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3. Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p.

Author

Weiner, Daniel, Ling, Emi, Erdin, Serkan, Tai, Derek, Yadav, Rachita, Grove, Jakob, Fu, Jack, Nadig, Ajay, Carey, Caitlin, Baya, Nikolas, Bybjerg-Grauholm, Jonas, Berretta, Sabina, Macosko, Evan, Sebat, Jonathan, OConnor, Luke, Hougaard, David, Børglum, Anders, Talkowski, Michael, McCarroll, Steven, and Robinson, Elise

Subjects
Humans, Autistic Disorder, DNA Copy Number Variations, Chromosomes, Chromosome Deletion, Chromosomes, Human, Pair 16
Abstract

The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autisms common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.

Published
2022

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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7. 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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8. Tissue- and cell-type-specific molecular and functional signatures of 16p11.2 reciprocal genomic disorder across mouse brain and human neuronal models

Author

Tai, Derek J.C., Razaz, Parisa, Erdin, Serkan, Gao, Dadi, Wang, Jennifer, Nuttle, Xander, de Esch, Celine E., Collins, Ryan L., Currall, Benjamin B., O’Keefe, Kathryn, Burt, Nicholas D., Yadav, Rachita, Wang, Lily, Mohajeri, Kiana, Aneichyk, Tatsiana, Ragavendran, Ashok, Stortchevoi, Alexei, Morini, Elisabetta, Ma, Weiyuan, Lucente, Diane, Hastie, Alex, Kelleher, Raymond J., Perlis, Roy H., Talkowski, Michael E., and Gusella, James F.

Published
2022
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9. Correction to: Tissue-specific and repeat length-dependent somatic instability of the X-linked dystonia parkinsonism-associated CCCTCT repeat

Author

Campion, Lindsey N., Mejia Maza, Alan, Yadav, Rachita, Penney, Ellen B., Murcar, Micaela G., Correia, Kevin, Gillis, Tammy, Fernandez-Cerado, Cara, Velasco-Andrada, M. Salvie, Legarda, G. Paul, Ganza-Bautista, Niecy G., Lagarde, J. Benedict B., Acuña, Patrick J., Multhaupt-Buell, Trisha, Aldykiewicz, Gabrielle, Supnet, Melanie L., De Guzman, Jan K., Go, Criscely, Sharma, Nutan, Munoz, Edwin L., Ang, Mark C., Diesta, Cid Czarina E., Bragg, D. Cristopher, Ozelius, Laurie J., and Wheeler, Vanessa C.

Published
2022
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10. Tissue-specific and repeat length-dependent somatic instability of the X-linked dystonia parkinsonism-associated CCCTCT repeat

Author

Campion, Lindsey N., Mejia Maza, Alan, Yadav, Rachita, Penney, Ellen B., Murcar, Micaela G., Correia, Kevin, Gillis, Tammy, Fernandez-Cerado, Cara, Velasco-Andrada, M. Salvie, Legarda, G. Paul, Ganza-Bautista, Niecy G., Lagarde, J. Benedict B., Acuña, Patrick J., Multhaupt-Buell, Trisha, Aldykiewicz, Gabrielle, Supnet, Melanie L., De Guzman, Jan K., Go, Criscely, Sharma, Nutan, Munoz, Edwin L., Ang, Mark C., Diesta, Cid Czarina E., Bragg, D. Cristopher, Ozelius, Laurie J., and Wheeler, Vanessa C.

Published
2022
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11. An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder

Author

Werling, Donna M, Brand, Harrison, An, Joon-Yong, Stone, Matthew R, Zhu, Lingxue, Glessner, Joseph T, Collins, Ryan L, Dong, Shan, Layer, Ryan M, Markenscoff-Papadimitriou, Eirene, Farrell, Andrew, Schwartz, Grace B, Wang, Harold Z, Currall, Benjamin B, Zhao, Xuefang, Dea, Jeanselle, Duhn, Clif, Erdman, Carolyn A, Gilson, Michael C, Yadav, Rachita, Handsaker, Robert E, Kashin, Seva, Klei, Lambertus, Mandell, Jeffrey D, Nowakowski, Tomasz J, Liu, Yuwen, Pochareddy, Sirisha, Smith, Louw, Walker, Michael F, Waterman, Matthew J, He, Xin, Kriegstein, Arnold R, Rubenstein, John L, Sestan, Nenad, McCarroll, Steven A, Neale, Benjamin M, Coon, Hilary, Willsey, A Jeremy, Buxbaum, Joseph D, Daly, Mark J, State, Matthew W, Quinlan, Aaron R, Marth, Gabor T, Roeder, Kathryn, Devlin, Bernie, Talkowski, Michael E, and Sanders, Stephan J

Subjects
Biological Sciences, Genetics, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Pediatric, Autism, Biotechnology, Mental Health, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Autism Spectrum Disorder, Female, Genetic Predisposition to Disease, Genome, Genome-Wide Association Study, Humans, INDEL Mutation, Male, Polymorphism, Single Nucleotide, Protein Isoforms, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here we present a comparable framework to evaluate rare and de novo noncoding single-nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism, the contribution of de novo noncoding variation is probably modest in comparison to that of de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple-testing burden.

Published
2018

12. Tissue- and cell-type-specific molecular and functional signatures of 16p11.2 reciprocal genomic disorder across mouse brain and human neuronal models

Author

Tai, Derek J.C., primary, Razaz, Parisa, additional, Erdin, Serkan, additional, Gao, Dadi, additional, Wang, Jennifer, additional, Nuttle, Xander, additional, de Esch, Celine E., additional, Collins, Ryan L., additional, Currall, Benjamin B., additional, O’Keefe, Kathryn, additional, Burt, Nicholas D., additional, Yadav, Rachita, additional, Wang, Lily, additional, Mohajeri, Kiana, additional, Aneichyk, Tatsiana, additional, Ragavendran, Ashok, additional, Stortchevoi, Alexei, additional, Morini, Elisabetta, additional, Ma, Weiyuan, additional, Lucente, Diane, additional, Hastie, Alex, additional, Kelleher, Raymond J., additional, Perlis, Roy H., additional, Talkowski, Michael E., additional, and Gusella, James F., additional

Published
2024
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15. Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children.

