Citations 3
Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes
Maury, Eduardo A. , Jones, Attila , Seplyarskiy, Vladimir , Nguyen, Thanh Thanh L. , Rosenbluh, Chaggai , Bae, Taejong, Wang, Yifan , Abyzov, Alexej , Khoshkhoo, Sattar , Chahine, Yasmine, Zhao, Sijing , Venkatesh, Sanan , Root, Elise, Voloudakis, Georgios , Roussos, Panagiotis , Network‡, Brain Somatic Mosaicism, Brennand, Kristen , Reilly, Steven K. , Sunyaev, Shamil , Chess, Andrew , Bae, Taejeong , Moran, John V. , Zhou, Weichen , Zhu, Xiaowei , Bizzotto, Sara , Galor, Alon , Yang, Xiaoxu , Bae, Taejeong , Park, Peter J , Akbarian, Schahram , Brennand, Kristen , Reilly, Steven , Lee, Eunjung A , Sunyaev, Shamil R , Walsh, Christopher A , Chess, Andrew , Nguyen, Thanh Thanh L. , Abyzov, Alexej , Wang, Yifan , Voloudakis, Georgios , Maury, Eduardo A. , Jones, Attila , Seplyarskiy, Vladimir , Root, Elise , Network‡, Brain Somatic Mosaicism, Park, Peter J. , Akbarian, Schahram , Walsh, Christopher A.
Science | October 10, 2024 | Volume: 386 | Issue: 6718 | Pages: 217-224
Germline mutations modulate the risk of developing schizophrenia (SCZ). Much less is known about the role of mosaic somatic mutations in the context of SCZ. Deep (239×) whole-genome sequencing (WGS) of brain neurons from 61 SCZ cases and 25 controls postmortem identified mutations occurring during prenatal neurogenesis. SCZ cases showed increased somatic variants in open chromatin, with increased mosaic CpG transversions (CpG>GpG) and T>G mutations at transcription factor binding sites (TFBSs) overlapping open chromatin, a result not seen in controls. Some of these variants alter gene expression, including SCZ risk genes and genes involved in neurodevelopment. Although these mutational processes can reflect a difference in factors indirectly involved in disease, increased somatic mutations at developmental TFBSs could also potentially contribute to SCZ.
Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability
Bae, Taejeong , Fasching, Liana , Wang, Yifan , Shin, Joo Heon , Šuvakov, Milovan , Jang, Yeongjun , Norton, Scott , Dias, Caroline , Mariani, Jessica , Jourdon, Alexandre , Wu, Feinan , Panda, Arijit , Pattni, Reenal , Chahine, Yasmine, Yeh, Rebecca C., Roberts, Rosalinda C. , Hüttner, Anita , Straub, Richard E. , Walsh, Christopher A. , Network§, Brain Somatic Mosaicism, Urban, Alexander E. , Weinberger, Daniel R. , Vaccarino, Flora M. , Abyzov, Alexej , Šestan, Nenad , Moran, John V. , Gleeson, Joseph G. , Mathern, Gary W. , Courchesne, Eric, Chess, Andrew , Bizzotto, Sara , D’Gama, Alissa M. , Hill, Robert , Kim, Sonia , Miller, Michael , Borges-Monroy, Rebeca , Bohrson, Craig L. , Galor, Alon , Kwon, Min‐Seok , Luquette, Joe, Sherman, Maxwell A. , Rosenbluh, Chaggai , Cho, Sean, Thorpe, Jeremy , McConnell, Michael J. , Narurkar, Rujuta, Paquola, Apuã C.M. , Shin, Jooheon, Molitor, Cindy, Peters, Mette A. , Linker, Sara B. , Reed, Patrick , Wang, Meiyan , Zhou, Bo , Amero, Aitor Serres, Lobón, Irene , Moruno, Manuel Solis, Pérez, Raquel García, Povolotskaya, Inna , Soriano, Eduardo , Antaki, Danny , Averbuj, Dan, Ball, Laurel, Yang, Xiaoxu , Chung, Changuk , Emery, Sarah B., Flasch, Diane A. , Sun, Chen , Zhao, Xuefang , Zhou, Weichen , Frisbie, Trenton J., Cherskov, Adriana , Pochareddy, Sirisha , Kleinman, Joel E , Hyde, Thomas M , Straub, Richard E , Walsh, Christopher A , Urban, Alexander E , Leckman, James F , Weinberger, Daniel R , Vaccarino, Flora M , Abyzov, Alexej , Shin, Joo Heon , Zhou, Bo , Šuvakov, Milovan , Bae, Taejeong , Wang, Yifan , Jang, Yeongjun , Network§, Brain Somatic Mosaicism, Leckman, James F. , Park, Peter J. , Gage, Fred H , Gleeson, Joseph G. , Courchesne, Eric, Roy, Subhojit , Akbarian, Schahram , Coulter, Michael E. , Ganz, Javier , Hill, Robert, Huang, August Yue , Khoshkhoo, Sattar , Lee, Alice , Lodato, Michael A. , Maury, Eduardo A. , Rodin, Rachel E. , Zhou, Zinan , Chu, Chong , Cortés‐Ciriano, Isidro , Dou, Yanmei , Gulhan, D. , Viswanadham, Vinay , Jones, Attila , Langmead, Ben , Erwin, Jennifer A. , Jaffe, Andrew E. , Zhu, Xiaowei , Juan, David , Marquès‐Bonet, Tomàs , Breuss, Martin W. , Kidd, Jeffrey M. , Kopera, Huira C. , Kwan, Kenneth Y , Mills, Ryan E. , Moldovan, John B. , Scuderi, Soraya
Science | July 28, 2022 | Volume: 377 | Issue: 6605 | Pages: 511-517
We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions. Somatic duplications, likely arising during development, were found in ~5% of normal and diseased brains, reflecting background mutagenesis. Brains with autism were associated with mutations creating putative transcription factor binding motifs in enhancer-like regions in the developing brain. The top-ranked affected motifs corresponded to MEIS (myeloid ectopic viral integration site) transcription factors, suggesting a potential link between their involvement in gene regulation and autism.
