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1. Reclassification of Appendiceal Mucinous Neoplasms and Associated Pseudomyxoma Peritonei According to the Peritoneal Surface Oncology Group International Consensus: Clinicopathological Reflections of a Two-Center Cohort Study

Author

Rauwerdink, Paulien, Al-Toma, Dania, Wassenaar, Emma C. E., Raicu, Mihaela G., Laclé, Miangela M., Milne, Anya N., Kuijpers, Karel C., Huysentruyt, Clément J. R., Poelmann, Floris B., van Ramshorst, Bert, Elias, Sjoerd G., Kranenburg, Onno, Borel Rinkes, Inne H. M., Witkamp, Arjen J., Wiezer, Marinus J., van Grevenstein, Helma M. U., and Boerma, Djamila

Published
2024
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2. OSNR Monitoring for QPSK and QAM in Fiber-Optic Networks Using Machine Learning

Author

Sahu, Shakrajit, Clement, J. Christopher, Kacprzyk, Janusz, Series Editor, Gomide, Fernando, Advisory Editor, Kaynak, Okyay, Advisory Editor, Liu, Derong, Advisory Editor, Pedrycz, Witold, Advisory Editor, Polycarpou, Marios M., Advisory Editor, Rudas, Imre J., Advisory Editor, Wang, Jun, Advisory Editor, Nanda, Umakanta, editor, Tripathy, Asis Kumar, editor, Sahoo, Jyoti Prakash, editor, Sarkar, Mahasweta, editor, and Li, Kuan-Ching, editor

Published
2024
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3. Identification of constrained sequence elements across 239 primate genomes

Author

Kuderna, Lukas F. K., Ulirsch, Jacob C., Rashid, Sabrina, Ameen, Mohamed, Sundaram, Laksshman, Hickey, Glenn, Cox, Anthony J., Gao, Hong, Kumar, Arvind, Aguet, Francois, Christmas, Matthew J., Clawson, Hiram, Haeussler, Maximilian, Janiak, Mareike C., Kuhlwilm, Martin, Orkin, Joseph D., Bataillon, Thomas, Manu, Shivakumara, Valenzuela, Alejandro, Bergman, Juraj, Rouselle, Marjolaine, Silva, Felipe Ennes, Agueda, Lidia, Blanc, Julie, Gut, Marta, de Vries, Dorien, Goodhead, Ian, Harris, R. Alan, Raveendran, Muthuswamy, Jensen, Axel, Chuma, Idriss S., Horvath, Julie E., Hvilsom, Christina, Juan, David, Frandsen, Peter, Schraiber, Joshua G., de Melo, Fabiano R., Bertuol, Fabrício, Byrne, Hazel, Sampaio, Iracilda, Farias, Izeni, Valsecchi, João, Messias, Malu, da Silva, Maria N. F., Trivedi, Mihir, Rossi, Rogerio, Hrbek, Tomas, Andriaholinirina, Nicole, Rabarivola, Clément J., Zaramody, Alphonse, Jolly, Clifford J., Phillips-Conroy, Jane, Wilkerson, Gregory, Abee, Christian, Simmons, Joe H., Fernandez-Duque, Eduardo, Kanthaswamy, Sree, Shiferaw, Fekadu, Wu, Dongdong, Zhou, Long, Shao, Yong, Zhang, Guojie, Keyyu, Julius D., Knauf, Sascha, Le, Minh D., Lizano, Esther, Merker, Stefan, Navarro, Arcadi, Nadler, Tilo, Khor, Chiea Chuen, Lee, Jessica, Tan, Patrick, Lim, Weng Khong, Kitchener, Andrew C., Zinner, Dietmar, Gut, Ivo, Melin, Amanda D., Guschanski, Katerina, Schierup, Mikkel Heide, Beck, Robin M. D., Karakikes, Ioannis, Wang, Kevin C., Umapathy, Govindhaswamy, Roos, Christian, Boubli, Jean P., Siepel, Adam, Kundaje, Anshul, Paten, Benedict, Lindblad-Toh, Kerstin, Rogers, Jeffrey, Marques Bonet, Tomas, and Farh, Kyle Kai-How

Published
2024
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7. The Role of TIM-1 and CD300a in Zika Virus Infection Investigated with Cell-Based Electrical Impedance

Author

Merel Oeyen, Clément J. F. Heymann, Maarten Jacquemyn, Dirk Daelemans, and Dominique Schols

Subjects
zika virus, impedance, TIM-1, CD300a, phosphatidylserine receptor, Biotechnology, TP248.13-248.65
Abstract

Orthoflaviviruses cause a major threat to global public health, and no antiviral treatment is available yet. Zika virus (ZIKV) entry, together with many other viruses, is known to be enhanced by phosphatidylserine (PS) receptors such as T-cell immunoglobulin mucin domain protein 1 (TIM-1). In this study, we demonstrate for the first time, using cell-based electrical impedance (CEI) biosensing, that ZIKV entry is also enhanced by expression of CD300a, another PS receptor. Furthermore, inhibiting CD300a in immature monocyte-derived dendritic cells partially but significantly inhibits ZIKV replication. As we have previously demonstrated that CEI is a useful tool to study Orthoflavivirus infection in real time, we now use this technology to determine how these PS receptors influence the kinetics of in vitro ZIKV infection. Results show that ZIKV entry is highly sensitive to minor changes in TIM-1 expression, both after overexpression of TIM-1 in infection-resistant HEK293T cells, as well as after partial knockout of TIM-1 in susceptible A549 cells. These results are confirmed by quantification of viral copy number and viral infectivity, demonstrating that CEI is highly suited to study and compare virus-host interactions. Overall, the results presented here demonstrate the potential of targeting this universal viral entry pathway.