Author

Xu, Heng, Zhang, Hui, Yang, Wenjian, Yadav, Rachita, Morrison, Alanna C, Qian, Maoxiang, Devidas, Meenakshi, Liu, Yu, Perez-Andreu, Virginia, Zhao, Xujie, Gastier-Foster, Julie M, Lupo, Philip J, Neale, Geoff, Raetz, Elizabeth, Larsen, Eric, Bowman, W Paul, Carroll, William L, Winick, Naomi, Williams, Richard, Hansen, Torben, Holm, Jens-Christian, Mardis, Elaine, Fulton, Robert, Pui, Ching-Hon, Zhang, Jinghui, Mullighan, Charles G, Evans, William E, Hunger, Stephen P, Gupta, Ramneek, Schmiegelow, Kjeld, Loh, Mignon L, Relling, Mary V, and Yang, Jun J

Subjects
Hematopoietic Stem Cells, Animals, Humans, Mice, Genetic Predisposition to Disease, DNA-Binding Proteins, Transcription Factors, Case-Control Studies, Mutagenesis, Site-Directed, Genotype, Germ-Line Mutation, Mutation, Missense, Child, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p15, Ikaros Transcription Factor, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Genetic Variation, Genome-Wide Association Study, HEK293 Cells, Mutagenesis, Site-Directed, Mutation, Missense
Abstract

There is increasing evidence from genome-wide association studies for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children, yet the effects of protein-coding variants on ALL risk have not been systematically evaluated. Here we show a missense variant in CDKN2A associated with the development of ALL at genome-wide significance (rs3731249, P=9.4 × 10(-23), odds ratio=2.23). Functional studies indicate that this hypomorphic variant results in reduced tumour suppressor function of p16(INK4A), increases the susceptibility to leukaemic transformation of haematopoietic progenitor cells, and is preferentially retained in ALL tumour cells. Resequencing the CDKN2A-CDKN2B locus in 2,407 childhood ALL cases reveals 19 additional putative functional germline variants. These results provide direct functional evidence for the influence of inherited genetic variation on ALL risk, highlighting the important and complex roles of CDKN2A-CDKN2B tumour suppressors in leukaemogenesis.

Published
2015

16. The genome of a Late Pleistocene human from a Clovis burial site in western Montana.

Author

Rasmussen, Morten, Anzick, Sarah, Waters, Michael, Skoglund, Pontus, DeGiorgio, Michael, Stafford, Thomas, Rasmussen, Simon, Moltke, Ida, Albrechtsen, Anders, Doyle, Shane, Poznik, G, Gudmundsdottir, Valborg, Yadav, Rachita, Malaspinas, Anna-Sapfo, White, Samuel, Allentoft, Morten, Tambets, Kristiina, Eriksson, Anders, Heintzman, Peter, Karmin, Monika, Korneliussen, Thorfinn, Meltzer, David, Pierre, Tracey, Stenderup, Jesper, Saag, Lauri, Warmuth, Vera, Lopes, Margarida, Malhi, Ripan, Brunak, Søren, Sicheritz-Ponten, Thomas, Barnes, Ian, Collins, Matthew, Orlando, Ludovic, Balloux, Francois, Manica, Andrea, Gupta, Ramneek, Metspalu, Mait, Bustamante, Carlos, Jakobsson, Mattias, Willerslev, Eske, Nielsen, Rasmus, and Cornejo, Omar

Subjects
Archaeology, Asia, Bone and Bones, Burial, Chromosomes, Human, Y, DNA, Mitochondrial, Emigration and Immigration, Europe, Gene Flow, Genome, Human, Haplotypes, History, Ancient, Humans, Indians, North American, Infant, Male, Models, Genetic, Molecular Sequence Data, Montana, Phylogeny, Population Dynamics, Radiometric Dating
Abstract

Clovis, with its distinctive biface, blade and osseous technologies, is the oldest widespread archaeological complex defined in North America, dating from 11,100 to 10,700 (14)C years before present (bp) (13,000 to 12,600 calendar years bp). Nearly 50 years of archaeological research point to the Clovis complex as having developed south of the North American ice sheets from an ancestral technology. However, both the origins and the genetic legacy of the people who manufactured Clovis tools remain under debate. It is generally believed that these people ultimately derived from Asia and were directly related to contemporary Native Americans. An alternative, Solutrean, hypothesis posits that the Clovis predecessors emigrated from southwestern Europe during the Last Glacial Maximum. Here we report the genome sequence of a male infant (Anzick-1) recovered from the Anzick burial site in western Montana. The human bones date to 10,705 ± 35 (14)C years bp (approximately 12,707-12,556 calendar years bp) and were directly associated with Clovis tools. We sequenced the genome to an average depth of 14.4× and show that the gene flow from the Siberian Upper Palaeolithic Malta population into Native American ancestors is also shared by the Anzick-1 individual and thus happened before 12,600 years bp. We also show that the Anzick-1 individual is more closely related to all indigenous American populations than to any other group. Our data are compatible with the hypothesis that Anzick-1 belonged to a population directly ancestral to many contemporary Native Americans. Finally, we find evidence of a deep divergence in Native American populations that predates the Anzick-1 individual.

Published
2014

17. Transcriptome analysis in a humanized mouse model of familial dysautonomia reveals tissue-specific gene expression disruption in the peripheral nervous system.

Author

GAO, DADI, primary, Harripaul, Ricardo S, additional, Morini, Elisabetta S, additional, Slaugenhaupt, Susan, additional, Chekuri, Anil, additional, Logan, Emily, additional, Kirchner, Emily Grace, additional, Bolduc, Jessica, additional, Erdin, Serkan, additional, Yadav, Rachita, additional, Talkowski, Michael E., additional, Salani, Monica, additional, and Currall, Benjamin, additional

Published
2023
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18. Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1

Author

Bragg, D. Cristopher, Mangkalaphiban, Kotchaphorn, Vaine, Christine A., Kulkarni, Nichita J., Shin, David, Yadav, Rachita, Dhakal, Jyotsna, Ton, Mai-Linh, Cheng, Anne, Russo, Christopher T., Ang, Mark, Acuña, Patrick, Go, Criscely, Franceour, Taylor N., Multhaupt-Buell, Trisha, Ito, Naoto, Müller, Ulrich, Hendriks, William T., Breakefield, Xandra O., Sharma, Nutan, and Ozelius, Laurie J.

Published
2017

20. A marker chromosome in psychosis identifies glycine decarboxylase (GLDC) as a novel regulator of neuronal and synaptic function in the hippocampus

Author

Kambali, Maltesh, primary, Li, Yan, additional, Unichenko, Petr, additional, Pliego, Jessica Feria, additional, Yadav, Rachita, additional, Liu, Jing, additional, McGuinness, Patrick, additional, Cobb, Johanna G, additional, Wang, Muxiao, additional, Nagarajan, Rajasekar, additional, Lyu, Jinrui, additional, Vongsouthi, Vanessa, additional, Jackson, Colin J, additional, Engin, Elif, additional, Coyle, Joseph, additional, Shin, Jeaweon, additional, Talkowski, Michael E, additional, Homanics, Gregg E., additional, Bolshakov, Vadim, additional, Henneberger, Christian, additional, and Rudolph, Uwe, additional

Published
2023
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21. A marker chromosome in psychosis identifies glycine decarboxylase (GLDC) as a novel regulator of neuronal and synaptic function in the hippocampus

Author

Kambali, Maltesh, Li, Yan, Unichenko, Petr, Pliego, Jessica Feria, Yadav, Rachita, Liu, Jing, McGuinness, Patrick, Cobb, Johanna G., Wang, Muxiao, Nagarajan, Rajasekar, Lyu, Jinrui, Vongsouthi, Vanessa, Jackson, Colin J., Engin, Elif, Coyle, Joseph T., Shin, Jeaweon, Talkowski, Michael E., Homanics, Gregg E., Bolshakov, Vadim Y., Henneberger, Christian, and Rudolph, Uwe

