A de novo paradigm for male infertility

Genetics of Male Infertility Initiative (GEMINI) consortium: Donald F. Conrad, Liina Nagirnaja, Kenneth I. Aston, Douglas T. Carrell, James M. Hotaling, Timothy G. Jenkins, Rob McLachlan, Moira K. O’Bryan, Peter N. Schlegel, Michael L. Eisenberg, Jay I. Sandlow, Emily S. Jungheim, Kenan R. Omurtag, Alexandra M. Lopes, Susana Seixas, Filipa Carvalho, Susana Fernandes, Alberto Barros, João Gonçalves, Iris Caetano, Graça Pinto, Sónia Correia, Maris Laan, Margus Punab, Ewa Rajpert-De Meyts, Niels Jørgensen, Kristian Almstrup, Csilla G. Krausz & Keith A. Jarvi.De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10−5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10−4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.This project was funded by The Netherlands Organization for Scientific Research (918-15-667) to J.A.V. as well as an Investigator Award in Science from the Wellcome Trust (209451) to J.A.V. a grant from the Catherine van Tussenbroek Foundation to M.S.O. a grant from MERCK to R.S. a UUKi Rutherford Fund Fellowship awarded to B.J.H. and the German Research Foundation Clinical Research Unit “Male Germ Cells” (DFG, CRU326) to C.F. and F.T. This project was also supported in part by funding from the Australian National Health and Medical Research Council (APP1120356) to M.K.O.B., by grants from the National Institutes of Health of the United States of America (R01HD078641 to D.F.C. and K.I.A., P50HD096723 to D.F.C.) and from the Biotechnology and Biological Sciences Research Council (BB/S008039/1) to D.J.E.info:eu-repo/semantics/publishedVersio

estudos artísticos

O quarto número da Revista GAMA percorre, no campo dos Estudos Artísticos, instâncias de memória e de enraizamento, problematizando o futuro através das questões resgatadas, de ontem. Dá-se seguimento ao rumo inicial desta revista, onde artistas escrevem sobre obras de outros artistas, mas agora tem-se uma melhor delimitação e focagem no que respeita ao uso criativo ou acidental da diacronia e suas interligações potenciadoras: o arquivo, a obra recordada, o registo, o projeto, a reativação, a meta-linguagem, a identidade. A Revista GAMA segue um caminho prudente, como o de um alpinista que, ao subir, procura registar na memória os pontos de referência do seu caminho, pontos que lhe possam vir a ser úteis, mais tarde, na descida. Aqueles que sobem, nesta revista, podem ser uns, e os que descem, podem ser outros, de outra geração. Os pontos de referência permanecem, à espera da sua utilidade. Este conjunto de artigos traduz um posicionamento geral de grande atenção aos referentes históricos e técnicos, com uma sensível preocupação pela recuperação e preservação dos objetos e criadores interventivos. Através do olhar dos criadores de hoje, a criatividade mantém-se ativa e interventiva, para ser fonte de recomeços que se anunciam.info:eu-repo/semantics/publishedVersio