Published
2024
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8. Anaerobutyricum soehngenii Reduces Hepatic Lipogenic Pathways and Increases Intestinal Gluconeogenic Gene Expression in Metabolic-Dysfunction-Associated Steatotic Liver Disease (MASLD) Mice

Author

Anne Linde Mak, Quinten J. J. Augustijn, Clément J. F. Heymann, Stefan Havik, Xanthe Verdoes, Melany Rios-Morales, Laura A. Bosmans, Joanne Verheij, Abraham S. Meijnikman, Patrick A. de Jonge, Hilde Herrema, Willem M. de Vos, Max Nieuwdorp, Aldo Grefhorst, and Adriaan G. Holleboom

Subjects
MASLD, gut microbiome, short-chain fatty acids, mice, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a growing health problem for which no therapy exists to date. The modulation of the gut microbiome may have treatment potential for MASLD. Here, we investigated Anaerobutyricum soehngenii, a butyrate-producing anaerobic bacterium with beneficial effects in metabolic syndrome, in a diet-induced MASLD mouse model. Male C57BL/6J mice received a Western-type high-fat diet and water with 15% fructose (WDF) to induce MASLD and were gavaged with A. soehngenii (108 or 109 colony-forming units (CFU) 3 times per week) or a placebo for 6 weeks. The A. soehngenii gavage increased the cecal butyrate concentrations. Although there was no effect on histological MASLD scores, A. soehngenii improved the glycemic response to insulin. In the liver, the WDF-associated altered expression of three genes relevant to the MASLD pathophysiology was reversed upon treatment with A. soehngenii: Lipin-1 (Lpin1), insulin-like growth factor binding protein 1 (Igfbp1) and Interleukin 1 Receptor Type 1 (Il1r1). A. soehngenii administration also increased the intestinal expression of gluconeogenesis and fructolysis genes. Although these effects did not translate into significant histological improvements in MASLD, these results provide a basis for combined gut microbial approaches to induce histological improvements in MASLD.

Published
2024
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9. Real-Time Rainfall Prediction System Using IoT and Machine Learning

Author

Sharma, Shreya Atul, Gangopadhyay, Abantee, Koushik, K. T., Sriharipriya, K. C., Clement, J. Christopher, Filipe, Joaquim, Editorial Board Member, Ghosh, Ashish, Editorial Board Member, Prates, Raquel Oliveira, Editorial Board Member, Zhou, Lizhu, Editorial Board Member, Arunachalam, V., editor, and Sivasankaran, K., editor

Published
2022
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14. The Role of TIM-1 and CD300a in Zika Virus Infection Investigated with Cell-Based Electrical Impedance.

Author

Oeyen, Merel, Heymann, Clément J. F., Jacquemyn, Maarten, Daelemans, Dirk, and Schols, Dominique

Subjects
HEPATITIS A virus cellular receptors, ZIKA virus infections, ELECTRIC impedance, ZIKA virus, IMMUNOGLOBULIN receptors
Abstract

Orthoflaviviruses cause a major threat to global public health, and no antiviral treatment is available yet. Zika virus (ZIKV) entry, together with many other viruses, is known to be enhanced by phosphatidylserine (PS) receptors such as T-cell immunoglobulin mucin domain protein 1 (TIM-1). In this study, we demonstrate for the first time, using cell-based electrical impedance (CEI) biosensing, that ZIKV entry is also enhanced by expression of CD300a, another PS receptor. Furthermore, inhibiting CD300a in immature monocyte-derived dendritic cells partially but significantly inhibits ZIKV replication. As we have previously demonstrated that CEI is a useful tool to study Orthoflavivirus infection in real time, we now use this technology to determine how these PS receptors influence the kinetics of in vitro ZIKV infection. Results show that ZIKV entry is highly sensitive to minor changes in TIM-1 expression, both after overexpression of TIM-1 in infection-resistant HEK293T cells, as well as after partial knockout of TIM-1 in susceptible A549 cells. These results are confirmed by quantification of viral copy number and viral infectivity, demonstrating that CEI is highly suited to study and compare virus-host interactions. Overall, the results presented here demonstrate the potential of targeting this universal viral entry pathway. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Electronic Health Records

Author

Melton, Genevieve B., McDonald, Clement J., Tang, Paul C., Hripcsak, George, Shortliffe, Edward H., editor, Cimino, James J., editor, and Chiang, Michael F., Section Editor

Published
2021
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19. Anaerobutyricum soehngenii Reduces Hepatic Lipogenic Pathways and Increases Intestinal Gluconeogenic Gene Expression in Metabolic-Dysfunction-Associated Steatotic Liver Disease (MASLD) Mice

Author

Mak, Anne Linde, primary, Augustijn, Quinten J. J., additional, Heymann, Clément J. F., additional, Havik, Stefan, additional, Verdoes, Xanthe, additional, Rios-Morales, Melany, additional, Bosmans, Laura A., additional, Verheij, Joanne, additional, Meijnikman, Abraham S., additional, de Jonge, Patrick A., additional, Herrema, Hilde, additional, de Vos, Willem M., additional, Nieuwdorp, Max, additional, Grefhorst, Aldo, additional, and Holleboom, Adriaan G., additional

Published
2024
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23. Pressurized Intraperitoneal Aerosol Chemotherapy (Oxaliplatin) for Unresectable Colorectal Peritoneal Metastases: A Multicenter, Single-Arm, Phase II Trial (CRC-PIPAC)

Author

Rovers, Koen P., Wassenaar, Emma C. E., Lurvink, Robin J., Creemers, Geert-Jan M., Burger, Jacobus W. A., Los, Maartje, Huysentruyt, Clément J. R., van Lijnschoten, Gesina, Nederend, Joost, Lahaye, Max J., Deenen, Maarten J., Wiezer, Marinus J., Nienhuijs, Simon W., Boerma, Djamila, and de Hingh, Ignace H. J. T.

Published
2021
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24. Detection of tumor‐derived cell‐free DNA from colorectal cancer peritoneal metastases in plasma and peritoneal fluid

Author

Iris van't Erve, Koen P Rovers, Alexander Constantinides, Karen Bolhuis, Emma CE Wassenaar, Robin J Lurvink, Clément J Huysentruyt, Petur Snaebjornsson, Djamila Boerma, Daan van denBroek, Tineke E Buffart, Max J Lahaye, Arend GJ Aalbers, Niels FM Kok, Gerrit A Meijer, Cornelis JA Punt, Onno Kranenburg, Ignace HJT deHingh, and Remond JA Fijneman

Subjects
colorectal neoplasms, liquid biopsy, circulating tumor DNA, peritoneum, ascitic fluid, plasma, Pathology, RB1-214
Abstract

