Search

Your search keyword '"AN, L."' showing total 72,962 results
Start Over Author "AN, L." Journal science
72,962 results on '"AN, L."'

1. Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program

Author

Verma, Anurag, Huffman, Jennifer E, Rodriguez, Alex, Conery, Mitchell, Liu, Molei, Ho, Yuk-Lam, Kim, Youngdae, Heise, David A, Guare, Lindsay, Panickan, Vidul Ayakulangara, Garcon, Helene, Linares, Franciel, Costa, Lauren, Goethert, Ian, Tipton, Ryan, Honerlaw, Jacqueline, Davies, Laura, Whitbourne, Stacey, Cohen, Jeremy, Posner, Daniel C, Sangar, Rahul, Murray, Michael, Wang, Xuan, Dochtermann, Daniel R, Devineni, Poornima, Shi, Yunling, Nandi, Tarak Nath, Assimes, Themistocles L, Brunette, Charles A, Carroll, Robert J, Clifford, Royce, Duvall, Scott, Gelernter, Joel, Hung, Adriana, Iyengar, Sudha K, Joseph, Jacob, Kember, Rachel, Kranzler, Henry, Kripke, Colleen M, Levey, Daniel, Luoh, Shiuh-Wen, Merritt, Victoria C, Overstreet, Cassie, Deak, Joseph D, Grant, Struan FA, Polimanti, Renato, Roussos, Panos, Shakt, Gabrielle, Sun, Yan V, Tsao, Noah, Venkatesh, Sanan, Voloudakis, Georgios, Justice, Amy, Begoli, Edmon, Ramoni, Rachel, Tourassi, Georgia, Pyarajan, Saiju, Tsao, Philip, O'Donnell, Christopher J, Muralidhar, Sumitra, Moser, Jennifer, Casas, Juan P, Bick, Alexander G, Zhou, Wei, Cai, Tianxi, Voight, Benjamin F, Cho, Kelly, Gaziano, J Michael, Madduri, Ravi K, Damrauer, Scott, and Liao, Katherine P

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, 2.1 Biological and endogenous factors, Mental health, Humans, Male, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Longitudinal Studies, Polymorphism, Single Nucleotide, Quantitative Trait Loci, United States, United States Department of Veterans Affairs, Veterans, Female, General Science & Technology
Abstract

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third (n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.

Published
2024

2. Cross-ancestry atlas of gene, isoform, and splicing regulation in the developing human brain

Author

Wen, Cindy, Margolis, Michael, Dai, Rujia, Zhang, Pan, Przytycki, Pawel F, Vo, Daniel D, Bhattacharya, Arjun, Matoba, Nana, Tang, Miao, Jiao, Chuan, Kim, Minsoo, Tsai, Ellen, Hoh, Celine, Aygün, Nil, Walker, Rebecca L, Chatzinakos, Christos, Clarke, Declan, Pratt, Henry, Peters, Mette A, Gerstein, Mark, Daskalakis, Nikolaos P, Weng, Zhiping, Jaffe, Andrew E, Kleinman, Joel E, Hyde, Thomas M, Weinberger, Daniel R, Bray, Nicholas J, Sestan, Nenad, Geschwind, Daniel H, Roeder, Kathryn, Gusev, Alexander, Pasaniuc, Bogdan, Stein, Jason L, Love, Michael I, Pollard, Katherine S, Liu, Chunyu, Gandal, Michael J, Akbarian, Schahram, Abyzov, Alexej, Ahituv, Nadav, Arasappan, Dhivya, Almagro Armenteros, Jose Juan, Beliveau, Brian J, Bendl, Jaroslav, Berretta, Sabina, Bharadwaj, Rahul A, Bicks, Lucy, Brennand, Kristen, Capauto, Davide, Champagne, Frances A, Chatterjee, Tanima, Chatzinakos, Chris, Chen, Yuhang, Chen, H Isaac, Cheng, Yuyan, Cheng, Lijun, Chess, Andrew, Chien, Jo-fan, Chu, Zhiyuan, Clement, Ashley, Collado-Torres, Leonardo, Cooper, Gregory M, Crawford, Gregory E, Davila-Velderrain, Jose, Deep-Soboslay, Amy, Deng, Chengyu, DiPietro, Christopher P, Dracheva, Stella, Drusinsky, Shiron, Duan, Ziheng, Duong, Duc, Dursun, Cagatay, Eagles, Nicholas J, Edelstein, Jonathan, Emani, Prashant S, Fullard, John F, Galani, Kiki, Galeev, Timur, Gaynor, Sophia, Girdhar, Kiran, Goes, Fernando S, Greenleaf, William, Grundman, Jennifer, Guo, Hanmin, Guo, Qiuyu, Gupta, Chirag, Hadas, Yoav, Hallmayer, Joachim, Han, Xikun, Haroutunian, Vahram, Hawken, Natalie, He, Chuan, Henry, Ella, Hicks, Stephanie C, Ho, Marcus, Ho, Li-Lun, Hoffman, Gabriel E, Huang, Yiling, Huuki-Myers, Louise A, and Hwang, Ahyeon

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Biological Psychology, Psychology, Mental Illness, Mental Health, Human Genome, Neurosciences, Brain Disorders, Mental health, Humans, Alternative Splicing, Atlases as Topic, Autism Spectrum Disorder, Brain, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Genome-Wide Association Study, Protein Isoforms, Quantitative Trait Loci, Schizophrenia, Transcriptome, Mental Disorders, PsychENCODE Consortium†, PsychENCODE Consortium, General Science & Technology
Abstract

Neuropsychiatric genome-wide association studies (GWASs), including those for autism spectrum disorder and schizophrenia, show strong enrichment for regulatory elements in the developing brain. However, prioritizing risk genes and mechanisms is challenging without a unified regulatory atlas. Across 672 diverse developing human brains, we identified 15,752 genes harboring gene, isoform, and/or splicing quantitative trait loci, mapping 3739 to cellular contexts. Gene expression heritability drops during development, likely reflecting both increasing cellular heterogeneity and the intrinsic properties of neuronal maturation. Isoform-level regulation, particularly in the second trimester, mediated the largest proportion of GWAS heritability. Through colocalization, we prioritized mechanisms for about 60% of GWAS loci across five disorders, exceeding adult brain findings. Finally, we contextualized results within gene and isoform coexpression networks, revealing the comprehensive landscape of transcriptome regulation in development and disease.

Published
2024

3. An evolutionary epigenetic clock in plants

Author

Yao, N, Zhang, Z, Yu, L, Hazarika, R, Yu, C, Jang, H, Smith, LM, Ton, J, Liu, L, Stachowicz, JJ, Reusch, TBH, Schmitz, RJ, and Johannes, F

Subjects
Climate Change Impacts and Adaptation, Biological Sciences, Genetics, Plant Biology, Environmental Sciences, General Science & Technology
Abstract

Molecular clocks are the basis for dating the divergence between lineages over macroevolutionary timescales (~105 to 108 years). However, classical DNA-based clocks tick too slowly to inform us about the recent past. Here, we demonstrate that stochastic DNA methylation changes at a subset of cytosines in plant genomes display a clocklike behavior. This "epimutation clock" is orders of magnitude faster than DNA-based clocks and enables phylogenetic explorations on a scale of years to centuries. We show experimentally that epimutation clocks recapitulate known topologies and branching times of intraspecies phylogenetic trees in the self-fertilizing plant Arabidopsis thaliana and the clonal seagrass Zostera marina, which represent two major modes of plant reproduction. This discovery will open new possibilities for high-resolution temporal studies of plant biodiversity.

