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1. The functional impact of rare variation across the regulatory cascade

Author

Li, Taibo, Ferraro, Nicole, Strober, Benjamin J, Aguet, Francois, Kasela, Silva, Arvanitis, Marios, Ni, Bohan, Wiel, Laurens, Hershberg, Elliot, Ardlie, Kristin, Arking, Dan E, Beer, Rebecca L, Brody, Jennifer, Blackwell, Thomas W, Clish, Clary, Gabriel, Stacey, Gerszten, Robert, Guo, Xiuqing, Gupta, Namrata, Johnson, W Craig, Lappalainen, Tuuli, Lin, Henry J, Liu, Yongmei, Nickerson, Deborah A, Papanicolaou, George, Pritchard, Jonathan K, Qasba, Pankaj, Shojaie, Ali, Smith, Josh, Sotoodehnia, Nona, Taylor, Kent D, Tracy, Russell P, Van Den Berg, David, Wheeler, Matthew T, Rich, Stephen S, Rotter, Jerome I, Battle, Alexis, and Montgomery, Stephen B

Subjects
Biological Sciences, Health Sciences, Genetics, Human Genome, Brain Disorders, Schizophrenia, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Generic health relevance, functional genomics, machine learning, methylome, multi-omics, proteome, rare variants, transcriptome
Abstract

Each human genome has tens of thousands of rare genetic variants; however, identifying impactful rare variants remains a major challenge. We demonstrate how use of personal multi-omics can enable identification of impactful rare variants by using the Multi-Ethnic Study of Atherosclerosis, which included several hundred individuals, with whole-genome sequencing, transcriptomes, methylomes, and proteomes collected across two time points, 10 years apart. We evaluated each multi-omics phenotype's ability to separately and jointly inform functional rare variation. By combining expression and protein data, we observed rare stop variants 62 times and rare frameshift variants 216 times as frequently as controls, compared to 13-27 times as frequently for expression or protein effects alone. We extended a Bayesian hierarchical model, "Watershed," to prioritize specific rare variants underlying multi-omics signals across the regulatory cascade. With this approach, we identified rare variants that exhibited large effect sizes on multiple complex traits including height, schizophrenia, and Alzheimer's disease.

Published
2023

4. Considerations for reporting variants in novel candidate genes identified during clinical genomic testing

Author

Abouhala, Siwaar, Albert, Jessica, Almalvez, Miguel, Alvarez, Raquel, Amin, Mutaz, Anderson, Peter, Aradhya, Swaroop, Ashley, Euan, Assimes, Themistocles, Auriga, Light, Austin-Tse, Christina, Bamshad, Mike, Barseghyan, Hayk, Baxter, Samantha, Behera, Sairam, Beheshti, Shaghayegh, Bejerano, Gill, Berger, Seth, Bernstein, Jon, Best, Sabrina, Blankenmeister, Benjamin, Blue, Elizabeth, Boerwinkle, Eric, Bonkowski, Emily, Bonner, Devon, Boone, Philip, Bornhorst, Miriam, Brand, Harrison, Buckingham, Kati, Calame, Daniel, Carter, Jennefer, Casadei, Silvia, Chadwick, Lisa, Chavez, Clarisa, Chen, Ziwei, Chinn, Ivan, Chong, Jessica, Coban-Akdemir, Zeynep, Cohen, Andrea J., Conner, Sarah, Conomos, Matthew, Coveler, Karen, Cui, Ya Allen, Currin, Sara, Daber, Robert, Dardas, Zain, Davis, Colleen, Dawood, Moez, de Dios, Ivan, de Esch, Celine, Delaney, Meghan, Delot, Emmanuele, DiTroia, Stephanie, Doddapaneni, Harsha, Du, Haowei, Duan, Ruizhi, Dugan-Perez, Shannon, Duong, Nhat, Duyzend, Michael, Eichler, Evan, Emami, Sara, Fraser, Jamie, Fusaro, Vincent, Galey, Miranda, Ganesh, Vijay, Garcia, Brandon, Garimella, Kiran, Gibbs, Richard, Gifford, Casey, Ginsburg, Amy, Goddard, Page, Gogarten, Stephanie, Gogate, Nikhita, Gordon, William, Gorzynski, John E., Greenleaf, William, Grochowski, Christopher, Groopman, Emily, Sousa, Rodrigo Guarischi, Gudmundsson, Sanna, Gulati, Ashima, Hall, Stacey, Harvey, William, Hawley, Megan, Heavner, Ben, Horike-Pyne, Martha, Hu, Jianhong, Huang, Yongqing, Hwang, James, Jarvik, Gail, Jensen, Tanner, Jhangiani, Shalini, Jimenez-Morales, David, Jin, Christopher, Saad, Ahmed K., Kahn-Kirby, Amanda, Kain, Jessica, Kaur, Parneet, Keehan, Laura, Knoblach, Susan, Ko, Arthur, Kundaje, Anshul, Kundu, Soumya, Lancaster, Samuel M., Larsson, Katie, Lee, Arthur, Lemire, Gabrielle, Lewis, Richard, Li, Wei, Li, Yidan, Liu, Pengfei, LoTempio, Jonathan, Lupski, James (Jim), Ma, Jialan, MacArthur, Daniel, Mahmoud, Medhat, Malani, Nirav, Mangilog, Brian, Marafi, Dana, Marmolejos, Sofia, Marten, Daniel, Martinez, Eva, Marvin, Colby, Marwaha, Shruti, Mastrorosa, Francesco Kumara, Matalon, Dena, May, Susanne, McGee, Sean, Meador, Lauren, Mefford, Heather, Mendez, Hector Rodrigo, Miller, Alexander, Miller, Danny E., Mitani, Tadahiro, Montgomery, Stephen, Moyses, Mariana, Munderloh, Chloe, Muzny, Donna, Nelson, Sarah, Nguyen, Thuy-mi P., Nguyen, Jonathan, Nussbaum, Robert, Nykamp, Keith, O'Callaghan, William, O'Heir, Emily, O'Leary, Melanie, Olsen, Jeren, Osei-Owusu, Ikeoluwa, O'Donnell-Luria, Anne, Padhi, Evin, Pais, Lynn, Pan, Miao, Panchal, Piyush, Patterson, Karynne, Payne, Sheryl, Pehlivan, Davut, Petrowski, Paul, Pham, Alicia, Pitsava, Georgia, Podesta, Astaria`Sara, Ponce, Sarah, Porter, Elizabeth, Posey, Jennifer, Prosser, Jaime, Quertermous, Thomas, Rai, Archana, Ramani, Arun, Rehm, Heidi, Reuter, Chloe, Reuter, Jason, Richardson, Matthew, Rivera-Munoz, Andres, Rubio, Oriane, Sabo, Aniko, Salani, Monica, Samocha, Kaitlin, Sanchis-Juan, Alba, Savage, Sarah, Scott, Evette, Scott, Stuart, Sedlazeck, Fritz, Shah, Gulalai, Shojaie, Ali, Singh, Mugdha, Smith, Kevin, Smith, Josh, Snow, Hana, Snyder, Michael, Socarras, Kayla, Starita, Lea, Stark, Brigitte, Stenton, Sarah, Stergachis, Andrew, Stilp, Adrienne, Sutton, V. Reid, Tai, Jui-Cheng, Talkowski, Michael (Mike), Tise, Christina, Tong, Catherine (Cat), Tsao, Philip, Ungar, Rachel, VanNoy, Grace, Vilain, Eric, Voutos, Isabella, Walker, Kim, Wei, Chia-Lin, Weisburd, Ben, Weiss, Jeff, Wellington, Chris, Weng, Ziming, Westheimer, Emily, Wheeler, Marsha, Wheeler, Matthew, Wiel, Laurens, Wilson, Michael, Wojcik, Monica, Wong, Quenna, Xiao, Changrui, Yadav, Rachita, Yi, Qian, Yuan, Bo, Zhao, Jianhua, Zhen, Jimmy, Zhou, Harry, Chong, Jessica X., Berger, Seth I., Smith, Erica, Calame, Daniel G., Hawley, Megan H., Rivera-Munoz, E. Andres, Bamshad, Michael J., and Rehm, Heidi L.