Abstract Tumor‐derived cell‐free DNA (cfDNA) is an emerging biomarker for guiding the personalized treatment of patients with metastatic colorectal cancer (CRC). While patients with CRC liver metastases (CRC‐LM) have relatively high levels of plasma cfDNA, little is known about patients with CRC peritoneal metastases (CRC‐PM). This study evaluated the presence of tumor‐derived cfDNA in plasma and peritoneal fluid (i.e. ascites or peritoneal washing) in 20 patients with isolated CRC‐PM and in the plasma of 100 patients with isolated CRC‐LM. Among tumor tissue KRAS/BRAF mutation carriers, tumor‐derived cfDNA was detected by droplet digital polymerase chain reaction (ddPCR) in plasma of 93% of CRC‐LM and 20% of CRC‐PM patients and in peritoneal fluid in all CRC‐PM patients. Mutant allele fraction (MAF) and mutant copies per ml (MTc/ml) were lower in CRC‐PM plasma than in CRC‐LM plasma (median MAF = 0.28 versus 18.9%, p

Published
2021
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25. Principios del tratamiento quirúrgico de los traumatismos anorrectales y de los órganos genitales

Author

Clément, J., Chiron, P., Arvieux, C., and Hornez, E.

Abstract

Este artículo es una actualización del tratamiento quirúrgico urgente de los traumatismos del recto subperitoneal, del ano y de los órganos genitales internos y externos en adultos. Estas lesiones se inscriben en el marco de los traumatismos pelviperineales, cuyos mecanismos son múltiples, la mayoría de las veces penetrantes. Su tratamiento es complejo, debido a la proximidad a los distintos tractos digestivo, urinario y ginecológico. Las posibles lesiones asociadas del marco óseo y de las estructuras vasculares próximas se añadan aún más a la complejidad del tratamiento inicial. La presentación inicial puede estar dominada por el carácter hemorrágico de las lesiones, pero el riesgo principal es sobre todo séptico, en particular para las lesiones digestivas. El tratamiento urgente requiere en primer lugar realizar una evaluación meticulosa, clínica y con pruebas de laboratorio, para no pasar por alto una lesión. Los objetivos del tratamiento son primero inmediatos, con el control de la hemorragia y de la sepsis, y después tardíos, con la prevención de las secuelas funcionales a medio plazo. El tratamiento de las heridas del recto intraperitoneal (idéntico al de las heridas del colon), de las lesiones hemorrágicas de la pelvis, así como de las secuelas de los traumatismos del ano y de los órganos genitales no se aborda en este artículo.

Published
2024
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26. Identification of constrained sequence elements across 239 primate genomes