Published
2023

4. Comparative genomics of Balto, a famous historic dog, captures lost diversity of 1920s sled dogs

Author

Moon, Katherine L, Huson, Heather J, Morrill, Kathleen, Wang, Ming-Shan, Li, Xue, Srikanth, Krishnamoorthy, Lindblad-Toh, Kerstin, Svenson, Gavin J, Karlsson, Elinor K, Shapiro, Beth, Andrews, Gregory, Armstrong, Joel C, Bianchi, Matteo, Birren, Bruce W, Bredemeyer, Kevin R, Breit, Ana M, Christmas, Matthew J, Clawson, Hiram, Damas, Joana, Di Palma, Federica, Diekhans, Mark, Dong, Michael X, Eizirik, Eduardo, Fan, Kaili, Fanter, Cornelia, Foley, Nicole M, Forsberg-Nilsson, Karin, Garcia, Carlos J, Gatesy, John, Gazal, Steven, Genereux, Diane P, Goodman, Linda, Grimshaw, Jenna, Halsey, Michaela K, Harris, Andrew J, Hickey, Glenn, Hiller, Michael, Hindle, Allyson G, Hubley, Robert M, Hughes, Graham M, Johnson, Jeremy, Juan, David, Kaplow, Irene M, Keough, Kathleen C, Kirilenko, Bogdan, Koepfli, Klaus-Peter, Korstian, Jennifer M, Kowalczyk, Amanda, Kozyrev, Sergey V, Lawler, Alyssa J, Lawless, Colleen, Lehmann, Thomas, Levesque, Danielle L, Lewin, Harris A, Lind, Abigail, Mackay-Smith, Ava, Marinescu, Voichita D, Marques-Bonet, Tomas, Mason, Victor C, Meadows, Jennifer RS, Meyer, Wynn K, Moore, Jill E, Moreira, Lucas R, Moreno-Santillan, Diana D, Morrill, Kathleen M, Muntané, Gerard, Murphy, William J, Navarro, Arcadi, Nweeia, Martin, Ortmann, Sylvia, Osmanski, Austin, Paten, Benedict, Paulat, Nicole S, Pfenning, Andreas R, Phan, BaDoi N, Pollard, Katherine S, Pratt, Henry E, Ray, David A, Reilly, Steven K, Rosen, Jeb R, Ruf, Irina, Ryan, Louise, Ryder, Oliver A, Sabeti, Pardis C, Schäffer, Daniel E, Serres, Aitor, Smit, Arian FA, Springer, Mark, Srinivasan, Chaitanya, Steiner, Cynthia, Storer, Jessica M, Sullivan, Kevin AM, Sullivan, Patrick F, Sundström, Elisabeth, Supple, Megan A, and Swofford, Ross

Subjects
Agricultural, Veterinary and Food Sciences, Biological Sciences, Genetics, Animals, Dogs, Male, Genome, Genomics, Genotype, Phenotype, Wolves, Biodiversity, Genetic Variation, Zoonomia Consortium, General Science & Technology
Abstract

We reconstruct the phenotype of Balto, the heroic sled dog renowned for transporting diphtheria antitoxin to Nome, Alaska, in 1925, using evolutionary constraint estimates from the Zoonomia alignment of 240 mammals and 682 genomes from dogs and wolves of the 21st century. Balto shares just part of his diverse ancestry with the eponymous Siberian husky breed. Balto's genotype predicts a combination of coat features atypical for modern sled dog breeds, and a slightly smaller stature. He had enhanced starch digestion compared with Greenland sled dogs and a compendium of derived homozygous coding variants at constrained positions in genes connected to bone and skin development. We propose that Balto's population of origin, which was less inbred and genetically healthier than that of modern breeds, was adapted to the extreme environment of 1920s Alaska.

Published
2023

5. Evolutionary constraint and innovation across hundreds of placental mammals

Author

Christmas, Matthew J, Kaplow, Irene M, Genereux, Diane P, Dong, Michael X, Hughes, Graham M, Li, Xue, Sullivan, Patrick F, Hindle, Allyson G, Andrews, Gregory, Armstrong, Joel C, Bianchi, Matteo, Breit, Ana M, Diekhans, Mark, Fanter, Cornelia, Foley, Nicole M, Goodman, Daniel B, Goodman, Linda, Keough, Kathleen C, Kirilenko, Bogdan, Kowalczyk, Amanda, Lawless, Colleen, Lind, Abigail L, Meadows, Jennifer RS, Moreira, Lucas R, Redlich, Ruby W, Ryan, Louise, Swofford, Ross, Valenzuela, Alejandro, Wagner, Franziska, Wallerman, Ola, Brown, Ashley R, Damas, Joana, Fan, Kaili, Gatesy, John, Grimshaw, Jenna, Johnson, Jeremy, Kozyrev, Sergey V, Lawler, Alyssa J, Marinescu, Voichita D, Morrill, Kathleen M, Osmanski, Austin, Paulat, Nicole S, Phan, BaDoi N, Reilly, Steven K, Schäffer, Daniel E, Steiner, Cynthia, Supple, Megan A, Wilder, Aryn P, Wirthlin, Morgan E, Xue, James R, Birren, Bruce W, Gazal, Steven, Hubley, Robert M, Koepfli, Klaus-Peter, Marques-Bonet, Tomas, Meyer, Wynn K, Nweeia, Martin, Sabeti, Pardis C, Shapiro, Beth, Smit, Arian FA, Springer, Mark S, Teeling, Emma C, Weng, Zhiping, Hiller, Michael, Levesque, Danielle L, Lewin, Harris A, Murphy, William J, Navarro, Arcadi, Paten, Benedict, Pollard, Katherine S, Ray, David A, Ruf, Irina, Ryder, Oliver A, Pfenning, Andreas R, Lindblad-Toh, Kerstin, Karlsson, Elinor K, Bredemeyer, Kevin R, Clawson, Hiram, Di Palma, Federica, Eizirik, Eduardo, Forsberg-Nilsson, Karin, Garcia, Carlos J, and Halsey, Michaela K

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Biotechnology, Human Genome, Animals, Female, Humans, Conserved Sequence, Eutheria, Evolution, Molecular, Genome, Human, Zoonomia Consortium§, General Science & Technology
Abstract

Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (~10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth's vast and imperiled biodiversity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.

Published
2023

6. Structural basis of gRNA stabilization and mRNA recognition in trypanosomal RNA editing

Author

Liu, Shiheng, Wang, Hong, Li, Xiaorun, Zhang, Fan, Lee, Jane KJ, Li, Zihang, Yu, Clinton, Hu, Jason J, Zhao, Xiaojing, Suematsu, Takuma, Alvarez-Cabrera, Ana L, Liu, Qiushi, Zhang, Liye, Huang, Lan, Aphasizheva, Inna, Aphasizhev, Ruslan, and Zhou, Z Hong

Subjects
Biochemistry and Cell Biology, Chemical Sciences, Biological Sciences, Genetics, Vector-Borne Diseases, Generic health relevance, Good Health and Well Being, Cryoelectron Microscopy, Protozoan Proteins, RNA Editing, RNA, Guide, Kinetoplastida, RNA, Messenger, Trypanosoma brucei brucei, RNA Stability, RNA, Protozoan, General Science & Technology
Abstract

In Trypanosoma brucei, the editosome, composed of RNA-editing substrate-binding complex (RESC) and RNA-editing catalytic complex (RECC), orchestrates guide RNA (gRNA)-programmed editing to recode cryptic mitochondrial transcripts into messenger RNAs (mRNAs). The mechanism of information transfer from gRNA to mRNA is unclear owing to a lack of high-resolution structures for these complexes. With cryo-electron microscopy and functional studies, we have captured gRNA-stabilizing RESC-A and gRNA-mRNA-binding RESC-B and RESC-C particles. RESC-A sequesters gRNA termini, thus promoting hairpin formation and blocking mRNA access. The conversion of RESC-A into RESC-B or -C unfolds gRNA and allows mRNA selection. The ensuing gRNA-mRNA duplex protrudes from RESC-B, likely exposing editing sites to RECC-catalyzed cleavage, uridine insertion or deletion, and ligation. Our work reveals a remodeling event facilitating gRNA-mRNA hybridization and assembly of a macromolecular substrate for the editosome's catalytic modality.