Intersection of diverse neuronal genomes and neuropsychiatric disease: The Brain Somatic Mosaicism Network
McConnell, Michael J. , Moran, John V. , Abyzov, Alexej , Akbarian, Schahram , Bae, Taejeong , Cortés‐Ciriano, Isidro , Erwin, Jennifer A. , Fasching, Liana , Flasch, Diane A. , Freed, Donald , Ganz, Javier , Jaffe, Andrew E. , Kwon, Min‐Seok , Lodato, Michael A. , Mills, Ryan E. , Paquola, Apuã C.M. , Rodin, Rachel E. , Rosenbluh, Chaggai , Šestan, Nenad , Sherman, Maxwell A. , Shin, Joo Heon , Song, Saera , Straub, Richard E. , Thorpe, Jeremy , Weinberger, Daniel R. , Urban, Alexander E. , Zhou, Bo , Lehner, Thomas , Senthil, Geetha , Chess, Andrew , Courchesne, Eric , Gleeson, Joseph G. , Kidd, Jeffrey M. , Park, Peter J., Pevsner, Jonathan , Vaccarino, Flora M. , Network, Brain Somatic Mosaicism, Bekiranov, Stefan , Bohrson, Craig L. , Burbulis, Ian , Chronister, William D., Coppola, Gianfilippo , Daily, Kenneth , D’Gama, Alissa M. , Emery, Sarah B., Frisbie, Trenton J., Gao, Tianliuyun , Gulyás-Kovács, Attila, Haakenson, Mark F., Keil, Jason M. , Lam, Mandy M. , Mathern, Gary W. , Omberg, Larsson , Peters, Mette A. , Pochareddy, Sirisha , Pramparo, Tiziano , Sanavia, Tiziana , Wang, Meiyan , Wierman, Margaret E. , Wolpert, Matthew J., Woodworth, Mollie B. , Zhao, Xuefang , Zhou, Weichen , Kwan, Kenneth Y , Lodato, Michael A , Mills, Ryan E , Paquola, Apua C M , Rodin, Rachel E , Rosenbluh, Chaggai , Sestan, Nenad , Shin, Joo Heon , Song, Saera , Straub, Richard E , Urban, Alexander E , Zhou, Bo , Gage, Fred H , Lehner, Thomas , Senthil, Geetha , Chess, Andrew , Courchesne, Eric , Kidd, Jeffrey M , Pevsner, Jonathan , Vaccarino, Flora M , McConnell, Michael J. , Walsh, Christopher A. , Gleeson, Joseph G. , Network, Brain Somatic Mosaicism, Barton, Alison R. , Kopera, Huira C. , Lee, Eunjung A , Marquès‐Bonet, Tomàs , Moldovan, John B. , Oetjens, Matthew T. , Ratan, Aakrosh , Shi, Lei , Škarica, Mario , Wang, Jia , Wang, Yifan , Abyzov, Alexej , Bae, Taejeong , Akbarian, Schahram
Science | April 27, 2017 | Volume: 356 | Issue: 6336 | Pages: No page available
Single-cell diversity in the brain The cells that make up an organism may all start from one genome, but somatic mutations mean that somewhere along the line of development, an organism's individual cellular genomes diverge. McConnell et al. review the implications and causes of single-cell genomic diversity for brain function. Somatic mutations caused by mobile genetic elements or errors in DNA repair may underlie certain neuropsychiatric disorders. Science , this issue p. eaal1641