Author

Natural Environment Research Council (UK), UK Research and Innovation, National Human Genome Research Institute (US), Fundación la Caixa, Vienna Science and Technology Fund, European Commission, Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), Fonds de la Recherche Scientifique (Fédération Wallonie-Bruxelles), Fundação de Amparo à Pesquisa do Estado do Amazonas, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brasil), German Research Foundation, Ministry of Science and Technology of Vietnam, Agencia Estatal de Investigación (España), Generalitat de Catalunya, Natural Sciences and Engineering Research Council of Canada, Canada Research Chairs, Wenner-Gren Foundation, Leakey Foundation, National Science Foundation (US), National Geographic Society, National Institute on Aging (US), Swedish Research Council, National Research Foundation Singapore, European Research Council, Ministerio de Ciencia e Innovación (España), Ministerio de Ciencia, Innovación y Universidades (España), Kuderna, Lukas F. K. [0000-0002-9992-9295], Kuhlwilm, Martin [0000-0002-0115-1797], Valenzuela, Alejandro [0000-0001-6120-6246], Juan, David [0000-0003-1912-9667], Lizano, Esther [0000-0003-3304-9807], Navarro, Arcadi [0000-0003-2162-8246], Marqués-Bonet, Tomàs [0000-0002-5597-3075], Kuderna, Lukas F. K., Ulirsch, Jacob C., Rashid, Sabrina, Ameen, Mohamed, Sundaram, Laksshman, Hickey, Glenn, Cox, Anthony J., Gao, Hong, Kumar, Arvind, Aguet, Francois, Christmas, Matthew J., Clawson, Hiram, Haeussler, Maximilian, Janiak, Mareike C., Kuhlwilm, Martin, Orkin, Joseph D., Bataillon, Thomas, Manu, Shivakumara, Valenzuela, Alejandro, Bergman, Juraj, Rousselle, Marjolaine, Silva, Felipe Ennes, Agueda, Lidia, Blanc, Julie, Gut, Marta, Vries, Dorien de, Goodhead, Ian, Harris, R. Alan, Raveendran, Muthuswamy, Jensen, Axel, Chuma, Idriss S., Horvath, Julie E., Hvilsom, Christina, Juan, David, Frandsen, Peter, Schraiber, Joshua G., Melo, Fabiano R. de, Bertuol, Fabrício, Byrne, Hazel, Sampaio, Iracilda, Farias, Izeni, Valsecchi, João, Messias, Malu, Silva, Maria N. F. da, Trivedi, Mihir, Rossi, Rogerio, Hrbek, Tomas, Andriaholinirina, Nicole, Rabarivola, Clément J., Zaramody, Alphonse, Jolly, Clifford J., Phillips-Conroy, Jane, Wilkerson, Gregory, Abee, Christian, Simmons, Joe H., Fernandez-Duque, Eduardo, Kanthaswamy, Sree, Shiferaw, Fekadu, Wu, Dongdong, Zhou, Long, Shao, Yong, Zhang, Guojie, Keyyu, Julius D., Knauf, Sascha, Le, Minh D., Lizano, Esther, Merker, Stefan, Navarro, Arcadi, Nadler, Tilo, Khor, Chiea Chuen, Lee, Jessica, Tan, Patrick, Lim, Weng Khong, Kitchener, Andrew C., Zinner, Dietmar, Gut, Ivo, Melin, Amanda D., Guschanski, Katerina, Schierup, Mikkel Heide, Beck, Robin M. D., Karakikes, Ioannis, Wang, Kevin C., Umapathy, Govindhaswamy, Roos, Christian, Boubli, Jean P., Siepel, Adam, Kundaje, Anshul, Paten, Benedict, Lindblad-Toh, Kerstin, Rogers, Jeffrey, Marqués-Bonet, Tomàs, Farh, Kyle Kai-How, Natural Environment Research Council (UK), UK Research and Innovation, National Human Genome Research Institute (US), Fundación la Caixa, Vienna Science and Technology Fund, European Commission, Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), Fonds de la Recherche Scientifique (Fédération Wallonie-Bruxelles), Fundação de Amparo à Pesquisa do Estado do Amazonas, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brasil), German Research Foundation, Ministry of Science and Technology of Vietnam, Agencia Estatal de Investigación (España), Generalitat de Catalunya, Natural Sciences and Engineering Research Council of Canada, Canada Research Chairs, Wenner-Gren Foundation, Leakey Foundation, National Science Foundation (US), National Geographic Society, National Institute on Aging (US), Swedish Research Council, National Research Foundation Singapore, European Research Council, Ministerio de Ciencia e Innovación (España), Ministerio de Ciencia, Innovación y Universidades (España), Kuderna, Lukas F. K. [0000-0002-9992-9295], Kuhlwilm, Martin [0000-0002-0115-1797], Valenzuela, Alejandro [0000-0001-6120-6246], Juan, David [0000-0003-1912-9667], Lizano, Esther [0000-0003-3304-9807], Navarro, Arcadi [0000-0003-2162-8246], Marqués-Bonet, Tomàs [0000-0002-5597-3075], Kuderna, Lukas F. K., Ulirsch, Jacob C., Rashid, Sabrina, Ameen, Mohamed, Sundaram, Laksshman, Hickey, Glenn, Cox, Anthony J., Gao, Hong, Kumar, Arvind, Aguet, Francois, Christmas, Matthew J., Clawson, Hiram, Haeussler, Maximilian, Janiak, Mareike C., Kuhlwilm, Martin, Orkin, Joseph D., Bataillon, Thomas, Manu, Shivakumara, Valenzuela, Alejandro, Bergman, Juraj, Rousselle, Marjolaine, Silva, Felipe Ennes, Agueda, Lidia, Blanc, Julie, Gut, Marta, Vries, Dorien de, Goodhead, Ian, Harris, R. Alan, Raveendran, Muthuswamy, Jensen, Axel, Chuma, Idriss S., Horvath, Julie E., Hvilsom, Christina, Juan, David, Frandsen, Peter, Schraiber, Joshua G., Melo, Fabiano R. de, Bertuol, Fabrício, Byrne, Hazel, Sampaio, Iracilda, Farias, Izeni, Valsecchi, João, Messias, Malu, Silva, Maria N. F. da, Trivedi, Mihir, Rossi, Rogerio, Hrbek, Tomas, Andriaholinirina, Nicole, Rabarivola, Clément J., Zaramody, Alphonse, Jolly, Clifford J., Phillips-Conroy, Jane, Wilkerson, Gregory, Abee, Christian, Simmons, Joe H., Fernandez-Duque, Eduardo, Kanthaswamy, Sree, Shiferaw, Fekadu, Wu, Dongdong, Zhou, Long, Shao, Yong, Zhang, Guojie, Keyyu, Julius D., Knauf, Sascha, Le, Minh D., Lizano, Esther, Merker, Stefan, Navarro, Arcadi, Nadler, Tilo, Khor, Chiea Chuen, Lee, Jessica, Tan, Patrick, Lim, Weng Khong, Kitchener, Andrew C., Zinner, Dietmar, Gut, Ivo, Melin, Amanda D., Guschanski, Katerina, Schierup, Mikkel Heide, Beck, Robin M. D., Karakikes, Ioannis, Wang, Kevin C., Umapathy, Govindhaswamy, Roos, Christian, Boubli, Jean P., Siepel, Adam, Kundaje, Anshul, Paten, Benedict, Lindblad-Toh, Kerstin, Rogers, Jeffrey, Marqués-Bonet, Tomàs, and Farh, Kyle Kai-How

Abstract

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3,4,5,6,7,8,9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