Published
2023

7. Correlated insulator of excitons in WSe2/WS2 moiré superlattices

Author

Xiong, Richen, Nie, Jacob H, Brantly, Samuel L, Hays, Patrick, Sailus, Renee, Watanabe, Kenji, Taniguchi, Takashi, Tongay, Sefaattin, and Jin, Chenhao

Subjects
General Science & Technology
Abstract

A panoply of unconventional electronic states has been observed in moiré superlattices. Engineering similar bosonic phases remains, however, largely unexplored. We report the observation of a bosonic correlated insulator in tungsten diselenide/tungsten disulfide (WSe2/WS2) moiré superlattices composed of excitons, that is, tightly bound electron-hole pairs. We develop a pump probe spectroscopy method that we use to observe an exciton incompressible state at exciton filling νex = 1 and charge neutrality, indicating a correlated insulator of excitons. With varying charge density, the bosonic correlated insulator continuously transitions into an electron correlated insulator at charge filling νe = 1, suggesting a mixed correlated insulating state between the two limits. Our studies establish semiconducting moiré superlattices as an intriguing platform for engineering bosonic phases.

Published
2023

8. A genomic timescale for placental mammal evolution

Author

Foley, Nicole M, Mason, Victor C, Harris, Andrew J, Bredemeyer, Kevin R, Damas, Joana, Lewin, Harris A, Eizirik, Eduardo, Gatesy, John, Karlsson, Elinor K, Lindblad-Toh, Kerstin, Springer, Mark S, Murphy, William J, Andrews, Gregory, Armstrong, Joel C, Bianchi, Matteo, Birren, Bruce W, Breit, Ana M, Christmas, Matthew J, Clawson, Hiram, Di Palma, Federica, Diekhans, Mark, Dong, Michael X, Fan, Kaili, Fanter, Cornelia, Forsberg-Nilsson, Karin, Garcia, Carlos J, Gazal, Steven, Genereux, Diane P, Goodman, Linda, Grimshaw, Jenna, Halsey, Michaela K, Hickey, Glenn, Hiller, Michael, Hindle, Allyson G, Hubley, Robert M, Hughes, Graham M, Johnson, Jeremy, Juan, David, Kaplow, Irene M, Keough, Kathleen C, Kirilenko, Bogdan, Koepfli, Klaus-Peter, Korstian, Jennifer M, Kowalczyk, Amanda, Kozyrev, Sergey V, Lawler, Alyssa J, Lawless, Colleen, Lehmann, Thomas, Levesque, Danielle L, Li, Xue, Lind, Abigail, Mackay-Smith, Ava, Marinescu, Voichita D, Marques-Bonet, Tomas, Meadows, Jennifer RS, Meyer, Wynn K, Moore, Jill E, Moreira, Lucas R, Moreno-Santillan, Diana D, Morrill, Kathleen M, Muntané, Gerard, Navarro, Arcadi, Nweeia, Martin, Ortmann, Sylvia, Osmanski, Austin, Paten, Benedict, Paulat, Nicole S, Pfenning, Andreas R, Phan, BaDoi N, Pollard, Katherine S, Pratt, Henry E, Ray, David A, Reilly, Steven K, Rosen, Jeb R, Ruf, Irina, Ryan, Louise, Ryder, Oliver A, Sabeti, Pardis C, Schäffer, Daniel E, Serres, Aitor, Shapiro, Beth, Smit, Arian FA, Springer, Mark, Srinivasan, Chaitanya, Steiner, Cynthia, Storer, Jessica M, Sullivan, Kevin AM, Sullivan, Patrick F, and Sundström, Elisabeth

Subjects
Genetics, Human Genome, Biotechnology, Animals, Female, Biological Evolution, Eutheria, Evolution, Molecular, Fossils, Genomics, Phylogeny, Genetic Variation, Time Factors, Zoonomia Consortium‡, General Science & Technology
Abstract

The precise pattern and timing of speciation events that gave rise to all living placental mammals remain controversial. We provide a comprehensive phylogenetic analysis of genetic variation across an alignment of 241 placental mammal genome assemblies, addressing prior concerns regarding limited genomic sampling across species. We compared neutral genome-wide phylogenomic signals using concatenation and coalescent-based approaches, interrogated phylogenetic variation across chromosomes, and analyzed extensive catalogs of structural variants. Interordinal relationships exhibit relatively low rates of phylogenomic conflict across diverse datasets and analytical methods. Conversely, X-chromosome versus autosome conflicts characterize multiple independent clades that radiated during the Cenozoic. Genomic time trees reveal an accumulation of cladogenic events before and immediately after the Cretaceous-Paleogene (K-Pg) boundary, implying important roles for Cretaceous continental vicariance and the K-Pg extinction in the placental radiation.

Published
2023

9. The contribution of historical processes to contemporary extinction risk in placental mammals

Author

Wilder, Aryn P, Supple, Megan A, Subramanian, Ayshwarya, Mudide, Anish, Swofford, Ross, Serres-Armero, Aitor, Steiner, Cynthia, Koepfli, Klaus-Peter, Genereux, Diane P, Karlsson, Elinor K, Lindblad-Toh, Kerstin, Marques-Bonet, Tomas, Munoz Fuentes, Violeta, Foley, Kathleen, Meyer, Wynn K, Ryder, Oliver A, Shapiro, Beth, Andrews, Gregory, Armstrong, Joel C, Bianchi, Matteo, Birren, Bruce W, Bredemeyer, Kevin R, Breit, Ana M, Christmas, Matthew J, Clawson, Hiram, Damas, Joana, Di Palma, Federica, Diekhans, Mark, Dong, Michael X, Eizirik, Eduardo, Fan, Kaili, Fanter, Cornelia, Foley, Nicole M, Forsberg-Nilsson, Karin, Garcia, Carlos J, Gatesy, John, Gazal, Steven, Goodman, Linda, Grimshaw, Jenna, Halsey, Michaela K, Harris, Andrew J, Hickey, Glenn, Hiller, Michael, Hindle, Allyson G, Hubley, Robert M, Hughes, Graham M, Johnson, Jeremy, Juan, David, Kaplow, Irene M, Keough, Kathleen C, Kirilenko, Bogdan, Korstian, Jennifer M, Kowalczyk, Amanda, Kozyrev, Sergey V, Lawler, Alyssa J, Lawless, Colleen, Lehmann, Thomas, Levesque, Danielle L, Lewin, Harris A, Li, Xue, Lind, Abigail, Mackay-Smith, Ava, Marinescu, Voichita D, Mason, Victor C, Meadows, Jennifer RS, Moore, Jill E, Moreira, Lucas R, Moreno-Santillan, Diana D, Morrill, Kathleen M, Muntané, Gerard, Murphy, William J, Navarro, Arcadi, Nweeia, Martin, Ortmann, Sylvia, Osmanski, Austin, Paten, Benedict, Paulat, Nicole S, Pfenning, Andreas R, Phan, BaDoi N, Pollard, Katherine S, Pratt, Henry E, Ray, David A, Reilly, Steven K, Rosen, Jeb R, Ruf, Irina, Ryan, Louise, Sabeti, Pardis C, Schäffer, Daniel E, Serres, Aitor, Smit, Arian FA, Springer, Mark, and Srinivasan, Chaitanya