Subjects
Article
Abstract

The biological significance of a small supernumerary marker chromosome that results in dosage alterations to chromosome 9p24.1, including triplication of the GLDC gene encoding glycine decarboxylase, in two patients with psychosis is unclear. In an allelic series of copy number variant mouse models, we identify that triplication of Gldc reduces extracellular glycine levels as determined by optical fluorescence resonance energy transfer (FRET) in dentate gyrus (DG) but not in CA1, suppresses long-term potentiation (LTP) in mPP-DG synapses but not in CA3-CA1 synapses, reduces the activity of biochemical pathways implicated in schizophrenia and mitochondrial bioenergetics, and displays deficits in prepulse inhibition, startle habituation, latent inhibition, working memory, sociability and social preference. Our results thus provide a link between a genomic copy number variation, biochemical, cellular and behavioral phenotypes, and further demonstrate that GLDC negatively regulates long-term synaptic plasticity at specific hippocampal synapses, possibly contributing to the development of neuropsychiatric disorders.

Published
2023

22. P159: Variants in cohesin release factors WAPL, PDS5A, and PDS5B define a new class of cohesinopathies*

Author

Boone, Philip, primary, Faour, Kamli, additional, Mohajeri, Kiana, additional, Lemanski, John, additional, Jana, Bimal, additional, Fu, Jack, additional, Kerkhof, Jennifer, additional, McConkey, Haley, additional, Collins, Ryan, additional, Lucente, Diane, additional, de Esch, Celine, additional, Moysés-Oliveira, Mariana, additional, Nuttle, Alexander, additional, Domingo, Aloysius, additional, Erdin, Serkan, additional, Hanley, Maris, additional, Watt, Amy, additional, Surette, Eric, additional, Lima, Gloria, additional, Smith, Laura, additional, Salani, Monica, additional, Yadav, Rachita, additional, Harripaul, Ricardo, additional, O’Keefe, Kathryn, additional, Burt, Nicholas, additional, Larson, Matthew, additional, Bhavsar, Riya, additional, Currall, Benjamin, additional, Sell, Susan, additional, Ladda, Roger, additional, Immken, LaDonna, additional, Buchanan, Catherine, additional, Yuan, Bo, additional, Lynch, Sally, additional, Gilissen, Christian, additional, Pfundt, Rolph, additional, Ockeloen, Charlotte, additional, Kleefstra, Tjitske, additional, Vanhoutte, Els, additional, Sinnema, Margje, additional, Stegmann, Sander, additional, Stevens, Servi, additional, Iascone, Maria, additional, Maitz, Silvia, additional, Cogne, Benjamin, additional, Le Caignec, Cedric, additional, Vincent, Marie, additional, Nizon, Mathilde, additional, Male, Alison, additional, Agrawal, Pankaj, additional, Thompson, Michelle, additional, Torring, Pernille, additional, Brasch-Andersen, Charlotte, additional, Faivre, Laurence, additional, Bruel, Ange-Line, additional, Isidor, Bertrand, additional, Philippe, Christophe, additional, Morleo, Manuela, additional, Wojcik, Monica, additional, Genetti, Casie, additional, Srivastava, Siddharth, additional, Ballal, Sonia, additional, Schließke, Sophia, additional, Jamra, Rami Abou, additional, Delahaye, Andree, additional, von Wintzingerode, Lydia, additional, Bothe, Viktoria, additional, Houlier, Marine, additional, Stout, Timothy, additional, Bergant, Gaber, additional, Peterlin, Borut, additional, Moldovan, Oana, additional, Martínez-Gil, Núria, additional, Argilli, Emanuela, additional, Sherr, Elliott, additional, Harel, Tamar, additional, Rosenberg-Fogler, Hallel, additional, Rosenfeld, Jill, additional, Wentzensen, Ingrid, additional, Westphal, Dominik, additional, Riedhammer, Korbinian, additional, Orec, Laura, additional, Gusella, James, additional, Sadikovic, Bekim, additional, Tai, Derek, additional, and Talkowski, Michael, additional

Published
2023
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24. Statistical and functional convergence of common and rare genetic influences on autism at chromosome 16p

Author

Weiner, Daniel J., Ling, Emi, Erdin, Serkan, Tai, Derek J. C., Yadav, Rachita, Grove, Jakob, Fu, Jack M., Nadig, Ajay, Carey, Caitlin E., Baya, Nikolas, Bybjerg-Grauholm, Jonas, Mortensen, Preben B., Werge, Thomas, Demontis, Ditte, Mors, Ole, Nordentoft, Merete, Als, Thomas D., Baekvad-Hansen, Marie, Rosengren, Anders, Havdahl, Alexandra, Hedemand, Anne, Palotie, Aarno, Chakravarti, Aravinda, Arking, Dan, Sulovari, Arvis, Starnawska, Anna, Thiruvahindrapuram, Bhooma, de Leeuw, Christiaan, Carey, Caitlin, Ladd-Acosta, Christine, van der Merwe, Celia, Devlin, Bernie, Cook, Edwin H., Eichler, Evan, Corfield, Elisabeth, Dieleman, Gwen, Schellenberg, Gerard, Hakonarson, Hakon, Coon, Hilary, Dziobek, Isabel, Vorstman, Jacob, Girault, Jessica, Sutcliffe, James S., Duan, Jinjie, Nurnberger, John, Hallmayer, Joachim, Buxbaum, Joseph, Piven, Joseph, Weiss, Lauren, Davis, Lea, Janecka, Magdalena, Mattheisen, Manuel, State, Matthew W., Gill, Michael, Daly, Mark, Uddin, Mohammed, Andreassen, Ole, Szatmari, Peter, Lee, Phil Hyoun, Anney, Richard, Ripke, Stephan, Satterstrom, Kyle, Santangelo, Susan, Kuo, Susan, van Elst, Ludger Tebartz, Rolland, Thomas, Bougeron, Thomas, Polderman, Tinca, Turner, Tychele, Underwood, Jack, Manikandan, Veera, Pillalamarri, Vamsee, Warrier, Varun, Philipsen, Alexandra, Reif, Andreas, Hinney, Anke, Cormand, Bru, Bau, Claiton H. D., Rovaris, Diego Luiz, Sonuga-Barke, Edmund, Corfield, Elizabeth, Grevet, Eugenio Horacio, Salum, Giovanni, Larsson, Henrik, Buitelaar, Jan, Haavik, Jan, McGough, James, Kuntsi, Jonna, Elia, Josephine, Lesch, Klaus-Peter, Klein, Marieke, Bellgrove, Mark, Tesli, Martin, Leung, Patrick W. L., Pan, Pedro M., Dalsgaard, Soren, Loo, Sandra, Medland, Sarah, Faraone, Stephen V., Reichborn-Kjennerud, Ted, Banaschewski, Tobias, Hawi, Ziarih, Berretta, Sabina, Macosko, Evan Z., Sebat, Jonathan, O’Connor, Luke J., Hougaard, David M., Børglum, Anders D., Talkowski, Michael E., McCarroll, Steven A., Robinson, Elise B., Pediatrics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Hinney, Anke (Beitragende*r), Child and Adolescent Psychiatry / Psychology, Centre of Excellence in Complex Disease Genetics, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Complex Trait Genetics, and Clinical Developmental Psychology

Subjects
Genètica humana, DNA Copy Number Variations, Autism, 3112 Neurosciences, Medizin, Chromosomes, Cromosomes, Human genetics, Genetics, Humans, Autistic Disorder, Chromosome Deletion, Chromosomes, Human, Pair 16/genetics, Autisme, Chromosomes, Human, Pair 16, Autistic Disorder/genetics
Abstract

in press, weitere Verfasser:innen aus Einrichtungen außerhalb der Universität Duisburg-Essen sind nicht aufgeführt. The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism’s common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.