Published
2024

27. Identification of constrained sequence elements across 239 primate genomes

Author

Kuderna, Lukas F.K., Ulirsch, Jacob C., Rashid, Sabrina, Ameen, Mohamed, Sundaram, Laksshman, Hickey, Glenn, Cox, Anthony J., Gao, Hong, Kumar, Arvind, Aguet, Francois, Christmas, Matthew J., Clawson, Hiram, Haeussler, Maximilian, Janiak, Mareike C., Kuhlwilm, Martin, Orkin, Joseph D., Bataillon, Thomas, Manu, Shivakumara, Valenzuela, Alejandro, Bergman, Juraj, Rouselle, Marjolaine, Silva, Felipe Ennes, Agueda, Lidia, Blanc, Julie, Gut, Marta, de Vries, Dorien, Goodhead, Ian, Harris, R. Alan, Raveendran, Muthuswamy, Jensen, Axel, Chuma, Idriss S., Horvath, Julie E., Hvilsom, Christina, Juan, David, Frandsen, Peter, Schraiber, Joshua G., de Melo, Fabiano R., Bertuol, Fabrício, Byrne, Hazel, Sampaio, Iracilda, Farias, Izeni, Valsecchi, João, Messias, Malu, da Silva, Maria N.F., Trivedi, Mihir, Rossi, Rogerio, Hrbek, Tomas, Andriaholinirina, Nicole, Rabarivola, Clément J., Zaramody, Alphonse, Jolly, Clifford J., Phillips-Conroy, Jane, Wilkerson, Gregory, Abee, Christian, Simmons, Joe H., Fernandez-Duque, Eduardo, Kanthaswamy, Sree, Shiferaw, Fekadu, Wu, Dongdong, Zhou, Long, Shao, Yong, Zhang, Guojie, Keyyu, Julius D., Knauf, Sascha, Le, Minh D., Lizano, Esther, Merker, Stefan, Navarro, Arcadi, Nadler, Tilo, Khor, Chiea Chuen, Lee, Jessica, Tan, Patrick, Lim, Weng Khong, Kitchener, Andrew C., Zinner, Dietmar, Gut, Ivo, Melin, Amanda D., Guschanski, Katerina, Schierup, Mikkel Heide, Beck, Robin M.D., Karakikes, Ioannis, Wang, Kevin C., Umapathy, Govindhaswamy, Roos, Christian, Boubli, Jean P., Siepel, Adam, Kundaje, Anshul, Paten, Benedict, Lindblad-Toh, Kerstin, Rogers, Jeffrey, Marques Bonet, Tomas, Farh, Kyle Kai How, Kuderna, Lukas F.K., Ulirsch, Jacob C., Rashid, Sabrina, Ameen, Mohamed, Sundaram, Laksshman, Hickey, Glenn, Cox, Anthony J., Gao, Hong, Kumar, Arvind, Aguet, Francois, Christmas, Matthew J., Clawson, Hiram, Haeussler, Maximilian, Janiak, Mareike C., Kuhlwilm, Martin, Orkin, Joseph D., Bataillon, Thomas, Manu, Shivakumara, Valenzuela, Alejandro, Bergman, Juraj, Rouselle, Marjolaine, Silva, Felipe Ennes, Agueda, Lidia, Blanc, Julie, Gut, Marta, de Vries, Dorien, Goodhead, Ian, Harris, R. Alan, Raveendran, Muthuswamy, Jensen, Axel, Chuma, Idriss S., Horvath, Julie E., Hvilsom, Christina, Juan, David, Frandsen, Peter, Schraiber, Joshua G., de Melo, Fabiano R., Bertuol, Fabrício, Byrne, Hazel, Sampaio, Iracilda, Farias, Izeni, Valsecchi, João, Messias, Malu, da Silva, Maria N.F., Trivedi, Mihir, Rossi, Rogerio, Hrbek, Tomas, Andriaholinirina, Nicole, Rabarivola, Clément J., Zaramody, Alphonse, Jolly, Clifford J., Phillips-Conroy, Jane, Wilkerson, Gregory, Abee, Christian, Simmons, Joe H., Fernandez-Duque, Eduardo, Kanthaswamy, Sree, Shiferaw, Fekadu, Wu, Dongdong, Zhou, Long, Shao, Yong, Zhang, Guojie, Keyyu, Julius D., Knauf, Sascha, Le, Minh D., Lizano, Esther, Merker, Stefan, Navarro, Arcadi, Nadler, Tilo, Khor, Chiea Chuen, Lee, Jessica, Tan, Patrick, Lim, Weng Khong, Kitchener, Andrew C., Zinner, Dietmar, Gut, Ivo, Melin, Amanda D., Guschanski, Katerina, Schierup, Mikkel Heide, Beck, Robin M.D., Karakikes, Ioannis, Wang, Kevin C., Umapathy, Govindhaswamy, Roos, Christian, Boubli, Jean P., Siepel, Adam, Kundaje, Anshul, Paten, Benedict, Lindblad-Toh, Kerstin, Rogers, Jeffrey, Marques Bonet, Tomas, and Farh, Kyle Kai How

Abstract

Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3,4,5,6,7,8,9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals., Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3–9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.

Published
2024

28. A CubeSat for Calibrating Ground-Based and Sub-Orbital Millimeter-Wave Polarimeters (CalSat)

Author

Johnson, Bradley R., Vourch, Clement J., Drysdale, Timothy D., Kalman, Andrew, Fujikawa, Steve, Keating, Brian, and Kaufman, Jon

Subjects
Astrophysics - Instrumentation and Methods for Astrophysics
Abstract

We describe a low-cost, open-access, CubeSat-based calibration instrument that is designed to support ground-based and sub-orbital experiments searching for various polarization signals in the cosmic microwave background (CMB). All modern CMB polarization experiments require a robust calibration program that will allow the effects of instrument-induced signals to be mitigated during data analysis. A bright, compact, and linearly polarized astrophysical source with polarization properties known to adequate precision does not exist. Therefore, we designed a space-based millimeter-wave calibration instrument, called CalSat, to serve as an open-access calibrator, and this paper describes the results of our design study. The calibration source on board CalSat is composed of five "tones" with one each at 47.1, 80.0, 140, 249 and 309 GHz. The five tones we chose are well matched to (i) the observation windows in the atmospheric transmittance spectra, (ii) the spectral bands commonly used in polarimeters by the CMB community, and (iii) The Amateur Satellite Service bands in the Table of Frequency Allocations used by the Federal Communications Commission. CalSat would be placed in a polar orbit allowing visibility from observatories in the Northern Hemisphere, such as Mauna Kea in Hawaii and Summit Station in Greenland, and the Southern Hemisphere, such as the Atacama Desert in Chile and the South Pole. CalSat also would be observable by balloon-borne instruments launched from a range of locations around the world. This global visibility makes CalSat the only source that can be observed by all terrestrial and sub-orbital observatories, thereby providing a universal standard that permits comparison between experiments using appreciably different measurement approaches.

Published
2015
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31. The response to re-emergence of yellow fever in Nigeria, 2017

Author

Nwachukwu, William E., Yusuff, H., Nwangwu, U., Okon, A., Ogunniyi, A., Imuetinyan-Clement, J., Besong, M., Ayo-Ajayi, P., Nikau, J., Baba, A., Dogunro, F., Akintunde, B., Oguntoye, M., Kamaldeen, K., Fakayode, O., Oyebanji, O., Emelife, O., Oteri, J., Aruna, O., Ilori, E., Ojo, O., Mba, N., Nguku, P., and Ihekweazu, C.

Published
2020
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32. Identification of constrained sequence elements across 239 primate genomes