Subjects
Biological Sciences, Evolutionary Biology, Genetics, Behavioral and Social Science, Human Genome, Basic Behavioral and Social Science, Life on Land, Animals, Female, Pregnancy, Eutheria, Extinction, Biological, Genetic Variation, Genome, Population Density, Risk, Zoonomia Consortium‡, General Science & Technology
Abstract

Species persistence can be influenced by the amount, type, and distribution of diversity across the genome, suggesting a potential relationship between historical demography and resilience. In this study, we surveyed genetic variation across single genomes of 240 mammals that compose the Zoonomia alignment to evaluate how historical effective population size (Ne) affects heterozygosity and deleterious genetic load and how these factors may contribute to extinction risk. We find that species with smaller historical Ne carry a proportionally larger burden of deleterious alleles owing to long-term accumulation and fixation of genetic load and have a higher risk of extinction. This suggests that historical demography can inform contemporary resilience. Models that included genomic data were predictive of species' conservation status, suggesting that, in the absence of adequate census or ecological data, genomic information may provide an initial risk assessment.

Published
2023

10. The functional and evolutionary impacts of human-specific deletions in conserved elements

Author

Xue, James R, Mackay-Smith, Ava, Mouri, Kousuke, Garcia, Meilin Fernandez, Dong, Michael X, Akers, Jared F, Noble, Mark, Li, Xue, Lindblad-Toh, Kerstin, Karlsson, Elinor K, Noonan, James P, Capellini, Terence D, Brennand, Kristen J, Tewhey, Ryan, Sabeti, Pardis C, Reilly, Steven K, Andrews, Gregory, Armstrong, Joel C, Bianchi, Matteo, Birren, Bruce W, Bredemeyer, Kevin R, Breit, Ana M, Christmas, Matthew J, Clawson, Hiram, Damas, Joana, Di Palma, Federica, Diekhans, Mark, Eizirik, Eduardo, Fan, Kaili, Fanter, Cornelia, Foley, Nicole M, Forsberg-Nilsson, Karin, Garcia, Carlos J, Gatesy, John, Gazal, Steven, Genereux, Diane P, Goodman, Linda, Grimshaw, Jenna, Halsey, Michaela K, Harris, Andrew J, Hickey, Glenn, Hiller, Michael, Hindle, Allyson G, Hubley, Robert M, Hughes, Graham M, Johnson, Jeremy, Juan, David, Kaplow, Irene M, Keough, Kathleen C, Kirilenko, Bogdan, Koepfli, Klaus-Peter, Korstian, Jennifer M, Kowalczyk, Amanda, Kozyrev, Sergey V, Lawler, Alyssa J, Lawless, Colleen, Lehmann, Thomas, Levesque, Danielle L, Lewin, Harris A, Lind, Abigail, Marinescu, Voichita D, Marques-Bonet, Tomas, Mason, Victor C, Meadows, Jennifer RS, Meyer, Wynn K, Moore, Jill E, Moreira, Lucas R, Moreno-Santillan, Diana D, Morrill, Kathleen M, Muntané, Gerard, Murphy, William J, Navarro, Arcadi, Nweeia, Martin, Ortmann, Sylvia, Osmanski, Austin, Paten, Benedict, Paulat, Nicole S, Pfenning, Andreas R, Phan, BaDoi N, Pollard, Katherine S, Pratt, Henry E, Ray, David A, Rosen, Jeb R, Ruf, Irina, Ryan, Louise, Ryder, Oliver A, Schäffer, Daniel E, Serres, Aitor, Shapiro, Beth, Smit, Arian FA, Springer, Mark, Srinivasan, Chaitanya, and Steiner, Cynthia

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Biotechnology, Neurosciences, Human Genome, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Neurological, Humans, Conserved Sequence, Evolution, Molecular, Genome, Genomics, RNA-Binding Proteins, Sequence Deletion, Brain, Gene Expression Regulation, Developmental, Zoonomia Consortium†, General Science & Technology
Abstract

Conserved genomic sequences disrupted in humans may underlie uniquely human phenotypic traits. We identified and characterized 10,032 human-specific conserved deletions (hCONDELs). These short (average 2.56 base pairs) deletions are enriched for human brain functions across genetic, epigenomic, and transcriptomic datasets. Using massively parallel reporter assays in six cell types, we discovered 800 hCONDELs conferring significant differences in regulatory activity, half of which enhance rather than disrupt regulatory function. We highlight several hCONDELs with putative human-specific effects on brain development, including HDAC5, CPEB4, and PPP2CA. Reverting an hCONDEL to the ancestral sequence alters the expression of LOXL2 and developmental genes involved in myelination and synaptic function. Our data provide a rich resource to investigate the evolutionary mechanisms driving new traits in humans and other species.

Published
2023

11. Integrating gene annotation with orthology inference at scale

Author

Kirilenko, Bogdan M, Munegowda, Chetan, Osipova, Ekaterina, Jebb, David, Sharma, Virag, Blumer, Moritz, Morales, Ariadna E, Ahmed, Alexis-Walid, Kontopoulos, Dimitrios-Georgios, Hilgers, Leon, Lindblad-Toh, Kerstin, Karlsson, Elinor K, Hiller, Michael, Andrews, Gregory, Armstrong, Joel C, Bianchi, Matteo, Birren, Bruce W, Bredemeyer, Kevin R, Breit, Ana M, Christmas, Matthew J, Clawson, Hiram, Damas, Joana, Di Palma, Federica, Diekhans, Mark, Dong, Michael X, Eizirik, Eduardo, Fan, Kaili, Fanter, Cornelia, Foley, Nicole M, Forsberg-Nilsson, Karin, Garcia, Carlos J, Gatesy, John, Gazal, Steven, Genereux, Diane P, Goodman, Linda, Grimshaw, Jenna, Halsey, Michaela K, Harris, Andrew J, Hickey, Glenn, Hindle, Allyson G, Hubley, Robert M, Hughes, Graham M, Johnson, Jeremy, Juan, David, Kaplow, Irene M, Keough, Kathleen C, Kirilenko, Bogdan, Koepfli, Klaus-Peter, Korstian, Jennifer M, Kowalczyk, Amanda, Kozyrev, Sergey V, Lawler, Alyssa J, Lawless, Colleen, Lehmann, Thomas, Levesque, Danielle L, Lewin, Harris A, Li, Xue, Lind, Abigail, Mackay-Smith, Ava, Marinescu, Voichita D, Marques-Bonet, Tomas, Mason, Victor C, Meadows, Jennifer RS, Meyer, Wynn K, Moore, Jill E, Moreira, Lucas R, Moreno-Santillan, Diana D, Morrill, Kathleen M, Muntané, Gerard, Murphy, William J, Navarro, Arcadi, Nweeia, Martin, Ortmann, Sylvia, Osmanski, Austin, Paten, Benedict, Paulat, Nicole S, Pfenning, Andreas R, Phan, BaDoi N, Pollard, Katherine S, Pratt, Henry E, Ray, David A, Reilly, Steven K, Rosen, Jeb R, Ruf, Irina, Ryan, Louise, Ryder, Oliver A, Sabeti, Pardis C, Schäffer, Daniel E, Serres, Aitor, Shapiro, Beth, Smit, Arian FA, Springer, Mark, Srinivasan, Chaitanya, Steiner, Cynthia, Storer, Jessica M, Sullivan, Kevin AM, and Sullivan, Patrick F

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Biotechnology, Human Genome, Generic health relevance, Animals, Female, Mice, Eutheria, Genome, Genomics, Molecular Sequence Annotation, Birds, Zoonomia Consortium‡, General Science & Technology
Abstract

Annotating coding genes and inferring orthologs are two classical challenges in genomics and evolutionary biology that have traditionally been approached separately, limiting scalability. We present TOGA (Tool to infer Orthologs from Genome Alignments), a method that integrates structural gene annotation and orthology inference. TOGA implements a different paradigm to infer orthologous loci, improves ortholog detection and annotation of conserved genes compared with state-of-the-art methods, and handles even highly fragmented assemblies. TOGA scales to hundreds of genomes, which we demonstrate by applying it to 488 placental mammal and 501 bird assemblies, creating the largest comparative gene resources so far. Additionally, TOGA detects gene losses, enables selection screens, and automatically provides a superior measure of mammalian genome quality. TOGA is a powerful and scalable method to annotate and compare genes in the genomic era.