Published
2024
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5. Molecular adaptations in response to exercise training are associated with tissue-specific transcriptomic and epigenomic signatures

Author

Adkins, Joshua N., Almagro Armenteros, Jose Juan, Ashley, Euan, Bae, Dam, Bamman, Marcas, Bararpour, Nasim, Bennett, Alexis, Bergman, Bryan C., Bessesen, Daniel H., Bodine, Sue C., Buford, Thomas W., Chambers, Toby L., Chavez, Clarisa, Cortes, Tiffany, Cutter, Gary, Espinoza, Sara, Fernández, Facundo M., Gagne, Nicole, Gaul, David A., Goodpaster, Bret H., Hung, Chia-Jui, Jackson, Bailey E., Jankowski, Catherine M., Jin, Christopher A., Kohrt, Wendy M., Kramer, Kyle S., Lester, Bridget, Lira, Ana K., May, Sandy, Marjanovic, Nada, Melanson, Edward L., Moore, Samuel G., Moreau, Kerrie L., Musi, Nicolas, Nachum, Daniel, Nudelman, German, Pahor, Marco, Patel, Darpan, Piehowski, Paul D., Qian, Wei-Jun, Rasmussen, Blake B., Rirak, Stas, Rooney, Jessica L., Sanford, James A., Savage, Evan M., Schauer, Irene E., Serra, Monica, Stowe, Cynthia L., Thalacker-Mercer, Anna, Trappe, Todd A., Trappe, Scott, Vetr, Nikolai G., Volpi, Elena, Wheeler, Matthew T., Wu, Si, Zebarjadi, Navid, Zhen, Jimmy, Nair, Venugopalan D., Pincas, Hanna, Smith, Gregory R., Zaslavsky, Elena, Ge, Yongchao, Amper, Mary Anne S., Vasoya, Mital, Chikina, Maria, Sun, Yifei, Raja, Archana Natarajan, Mao, Weiguang, Gay, Nicole R., Esser, Karyn A., Smith, Kevin S., Zhao, Bingqing, Wiel, Laurens, Singh, Aditya, Lindholm, Malene E., Amar, David, Montgomery, Stephen, Snyder, Michael P., Walsh, Martin J., and Sealfon, Stuart C.

Published
2024
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6. The mitochondrial multi-omic response to exercise training across rat tissues

Author

Adkins, Joshua N., Armenteros, Jose Juan Almagro, Amper, Mary Anne S., Bae, Dam, Bamman, Marcas, Bararpour, Nasim, Barnes, Jerry, Bergman, Bryan C., Bessesen, Daniel H., Broskey, Nicholas T., Buford, Thomas W., Carr, Steven, Chambers, Toby L., Chavez, Clarisa, Chiu, Roxanne, Clark, Natalie, Cutter, Gary, Evans, Charles R., Franczak, Edziu, Gagne, Nicole, Ge, Yongchao, Hennig, Krista M., Houmard, Joseph A., Huffman, Kim M., Hung, Chia-Jui, Hutchinson-Bunch, Chelsea, Ilkayeva, Olga, Jackson, Bailey E., Jankowski, Catherine M., Jin, Christopher A., Johannsen, Neil M., Katz, Daniel H., Keshishian, Hasmik, Kohrt, Wendy M., Kramer, Kyle S., Kraus, William E., Lester, Bridget, Li, Jun Z., Lira, Ana K., Lowe, Adam, Mani, D.R., Many, Gina M., May, Sandy, Melanson, Edward L., Moore, Samuel G., Moreau, Kerrie L., Musi, Nicolas, Nachun, Daniel, Nair, Venugopalan D., Newgard, Christopher, Nudelman, German, Piehowski, Paul D., Pincas, Hanna, Qian, Wei-Jun, Rankinen, Tuomo, Rasmussen, Blake B., Ravussin, Eric, Rooney, Jessica L., Rushing, Scott, Samdarshi, Mihir, Sanford, James A., Schauer, Irene E., Sealfon, Stuart C., Smith, Kevin S., Smith, Gregory R., Snyder, Michael, Stowe, Cynthia L., Talton, Jennifer W., Teng, Christopher, Thalacker-Mercer, Anna, Tracy, Russell, Trappe, Scott, Trappe, Todd A., Vasoya, Mital, Vetr, Nikolai G., Volpi, Elena, Walkup, Michael P., Wiel, Laurens, Wu, Si, Yan, Zhen, Yu, Jiye, Zaslavsky, Elena, Zebarjadi, Navid, Zhen, Jimmy, Amar, David, Gay, Nicole R., Jimenez-Morales, David, Jean Beltran, Pierre M., Ramaker, Megan E., Raja, Archana Natarajan, Zhao, Bingqing, Sun, Yifei, Marwaha, Shruti, Gaul, David A., Hershman, Steven G., Ferrasse, Alexis, Xia, Ashley, Lanza, Ian, Fernández, Facundo M., Montgomery, Stephen B., Hevener, Andrea L., Ashley, Euan A., Walsh, Martin J., Sparks, Lauren M., Burant, Charles F., Rector, R. Scott, Thyfault, John, Wheeler, Matthew T., Goodpaster, Bret H., Coen, Paul M., Schenk, Simon, Bodine, Sue C., and Lindholm, Malene E.