Author

Kuderna, Lukas F. K., primary, Ulirsch, Jacob C., additional, Rashid, Sabrina, additional, Ameen, Mohamed, additional, Sundaram, Laksshman, additional, Hickey, Glenn, additional, Cox, Anthony J., additional, Gao, Hong, additional, Kumar, Arvind, additional, Aguet, Francois, additional, Christmas, Matthew J., additional, Clawson, Hiram, additional, Haeussler, Maximilian, additional, Janiak, Mareike C., additional, Kuhlwilm, Martin, additional, Orkin, Joseph D., additional, Bataillon, Thomas, additional, Manu, Shivakumara, additional, Valenzuela, Alejandro, additional, Bergman, Juraj, additional, Rouselle, Marjolaine, additional, Silva, Felipe Ennes, additional, Agueda, Lidia, additional, Blanc, Julie, additional, Gut, Marta, additional, de Vries, Dorien, additional, Goodhead, Ian, additional, Harris, R. Alan, additional, Raveendran, Muthuswamy, additional, Jensen, Axel, additional, Chuma, Idriss S., additional, Horvath, Julie E., additional, Hvilsom, Christina, additional, Juan, David, additional, Frandsen, Peter, additional, Schraiber, Joshua G., additional, de Melo, Fabiano R., additional, Bertuol, Fabrício, additional, Byrne, Hazel, additional, Sampaio, Iracilda, additional, Farias, Izeni, additional, Valsecchi, João, additional, Messias, Malu, additional, da Silva, Maria N. F., additional, Trivedi, Mihir, additional, Rossi, Rogerio, additional, Hrbek, Tomas, additional, Andriaholinirina, Nicole, additional, Rabarivola, Clément J., additional, Zaramody, Alphonse, additional, Jolly, Clifford J., additional, Phillips-Conroy, Jane, additional, Wilkerson, Gregory, additional, Abee, Christian, additional, Simmons, Joe H., additional, Fernandez-Duque, Eduardo, additional, Kanthaswamy, Sree, additional, Shiferaw, Fekadu, additional, Wu, Dongdong, additional, Zhou, Long, additional, Shao, Yong, additional, Zhang, Guojie, additional, Keyyu, Julius D., additional, Knauf, Sascha, additional, Le, Minh D., additional, Lizano, Esther, additional, Merker, Stefan, additional, Navarro, Arcadi, additional, Nadler, Tilo, additional, Khor, Chiea Chuen, additional, Lee, Jessica, additional, Tan, Patrick, additional, Lim, Weng Khong, additional, Kitchener, Andrew C., additional, Zinner, Dietmar, additional, Gut, Ivo, additional, Melin, Amanda D., additional, Guschanski, Katerina, additional, Schierup, Mikkel Heide, additional, Beck, Robin M. D., additional, Karakikes, Ioannis, additional, Wang, Kevin C., additional, Umapathy, Govindhaswamy, additional, Roos, Christian, additional, Boubli, Jean P., additional, Siepel, Adam, additional, Kundaje, Anshul, additional, Paten, Benedict, additional, Lindblad-Toh, Kerstin, additional, Rogers, Jeffrey, additional, Marques Bonet, Tomas, additional, and Farh, Kyle Kai-How, additional

Published
2023
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35. Investigating the agreement between force platform and plantar pressure insole data in barefoot and skating-specific footwear conditions across four different movement patterns.

Author

Dunne, C., Hsu, T., Lockwood, K., Holmes, M., Wagnac, E., and Clément, J.

Abstract

Conducting applied sport research in real-world settings is challenged by the lack of portable instrumentation capable of producing valid and reliable data that is collected without interfering with the athletes' movement and is meaningful to sport performance. The purpose of this study was to compare and contrast data collected simultaneously from a force platform and a plantar pressure insole to provide support for the use of the XSENSOR® plantar pressure insoles in a skating-performance application. Data was collected in two conditions. The barefoot condition consisted of the insole on a force platform in isolation and the in-skate condition consisted of the insole inside a speed skate boot on a force platform. A single-participant design was conducted whereby an injury-free female completed multiple trials in both conditions. A P6000 Force Platform (BTS Bioengineering Corp., MI, Italy) was used to collect force data and an X4 Foot and Gait Measurement Systems plantar pressure insole (XSENSOR® Technology Corporation, AB, Canada) was used to collect pressure data in the two conditions across four movement patterns; static stance (SS), anterior-posterior sway (AP), medial-lateral sway (ML), and lateral jump (LJ). Intraclass correlation coefficients (ICC) and Bland-Altman plots revealed excellent agreement between the cumulative centre of pressure path length (mm) measured from the force platform and insole in the barefoot condition and moderate to excellent agreement between impulse (Ns) measured from the force platform and insole, in both conditions. These outcomes provide researchers and practitioners with empirical support and confidence to employ the XSENSOR® plantar pressure insoles outside of a laboratory setting in a real-world skating environment to collect and analyse in-skate kinetic data during on ice performance. [ABSTRACT FROM AUTHOR]

Published
2024
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40. A global catalog of whole-genome diversity from 233 primate species

Author

Kuderna, Lukas F. K., primary, Gao, Hong, additional, Janiak, Mareike C., additional, Kuhlwilm, Martin, additional, Orkin, Joseph D., additional, Bataillon, Thomas, additional, Manu, Shivakumara, additional, Valenzuela, Alejandro, additional, Bergman, Juraj, additional, Rousselle, Marjolaine, additional, Silva, Felipe Ennes, additional, Agueda, Lidia, additional, Blanc, Julie, additional, Gut, Marta, additional, de Vries, Dorien, additional, Goodhead, Ian, additional, Harris, R. Alan, additional, Raveendran, Muthuswamy, additional, Jensen, Axel, additional, Chuma, Idrissa S., additional, Horvath, Julie E., additional, Hvilsom, Christina, additional, Juan, David, additional, Frandsen, Peter, additional, Schraiber, Joshua G., additional, de Melo, Fabiano R., additional, Bertuol, Fabrício, additional, Byrne, Hazel, additional, Sampaio, Iracilda, additional, Farias, Izeni, additional, Valsecchi, João, additional, Messias, Malu, additional, da Silva, Maria N. F., additional, Trivedi, Mihir, additional, Rossi, Rogerio, additional, Hrbek, Tomas, additional, Andriaholinirina, Nicole, additional, Rabarivola, Clément J., additional, Zaramody, Alphonse, additional, Jolly, Clifford J., additional, Phillips-Conroy, Jane, additional, Wilkerson, Gregory, additional, Abee, Christian, additional, Simmons, Joe H., additional, Fernandez-Duque, Eduardo, additional, Kanthaswamy, Sree, additional, Shiferaw, Fekadu, additional, Wu, Dongdong, additional, Zhou, Long, additional, Shao, Yong, additional, Zhang, Guojie, additional, Keyyu, Julius D., additional, Knauf, Sascha, additional, Le, Minh D., additional, Lizano, Esther, additional, Merker, Stefan, additional, Navarro, Arcadi, additional, Nadler, Tilo, additional, Khor, Chiea Chuen, additional, Lee, Jessica, additional, Tan, Patrick, additional, Lim, Weng Khong, additional, Kitchener, Andrew C., additional, Zinner, Dietmar, additional, Gut, Ivo, additional, Melin, Amanda D., additional, Guschanski, Katerina, additional, Schierup, Mikkel Heide, additional, Beck, Robin M. D., additional, Umapathy, Govindhaswamy, additional, Roos, Christian, additional, Boubli, Jean P., additional, Rogers, Jeffrey, additional, Farh, Kyle Kai-How, additional, and Marques Bonet, Tomas, additional