Published
2023

12. Relating enhancer genetic variation across mammals to complex phenotypes using machine learning

Author

Kaplow, Irene M, Lawler, Alyssa J, Schäffer, Daniel E, Srinivasan, Chaitanya, Sestili, Heather H, Wirthlin, Morgan E, Phan, BaDoi N, Prasad, Kavya, Brown, Ashley R, Zhang, Xiaomeng, Foley, Kathleen, Genereux, Diane P, Karlsson, Elinor K, Lindblad-Toh, Kerstin, Meyer, Wynn K, Pfenning, Andreas R, Andrews, Gregory, Armstrong, Joel C, Bianchi, Matteo, Birren, Bruce W, Bredemeyer, Kevin R, Breit, Ana M, Christmas, Matthew J, Clawson, Hiram, Damas, Joana, Di Palma, Federica, Diekhans, Mark, Dong, Michael X, Eizirik, Eduardo, Fan, Kaili, Fanter, Cornelia, Foley, Nicole M, Forsberg-Nilsson, Karin, Garcia, Carlos J, Gatesy, John, Gazal, Steven, Goodman, Linda, Grimshaw, Jenna, Halsey, Michaela K, Harris, Andrew J, Hickey, Glenn, Hiller, Michael, Hindle, Allyson G, Hubley, Robert M, Hughes, Graham M, Johnson, Jeremy, Juan, David, Keough, Kathleen C, Kirilenko, Bogdan, Koepfli, Klaus-Peter, Korstian, Jennifer M, Kowalczyk, Amanda, Kozyrev, Sergey V, Lawless, Colleen, Lehmann, Thomas, Levesque, Danielle L, Lewin, Harris A, Li, Xue, Lind, Abigail, Mackay-Smith, Ava, Marinescu, Voichita D, Marques-Bonet, Tomas, Mason, Victor C, Meadows, Jennifer RS, Moore, Jill E, Moreira, Lucas R, Moreno-Santillan, Diana D, Morrill, Kathleen M, Muntané, Gerard, Murphy, William J, Navarro, Arcadi, Nweeia, Martin, Ortmann, Sylvia, Osmanski, Austin, Paten, Benedict, Paulat, Nicole S, Pollard, Katherine S, Pratt, Henry E, Ray, David A, Reilly, Steven K, Rosen, Jeb R, Ruf, Irina, Ryan, Louise, Ryder, Oliver A, Sabeti, Pardis C, Serres, Aitor, Shapiro, Beth, Smit, Arian FA, Springer, Mark, and Steiner, Cynthia

Subjects
Biological Sciences, Genetics, Pediatric, Human Genome, Rare Diseases, Congenital Structural Anomalies, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Mental health, Animals, Enhancer Elements, Genetic, Genetic Variation, Machine Learning, Mammals, Phenotype, Zoonomia Consortium**, General Science & Technology
Abstract

Protein-coding differences between species often fail to explain phenotypic diversity, suggesting the involvement of genomic elements that regulate gene expression such as enhancers. Identifying associations between enhancers and phenotypes is challenging because enhancer activity can be tissue-dependent and functionally conserved despite low sequence conservation. We developed the Tissue-Aware Conservation Inference Toolkit (TACIT) to associate candidate enhancers with species' phenotypes using predictions from machine learning models trained on specific tissues. Applying TACIT to associate motor cortex and parvalbumin-positive interneuron enhancers with neurological phenotypes revealed dozens of enhancer-phenotype associations, including brain size-associated enhancers that interact with genes implicated in microcephaly or macrocephaly. TACIT provides a foundation for identifying enhancers associated with the evolution of any convergently evolved phenotype in any large group of species with aligned genomes.

Published
2023

13. Three-dimensional genome rewiring in loci with human accelerated regions

Author

Keough, Kathleen C, Whalen, Sean, Inoue, Fumitaka, Przytycki, Pawel F, Fair, Tyler, Deng, Chengyu, Steyert, Marilyn, Ryu, Hane, Lindblad-Toh, Kerstin, Karlsson, Elinor, Nowakowski, Tomasz, Ahituv, Nadav, Pollen, Alex, Pollard, Katherine S, Andrews, Gregory, Armstrong, Joel C, Bianchi, Matteo, Birren, Bruce W, Bredemeyer, Kevin R, Breit, Ana M, Christmas, Matthew J, Clawson, Hiram, Damas, Joana, Di Palma, Federica, Diekhans, Mark, Dong, Michael X, Eizirik, Eduardo, Fan, Kaili, Fanter, Cornelia, Foley, Nicole M, Forsberg-Nilsson, Karin, Garcia, Carlos J, Gatesy, John, Gazal, Steven, Genereux, Diane P, Goodman, Linda, Grimshaw, Jenna, Halsey, Michaela K, Harris, Andrew J, Hickey, Glenn, Hiller, Michael, Hindle, Allyson G, Hubley, Robert M, Hughes, Graham M, Johnson, Jeremy, Juan, David, Kaplow, Irene M, Karlsson, Elinor K, Kirilenko, Bogdan, Koepfli, Klaus-Peter, Korstian, Jennifer M, Kowalczyk, Amanda, Kozyrev, Sergey V, Lawler, Alyssa J, Lawless, Colleen, Lehmann, Thomas, Levesque, Danielle L, Lewin, Harris A, Li, Xue, Lind, Abigail, Mackay-Smith, Ava, Marinescu, Voichita D, Marques-Bonet, Tomas, Mason, Victor C, Meadows, Jennifer RS, Meyer, Wynn K, Moore, Jill E, Moreira, Lucas R, Moreno-Santillan, Diana D, Morrill, Kathleen M, Muntané, Gerard, Murphy, William J, Navarro, Arcadi, Nweeia, Martin, Ortmann, Sylvia, Osmanski, Austin, Paten, Benedict, Paulat, Nicole S, Pfenning, Andreas R, Phan, BaDoi N, Pratt, Henry E, Ray, David A, Reilly, Steven K, Rosen, Jeb R, Ruf, Irina, Ryan, Louise, Ryder, Oliver A, Sabeti, Pardis C, Schäffer, Daniel E, Serres, Aitor, Shapiro, Beth, Smit, Arian FA, Springer, Mark, Srinivasan, Chaitanya, Steiner, Cynthia, Storer, Jessica M, and Sullivan, Kevin AM

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Stem Cell Research, Human Genome, Biotechnology, Underpinning research, 1.1 Normal biological development and functioning, Animals, Humans, Chromatin, Genome, Human, Genomics, Pan troglodytes, Genetic Loci, Neurogenesis, Deep Learning, Zoonomia Consortium§, General Science & Technology
Abstract

Human accelerated regions (HARs) are conserved genomic loci that evolved at an accelerated rate in the human lineage and may underlie human-specific traits. We generated HARs and chimpanzee accelerated regions with an automated pipeline and an alignment of 241 mammalian genomes. Combining deep learning with chromatin capture experiments in human and chimpanzee neural progenitor cells, we discovered a significant enrichment of HARs in topologically associating domains containing human-specific genomic variants that change three-dimensional (3D) genome organization. Differential gene expression between humans and chimpanzees at these loci suggests rewiring of regulatory interactions between HARs and neurodevelopmental genes. Thus, comparative genomics together with models of 3D genome folding revealed enhancer hijacking as an explanation for the rapid evolution of HARs.