Published
2024
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7. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

Author

den Hoed, Joery, de Boer, Elke, Voisin, Norine, Dingemans, Alexander, Guex, Nicolas, Wiel, Laurens, Nellaker, Christoffer, Amudhavalli, Shivarajan, Banka, Siddharth, Bena, Frederique, Ben-Zeev, Bruria, Bonagura, Vincent, Bruel, Ange-Line, Brunet, Theresa, Brunner, Han, Chew, Hui, Chrast, Jacqueline, Cimbalistienė, Loreta, Coon, Hilary, Délot, Emmanuèlle, Démurger, Florence, Denommé-Pichon, Anne-Sophie, Depienne, Christel, Donnai, Dian, Dyment, David, Elpeleg, Orly, Faivre, Laurence, Gilissen, Christian, Granger, Leslie, Haber, Benjamin, Hachiya, Yasuo, Abedi, Yasmin, Hanebeck, Jennifer, Hehir-Kwa, Jayne, Horist, Brooke, Itai, Toshiyuki, Jackson, Adam, Jewell, Rosalyn, Jones, Kelly, Joss, Shelagh, Kashii, Hirofumi, Kato, Mitsuhiro, Kattentidt-Mouravieva, Anja, Kok, Fernando, Kotzaeridou, Urania, Krishnamurthy, Vidya, Kučinskas, Vaidutis, Kuechler, Alma, Lavillaureix, Alinoë, Liu, Pengfei, Manwaring, Linda, Matsumoto, Naomichi, Mazel, Benoît, McWalter, Kirsty, Meiner, Vardiella, Mikati, Mohamad, Miyatake, Satoko, Mizuguchi, Takeshi, Moey, Lip, Mohammed, Shehla, Mor-Shaked, Hagar, Mountford, Hayley, Newbury-Ecob, Ruth, Odent, Sylvie, Orec, Laura, Osmond, Matthew, Palculict, Timothy, Parker, Michael, Petersen, Andrea, Pfundt, Rolph, Preikšaitienė, Eglė, Radtke, Kelly, Ranza, Emmanuelle, Rosenfeld, Jill, Santiago-Sim, Teresa, Schwager, Caitlin, Sinnema, Margje, Snijders Blok, Lot, Spillmann, Rebecca, Stegmann, Alexander, Thiffault, Isabelle, Tran, Linh, Vaknin-Dembinsky, Adi, Vedovato-Dos-Santos, Juliana, Schrier Vergano, Samantha, Vilain, Eric, Vitobello, Antonio, Wagner, Matias, Waheeb, Androu, Willing, Marcia, Zuccarelli, Britton, Kini, Usha, Newbury, Dianne, Kleefstra, Tjitske, Reymond, Alexandre, Fisher, Simon, and Vissers, Lisenka

Subjects
HPO-based analysis, SATB1, cell-based functional assays, de novo variants, intellectual disability, neurodevelopmental disorders, seizures, teeth abnormalities, Chromatin, Female, Genetic Association Studies, Haploinsufficiency, Humans, Male, Matrix Attachment Region Binding Proteins, Models, Molecular, Mutation, Mutation, Missense, Neurodevelopmental Disorders, Protein Binding, Protein Domains, Transcription, Genetic
Abstract