Published
2023
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41. The landscape of tolerated genetic variation in humans and primates

Author

Gao, Hong, primary, Hamp, Tobias, additional, Ede, Jeffrey, additional, Schraiber, Joshua G., additional, McRae, Jeremy, additional, Singer-Berk, Moriel, additional, Yang, Yanshen, additional, Dietrich, Anastasia S. D., additional, Fiziev, Petko P., additional, Kuderna, Lukas F. K., additional, Sundaram, Laksshman, additional, Wu, Yibing, additional, Adhikari, Aashish, additional, Field, Yair, additional, Chen, Chen, additional, Batzoglou, Serafim, additional, Aguet, Francois, additional, Lemire, Gabrielle, additional, Reimers, Rebecca, additional, Balick, Daniel, additional, Janiak, Mareike C., additional, Kuhlwilm, Martin, additional, Orkin, Joseph D., additional, Manu, Shivakumara, additional, Valenzuela, Alejandro, additional, Bergman, Juraj, additional, Rousselle, Marjolaine, additional, Silva, Felipe Ennes, additional, Agueda, Lidia, additional, Blanc, Julie, additional, Gut, Marta, additional, de Vries, Dorien, additional, Goodhead, Ian, additional, Harris, R. Alan, additional, Raveendran, Muthuswamy, additional, Jensen, Axel, additional, Chuma, Idriss S., additional, Horvath, Julie E., additional, Hvilsom, Christina, additional, Juan, David, additional, Frandsen, Peter, additional, de Melo, Fabiano R., additional, Bertuol, Fabrício, additional, Byrne, Hazel, additional, Sampaio, Iracilda, additional, Farias, Izeni, additional, do Amaral, João Valsecchi, additional, Messias, Mariluce, additional, da Silva, Maria N. F., additional, Trivedi, Mihir, additional, Rossi, Rogerio, additional, Hrbek, Tomas, additional, Andriaholinirina, Nicole, additional, Rabarivola, Clément J., additional, Zaramody, Alphonse, additional, Jolly, Clifford J., additional, Phillips-Conroy, Jane, additional, Wilkerson, Gregory, additional, Abee, Christian, additional, Simmons, Joe H., additional, Fernandez-Duque, Eduardo, additional, Kanthaswamy, Sree, additional, Shiferaw, Fekadu, additional, Wu, Dongdong, additional, Zhou, Long, additional, Shao, Yong, additional, Zhang, Guojie, additional, Keyyu, Julius D., additional, Knauf, Sascha, additional, Le, Minh D., additional, Lizano, Esther, additional, Merker, Stefan, additional, Navarro, Arcadi, additional, Bataillon, Thomas, additional, Nadler, Tilo, additional, Khor, Chiea Chuen, additional, Lee, Jessica, additional, Tan, Patrick, additional, Lim, Weng Khong, additional, Kitchener, Andrew C., additional, Zinner, Dietmar, additional, Gut, Ivo, additional, Melin, Amanda, additional, Guschanski, Katerina, additional, Schierup, Mikkel Heide, additional, Beck, Robin M. D., additional, Umapathy, Govindhaswamy, additional, Roos, Christian, additional, Boubli, Jean P., additional, Lek, Monkol, additional, Sunyaev, Shamil, additional, O’Donnell-Luria, Anne, additional, Rehm, Heidi L., additional, Xu, Jinbo, additional, Rogers, Jeffrey, additional, Marques-Bonet, Tomas, additional, and Farh, Kyle Kai-How, additional

Published
2023
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46. Functionalisation of natural fibers using ionizing radiations

Author

Brendlé, Clément, El Hage, Roland, Sonnier, Rodolphe, Otazaghine, Belkacem, Rouif, Sophie, Clément, J-C, Polymères Composites et Hybrides (PCH - IMT Mines Alès), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Ionisos SAS, Aix-Marseille Université - Faculté des Sciences (AMU SCI), Aix Marseille Université (AMU), and Projet SABRES

Subjects
[SPI.MAT]Engineering Sciences [physics]/Materials
Abstract

International audience; Plant products arouse great interest in many fields (construction, automotive, textiles, etc …).However, some of their characteristics as their flammability represent major disadvantagesfor some applications. Research is now being conducted in academia and industry to developeffective methods of functionalizing or modifying the surface of these fibers to improve theirperformance. In this respect, radiation-grafting, based on the use of ionizing radiation(gamma or e-beam), represents an interesting method compared to chemical or enzymaticmethods. This technique makes it possible to generate radicals on the fibers allowing thegrafting of molecules of interest, thus offering a large spectrum of possibilities for themodification of the fibers [1][2]. Two ways for grafting under ionizing conditions can beused (Figure 1), pre irradiation and mutual irradiation. In any case, many factors conditionthe success of grafting reactions. In particular, the structure and the composition of thesubstrate influence the nature of the active species formed, and therefore, the feasibility ofthe grafting reaction. Some techniques, such as Electronic Paramagnetic Resonance (EPR),helps us to better understand these parameters, which will be the subject of this presentation.