Published
2023

14. Leveraging base-pair mammalian constraint to understand genetic variation and human disease

Author

Sullivan, Patrick F, Meadows, Jennifer RS, Gazal, Steven, Phan, BaDoi N, Li, Xue, Genereux, Diane P, Dong, Michael X, Bianchi, Matteo, Andrews, Gregory, Sakthikumar, Sharadha, Nordin, Jessika, Roy, Ananya, Christmas, Matthew J, Marinescu, Voichita D, Wang, Chao, Wallerman, Ola, Xue, James, Yao, Shuyang, Sun, Quan, Szatkiewicz, Jin, Wen, Jia, Huckins, Laura M, Lawler, Alyssa, Keough, Kathleen C, Zheng, Zhili, Zeng, Jian, Wray, Naomi R, Li, Yun, Johnson, Jessica, Chen, Jiawen, Paten, Benedict, Reilly, Steven K, Hughes, Graham M, Weng, Zhiping, Pollard, Katherine S, Pfenning, Andreas R, Forsberg-Nilsson, Karin, Karlsson, Elinor K, Lindblad-Toh, Kerstin, Armstrong, Joel C, Birren, Bruce W, Bredemeyer, Kevin R, Breit, Ana M, Clawson, Hiram, Damas, Joana, Di Palma, Federica, Diekhans, Mark, Eizirik, Eduardo, Fan, Kaili, Fanter, Cornelia, Foley, Nicole M, Garcia, Carlos J, Gatesy, John, Goodman, Linda, Grimshaw, Jenna, Halsey, Michaela K, Harris, Andrew J, Hickey, Glenn, Hiller, Michael, Hindle, Allyson G, Hubley, Robert M, Johnson, Jeremy, Juan, David, Kaplow, Irene M, Kirilenko, Bogdan, Koepfli, Klaus-Peter, Korstian, Jennifer M, Kowalczyk, Amanda, Kozyrev, Sergey V, Lawler, Alyssa J, Lawless, Colleen, Lehmann, Thomas, Levesque, Danielle L, Lewin, Harris A, Lind, Abigail, Mackay-Smith, Ava, Marques-Bonet, Tomas, Mason, Victor C, Meyer, Wynn K, Moore, Jill E, Moreira, Lucas R, Moreno-Santillan, Diana D, Morrill, Kathleen M, Muntané, Gerard, Murphy, William J, and Navarro, Arcadi

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Biotechnology, Clinical Research, Human Genome, Brain Disorders, Generic health relevance, Animals, Humans, Biological Evolution, Genetic Variation, Genome, Human, Genome-Wide Association Study, Genomics, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Disease, Zoonomia Consortium§, General Science & Technology
Abstract

Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function, agnostic to cell type or disease mechanism. Single-base phyloP scores from 240 mammals identified 3.3% of the human genome as significantly constrained and likely functional. We compared phyloP scores to genome annotation, association studies, copy-number variation, clinical genetics findings, and cancer data. Constrained positions are enriched for variants that explain common disease heritability more than other functional annotations. Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.

Published
2023

15. Brain activity of diving seals reveals short sleep cycles at depth

Author

Kendall-Bar, Jessica M, Williams, Terrie M, Mukherji, Ritika, Lozano, Daniel A, Pitman, Julie K, Holser, Rachel R, Keates, Theresa, Beltran, Roxanne S, Robinson, Patrick W, Crocker, Daniel E, Adachi, Taiki, Lyamin, Oleg I, Vyssotski, Alexei L, and Costa, Daniel P

Subjects
Environmental Sciences, Environmental Management, Sleep Research, Animals, Brain, Seals, Earless, Sleep, Time Factors, General Science & Technology
Abstract

Sleep is a crucial part of the daily activity patterns of mammals. However, in marine species that spend months or entire lifetimes at sea, the location, timing, and duration of sleep may be constrained. To understand how marine mammals satisfy their daily sleep requirements while at sea, we monitored electroencephalographic activity in wild northern elephant seals (Mirounga angustirostris) diving in Monterey Bay, California. Brain-wave patterns showed that seals took short (less than 20 minutes) naps while diving (maximum depth 377 meters; 104 sleeping dives). Linking these patterns to accelerometry and the time-depth profiles of 334 free-ranging seals (514,406 sleeping dives) revealed a North Pacific sleepscape in which seals averaged only 2 hours of sleep per day for 7 months, rivaling the record for the least sleep among all mammals, which is currently held by the African elephant (about 2 hours per day).

Published
2023

16. Variation in human water turnover associated with environmental and lifestyle factors

Author

Yamada, Yosuke, Zhang, Xueying, Henderson, Mary ET, Sagayama, Hiroyuki, Pontzer, Herman, Watanabe, Daiki, Yoshida, Tsukasa, Kimura, Misaka, Ainslie, Philip N, Andersen, Lene F, Anderson, Liam J, Arab, Lenore, Baddou, Issad, Bedu-Addo, Kweku, Blaak, Ellen E, Blanc, Stephane, Bonomi, Alberto G, Bouten, Carlijn VC, Bovet, Pascal, Buchowski, Maciej S, Butte, Nancy F, Camps, Stefan G, Close, Graeme L, Cooper, Jamie A, Cooper, Richard, Das, Sai Krupa, Dugas, Lara R, Eaton, Simon, Ekelund, Ulf, Entringer, Sonja, Forrester, Terrence, Fudge, Barry W, Goris, Annelies H, Gurven, Michael, Halsey, Lewis G, Hambly, Catherine, Hamdouchi, Asmaa El, Hoos, Marije B, Hu, Sumei, Joonas, Noorjehan, Joosen, Annemiek M, Katzmarzyk, Peter, Kempen, Kitty P, Kraus, William E, Kriengsinyos, Wantanee, Kushner, Robert F, Lambert, Estelle V, Leonard, William R, Lessan, Nader, Martin, Corby K, Medin, Anine C, Meijer, Erwin P, Morehen, James C, Morton, James P, Neuhouser, Marian L, Nicklas, Theresa A, Ojiambo, Robert M, Pietiläinen, Kirsi H, Pitsiladis, Yannis P, Plange-Rhule, Jacob, Plasqui, Guy, Prentice, Ross L, Rabinovich, Roberto A, Racette, Susan B, Raichlen, David A, Ravussin, Eric, Redman, Leanne M, Reilly, John J, Reynolds, Rebecca M, Roberts, Susan B, Schuit, Albertine J, Sardinha, Luis B, Silva, Analiza M, Sjödin, Anders M, Stice, Eric, Urlacher, Samuel S, Valenti, Giulio, Van Etten, Ludo M, Van Mil, Edgar A, Wells, Jonathan CK, Wilson, George, Wood, Brian M, Yanovski, Jack A, Murphy-Alford, Alexia J, Loechl, Cornelia U, Luke, Amy H, Rood, Jennifer, Westerterp, Klaas R, Wong, William W, Miyachi, Motohiko, Schoeller, Dale A, Speakman, John R, and Consortium§, International Atomic Energy Agency Doubly Labeled Water Database