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

Published
2021

8. Beyond the exome: What’s next in diagnostic testing for Mendelian conditions

Author

Abouhala, Siwaar, Albert, Jessica, Almalvez, Miguel, Alvarez, Raquel, Amin, Mutaz, Anderson, Peter, Aradhya, Swaroop, Ashley, Euan, Assimes, Themistocles, Auriga, Light, Austin-Tse, Christina, Bamshad, Mike, Barseghyan, Hayk, Baxter, Samantha, Behera, Sairam, Beheshti, Shaghayegh, Bejerano, Gill, Berger, Seth, Bernstein, Jon, Best, Sabrina, Blankenmeister, Benjamin, Blue, Elizabeth, Boerwinkle, Eric, Bonkowski, Emily, Bonner, Devon, Boone, Philip, Bornhorst, Miriam, Bozkurt-Yozgatli, Tugce, Brand, Harrison, Buckingham, Kati, Calame, Daniel, Casadei, Silvia, Chadwick, Lisa, Chavez, Clarisa, Chen, Ziwei, Chinn, Ivan, Chong, Jessica, Coban-Akdemir, Zeynep, Cohen, Andrea J., Conner, Sarah, Conomos, Matthew, Coveler, Karen, Cui, Ya Allen, Currin, Sara, Daber, Robert, Dardas, Zain, Davis, Colleen, Dawood, Moez, de Dios, Ivan, de Esch, Celine, Delaney, Meghan, Délot, Emmanuèle, DiTroia, Stephanie, Doddapaneni, Harsha, Du, Haowei, Duan, Ruizhi, Dugan-Perez, Shannon, Duong, Nhat, Duyzend, Michael, Eichler, Evan, Emami, Sara, Fatih, Jawid, Fraser, Jamie, Fusaro, Vincent, Galey, Miranda, Ganesh, Vijay, Garimella, Kiran, Gibbs, Richard, Gifford, Casey, Ginsburg, Amy, Goddard, Pagé, Gogarten, Stephanie, Gogate, Nikhita, Gordon, William, Gorzynski, John E., Greenleaf, William, Grochowski, Christopher, Groopman, Emily, Guarischi Sousa, Rodrigo, Gudmundsson, Sanna, Gulati, Ashima, Guo, Daniel, Hale, Walker, Hall, Stacey, Harvey, William, Hawley, Megan, Heavner, Ben, Herman, Isabella, Horike-Pyne, Martha, Hu, Jianhong, Huang, Yongqing, Hwang, James, Jarvik, Gail, Jensen, Tanner, Jhangiani, Shalini, Jimenez-Morales, David, Jin, Christopher, Saad, Ahmed K., Kahn-Kirby, Amanda, Kain, Jessica, Kaur, Parneet, Keehan, Laura, Knoblach, Susan, Ko, Arthur, Kohler, Jennefer, Kundaje, Anshul, Kundu, Soumya, Lancaster, Samuel M., Larsson, Katie, Lemire, Gabrielle, Lewis, Richard, Li, Wei, Li, Yidan, Liu, Pengfei, LoTempio, Jonathan, Lupski, James, Ma, Jialan, MacArthur, Daniel, Mahmoud, Medhat, Malani, Nirav, Mangilog, Brian, Marafi, Dana, Marmolejos, Sofia, Marten, Daniel, Martinez, Eva, Marvin, Colby, Marwaha, Shruti, Kumara Mastrorosa, Francesco, Matalon, Dena, May, Susanne, McGee, Sean, Meador, Lauren, Mefford, Heather, Rodrigo Mendez, Hector, Miller, Alexander, Miller, Danny E., Mitani, Tadahiro, Montgomery, Stephen, Moussa, Hala Mohamed, Moyses, Mariana, Munderloh, Chloe, Muzny, Donna, Nelson, Sarah, Neu, Matthew B., Nguyen, Jonathan, Nguyen, Thuy-mi P., Nussbaum, Robert, Nykamp, Keith, O'Callaghan, William, O'Heir, Emily, O'Leary, Melanie, Olsen, Jeren, Osei-Owusu, Ikeoluwa, O'Donnell-Luria, Anne, Padhi, Evin, Pais, Lynn, Pan, Miao, Panchal, Piyush, Patterson, Karynne, Payne, Sheryl, Pehlivan, Davut, Petrowski, Paul, Pham, Alicia, Pitsava, Georgia, Podesta, Astaria, Ponce, Sarah, Posey, Jennifer, Prosser, Jaime, Quertermous, Thomas, Rai, Archana, Ramani, Arun, Rehm, Heidi, Reuter, Chloe, Reuter, Jason, Richardson, Matthew, Rivera-Munoz, Andres, Rubio, Oriane, Sabo, Aniko, Salani, Monica, Samocha, Kaitlin, Sanchis-Juan, Alba, Savage, Sarah, Scott, Stuart, Scott, Evette, Sedlazeck, Fritz, Shah, Gulalai, Shojaie, Ali, Singh, Mugdha, Smith, Josh, Smith, Kevin, Snow, Hana, Snyder, Michael, Socarras, Kayla, Starita, Lea, Stark, Brigitte, Stenton, Sarah, Stergachis, Andrew, Stilp, Adrienne, Sundaram, Laksshman, Sutton, V. Reid, Tai, Jui-Cheng, Talkowski, Michael, Tise, Christina, Tong, Catherine, Tsao, Philip, Ungar, Rachel, VanNoy, Grace, Vilain, Eric, Voutos, Isabella, Walker, Kim, Weisburd, Ben, Weiss, Jeff, Wellington, Chris, Weng, Ziming, Westheimer, Emily, Wheeler, Marsha, Wheeler, Matthew, Wiel, Laurens, Wilson, Michael, Wojcik, Monica, Wong, Quenna, Wong, Issac, Xiao, Changrui, Yadav, Rachita, Yi, Qian, Yuan, Bo, Zhao, Jianhua, Zhen, Jimmy, Zhou, Harry, Wojcik, Monica H., Reuter, Chloe M., Duyzend, Michael H., Boone, Philip M., Groopman, Emily E., Délot, Emmanuèle C., Jain, Deepti, Starita, Lea M., Montgomery, Stephen B., Bamshad, Michael J., Chong, Jessica X., Wheeler, Matthew T., Berger, Seth I., and Sedlazeck, Fritz J.

Published
2023
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9. Molecular adaptations in response to exercise training are associated with tissue-specific transcriptomic and epigenomic signatures

Author

Nair, Venugopalan D., primary, Pincas, Hanna, additional, Smith, Gregory R., additional, Zaslavsky, Elena, additional, Ge, Yongchao, additional, Amper, Mary Anne S., additional, Vasoya, Mital, additional, Chikina, Maria, additional, Sun, Yifei, additional, Raja, Archana Natarajan, additional, Mao, Weiguang, additional, Gay, Nicole R., additional, Esser, Karyn A., additional, Smith, Kevin S., additional, Zhao, Bingqing, additional, Wiel, Laurens, additional, Singh, Aditya, additional, Lindholm, Malene E., additional, Amar, David, additional, Montgomery, Stephen, additional, Snyder, Michael P., additional, Walsh, Martin J., additional, and Sealfon, Stuart C., additional

Published
2024
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11. Evidence for 28 genetic disorders discovered by combining healthcare and research data

Author

Kaplanis, Joanna, Samocha, Kaitlin E., Wiel, Laurens, Zhang, Zhancheng, Arvai, Kevin J., Eberhardt, Ruth Y., and Gallone, Giuseppe

Subjects
Genetic disorders -- Discovery and exploration, Medical research -- Usage, Medicine, Experimental -- Usage, Medical statistics -- Usage, Evidence-based medicine -- Analysis, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

De novo mutations in protein-coding genes are a well-established cause of developmental disorders.sup.1. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations.sup.1,2. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent-offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders. By integrating healthcare and exome-sequencing data from parent-offspring trios of patients with developmental disorders, 28 genes that had not previously been associated with developmental disorders were identified., Author(s): Joanna Kaplanis [sup.1] , Kaitlin E. Samocha [sup.1] , Laurens Wiel [sup.2] [sup.3] , Zhancheng Zhang [sup.4] , Kevin J. Arvai [sup.4] , Ruth Y. Eberhardt [sup.1] , Giuseppe [...]

Published
2020
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12. De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy

Author

Nabais Sá, Maria J., Venselaar, Hanka, Wiel, Laurens, Trimouille, Aurélien, Lasseaux, Eulalie, Naudion, Sophie, Lacombe, Didier, Piton, Amélie, Vincent-Delorme, Catherine, Zweier, Christiane, Reis, André, Trollmann, Regina, Ruiz, Anna, Gabau, Elisabeth, Vetro, Annalisa, Guerrini, Renzo, Bakhtiari, Somayeh, Kruer, Michael C., Amor, David J., Cooper, Monica S., Bijlsma, Emilia K., Barakat, Tahsin Stefan, van Dooren, Marieke F., van Slegtenhorst, Marjon, Pfundt, Rolph, Gilissen, Christian, Willemsen, Michèl A., de Vries, Bert B. A., de Brouwer, Arjan P. M., and Koolen, David A.