Published
2022

25. Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models

Author

Mohajeri, Kiana, primary, Yadav, Rachita, additional, D'haene, Eva, additional, Boone, Philip M., additional, Erdin, Serkan, additional, Gao, Dadi, additional, Moyses-Oliveira, Mariana, additional, Bhavsar, Riya, additional, Currall, Benjamin B., additional, O'Keefe, Kathryn, additional, Burt, Nicholas D., additional, Lowther, Chelsea, additional, Lucente, Diane, additional, Salani, Monica, additional, Larson, Mathew, additional, Redin, Claire, additional, Dudchenko, Olga, additional, Aiden, Erez Lieberman, additional, Menten, Björn, additional, Tai, Derek J.C., additional, Gusella, James F., additional, Vergult, Sarah, additional, and Talkowski, Michael E., additional

Published
2022
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26. STATISTICAL AND FUNCTIONAL CONVERGENCE OF COMMON AND RARE VARIANT RISK FOR AUTISM SPECTRUM DISORDERS AT CHROMOSOME 16P

Author

Weiner, Daniel, primary, Ling, Emi, additional, Erdin, Serkan, additional, Tai, Derek, additional, Yadav, Rachita, additional, Grove, Jakob, additional, Fu, Jack, additional, Nadig, Ajay, additional, Sebat, Jonathan, additional, O'Connor, Luke, additional, Hougaard, David, additional, Børglum, Anders, additional, Talkowski, Michael, additional, McCarroll, Steve, additional, and Robinson, Elise, additional

Published
2022
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27. Can Machine Learning Models Predict Asparaginase-associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia

Author

Nielsen, Rikke L., Wolthers, Benjamin O., Helenius, Marianne, Albertsen, Birgitte K., Clemmensen, Line, Nielsen, Kasper, Kanerva, Jukka, Niinimäki, Riitta, Frandsen, Thomas L., Attarbaschi, Andishe, Barzilai, Shlomit, Colombini, Antonella, Escherich, Gabriele, Aytan-Aktug, Derya, Liu, Hsi Che, Möricke, Anja, Samarasinghe, Sujith, Van Der Sluis, Inge M., Stanulla, Martin, Tulstrup, Morten, Yadav, Rachita, Zapotocka, Ester, Schmiegelow, Kjeld, Gupta, Ramneek, Nielsen, Rikke L., Wolthers, Benjamin O., Helenius, Marianne, Albertsen, Birgitte K., Clemmensen, Line, Nielsen, Kasper, Kanerva, Jukka, Niinimäki, Riitta, Frandsen, Thomas L., Attarbaschi, Andishe, Barzilai, Shlomit, Colombini, Antonella, Escherich, Gabriele, Aytan-Aktug, Derya, Liu, Hsi Che, Möricke, Anja, Samarasinghe, Sujith, Van Der Sluis, Inge M., Stanulla, Martin, Tulstrup, Morten, Yadav, Rachita, Zapotocka, Ester, Schmiegelow, Kjeld, and Gupta, Ramneek

Abstract

Asparaginase-associated pancreatitis (AAP) frequently affects children treated for acute lymphoblastic leukemia (ALL) causing severe acute and persisting complications. Known risk factors such as asparaginase dosing, older age and single nucleotide polymorphisms (SNPs) have insufficient odds ratios to allow personalized asparaginase therapy. In this study, we explored machine learning strategies for prediction of individual AAP risk. We integrated information on age, sex, and SNPs based on Illumina Omni2.5exome-8 arrays of patients with childhood ALL (N=1564, 244 with AAP aged 1.0 to 17.9 y) from 10 international ALL consortia into machine learning models including regression, random forest, AdaBoost and artificial neural networks. A model with only age and sex had area under the receiver operating characteristic curve (ROC-AUC) of 0.62. Inclusion of 6 pancreatitis candidate gene SNPs or 4 validated pancreatitis SNPs boosted ROC-AUC somewhat (0.67) while 30 SNPs, identified through our AAP genome-wide association study cohort, boosted performance (0.80). Most predictive features included rs10273639 (PRSS1-PRSS2), rs10436957 (CTRC), rs13228878 (PRSS1/PRSS2), rs1505495 (GALNTL6), rs4655107 (EPHB2) and age (1 to 7 y). Second AAP following asparaginase re-exposure was predicted with ROC-AUC: 0.65. The machine learning models assist individual-level risk assessment of AAP for future prevention trials, and may legitimize asparaginase re-exposure when AAP risk is predicted to be low.

Published
2022

28. Tissue and cell-type specific molecular and functional signatures of 16p11.2 reciprocal genomic disorder across mouse brain and human neuronal models

Author

Tai, Derek J.C., primary, Razaz, Parisa, additional, Erdin, Serkan, additional, Gao, Dadi, additional, Wang, Jennifer, additional, Nuttle, Xander, additional, de Esch, Celine E., additional, Collins, Ryan L, additional, Currall, Benjamin B., additional, O’Keefe, Kathryn, additional, Burt, Nicholas D., additional, Yadav, Rachita, additional, Wang, Lily, additional, Mohajeri, Kiana, additional, Aneichyk, Tatsiana, additional, Ragavendran, Ashok, additional, Stortchevoi, Alexei, additional, Morini, Elisabetta, additional, Ma, Weiyuan, additional, Lucente, Diane, additional, Hastie, Alex, additional, Kelleher, Raymond J., additional, Perlis, Roy H., additional, Talkowski, Michael E., additional, and Gusella, James F., additional

Published
2022
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29. Additional file 2 of Tissue-specific and repeat length-dependent somatic instability of the X-linked dystonia parkinsonism-associated CCCTCT repeat

Author

Campion, Lindsey N., Meijia Maza, Alan, Yadav, Rachita, Penney, Ellen B., Murcar, Micaela G., Correia, Kevin, Gillis, Tammy, Fernandez-Cerado, Cara, Velasco-Andrada, M. Salvie, Legarda, G. Paul, Ganza-Bautista, Niecy G., Lagarde, J. Benedict B., Acuña, Patrick J., Multhaupt-Buell, Trisha, Aldykiewicz, Gabrielle, Supnet, Melanie L., De Guzman, Jan K., Go, Criscely, Sharma, Nutan, Munoz, Edwin L., Ang, Mark C., Diesta, Cid Czarina E., Bragg, D. Cristopher, Ozelius, Laurie J., and Wheeler, Vanessa C.