Subjects
Prevention, Clean Water and Sanitation, Female, Humans, Pregnancy, Exercise, Humidity, Life Style, Social Class, Water, Infant, Newborn, Infant, Child, Preschool, Child, Adolescent, Young Adult, Adult, Middle Aged, Aged, Aged, 80 and over, Drinking, International Atomic Energy Agency (IAEA) Doubly Labeled Water (DLW) Database Consortium§, General Science & Technology
Abstract

Water is essential for survival, but one in three individuals worldwide (2.2 billion people) lacks access to safe drinking water. Water intake requirements largely reflect water turnover (WT), the water used by the body each day. We investigated the determinants of human WT in 5604 people from the ages of 8 days to 96 years from 23 countries using isotope-tracking (2H) methods. Age, body size, and composition were significantly associated with WT, as were physical activity, athletic status, pregnancy, socioeconomic status, and environmental characteristics (latitude, altitude, air temperature, and humidity). People who lived in countries with a low human development index (HDI) had higher WT than people in high-HDI countries. On the basis of this extensive dataset, we provide equations to predict human WT in relation to anthropometric, economic, and environmental factors.

Published
2022

17. A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation

Author

Yanchus, Connor, Drucker, Kristen L, Kollmeyer, Thomas M, Tsai, Ricky, Winick-Ng, Warren, Liang, Minggao, Malik, Ahmad, Pawling, Judy, De Lorenzo, Silvana B, Ali, Asma, Decker, Paul A, Kosel, Matt L, Panda, Arijit, Al-Zahrani, Khalid N, Jiang, Lingyan, Browning, Jared WL, Lowden, Chris, Geuenich, Michael, Hernandez, J Javier, Gosio, Jessica T, Ahmed, Musaddeque, Loganathan, Sampath Kumar, Berman, Jacob, Trcka, Daniel, Michealraj, Kulandaimanuvel Antony, Fortin, Jerome, Carson, Brittany, Hollingsworth, Ethan W, Jacinto, Sandra, Mazrooei, Parisa, Zhou, Lily, Elia, Andrew, Lupien, Mathieu, He, Housheng Hansen, Murphy, Daniel J, Wang, Liguo, Abyzov, Alexej, Dennis, James W, Maass, Philipp G, Campbell, Kieran, Wilson, Michael D, Lachance, Daniel H, Wrensch, Margaret, Wiencke, John, Mak, Tak, Pennacchio, Len A, Dickel, Diane E, Visel, Axel, Wrana, Jeffrey, Taylor, Michael D, Zadeh, Gelareh, Dirks, Peter, Eckel-Passow, Jeanette E, Attisano, Liliana, Pombo, Ana, Ida, Cristiane M, Kvon, Evgeny Z, Jenkins, Robert B, and Schramek, Daniel

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Brain Cancer, Brain Disorders, Human Genome, Neurosciences, Rare Diseases, Genetics, Cancer Genomics, Cancer, 2.1 Biological and endogenous factors, Animals, Brain Neoplasms, Chromosomes, Human, Pair 8, Glioma, Humans, Isocitrate Dehydrogenase, Mice, Mutation, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1R132H-driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.

Published
2022

18. The Huanan Seafood Wholesale Market in Wuhan was the early epicenter of the COVID-19 pandemic

Author

Worobey, Michael, Levy, Joshua I, Serrano, Lorena Malpica, Crits-Christoph, Alexander, Pekar, Jonathan E, Goldstein, Stephen A, Rasmussen, Angela L, Kraemer, Moritz UG, Newman, Chris, Koopmans, Marion PG, Suchard, Marc A, Wertheim, Joel O, Lemey, Philippe, Robertson, David L, Garry, Robert F, Holmes, Edward C, Rambaut, Andrew, and Andersen, Kristian G

Subjects
Prevention, Emerging Infectious Diseases, Biodefense, Vaccine Related, Lung, Good Health and Well Being, Animals, COVID-19, China, Humans, Pandemics, SARS-CoV-2, Seafood, Viral Zoonoses, General Science & Technology
Abstract

Understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 is critical to preventing future zoonotic outbreaks before they become the next pandemic. The Huanan Seafood Wholesale Market in Wuhan, China, was identified as a likely source of cases in early reports, but later this conclusion became controversial. We show here that the earliest known COVID-19 cases from December 2019, including those without reported direct links, were geographically centered on this market. We report that live SARS-CoV-2-susceptible mammals were sold at the market in late 2019 and that within the market, SARS-CoV-2-positive environmental samples were spatially associated with vendors selling live mammals. Although there is insufficient evidence to define upstream events, and exact circumstances remain obscure, our analyses indicate that the emergence of SARS-CoV-2 occurred through the live wildlife trade in China and show that the Huanan market was the epicenter of the COVID-19 pandemic.

Published
2022

19. The molecular epidemiology of multiple zoonotic origins of SARS-CoV-2

Author

Pekar, Jonathan E, Magee, Andrew, Parker, Edyth, Moshiri, Niema, Izhikevich, Katherine, Havens, Jennifer L, Gangavarapu, Karthik, Malpica Serrano, Lorena Mariana, Crits-Christoph, Alexander, Matteson, Nathaniel L, Zeller, Mark, Levy, Joshua I, Wang, Jade C, Hughes, Scott, Lee, Jungmin, Park, Heedo, Park, Man-Seong, Ching Zi Yan, Katherine, Lin, Raymond Tzer Pin, Mat Isa, Mohd Noor, Noor, Yusuf Muhammad, Vasylyeva, Tetyana I, Garry, Robert F, Holmes, Edward C, Rambaut, Andrew, Suchard, Marc A, Andersen, Kristian G, Worobey, Michael, and Wertheim, Joel O

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Pneumonia, Biodefense, Lung, Vaccine Related, Emerging Infectious Diseases, Infectious Diseases, Prevention, Pneumonia & Influenza, Infection, Good Health and Well Being, Animals, COVID-19, Computer Simulation, Genetic Variation, Genomics, Humans, Molecular Epidemiology, Pandemics, Phylogeny, SARS-CoV-2, Viral Zoonoses, General Science & Technology
Abstract

Understanding the circumstances that lead to pandemics is important for their prevention. We analyzed the genomic diversity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) early in the coronavirus disease 2019 (COVID-19) pandemic. We show that SARS-CoV-2 genomic diversity before February 2020 likely comprised only two distinct viral lineages, denoted "A" and "B." Phylodynamic rooting methods, coupled with epidemic simulations, reveal that these lineages were the result of at least two separate cross-species transmission events into humans. The first zoonotic transmission likely involved lineage B viruses around 18 November 2019 (23 October to 8 December), and the separate introduction of lineage A likely occurred within weeks of this event. These findings indicate that it is unlikely that SARS-CoV-2 circulated widely in humans before November 2019 and define the narrow window between when SARS-CoV-2 first jumped into humans and when the first cases of COVID-19 were reported. As with other coronaviruses, SARS-CoV-2 emergence likely resulted from multiple zoonotic events.