Published
2020
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15. KeCo: Kernel-Based Online Co-agreement Algorithm

Author

Wiel, Laurens, Heskes, Tom, Levin, Evgeni, Hutchison, David, Series editor, Kanade, Takeo, Series editor, Kittler, Josef, Series editor, Kleinberg, Jon M., Series editor, Mattern, Friedemann, Series editor, Mitchell, John C., Series editor, Naor, Moni, Series editor, Pandu Rangan, C., Series editor, Steffen, Bernhard, Series editor, Terzopoulos, Demetri, Series editor, Tygar, Doug, Series editor, Weikum, Gerhard, Series editor, Japkowicz, Nathalie, editor, and Matwin, Stan, editor

Published
2015
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16. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Author

Wesdorp, Mieke, de Koning Gans, Pia A. M., Schraders, Margit, Oostrik, Jaap, Huynen, Martijn A., Venselaar, Hanka, Beynon, Andy J., van Gaalen, Judith, Piai, Vitória, Voermans, Nicol, van Rossum, Michelle M., Hartel, Bas P., Lelieveld, Stefan H., Wiel, Laurens, Verbist, Berit, Rotteveel, Liselotte J., van Dooren, Marieke F., Lichtner, Peter, Kunst, Henricus P. M., Feenstra, Ilse, Admiraal, Ronald J. C., DOOFNL Consortium, Yntema, Helger G., Hoefsloot, Lies H., Pennings, Ronald J. E., and Kremer, Hannie

Published
2018
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19. The functional impact of rare variation across the regulatory cascade

Author

Li, Taibo, primary, Ferraro, Nicole, additional, Strober, Benjamin J., additional, Aguet, Francois, additional, Kasela, Silva, additional, Arvanitis, Marios, additional, Ni, Bohan, additional, van de Wiel, Laurens, additional, Hershberg, Elliot, additional, Ardlie, Kristin, additional, Arking, Dan E., additional, Beer, Rebecca L., additional, Brody, Jennifer, additional, Blackwell, Thomas W, additional, Clish, Clary, additional, Gabriel, Stacey, additional, Gerszten, Robert, additional, Guo, Xiuqing, additional, Gupta, Namrata, additional, Johnson, W. Craig, additional, Lappalainen, Tuuli, additional, Lin, Henry J., additional, Liu, Yongmei, additional, Nickerson, Deborah A., additional, Papanicolaou, George, additional, Pritchard, Jonathan K., additional, Qasba, Pankaj, additional, Shojaie, Ali, additional, Smith, Josh, additional, Sotoodehnia, Nona, additional, Taylor, Kent D., additional, Tracy, Russell P., additional, Van Den Berg, David, additional, Wheeler, Matthew, additional, Rich, Stephen S., additional, Rotter, Jerome I., additional, Battle, Alexis, additional, and Montgomery, Stephen B., additional

Published
2022
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24. Integrating healthcare and research genetic data empowers the discovery of 49 novel developmental disorders

Author

Kaplanis, Joanna, Samocha, Kaitlin E., Wiel, Laurens, Zhang, Zhancheng, Arvai, Kevin J., Eberhardt, Ruth Y., Gallone, Giuseppe, Lelieveld, Stefan H., Martin, Hilary C., McRae, Jeremy F., Short, Patrick J., Torene, Rebecca I., de Boer, Elke, Danecek, Petr, Gardner, Eugene J., Huang, Ni, Lord, Jenny, Martincorena, Iñigo, Pfundt, Rolph, Reijnders, Margot R. F., Yeung, Alison, Yntema, Helger G., Vissers, Lisenka E. L. M., Juusola, Jane, Wright, Caroline F., Brunner, Han G., Firth, Helen V., FitzPatrick, David R., Barrett, Jeffrey C., Hurles, Matthew E., Gilissen, Christian, and Retterer, Kyle

Abstract

Summary De novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated genes only account for a minority of the observed excess of such DNMs. To identify novel DD-associated genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We identified 299 significantly DD-associated genes, including 49 not previously robustly associated with DDs. Despite detecting more DD-associated genes than in any previous study, much of the excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that over 500 novel DD-associated genes await discovery, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of dominant DDs.

Published
2019
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25. De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders

Author

Nabais Sá, Maria J., primary, El Tekle, Geniver, additional, de Brouwer, Arjan P.M., additional, Sawyer, Sarah L., additional, del Gaudio, Daniela, additional, Parker, Michael J., additional, Kanani, Farah, additional, van den Boogaard, Marie-José H., additional, van Gassen, Koen, additional, Van Allen, Margot I., additional, Wierenga, Klaas, additional, Purcarin, Gabriela, additional, Elias, Ellen Roy, additional, Begtrup, Amber, additional, Keller-Ramey, Jennifer, additional, Bernasocchi, Tiziano, additional, van de Wiel, Laurens, additional, Gilissen, Christian, additional, Venselaar, Hanka, additional, Pfundt, Rolph, additional, Vissers, Lisenka E.L.M., additional, Theurillat, Jean-Philippe P., additional, and de Vries, Bert B.A., additional

Published
2020
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26. Integrating healthcare and research genetic data empowers the discovery of 28 novel developmental disorders

Author

Kaplanis, Joanna, primary, Samocha, Kaitlin E., additional, Wiel, Laurens, additional, Zhang, Zhancheng, additional, Arvai, Kevin J., additional, Eberhardt, Ruth Y., additional, Gallone, Giuseppe, additional, Lelieveld, Stefan H., additional, Martin, Hilary C., additional, McRae, Jeremy F., additional, Short, Patrick J., additional, Torene, Rebecca I., additional, de Boer, Elke, additional, Danecek, Petr, additional, Gardner, Eugene J., additional, Huang, Ni, additional, Lord, Jenny, additional, Martincorena, Iñigo, additional, Pfundt, Rolph, additional, Reijnders, Margot R. F., additional, Yeung, Alison, additional, Yntema, Helger G., additional, Study, DDD, additional, Vissers, Lisenka E. L. M., additional, Juusola, Jane, additional, Wright, Caroline F., additional, Brunner, Han G., additional, Firth, Helen V., additional, FitzPatrick, David R., additional, Barrett, Jeffrey C., additional, Hurles, Matthew E., additional, Gilissen, Christian, additional, and Retterer, Kyle, additional

Published
2019
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27. De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder

Author

Snijders Blok, Lot, primary, Kleefstra, Tjitske, additional, Venselaar, Hanka, additional, Maas, Saskia, additional, Kroes, Hester Y., additional, Lachmeijer, Augusta M.A., additional, van Gassen, Koen L.I., additional, Firth, Helen V., additional, Tomkins, Susan, additional, Bodek, Simon, additional, Õunap, Katrin, additional, Wojcik, Monica H., additional, Cunniff, Christopher, additional, Bergstrom, Katherine, additional, Powis, Zoë, additional, Tang, Sha, additional, Shinde, Deepali N., additional, Au, Catherine, additional, Iglesias, Alejandro D., additional, Izumi, Kosuke, additional, Leonard, Jacqueline, additional, Abou Tayoun, Ahmad, additional, Baker, Samuel W., additional, Tartaglia, Marco, additional, Niceta, Marcello, additional, Dentici, Maria Lisa, additional, Okamoto, Nobuhiko, additional, Miyake, Noriko, additional, Matsumoto, Naomichi, additional, Vitobello, Antonio, additional, Faivre, Laurence, additional, Philippe, Christophe, additional, Gilissen, Christian, additional, Wiel, Laurens, additional, Pfundt, Rolph, additional, Deriziotis, Pelagia, additional, Brunner, Han G., additional, and Fisher, Simon E., additional

Published
2019
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28. Front Cover, Volume 40, Issue 8

Author

Wiel, Laurens, primary, Baakman, Coos, additional, Gilissen, Daan, additional, Veltman, Joris A., additional, Vriend, Gerrit, additional, and Gilissen, Christian, additional

Published
2019
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30. De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

Author

Diets, Illja J., primary, van der Donk, Roos, additional, Baltrunaite, Kristina, additional, Waanders, Esmé, additional, Reijnders, Margot R.F., additional, Dingemans, Alexander J.M., additional, Pfundt, Rolph, additional, Vulto-van Silfhout, Anneke T., additional, Wiel, Laurens, additional, Gilissen, Christian, additional, Thevenon, Julien, additional, Perrin, Laurence, additional, Afenjar, Alexandra, additional, Nava, Caroline, additional, Keren, Boris, additional, Bartz, Sarah, additional, Peri, Bethany, additional, Beunders, Gea, additional, Verbeek, Nienke, additional, van Gassen, Koen, additional, Thiffault, Isabelle, additional, Cadieux-Dion, Maxime, additional, Huerta-Saenz, Lina, additional, Wagner, Matias, additional, Konstantopoulou, Vassiliki, additional, Vodopiutz, Julia, additional, Griese, Matthias, additional, Boel, Annekatrien, additional, Callewaert, Bert, additional, Brunner, Han G., additional, Kleefstra, Tjitske, additional, Hoogerbrugge, Nicoline, additional, de Vries, Bert B.A., additional, Hwa, Vivian, additional, Dauber, Andrew, additional, Hehir-Kwa, Jayne Y., additional, Kuiper, Roland P., additional, and Jongmans, Marjolijn C.J., additional

Published
2019
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31. Genome-scale detection of positive selection in nine primates predicts human-virus evolutionary conflicts

Author

van der Lee, Robin, Wiel, Laurens, van Dam, Teunis J P, Huynen, Martijn A, Sub Bioinformatics, Theoretical Biology and Bioinformatics, Sub Bioinformatics, and Theoretical Biology and Bioinformatics

Subjects
0301 basic medicine, Primates, Genome evolution, Evolution, Gene Conversion, Genomics, Computational biology, Major histocompatibility complex, Genome, Evolution, Molecular, 03 medical and health sciences, Viral Proteins, Genetic, Receptors, Genetics, Journal Article, Animals, Humans, Selection, Genetic, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Gene, Selection, Selection (genetic algorithm), biology, Immunity, Molecular, Genetic Variation, Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Acquired immune system, Phenotype, Virus, 030104 developmental biology, Virus Diseases, Multigene Family, Host-Pathogen Interactions, biology.protein, Receptors, Virus, Artifacts, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]
Abstract

Hotspots of rapid genome evolution hold clues about human adaptation. We present a comparative analysis of nine whole-genome sequenced primates to identify high-confidence targets of positive selection. We find strong statistical evidence for positive selection in 331 protein-coding genes (3%), pinpointing 934 adaptively evolving codons (0.014%). Our new procedure is stringent and reveals substantial artefacts (20% of initial predictions) that have inflated previous estimates. The final 331 positively selected genes (PSG) are strongly enriched for innate and adaptive immunity, secreted and cell membrane proteins (e.g. pattern recognition, complement, cytokines, immune receptors, MHC, Siglecs). We also find evidence for positive selection in reproduction and chromosome segregation (e.g. centromere-associated CENPO, CENPT), apolipoproteins, smell/taste receptors and mitochondrial proteins. Focusing on the virus–host interaction, we retrieve most evolutionary conflicts known to influence antiviral activity (e.g. TRIM5, MAVS, SAMHD1, tetherin) and predict 70 novel cases through integration with virus–human interaction data. Protein structure analysis further identifies positive selection in the interaction interfaces between viruses and their cellular receptors (CD4-HIV; CD46-measles, adenoviruses; CD55-picornaviruses). Finally, primate PSG consistently show high sequence variation in human exomes, suggesting ongoing evolution. Our curated dataset of positive selection is a rich source for studying the genetics underlying human (antiviral) phenotypes. Procedures and data are available at https://github.com/robinvanderlee/positive-selection.