Abstract

Additional file 2. Figures S1–S5.

Published
2022
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30. Additional file 1 of Tissue-specific and repeat length-dependent somatic instability of the X-linked dystonia parkinsonism-associated CCCTCT repeat

Author

Campion, Lindsey N., Mejia Maza, Alan, Yadav, Rachita, Penney, Ellen B., Murcar, Micaela G., Correia, Kevin, Gillis, Tammy, Fernandez-Cerado, Cara, Velasco-Andrada, M. Salvie, Legarda, G. Paul, Ganza-Bautista, Niecy G., Lagarde, J. Benedict B., Acuña, Patrick J., Multhaupt-Buell, Trisha, Aldykiewicz, Gabrielle, Supnet, Melanie L., De Guzman, Jan K., Go, Criscely, Sharma, Nutan, Munoz, Edwin L., Ang, Mark C., Diesta, Cid Czarina E., Bragg, D. Cristopher, Ozelius, Laurie J., and Wheeler, Vanessa C.

Abstract

Additional file 1. Tables S1–S7.

Published
2022
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31. Tissue-specific and repeat length-dependent somatic instability of the X-linked dystonia parkinsonism-associated CCCTCT repeat

Author

Campion, Lindsey N., primary, Yadav, Rachita, additional, Penney, Ellen B., additional, Murcar, Micaela G., additional, Correia, Kevin, additional, Gillis, Tammy, additional, Fernandez-Cerado, Cara, additional, Velasco-Andrada, M. Salvie, additional, Legarda, G. Paul, additional, Ganza-Bautista, Niecy G., additional, Lagarde, J. Benedict B., additional, Acu&ntildea, Patrick J, additional, Multhaupt-Buell, Trisha, additional, Aldykiewicz, Gabrielle, additional, Supnet, Melanie L., additional, DeGuzman, Jan K., additional, Go, Criscely, additional, Sharma, Nutan, additional, Munoz, Edwin L., additional, Ang, Mark C., additional, Diesta, Cid Czarina E., additional, Bragg, D. Cristopher, additional, Ozelius, Laurie J., additional, and Wheeler, Vanessa C., additional

Published
2022
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33. Dystonia-specific mutations in THAP1 alter transcription of genes associated with neurodevelopment and myelin

Author

Domingo, Aloysius, primary, Yadav, Rachita, additional, Shah, Shivangi, additional, Hendriks, William T., additional, Erdin, Serkan, additional, Gao, Dadi, additional, O’Keefe, Kathryn, additional, Currall, Benjamin, additional, Gusella, James F., additional, Sharma, Nutan, additional, Ozelius, Laurie J., additional, Ehrlich, Michelle E., additional, Talkowski, Michael E., additional, and Bragg, D. Cristopher, additional

Published
2021
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34. Can Machine Learning Models Predict Asparaginase-associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia

Author

Nielsen, Rikke L., primary, Wolthers, Benjamin O., additional, Helenius, Marianne, additional, Albertsen, Birgitte K., additional, Clemmensen, Line, additional, Nielsen, Kasper, additional, Kanerva, Jukka, additional, Niinimäki, Riitta, additional, Frandsen, Thomas L., additional, Attarbaschi, Andishe, additional, Barzilai, Shlomit, additional, Colombini, Antonella, additional, Escherich, Gabriele, additional, Aytan-Aktug, Derya, additional, Liu, Hsi-Che, additional, Möricke, Anja, additional, Samarasinghe, Sujith, additional, van der Sluis, Inge M., additional, Stanulla, Martin, additional, Tulstrup, Morten, additional, Yadav, Rachita, additional, Zapotocka, Ester, additional, Schmiegelow, Kjeld, additional, and Gupta, Ramneek, additional

Published
2021
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36. GnRH Neurogeneration from Human Stem Cell

Author

Keen, Kim, Petersen, Andrew, Figueroa, Alexander, Fordyce, Benjamin, Shin, Jaeweon, Yadav, Rachita, Erdin, Serkan, Pearce, Robert, Talkowski, Michael E., Bhattacharyya, Anita, and Terasawa, Ei

Abstract

Supplementary figures and tables supporting the main text of paper to be published in Endocrinology, including a large number of Excel files from transcriptome analysis by RNAseq obtained from human induced pluripotent and embryonic stem cell differentiation into GnRH neurons.

Published
2021
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37. Novel variation and de novo mutation rates in population-wide de novo assembled Danish trios

Author

Besenbacher, Søren, Liu, Siyang, Izarzugaza, José M. G., Grove, Jakob, Belling, Kirstine, Bork-Jensen, Jette, Huang, Shujia, Als, Thomas D., Li, Shengting, Yadav, Rachita, Rubio-García, Arcadio, Lescai, Francesco, Demontis, Ditte, Rao, Junhua, Ye, Weijian, Mailund, Thomas, Friborg, Rune M., Pedersen, Christian N. S., Xu, Ruiqi, Sun, Jihua, Liu, Hao, Wang, Ou, Cheng, Xiaofang, Flores, David, Rydza, Emil, Rapacki, Kristoffer, Damm Sørensen, John, Chmura, Piotr, Westergaard, David, Dworzynski, Piotr, Sørensen, Thorkild I. A., Lund, Ole, Hansen, Torben, Xu, Xun, Li, Ning, Bolund, Lars, Pedersen, Oluf, Eiberg, Hans, Krogh, Anders, Børglum, Anders D., Brunak, Søren, Kristiansen, Karsten, Schierup, Mikkel H., Wang, Jun, Gupta, Ramneek, Villesen, Palle, and Rasmussen, Simon

Published
2015
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39. 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, 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 diseases. 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 such as 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, and 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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40. Sequencing and de novo assembly of 150 genomes from Denmark as a population reference

Author

Maretty, Lasse, Jensen, Jacob Malte, Petersen, Bent, Sibbesen, Jonas Andreas, Liu, Siyang, Villesen, Palle, Skov, Laurits, Belling, Kirstine, Theil Have, Christian, Izarzugaza, Jose M. G., Grosjean, Marie, Bork-Jensen, Jette, Grove, Jakob, Als, Thomas D., Huang, Shujia, Chang, Yuqi, Xu, Ruiqi, Ye, Weijian, Rao, Junhua, Guo, Xiaosen, Sun, Jihua, Cao, Hongzhi, Ye, Chen, van Beusekom, Johan, Espeseth, Thomas, Flindt, Esben, Friborg, Rune M., Halager, Anders E., Le Hellard, Stephanie, Hultman, Christina M., Lescai, Francesco, Li, Shengting, Lund, Ole, Lngren, Peter, Mailund, Thomas, Matey-Hernandez, Maria Luisa, Mors, Ole, Pedersen, Christian N. S., Sicheritz-Pontn, Thomas, Sullivan, Patrick, Syed, Ali, Westergaard, David, Yadav, Rachita, Li, Ning, Xu, Xun, Hansen, Torben, Krogh, Anders, Bolund, Lars, Srensen, Thorkild I. A., Pedersen, Oluf, Gupta, Ramneek, Rasmussen, Simon, Besenbacher, Sren, Brglum, Anders D., Wang, Jun, Eiberg, Hans, Kristiansen, Karsten, Brunak, Sren, and Schierup, Mikkel Heide

Subjects
DNA sequencing -- Methods, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Lasse Maretty [1]; Jacob Malte Jensen [2, 3]; Bent Petersen [4]; Jonas Andreas Sibbesen [1]; Siyang Liu [1, 5]; Palle Villesen [2, 3, 6]; Laurits Skov [2, 3]; Kirstine [...]