Published
2023

47. A global catalog of whole-genome diversity from 233 primate species

Author

Lukas F.K. Kuderna, Hong Gao, Mareike C. Janiak, Martin Kuhlwilm, Joseph D. Orkin, Thomas Bataillon, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rouselle, Felipe Ennes Silva, Lidia Agueda, Julie Blanc, Marta Gut, Dorien de Vries, Ian Goodhead, R. Alan Harris, Muthuswamy Raveendran, Axel Jensen, Idriss S. Chuma, Julie Horvath, Christina Hvilsom, David Juan, Peter Frandsen, Joshua G. Schraiber, Fabiano R. de Melo, Fabricio Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Farias, João Valsecchi do Amaral, Malu Messias, Maria N. F. da Silva, Mihir Trivedi, Rogerio Rossi, Tomas Hrbek, Nicole Andriaholinirina, Clément J. Rabarivola, Alphonse Zaramody, Clifford J. Jolly, Jane Phillips-Conroy, Gregory Wilkerson, Christian Abee, Joe H. Simmons, Eduardo Fernandez-Duque, Sree Kanthaswamy, Fekadu Shiferaw, Dongdong Wu, Long Zhou, Yong Shao, Guojie Zhang, Julius D. Keyyu, Sascha Knauf, Minh D. Le, Esther Lizano, Stefan Merker, Arcadi Navarro, Tilo Nadler, Chiea Chuen Khor, Jessica Lee, Patrick Tan, Weng Khong Lim, Andrew C. Kitchener, Dietmar Zinner, Ivo Gut, Amanda Melin, Katerina Guschanski, Mikkel Heide Schierup, Robin M. D. Beck, Govindhaswamy Umapathy, Christian Roos, Jean P. Boubli, Jeffrey Rogers, Kyle Farh, and Tomas Marques Bonet

Abstract

The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology, and is urgent given severe threats these species are facing. Here, we present high coverage whole-genome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families and geographic regions to be associated with climate and sociality, but not with extinction risk. Furthermore, mutation rates differ across species, potentially influenced by effective population sizes. Lastly, we identified extensive recurrence of missense mutations previously thought to be human-specific. This study will open a wide range of research avenues for future primate genomic research.One-Sentence SummaryThe whole genome sequences of 233 primate species provide insight into the determinants of genetic diversity, phylogenomics, and human uniqueness.

Published
2023

48. The landscape of tolerated genetic variation in humans and primates

Author

Hong Gao, Tobias Hamp, Jeffrey Ede, Joshua G. Schraiber, Jeremy McRae, Moriel Singer-Berk, Yanshen Yang, Anastasia Dietrich, Petko Fiziev, Lukas Kuderna, Laksshman Sundaram, Yibing Wu, Aashish Adhikari, Yair Field, Chen Chen, Serafim Batzoglou, Francois Aguet, Gabrielle Lemire, Rebecca Reimers, Daniel Balick, Mareike C. Janiak, Martin Kuhlwilm, Joseph D. Orkin, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rouselle, Felipe Ennes Silva, Lidia Agueda, Julie Blanc, Marta Gut, Dorien de Vries, Ian Goodhead, R. Alan Harris, Muthuswamy Raveendran, Axel Jensen, Idriss S. Chuma, Julie Horvath, Christina Hvilsom, David Juan, Peter Frandsen, Fabiano R. de Melo, Fabricio Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Farias, João Valsecchi do Amaral, Mariluce Messias, Maria N. F. da Silva, Mihir Trivedi, Rogerio Rossi, Tomas Hrbek, Nicole Andriaholinirina, Clément J. Rabarivola, Alphonse Zaramody, Clifford J. Jolly, Jane Phillips-Conroy, Gregory Wilkerson, Christian Abee, Joe H. Simmons, Eduardo Fernandez-Duque, ee Kanthaswamy, Fekadu Shiferaw, Dongdong Wu, Long Zhou, Yong Shao, Guojie Zhang, Julius D. Keyyu, Sascha Knauf, Minh D. Le, Esther Lizano, Stefan Merker, Arcadi Navarro, Thomas Batallion, Tilo Nadler, Chiea Chuen Khor, Jessica Lee, Patrick Tan, Weng Khong Lim, Andrew C. Kitchener, Dietmar Zinner, Ivo Gut, Amanda Melin, Katerina Guschanski, Mikkel Heide Schierup, Robin M. D. Beck, Govindhaswamy Umapathy, Christian Roos, Jean P. Boubli, Monkol Lek, Shamil Sunyaev, Anne O’Donnell, Heidi Rehm, Jinbo Xu, Jeffrey Rogers, Tomas Marques-Bonet, and Kyle Kai-How Farh

Subjects
Article
Abstract

INTRODUCTIONMillions of people have received genome and exome sequencing to date, a collective effort that has illuminated for the first time the vast catalog of small genetic differences that distinguish us as individuals within our species. However, the effects of most of these genetic variants remain unknown, limiting their clinical utility and actionability. New approaches that can accurately discern disease-causing from benign mutations and interpret genetic variants on a genome-wide scale would constitute a meaningful initial step towards realizing the potential of personalized genomic medicine.RATIONALEAs a result of the short evolutionary distance between humans and nonhuman primates, our proteins share near-perfect amino acid sequence identity. Hence, the effects of a protein-altering mutation found in one species are likely to be concordant in the other species. By systematically cataloging common variants of nonhuman primates, we aimed to annotate these variants as being unlikely to cause human disease as they are tolerated by natural selection in a closely related species. Once collected, the resulting resource may be applied to infer the effects of unobserved variants across the genome using machine learning.RESULTSFollowing the strategy outlined above we obtained whole-genome sequencing data for 809 individuals from 233 primate species and cataloged 4.3 million common missense variants. We confirmed that human missense variants seen in at least one nonhuman primate species were annotated as benign in the ClinVar clinical variant database in 99% of cases. By contrast, common variants from mammals and vertebrates outside the primate lineage were substantially less likely to be benign in the ClinVar database (71 to 87% benign), restricting this strategy to nonhuman primates. Overall, we reclassified more than 4 million human missense variants of previously unknown consequence as likely benign, resulting in a greater than 50-fold increase in the number of annotated missense variants compared to existing clinical databases.To infer the pathogenicity of the remaining missense variants in the human genome, we constructed PrimateAI-3D, a semisupervised 3D-convolutional neural network that operates on voxelized protein structures. We trained PrimateAI-3D to separate common primate variants from matched control variants in 3D space as a semisupervised learning task. We evaluated the trained PrimateAI-3D model alongside 15 other published machine learning methods on their ability to distinguish between benign and pathogenic variants in six different clinical benchmarks and demonstrated that PrimateAI-3D outperformed all other classifiers in each of the tasks.CONCLUSIONOur study addresses one of the key challenges in the variant interpretation field, namely, the lack of sufficient labeled data to effectively train large machine learning models. By generating the most comprehensive primate sequencing dataset to date and pairing this resource with a deep learning architecture that leverages 3D protein structures, we were able to achieve meaningful improvements in variant effect prediction across multiple clinical benchmarks. Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.

Published
2023

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