Citations 2
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.
Early‐life decline in neurogenesis markers and age‐related changes of TrkB splice variant expression in the human subependymal zone
Weissleder, Christin , Kondo, Mari , Yang, Chunhui , Fung, Samantha J., Rothmond, Debora A. , Wong, Matthew Wai Kin , Halliday, Glenda M. , Herman, Mary M., Weickert, Cynthia Shannon , Kleinman, Joel E , Webster, Maree J. , Halliday, Glenda , Weissleder, Christin
European Journal of Neuroscience | June 14, 2017 | Volume: 46 | Issue: 2 | Pages: 1768-1778
AbstractNeurogenesis in the subependymal zone (SEZ) declines across the human lifespan, and reduced local neurotrophic support is speculated to be a contributing factor. While tyrosine receptor kinase B (TrkB) signalling is critical for neuronal differentiation, maturation and survival, little is known about subependymal TrkB expression changes during postnatal human life. In this study, we used quantitative PCR and in situ hybridisation to determine expression of the cell proliferation marker Ki67, the immature neuron marker doublecortin (DCX) and both full‐length (TrkB‐TK+) and truncated TrkB receptors (TrkB‐TK‐) in the human SEZ from infancy to middle age (n = 26–35, 41 days to 43 years). We further measured TrkB‐TK+ and TrkB‐TK‐ mRNAs in the SEZ from young adulthood into ageing (n = 50, 21–103 years), and related their transcript levels to neurogenic and glial cell markers. Ki67, DCX and both TrkB splice variant mRNAs significantly decreased in the SEZ from infancy to middle age. In contrast, TrkB‐TK‐ mRNA increased in the SEZ from young adulthood into ageing, whereas TrkB‐TK+ mRNA remained stable. TrkB‐TK‐ mRNA positively correlated with expression of neural precursor (glial fibrillary acidic protein delta and achaete‐scute homolog 1) and glial cell markers (vimentin and pan glial fibrillary acidic protein). TrkB‐TK+ mRNA positively correlated with expression of neuronal cell markers (DCX and tubulin beta 3 class III). Our results indicate that cells residing in the human SEZ maintain their responsiveness to neurotrophins; however, this capability may change across postnatal life. We suggest that TrkB splice variants may differentially influence neuronal and glial differentiation in the human SEZ.