exactly the set of all possible measured foliations in the homotopy class of $\nu$. With further adjustment of the parameters, one can even take $\nu$ to be an ergodic measure on a non-uniquely ergodic foliation

The relevance of social policies for democracy: preventing autocratisation through synergies between SDG 10 and SDG 16

This paper was prepared as a background paper for the Global Sustainable Development Report of the United Nations, which will be presented to the UN General Assembly in September 2019. It was made possible with financial support from the Deutsche Gesellschaft für Internationale Zusammenarbeit GmbH (GIZ).The article of record as published may be found at http://dx.doi.org/10.23661/dp7.2019Global threats to democracy – one of the world’s most important forms of inclusive governance – have been rising recently. This paper assesses the effects of social and economic inequalities on autocratisation, meaning a decline in the democratic qualities of a political regime. The key question we study is whether different types, levels and changes in distributional inequalities (Sustainable Development Goal 10) contribute to the erosion of democratic institutions, thereby making governance less inclusive (SDG 16). The paper focusses, in particular, on distributional inequalities and more or less inclusive forms of governance (autocracy vs. democracy). Our findings suggest that conventional measures of income inequality – namely the Gini coefficient – have little to no discernible relationship to the likelihood of a decline in the democratic qualities of a political system. By contrast, inequalities in the provision of social services, particularly healthcare and education, have a clear and consistent relationship to the likelihood of autocratisation. As countries provide social opportunities more equally across their population, they are significantly less likely to experience a weakening of their democratic qualities.. The paper provides an empirical analysis of data from a global sample of countries from 1945 to 2017. Unlike most studies of the effects of inequality on political outcomes, we consider not only income inequality but also inequalities in the distribution of social services such as healthcare, education and welfare. Unequal social opportunities are potentially important for understanding a decrease in democratic quality because they represent individuals’ experiences with the government beyond simply paying taxes, and they affect citizens’ prospects for future social and economic mobility. In addition, citizens with access to social goods and services such as healthcare and education are more empowered to hold the government accountable. In other words, (better) access to social goods and services (SDG 10) helps to achieve SDG 16. The findings provided in this discussion paper are meant to be a starting point for further studying how – and through which mechanisms – equality and inclusive institutions are linked to each other