Published
2017
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44. Assembly and analysis of 100 full MHC haplotypes from the Danish population

Author

Jensen, Jacob M., Villesen, Palle, Friborg, Rune M., Mailund, Thomas, Besenbacher, Søren, Sørensen, Lasse Maretty, Petersen, Bent, Sibbesen, Jonas Andreas, Liu, Siyang, Skov, Laurits, Belling, Kirstine G, Have, Christian Theil, Izarzugaza, Jose M. G., Grosjean, Marie, Bork-Jensen, Jette, Grove, Jakob, Als, Thomas D., Huang, Shujia, Chang, Yuqi, Xu, Ruiqi, Ye, Weijian, Rao, Junhua, Guo, Xiaosen, Sun, Jihua, Cao, Hongzhi, Ye, Chen, Beusekom, Johan V., Espeseth, Thomas, Flindt, Esben, Halager, Anders E., Hellard, Stephanie Le, Hultman, Christina M., Lescai, Francesco, Li, Shengting, Lund, Ole, Løngren, Peter, Matey-Hernandez, Maria Luisa, Mors, Ole, Pedersen, Christian N. S., Sicheritz-Pontén, Thomas, Sullivan, Patrick, Syed, Ali, Westergaard, David, Yadav, Rachita, Li, Ning, Xu, Xun, Hansen, Torben, Bolund, Lars, Krogh, Anders, Sørensen, Thorkild I. A., Pedersen, Oluf Borbye, Gupta, Ramneek, Rasmussen, Simon, Børglum, Anders D., Wang, Jun, Eiberg, Hans Rudolf Lytchoff, Kristiansen, Karsten, Brunak, Søren, and Schierup, Mikkel Heide

Subjects
Resource, 0301 basic medicine, Linkage disequilibrium, Denmark, Human leukocyte antigen, Biology, Balancing selection, Major histocompatibility complex, Polymorphism, Single Nucleotide, Genome, Linkage Disequilibrium, Major Histocompatibility Complex, 03 medical and health sciences, 0302 clinical medicine, Journal Article, Genetics, Humans, Alleles, Genetics (clinical), Haplotype, Chromosome Mapping, Genetic Variation, Genetics, Population, 030104 developmental biology, Haplotypes, Evolutionary biology, biology.protein, 030217 neurology & neurosurgery, Imputation (genetics), Reference genome
Abstract

Genes in the major histocompatibility complex (MHC, also known as HLA) play a critical role in the immune response and variation within the extended 4-Mb region shows association with major risks of many diseases. Yet, deciphering the underlying causes of these associations is difficult because the MHC is the most polymorphic region of the genome with a complex linkage disequilibrium structure. Here, we reconstruct full MHC haplotypes from de novo assembled trios without relying on a reference genome and perform evolutionary analyses. We report 100 full MHC haplotypes and call a large set of structural variants in the regions for future use in imputation with GWAS data. We also present the first complete analysis of the recombination landscape in the entire region and show how balancing selection at classical genes have linked effects on the frequency of variants throughout the region.

Published
2017

45. Trypsin encoding PRSS1-PRSS2 variation influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report

Author

Wolthers, Benjamin O., Frandsen, Thomas L., Patel, Chirag J, Abaji, Rachid, Attarbaschi, Andishe, Barzilai, Shlomit, Colombini, Antonella, Escherich, Gabriele, Grosjean, Marie, Krajinovic, Maja, Larsen, Eric, Liang, Der-Cherng, Möricke, Anja, Rasmussen, Kirsten K., Samarasinghe, Sujith, Silverman, Lewis B., van der Sluis, Inge M., Stanulla, Martin, Tulstrup, Morten, Yadav, Rachita, Yang, Wenjian, Zapotocka, Ester, Gupta, Ramneek, Schmiegelow, Kjeld, Wolthers, Benjamin O., Frandsen, Thomas L., Patel, Chirag J, Abaji, Rachid, Attarbaschi, Andishe, Barzilai, Shlomit, Colombini, Antonella, Escherich, Gabriele, Grosjean, Marie, Krajinovic, Maja, Larsen, Eric, Liang, Der-Cherng, Möricke, Anja, Rasmussen, Kirsten K., Samarasinghe, Sujith, Silverman, Lewis B., van der Sluis, Inge M., Stanulla, Martin, Tulstrup, Morten, Yadav, Rachita, Yang, Wenjian, Zapotocka, Ester, Gupta, Ramneek, and Schmiegelow, Kjeld

Abstract

Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten acute lymphoblastic leukemia trial groups contributed remission samples from patients aged 1.0-17.9 years and treated from 2000-2016. Cases were defined (n=244) by at least two of the following criteria: i) abdominal pain, ii) pancreatic enzymes >3 x upper normal limit, iii) imaging compatible with asparaginase-associated pancreatitis. Controls (n=1320) completed intended asparaginase therapy, 78% receiving ≥8 pegylated-asparaginase injections, without developing aparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association (OR=3.75; P=5.2x10-8). Moreover, rs13228878 (OR=0.61; P=7.1x10-6) and rs10273639 (OR=0.62; P=1.1x10-5) on 7q34 showed significant association. A Dana Farber Cancer Institute ALL Consortium cohort consisting of patients treated protocols from 1987-2004 (controls=285, cases=33), and the Children's Oncology Group AALL0232 cohort (controls=2653, cases=76) were available as replication cohorts for the 20q13.2 and 7q34 variants, respectively. While rs62228256 was not validated (P=0.86), both rs13228878 (P=0.03) and rs10273639 (P=0.04) were. rs13228878 and rs10273639 are in high linkage disequilibrium (r2=0.94) and associated with elevated expression of the trypsinogen encoding PRSS1 gene and are known risk variants for alcohol-associated and sporadic pancreatitis in adults. Intra-pancreatic trypsinogen cleavage to proteolytic trypsin induces autodigestion and pancreatitis. Asparaginase-associated pancreatitis and non-asparaginase associated pancreatitis shares genetic predisposition and targeting the trypsinogen activation pathway may enable identification of effective interventions towards asparaginase-associated pancreatitis.