Published
2017

32. Considerations for reporting variants in novel candidate genes identified during clinical genomic testing

Author

Chong, Jessica X., Berger, Seth I., Baxter, Samantha, Smith, Erica, Xiao, Changrui, Calame, Daniel G., Hawley, Megan H., Rivera-Munoz, E. Andres, DiTroia, Stephanie, Abouhala, Siwaar, Albert, Jessica, Almalvez, Miguel, Alvarez, Raquel, Amin, Mutaz, Anderson, Peter, Aradhya, Swaroop, Ashley, Euan, Assimes, Themistocles, Auriga, Light, Austin-Tse, Christina, Bamshad, Mike, Barseghyan, Hayk, Baxter, Samantha, Behera, Sairam, Beheshti, Shaghayegh, Bejerano, Gill, Berger, Seth, Bernstein, Jon, Best, Sabrina, Blankenmeister, Benjamin, Blue, Elizabeth, Boerwinkle, Eric, Bonkowski, Emily, Bonner, Devon, Boone, Philip, Bornhorst, Miriam, Brand, Harrison, Buckingham, Kati, Calame, Daniel, Carter, Jennefer, Casadei, Silvia, Chadwick, Lisa, Chavez, Clarisa, Chen, Ziwei, Chinn, Ivan, Chong, Jessica, Coban-Akdemir, Zeynep, Cohen, Andrea J., Conner, Sarah, Conomos, Matthew, Coveler, Karen, Cui, Ya Allen, Currin, Sara, Daber, Robert, Dardas, Zain, Davis, Colleen, Dawood, Moez, de Dios, Ivan, de Esch, Celine, Delaney, Meghan, Delot, Emmanuele, DiTroia, Stephanie, Doddapaneni, Harsha, Du, Haowei, Duan, Ruizhi, Dugan-Perez, Shannon, Duong, Nhat, Duyzend, Michael, Eichler, Evan, Emami, Sara, Fraser, Jamie, Fusaro, Vincent, Galey, Miranda, Ganesh, Vijay, Garcia, Brandon, Garimella, Kiran, Gibbs, Richard, Gifford, Casey, Ginsburg, Amy, Goddard, Page, Gogarten, Stephanie, Gogate, Nikhita, Gordon, William, Gorzynski, John E., Greenleaf, William, Grochowski, Christopher, Groopman, Emily, Sousa, Rodrigo Guarischi, Gudmundsson, Sanna, Gulati, Ashima, Hall, Stacey, Harvey, William, Hawley, Megan, Heavner, Ben, Horike-Pyne, Martha, Hu, Jianhong, Huang, Yongqing, Hwang, James, Jarvik, Gail, Jensen, Tanner, Jhangiani, Shalini, Jimenez-Morales, David, Jin, Christopher, Saad, Ahmed K., Kahn-Kirby, Amanda, Kain, Jessica, Kaur, Parneet, Keehan, Laura, Knoblach, Susan, Ko, Arthur, Kundaje, Anshul, Kundu, Soumya, Lancaster, Samuel M., Larsson, Katie, Lee, Arthur, Lemire, Gabrielle, Lewis, Richard, Li, Wei, Li, Yidan, Liu, Pengfei, LoTempio, Jonathan, Lupski, James (Jim), Ma, Jialan, MacArthur, Daniel, Mahmoud, Medhat, Malani, Nirav, Mangilog, Brian, Marafi, Dana, Marmolejos, Sofia, Marten, Daniel, Martinez, Eva, Marvin, Colby, Marwaha, Shruti, Mastrorosa, Francesco Kumara, Matalon, Dena, May, Susanne, McGee, Sean, Meador, Lauren, Mefford, Heather, Mendez, Hector Rodrigo, Miller, Alexander, Miller, Danny E., Mitani, Tadahiro, Montgomery, Stephen, Moyses, Mariana, Munderloh, Chloe, Muzny, Donna, Nelson, Sarah, Nguyen, Thuy-mi P., Nguyen, Jonathan, Nussbaum, Robert, Nykamp, Keith, O'Callaghan, William, O'Heir, Emily, O'Leary, Melanie, Olsen, Jeren, Osei-Owusu, Ikeoluwa, O'Donnell-Luria, Anne, Padhi, Evin, Pais, Lynn, Pan, Miao, Panchal, Piyush, Patterson, Karynne, Payne, Sheryl, Pehlivan, Davut, Petrowski, Paul, Pham, Alicia, Pitsava, Georgia, Podesta, Astaria Sara, Ponce, Sarah, Porter, Elizabeth, Posey, Jennifer, Prosser, Jaime, Quertermous, Thomas, Rai, Archana, Ramani, Arun, Rehm, Heidi, Reuter, Chloe, Reuter, Jason, Richardson, Matthew, Rivera-Munoz, Andres, Rubio, Oriane, Sabo, Aniko, Salani, Monica, Samocha, Kaitlin, Sanchis-Juan, Alba, Savage, Sarah, Scott, Evette, Scott, Stuart, Sedlazeck, Fritz, Shah, Gulalai, Shojaie, Ali, Singh, Mugdha, Smith, Kevin, Smith, Josh, Snow, Hana, Snyder, Michael, Socarras, Kayla, Starita, Lea, Stark, Brigitte, Stenton, Sarah, Stergachis, Andrew, Stilp, Adrienne, Sutton, V. Reid, Tai, Jui-Cheng, Talkowski, Michael (Mike), Tise, Christina, Tong, Catherine (Cat), Tsao, Philip, Ungar, Rachel, VanNoy, Grace, Vilain, Eric, Voutos, Isabella, Walker, Kim, Wei, Chia-Lin, Weisburd, Ben, Weiss, Jeff, Wellington, Chris, Weng, Ziming, Westheimer, Emily, Wheeler, Marsha, Wheeler, Matthew, Wiel, Laurens, Wilson, Michael, Wojcik, Monica, Wong, Quenna, Xiao, Changrui, Yadav, Rachita, Yi, Qian, Yuan, Bo, Zhao, Jianhua, Zhen, Jimmy, Zhou, Harry, Bamshad, Michael J., and Rehm, Heidi L.

Abstract

Since the first novel gene discovery for a Mendelian condition was made via exome sequencing (ES), the rapid increase in the number of genes known to underlie Mendelian conditions coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare disease. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic diagnosis but frequently overlooks the identification of novel candidate genes. Such candidates are also less likely to be identified in the absence of large-scale gene discovery research programs. Accordingly, clinical laboratories have both the opportunity, and some might argue a responsibility, to contribute to novel gene discovery which should in turn increase the diagnostic yield for many conditions. However, clinical diagnostic laboratories must necessarily balance priorities for throughput, turnaround time, cost efficiency, clinician preferences, and regulatory constraints, and often do not have the infrastructure or resources to effectively participate in either clinical translational or basic genome science research efforts. For these and other reasons, many laboratories have historically refrained from broadly sharing potentially pathogenic variants in novel genes via networks like Matchmaker Exchange, much less reporting such results to ordering providers. Efforts to report such results are further complicated by a lack of guidelines for clinical reporting and interpretation of variants in novel candidate genes. Nevertheless, there are myriad benefits for many stakeholders, including patients/families, clinicians, researchers, if clinical laboratories systematically and routinely identify, share, and report novel candidate genes. To facilitate this change in practice, we developed criteria for triaging, sharing, and reporting novel candidate genes that are most likely to be promptly validated as underlying a Mendelian condition and translated to use in clinical settings.

