%0 Journal Article %J Sci Transl Med %D 2021 %T Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis. %A Tapmeier, Thomas T %A Rahmioglu, Nilufer %A Lin, Jianghai %A De Leo, Bianca %A Obendorf, Maik %A Raveendran, Muthuswamy %A Fischer, Oliver M %A Bafligil, Cemsel %A Guo, Manman %A R. Alan Harris %A Hess-Stumpp, Holger %A Laux-Biehlmann, Alexis %A Lowy, Ernesto %A Lunter, Gerton %A Malzahn, Jessica %A Martin, Nicholas G %A Martinez, Fernando O %A Manek, Sanjiv %A Mesch, Stefanie %A Montgomery, Grant W %A Morris, Andrew P %A Nagel, Jens %A Simmons, Heather A %A Brocklebank, Denise %A Shang, Catherine %A Treloar, Susan %A Wells, Graham %A Becker, Christian M %A Oppermann, Udo %A Zollner, Thomas M %A Kennedy, Stephen H %A Kemnitz, Joseph W %A Jeffrey Rogers %A Zondervan, Krina T %K Animals %K Endometriosis %K Endometrium %K Female %K Humans %K Macaca mulatta %K Mice %K Receptors, G-Protein-Coupled %K Tumor Necrosis Factor-alpha %X

Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in , the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls ( = 7.8 × 10). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques ( = 0.0095). Targeted association analyses in 3194 surgically confirmed, unrelated cases and 7060 controls revealed that a common insertion/deletion variant, rs142885915, was significantly associated with stage III/IV endometriosis ( = 5.2 × 10; odds ratio, 1.23; 95% CI, 1.09 to 1.39). Immunohistochemistry, qRT-PCR, and flow cytometry experiments demonstrated that NPSR1 was expressed in glandular epithelium from eutopic and ectopic endometrium, and on monocytes in peritoneal fluid. The NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro ( < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain ( < 0.05) in a mouse model of peritoneal inflammation as well as in a mouse model of endometriosis. We conclude that the NPSR1/NPS system is a genetically validated, nonhormonal target for the treatment of endometriosis with likely increased relevance to stage III/IV disease.

%B Sci Transl Med %V 13 %8 2021 Aug 25 %G eng %N 608 %1 https://www.ncbi.nlm.nih.gov/pubmed/34433639?dopt=Abstract %R 10.1126/scitranslmed.abd6469 %0 Journal Article %J Science %D 2020 %T Sequence diversity analyses of an improved rhesus macaque genome enhance its biomedical utility. %A Warren, Wesley C %A R. Alan Harris %A Haukness, Marina %A Fiddes, Ian T %A Murali, Shwetha C %A Fernandes, Jason %A Dishuck, Philip C %A Storer, Jessica M %A Raveendran, Muthuswamy %A Hillier, LaDeana W %A Porubsky, David %A Mao, Yafei %A Gordon, David %A Vollger, Mitchell R %A Lewis, Alexandra P %A Munson, Katherine M %A DeVogelaere, Elizabeth %A Armstrong, Joel %A Diekhans, Mark %A Walker, Jerilyn A %A Tomlinson, Chad %A Graves-Lindsay, Tina A %A Kremitzki, Milinn %A Salama, Sofie R %A Audano, Peter A %A Escalona, Merly %A Maurer, Nicholas W %A Antonacci, Francesca %A Mercuri, Ludovica %A Maggiolini, Flavia A M %A Catacchio, Claudia Rita %A Underwood, Jason G %A O'Connor, David H %A Sanders, Ashley D %A Korbel, Jan O %A Ferguson, Betsy %A Kubisch, H Michael %A Picker, Louis %A Kalin, Ned H %A Rosene, Douglas %A Levine, Jon %A Abbott, David H %A Gray, Stanton B %A Sanchez, Mar M %A Kovacs-Balint, Zsofia A %A Kemnitz, Joseph W %A Thomasy, Sara M %A Roberts, Jeffrey A %A Kinnally, Erin L %A Capitanio, John P %A Skene, J H Pate %A Platt, Michael %A Cole, Shelley A %A Green, Richard E %A Ventura, Mario %A Wiseman, Roger W %A Paten, Benedict %A Batzer, Mark A %A Jeffrey Rogers %A Eichler, Evan E %K Animals %K Genetic Predisposition to Disease %K Genetic Variation %K Genome %K Humans %K Macaca mulatta %K Molecular Sequence Annotation %K Polymorphism, Single Nucleotide %K Whole Genome Sequencing %X

The rhesus macaque () is the most widely studied nonhuman primate (NHP) in biomedical research. We present an updated reference genome assembly (Mmul_10, contig N50 = 46 Mbp) that increases the sequence contiguity 120-fold and annotate it using 6.5 million full-length transcripts, thus improving our understanding of gene content, isoform diversity, and repeat organization. With the improved assembly of segmental duplications, we discovered new lineage-specific genes and expanded gene families that are potentially informative in studies of evolution and disease susceptibility. Whole-genome sequencing (WGS) data from 853 rhesus macaques identified 85.7 million single-nucleotide variants (SNVs) and 10.5 million indel variants, including potentially damaging variants in genes associated with human autism and developmental delay, providing a framework for developing noninvasive NHP models of human disease.

%B Science %V 370 %8 2020 Dec 18 %G eng %N 6523 %1 https://www.ncbi.nlm.nih.gov/pubmed/33335035?dopt=Abstract %R 10.1126/science.abc6617 %0 Journal Article %J Anal Biochem %D 2009 %T High-quality genomic DNA extraction from formalin-fixed and paraffin-embedded samples deparaffinized using mineral oil. %A Lin, Jianghai %A Kennedy, Stephen H %A Svarovsky, Therese %A Rogers, Jeffrey %A Kemnitz, Joseph W %A Xu, Anlong %A Zondervan, Krina T %K DNA %K Fixatives %K Formaldehyde %K Mineral Oil %K Paraffin Embedding %K Polymerase Chain Reaction %K Time Factors %X

Extracting DNA from formalin-fixed and paraffin-embedded (FFPE) tissue remains a challenge, despite numerous attempts to develop a more effective method. Polymerase chain reaction (PCR) success rates with DNA extracted using current methods remain low. We extracted DNA from 140 long-term archived FFPE samples using a simple but effective deparaffinization method, removing the wax with mineral oil, and a commercially available DNA extraction kit. DNA quality was subsequently tested in a genotyping experiment with 14 microsatellite markers. High-quality DNA was obtained with a mean PCR success rate of 97% (range: 88-100%) across markers. The results suggested that DNA extracted using this novel method is likely to be suitable for genetic studies involving DNA fragments <200 bp.

%B Anal Biochem %V 395 %P 265-7 %8 2009 Dec 15 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/19698695?dopt=Abstract %R 10.1016/j.ab.2009.08.016