Published
2019

46. Benchmarking the HLA typing performance of Polysolver and Optitype in 50 Danish parental trios

Author

Matey-Hernandez, María Luisa, Maretty, Lasse, Jensen, Jacob Malte, Petersen, Bent, Andreas Sibbesen, Jonas, Liu, Siyang, Villesen, Palle, Skov, Laurits, Belling, Kirstine, Theil Have, Christian, Gonzalez-Izarzugaza, Jose Maria, Grosjean, Marie, Bork-Jensen, Jette, Grove, Jakob, Als, Thomas D., Huang, Shujia, Chang, Yuqi, Xu, Ruiqi, Ye, Weijian, Rao, Junhua, Guo, Xiaosen, Sun, Jihua, Cao, Hongzhi, Ye, Chen, Beusekom, Johan v., Espeseth, Thomas, Flindt, Esben N., Friborg, Rune M., Halager, Anders Egerup, Le Hellard, Stephanie, Hultman, Christina M., Lescai, Francesco, Li, Shengting, Lund, Ole, Løngren, Peter, Mailund, Thomas, Mors, Ole, Pedersen, Christian N. S., Sicheritz-Pontén, Thomas, Sullivan, Patrick F., Ali , Syed, Westergaard, David, Yadav, Rachita, Li, Ning, Xu, Xun, Hansen, Torben, Krogh, Anders, Bolund, Lars, Sørensen, Thorkild I. A., Pedersen, Oluf, Gupta, Ramneek, Besenbacher, Søren, Børglum, Anders D., Wang, Jun, Eiberg, Hans, Kristiansen, Karsten, Brunak, Søren, Schierup, Mikkel Heide, and Izarzugaza, Jose M. G.

Subjects
0301 basic medicine, Parents, Clinical genomics, Genotyping Techniques, Population genetics, Computational biology, Human leukocyte antigen, Biology, lcsh:Computer applications to medicine. Medical informatics, Biochemistry, Genome, Deep sequencing, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Structural Biology, HLA Antigens, Humans, HLA genotyping, Family, Allele, lcsh:QH301-705.5, Molecular Biology, Allele frequency, Whole genome sequencing, Sweden, Applied Mathematics, Histocompatibility Testing, Genomics, Computer Science Applications, Benchmarking, 030104 developmental biology, lcsh:Biology (General), 030220 oncology & carcinogenesis, NGS, lcsh:R858-859.7, DNA microarray, Prediction, Research Article
Abstract

BACKGROUND: The adaptive immune response intrinsically depends on hypervariable human leukocyte antigen (HLA) genes. Concomitantly, correct HLA phenotyping is crucial for successful donor-patient matching in organ transplantation. The cost and technical limitations of current laboratory techniques, together with advances in next-generation sequencing (NGS) methodologies, have increased the need for precise computational typing methods.RESULTS: We tested two widespread HLA typing methods using high quality full genome sequencing data from 150 individuals in 50 family trios from the Genome Denmark project. First, we computed descendant accuracies assessing the agreement in the inheritance of alleles from parents to offspring. Second, we compared the locus-specific homozygosity rates as well as the allele frequencies; and we compared those to the observed values in related populations. We provide guidelines for testing the accuracy of HLA typing methods by comparing family information, which is independent of the availability of curated alleles.CONCLUSIONS: Although current computational methods for HLA typing generally provide satisfactory results, our benchmark - using data with ultra-high sequencing depth - demonstrates the incompleteness of current reference databases, and highlights the importance of providing genomic databases addressing current sequencing standards, a problem yet to be resolved before benefiting fully from personalised medicine approaches HLA phenotyping is essential.

Published
2018

47. DYT-TUBB4A (DYT4 Dystonia): New Clinical and Genetic Observations.

Author

Bally, Julien F., Camargos, Sarah, Oliveira dos Santos, Camila, Kern, Drew S., Lee, Teresa, Pereira da Silva-Junior, Francisco, David Puga, Renato, Cardoso, Francisco, Reis Barbosa, Egberto, Yadav, Rachita, Ozelius, Laurie J., de Carvalho Aguiar, Patricia, Lang, Anthony E., Puga, Renato David, and Barbosa, Egberto Reis

Published
2021
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48. An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder.

Author

Werling, Donna, Werling, Donna, Brand, Harrison, An, Joon-Yong, Stone, Matthew, Zhu, Lingxue, Glessner, Joseph, Collins, Ryan, Dong, Shan, Layer, Ryan, Markenscoff-Papadimitriou, Eirene, Farrell, Andrew, Schwartz, Grace, Wang, Harold, Currall, Benjamin, Zhao, Xuefang, Dea, Jeanselle, Duhn, Clif, Erdman, Carolyn, Gilson, Michael, Yadav, Rachita, Handsaker, Robert, Kashin, Seva, Klei, Lambertus, Mandell, Jeffrey, Nowakowski, Tomasz, Liu, Yuwen, Pochareddy, Sirisha, Smith, Louw, Waterman, Matthew, He, Xin, Sestan, Nenad, McCarroll, Steven, Neale, Benjamin, Coon, Hilary, Buxbaum, Joseph, Daly, Mark, State, Matthew, Quinlan, Aaron, Marth, Gabor, Roeder, Kathryn, Devlin, Bernie, Talkowski, Michael, Kriegstein, Arnold, Rubenstein, John, Sanders, Stephan, Willsey, Arthur, Walker, Michael, Werling, Donna, Werling, Donna, Brand, Harrison, An, Joon-Yong, Stone, Matthew, Zhu, Lingxue, Glessner, Joseph, Collins, Ryan, Dong, Shan, Layer, Ryan, Markenscoff-Papadimitriou, Eirene, Farrell, Andrew, Schwartz, Grace, Wang, Harold, Currall, Benjamin, Zhao, Xuefang, Dea, Jeanselle, Duhn, Clif, Erdman, Carolyn, Gilson, Michael, Yadav, Rachita, Handsaker, Robert, Kashin, Seva, Klei, Lambertus, Mandell, Jeffrey, Nowakowski, Tomasz, Liu, Yuwen, Pochareddy, Sirisha, Smith, Louw, Waterman, Matthew, He, Xin, Sestan, Nenad, McCarroll, Steven, Neale, Benjamin, Coon, Hilary, Buxbaum, Joseph, Daly, Mark, State, Matthew, Quinlan, Aaron, Marth, Gabor, Roeder, Kathryn, Devlin, Bernie, Talkowski, Michael, Kriegstein, Arnold, Rubenstein, John, Sanders, Stephan, Willsey, Arthur, and Walker, Michael

Abstract

Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here we present a comparable framework to evaluate rare and de novo noncoding single-nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism, the contribution of de novo noncoding variation is probably modest in comparison to that of de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple-testing burden.