Published
2024
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33. Integrating healthcare and research genetic data empowers the discovery of 49 novel developmental disorders

Author

Kaplanis, Joanna, primary, Samocha, Kaitlin E., additional, Wiel, Laurens, additional, Zhang, Zhancheng, additional, Arvai, Kevin J., additional, Eberhardt, Ruth Y., additional, Gallone, Giuseppe, additional, Lelieveld, Stefan H., additional, Martin, Hilary C., additional, McRae, Jeremy F., additional, Short, Patrick J., additional, Torene, Rebecca I., additional, Boer, Elke de, additional, Danecek, Petr, additional, Gardner, Eugene J., additional, Huang, Ni, additional, Lord, Jenny, additional, Martincorena, Iñigo, additional, Pfundt, Rolph, additional, Reijnders, Margot R. F., additional, Yeung, Alison, additional, Yntema, Helger G., additional, Study, DDD, additional, Vissers, Lisenka E. L. M., additional, Juusola, Jane, additional, Wright, Caroline F., additional, Brunner, Han G., additional, Firth, Helen V., additional, FitzPatrick, David R., additional, Barrett, Jeffrey C., additional, Hurles, Matthew E., additional, Gilissen, Christian, additional, and Retterer, Kyle, additional

Published
2018
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37. De novo CLTCvariants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy

Author

Nabais Sá, Maria J., Venselaar, Hanka, Wiel, Laurens, Trimouille, Aurélien, Lasseaux, Eulalie, Naudion, Sophie, Lacombe, Didier, Piton, Amélie, Vincent-Delorme, Catherine, Zweier, Christiane, Reis, André, Trollmann, Regina, Ruiz, Anna, Gabau, Elisabeth, Vetro, Annalisa, Guerrini, Renzo, Bakhtiari, Somayeh, Kruer, Michael C., Amor, David J., Cooper, Monica S., Bijlsma, Emilia K., Barakat, Tahsin Stefan, van Dooren, Marieke F., van Slegtenhorst, Marjon, Pfundt, Rolph, Gilissen, Christian, Willemsen, Michèl A., de Vries, Bert B. A., de Brouwer, Arjan P. M., and Koolen, David A.

Abstract

Purpose: To delineate the genotype–phenotype correlation in individuals with likely pathogenic variants in the CLTCgene. Methods: We describe 13 individuals with de novo CLTCvariants. Causality of variants was determined by using the tolerance landscape of CLTCand computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC. Results: All de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n?=?27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant. Conclusions: The wide phenotypic variability associated with likely pathogenic CLTCvariants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTCvariants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.

Published
2020
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38. De typische verleidingsscène in de Griekse epiek.

Author

VAN DER WIEL, Laurens

Abstract

This article aims to provide a more exact overview of the structure of the traditional type scene of seduction in ancient Greek epic poems, based on the insights of the previous research of Forsyth and Sowa. All instances of such seduction scenes have at least some of the following elements: divine inducement, preparation, departure and approach, and reaction of the male audience. In some cases, the characters go a step further: when the reluctance of one of the participants has been overcome, the man and the woman have sex, after which they realize the painful consequences. The poets sometimes deviate from this scheme, usually due to the requirements of the context. However, in some cases this deviation indicates an original intervention of the poet. Two examples of this will be discussed. [ABSTRACT FROM AUTHOR]

Published
2018

40. An Opaque Mirror for Trajan

Author

van der Wiel, Laurens

Subjects
Plutarch, Trajan, Exemplary literature, Apophthegms, Anecdote collections, thema EDItEUR::Q Philosophy and Religion::QD Philosophy::QDH Philosophical traditions and schools of thought::QDHA Ancient Greek and Roman philosophy
Abstract

The first full in-depth analysis and interpretation of Plutarch’s Regum et imperatorum apophthegmata in its entirety as a literary piece of art. Plutarch’s Regum et imperatorum apophthegmata (Sayings of Kings and Commanders) holds a peculiar position in his oeuvre. This collection of almost 500 anecdotes of barbarian, Greek, and Roman rulers and generals is introduced by a dedicatory letter to Trajan as a summary of the author’s well-known and widely read Parallel Lives. The work is therefore Plutarch’s only text that explicitly addresses a Roman emperor and is likely to shed light on his biographical technique. Yet the collection has been understudied, because its authenticity has been generally rejected since the nineteenth century. Recent scholarship defends Plutarch's authorship of the text, but some remain sceptical. This book restores its reputation and provides a first full literary analysis of the letter and collection as a genuine work of Plutarch, wherein he attempts to educate his ruler by means of great role models of the past. Plutarch’s thinking about the function of role models (exempla) is not only relevant for Plutarchan research, but also for our knowledge of exemplarity, a key feature both in Greek and Latin literature in the early imperial period in general. Therefore An Opaque Mirror for Trajan is also of interest for literary and historical scholars who study the broader context of ancient literature of the first centuries CE. Ebook available in Open Access. This publication is GPRC-labeled (Guaranteed Peer-Reviewed Content).

Published
2024
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42. Genome-scale detection of positive selection in nine primates predicts human-virus evolutionary conflicts.

Author

van der Lee R, Wiel L, van Dam TJP, and Huynen MA

Subjects
Animals, Artifacts, Gene Conversion, Genetic Variation, Genomics, Host-Pathogen Interactions genetics, Humans, Immunity genetics, Multigene Family, Primates genetics, Proteins genetics, Receptors, Virus chemistry, Viral Proteins chemistry, Virus Diseases genetics, Evolution, Molecular, Selection, Genetic
Abstract

Hotspots of rapid genome evolution hold clues about human adaptation. We present a comparative analysis of nine whole-genome sequenced primates to identify high-confidence targets of positive selection. We find strong statistical evidence for positive selection in 331 protein-coding genes (3%), pinpointing 934 adaptively evolving codons (0.014%). Our new procedure is stringent and reveals substantial artefacts (20% of initial predictions) that have inflated previous estimates. The final 331 positively selected genes (PSG) are strongly enriched for innate and adaptive immunity, secreted and cell membrane proteins (e.g. pattern recognition, complement, cytokines, immune receptors, MHC, Siglecs). We also find evidence for positive selection in reproduction and chromosome segregation (e.g. centromere-associated CENPO, CENPT), apolipoproteins, smell/taste receptors and mitochondrial proteins. Focusing on the virus-host interaction, we retrieve most evolutionary conflicts known to influence antiviral activity (e.g. TRIM5, MAVS, SAMHD1, tetherin) and predict 70 novel cases through integration with virus-human interaction data. Protein structure analysis further identifies positive selection in the interaction interfaces between viruses and their cellular receptors (CD4-HIV; CD46-measles, adenoviruses; CD55-picornaviruses). Finally, primate PSG consistently show high sequence variation in human exomes, suggesting ongoing evolution. Our curated dataset of positive selection is a rich source for studying the genetics underlying human (antiviral) phenotypes. Procedures and data are available at https://github.com/robinvanderlee/positive-selection., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Published
2017
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