Published
2018

49. Transcriptome analysis of root-knot nematode (Meloidogyne incognita)-infected tomato (Solanum lycopersicum) roots reveals complex gene expression profiles and metabolic networks of both host and nematode during susceptible and resistance responses

Author

Shukla, Neha, Yadav, Rachita, Kaur, Pritam, Rasmussen, Simon, Goel, Shailendra, Agarwal, Manu, Jagannath, Arun, Gupta, Ramneek, Kumar, Amar, Shukla, Neha, Yadav, Rachita, Kaur, Pritam, Rasmussen, Simon, Goel, Shailendra, Agarwal, Manu, Jagannath, Arun, Gupta, Ramneek, and Kumar, Amar

Abstract

Root knot nematodes (RKNs, Meloidogyne incognita) are economically important endoparasites having a wide-host range. We have taken a comprehensive transcriptomic approach to investigate the expression of both tomato and RKN genes in tomato roots at five infection time intervals from susceptible plants and two infection time intervals from resistant plants, grown under soil conditions. Differentially expressed genes during susceptible (1827-tomato, 462-RKN) and resistance (25-tomato, 160-RKN) interactions were identified. In susceptible responses, tomato genes involved in cell wall structure, development, primary and secondary metabolites and defense signalling pathways along with RKN genes involved in host parasitism, development and defense are discussed. In resistance responses, tomato genes involved in secondary metabolite and hormone-mediated defense responses along with RKN genes involved in starvation stress-induced apoptosis are discussed. Also, forty novel differentially expressed RKN genes encoding secretory proteins were identified. Our findings, for the first time, provide novel insights into temporal regulation of genes involved in various biological processes from tomato and RKN simultaneously during susceptible and resistance responses, and reveals involvement of a complex network of biosynthetic pathways during disease development.

Published
2018

50. Analysis of 62 hybrid assembled human Y chromosomes exposes rapid structural changes and high rates of gene conversion

Author

Gonzalez-Izarzugaza, Jose Maria, Skov, Laurits, Maretty, Lasse, Jensen, Jacob Malte, Petersen, Bent, Andreas Sibbesen, Jonas, Liu, Siyang, Villesen, Palle, Belling, Kirstine González-Izarzugaza, Theil Have, Christian, Grosjean, Marie, Bork-Jensen, Jette, Grove, Jakob, Als, Thomas D., Huang, Shujia, Chang, Yuqi, Xu, Ruiqi, Ye, Weijian, Rao, Junhua, Guo, Xiaosen, Sun, Jihua, Cao, Hongzhi, Ye, Chen, van Beusekom, Johan, Espeseth, Thomas, Flindt, Esben, Friborg, Rune M., Halager, Anders E., Le Hellard, Stephanie, Hultman, Christina M., Lescai, Francesco, Li, Shengting, Lund, Ole, Løngren, Peter, Mailund, Thomas, Matey-Hernandez, María Luisa, Mors, Ole, Pedersen, Christian N. S., Sicheritz-Pontén, Thomas, Sullivan, Patrick F., Qaswar Ali Shah, Syed, Westergaard, David, Yadav, Rachita, Li, Ning, Xu, Xun, Hansen, Torben, Krogh, Anders, Bolund, Lars, Sørensen, Thorkild I. A., Pedersen, Oluf, Gupta, Ramneek, Rasmussen, Simon, Besenbacher, Søren, Børglum, Anders D., Wang, Jun, Eiberg, Hans, Kristiansen, Karsten, Brunak, Søren, and Schierup, Mikkel Heide

Subjects
0301 basic medicine, Male, Cancer Research, Inverted repeat, Denmark, Biochemistry, Haplogroup, Fathers, 0302 clinical medicine, INDEL Mutation, Heterochromatin, MUTATION, Genetics (clinical), Phylogeny, POPULATION, Data Management, Genetics, Sex Chromosomes, Insertion Mutation, Chromosome Biology, Phylogenetic Analysis, Y Chromosomes, Nucleic acids, Phylogenetics, GENOME, ALIGNMENT, Deletion Mutation, Mutation (genetic algorithm), Research Article, EXPRESSION, Computer and Information Sciences, lcsh:QH426-470, DNA recombination, Gene Conversion, Biology, Y chromosome, Polymorphism, Single Nucleotide, SEQUENCE, Chromosomes, Nuclear Family, Evolution, Molecular, 03 medical and health sciences, Humans, Evolutionary Systematics, Gene conversion, Insertion, Indel, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Infertility, Male, Taxonomy, COPY NUMBER VARIATION, Evolutionary Biology, Chromosomes, Human, Y, Population Biology, MALE-INFERTILITY, Inverted Repeat Sequences, Biology and Life Sciences, Cell Biology, DNA, POLYMORPHISM, EVOLUTION, lcsh:Genetics, 030104 developmental biology, Evolutionary biology, Mutation, Haplogroups, 030217 neurology & neurosurgery, Population Genetics, Reference genome
Abstract

The human Y-chromosome does not recombine across its male-specific part and is therefore an excellent marker of human migrations. It also plays an important role in male fertility. However, its evolution is difficult to fully understand because of repetitive sequences, inverted repeats and the potentially large role of gene conversion. Here we perform an evolutionary analysis of 62 Y-chromosomes of Danish descent sequenced using a wide range of library insert sizes and high coverage, thus allowing large regions of these chromosomes to be well assembled. These include 17 father-son pairs, which we use to validate variation calling. Using a recent method that can integrate variants based on both mapping and de novo assembly, we genotype 10898 SNVs and 2903 indels (max length of 27241 bp) in our sample and show by father-son concordance and experimental validation that the non-recurrent SNP and indel variation on the Y chromosome tree is called very accurately. This includes variation called in a 0.9 Mb centromeric heterochromatic region, which is by far the most variable in the Y chromosome. Among the variation is also longer sequence-stretches not present in the reference genome but shared with the chimpanzee Y chromosome. We analyzed 2.7 Mb of large inverted repeats (palindromes) for variation patterns among the two palindrome arms and identified 603 mutation and 416 gene conversions events. We find clear evidence for GC-biased gene conversion in the palindromes (and a balancing AT mutation bias), but irrespective of this, also a strong bias towards gene conversion towards the ancestral state, suggesting that palindromic gene conversion may alleviate Muller’s ratchet. Finally, we also find a large number of large-scale gene duplications and deletions in the palindromic regions (at least 24) and find that such events can consist of complex combinations of simultaneous insertions and deletions of long stretches of the Y chromosome., Author summary The Y chromosome is extraordinary in many respects; it is non-recombining along most of its length, it carries many testis-expressed genes that are often found in palindromes and thus in several copies, and it is generally highly repetitive with very few unique genes. Its evolutionary process is not well understood in general because short-read mapping in such complex sequence is difficult. We combine de novo assembly and mapping to investigate evolution in more than 60% of the length of 62 Y chromosomes of Danish descent. We find that Y chromosome evolution is very dynamic even among the set of closely related Y chromosomes in Denmark with many cases of complex duplications and deletions of large regions including whole genes, clear evidence of GC-biased gene conversion in the palindromes and a tendency for gene conversion to revert mutations to their ancestral state.

Published
2017

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