Published
2022

20. CD5 expression by dendritic cells directs T cell immunity and sustains immunotherapy responses

Author

He, Mingyu, Roussak, Kate, Ma, Feiyang, Borcherding, Nicholas, Garin, Vince, White, Mike, Schutt, Charles, Jensen, Trine I, Zhao, Yun, Iberg, Courtney A, Shah, Kairav, Bhatia, Himanshi, Korenfeld, Daniel, Dinkel, Sabrina, Gray, Judah, Ulezko Antonova, Alina, Ferris, Stephen, Donermeyer, David, Lindestam Arlehamn, Cecilia, Gubin, Matthew M, Luo, Jingqin, Gorvel, Laurent, Pellegrini, Matteo, Sette, Alessandro, Tung, Thomas, Bak, Rasmus, Modlin, Robert L, Fields, Ryan C, Schreiber, Robert D, Allen, Paul M, and Klechevsky, Eynav

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Vaccine Related, Cancer, Immunization, Inflammatory and immune system, Good Health and Well Being, Humans, CD8-Positive T-Lymphocytes, Cell Differentiation, Dendritic Cells, Immunotherapy, Melanoma, CD5 Antigens, Immune Checkpoint Inhibitors, T-Lymphocytes, Helper-Inducer, General Science & Technology
Abstract

The induction of proinflammatory T cells by dendritic cell (DC) subtypes is critical for antitumor responses and effective immune checkpoint blockade (ICB) therapy. Here, we show that human CD1c+CD5+ DCs are reduced in melanoma-affected lymph nodes, with CD5 expression on DCs correlating with patient survival. Activating CD5 on DCs enhanced T cell priming and improved survival after ICB therapy. CD5+ DC numbers increased during ICB therapy, and low interleukin-6 (IL-6) concentrations promoted their de novo differentiation. Mechanistically, CD5 expression by DCs was required to generate optimally protective CD5hi T helper and CD8+ T cells; further, deletion of CD5 from T cells dampened tumor elimination in response to ICB therapy in vivo. Thus, CD5+ DCs are an essential component of optimal ICB therapy.

Published
2023

21. Synthetic cytokine circuits that drive T cells into immune-excluded tumors

Author

Allen, Greg M, Frankel, Nicholas W, Reddy, Nishith R, Bhargava, Hersh K, Yoshida, Maia A, Stark, Sierra R, Purl, Megan, Lee, Jungmin, Yee, Jacqueline L, Yu, Wei, Li, Aileen W, Garcia, K Christopher, El-Samad, Hana, Roybal, Kole T, Spitzer, Matthew H, and Lim, Wendell A

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Inflammatory and immune system, Humans, Immunotherapy, Adoptive, Interleukin-2, Neoplasms, Receptors, Antigen, T-Cell, T-Lymphocytes, Tumor Microenvironment, Animals, Mice, Receptors, Chimeric Antigen, Cell Engineering, Receptors, Notch, Immunosuppression Therapy, General Science & Technology
Abstract

Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors with immunosuppressive microenvironments. To overcome suppression, we engineered circuits in which tumor-specific synNotch receptors locally induce production of the cytokine IL-2. These circuits potently enhance CAR T cell infiltration and clearance of immune-excluded tumors, without systemic toxicity. The most effective IL-2 induction circuit acts in an autocrine and T cell receptor (TCR)- or CAR-independent manner, bypassing suppression mechanisms including consumption of IL-2 or inhibition of TCR signaling. These engineered cells establish a foothold in the target tumors, with synthetic Notch-induced IL-2 production enabling initiation of CAR-mediated T cell expansion and cell killing. Thus, it is possible to reconstitute synthetic T cell circuits that activate the outputs ultimately required for an antitumor response, but in a manner that evades key points of tumor suppression.

Published
2022

22. KIR+CD8+ T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19

Author

Li, Jing, Zaslavsky, Maxim, Su, Yapeng, Guo, Jing, Sikora, Michael J, van Unen, Vincent, Christophersen, Asbjørn, Chiou, Shin-Heng, Chen, Liang, Li, Jiefu, Ji, Xuhuai, Wilhelmy, Julie, McSween, Alana M, Palanski, Brad A, Mallajosyula, Venkata Vamsee Aditya, Bracey, Nathan A, Dhondalay, Gopal Krishna R, Bhamidipati, Kartik, Pai, Joy, Kipp, Lucas B, Dunn, Jeffrey E, Hauser, Stephen L, Oksenberg, Jorge R, Satpathy, Ansuman T, Robinson, William H, Dekker, Cornelia L, Steinmetz, Lars M, Khosla, Chaitan, Utz, Paul J, Sollid, Ludvig M, Chien, Yueh-Hsiu, Heath, James R, Fernandez-Becker, Nielsen Q, Nadeau, Kari C, Saligrama, Naresha, and Davis, Mark M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Autoimmune Disease, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Good Health and Well Being, Animals, Autoimmune Diseases, CD8-Positive T-Lymphocytes, COVID-19, Humans, Mice, Receptors, KIR, T-Lymphocytes, Regulatory, General Science & Technology
Abstract

In this work, we find that CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49+CD8+ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8+ T cells efficiently eliminated pathogenic gliadin-specific CD4+ T cells from the leukocytes of celiac disease patients in vitro. We also find elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 patients, correlating with disease severity and vasculitis. Selective ablation of Ly49+CD8+ T cells in virus-infected mice led to autoimmunity after infection. Our results indicate that in both species, these regulatory CD8+ T cells act specifically to suppress pathogenic T cells in autoimmune and infectious diseases.

Published
2022

23. High-precision measurement of the W boson mass with the CDF II detector

Author

Collaboration†‡, CDF, Aaltonen, T, Amerio, S, Amidei, D, Anastassov, A, Annovi, A, Antos, J, Apollinari, G, Appel, JA, Arisawa, T, Artikov, A, Asaadi, J, Ashmanskas, W, Auerbach, B, Aurisano, A, Azfar, F, Badgett, W, Bae, T, Barbaro-Galtieri, A, Barnes, VE, Barnett, BA, Barria, P, Bartos, P, Bauce, M, Bedeschi, F, Behari, S, Bellettini, G, Bellinger, J, Benjamin, D, Beretvas, A, Bhatti, A, Bland, KR, Blumenfeld, B, Bocci, A, Bodek, A, Bortoletto, D, Boudreau, J, Boveia, A, Brigliadori, L, Bromberg, C, Brucken, E, Budagov, J, Budd, HS, Burkett, K, Busetto, G, Bussey, P, Butti, P, Buzatu, A, Calamba, A, Camarda, S, Campanelli, M, Carls, B, Carlsmith, D, Carosi, R, Carrillo, S, Casal, B, Casarsa, M, Castro, A, Catastini, P, Cauz, D, Cavaliere, V, Cerri, A, Cerrito, L, Chen, YC, Chertok, M, Chiarelli, G, Chlachidze, G, Cho, K, Chokheli, D, Clark, A, Clarke, C, Convery, ME, Conway, J, Corbo, M, Cordelli, M, Cox, CA, Cox, DJ, Cremonesi, M, Cruz, D, Cuevas, J, Culbertson, R, d’Ascenzo, N, Datta, M, de Barbaro, P, Demortier, L, Deninno, M, D’Errico, M, Devoto, F, Di Canto, A, Di Ruzza, B, Dittmann, JR, Donati, S, D’Onofrio, M, Dorigo, M, Driutti, A, Ebina, K, Edgar, R, Elagin, A, Erbacher, R, and Errede, S

Subjects
Nuclear and Plasma Physics, Particle and High Energy Physics, Physical Sciences, CDF Collaboration†‡, General Science & Technology
Abstract

The mass of the W boson, a mediator of the weak force between elementary particles, is tightly constrained by the symmetries of the standard model of particle physics. The Higgs boson was the last missing component of the model. After observation of the Higgs boson, a measurement of the W boson mass provides a stringent test of the model. We measure the W boson mass, MW, using data corresponding to 8.8 inverse femtobarns of integrated luminosity collected in proton-antiproton collisions at a 1.96 tera-electron volt center-of-mass energy with the CDF II detector at the Fermilab Tevatron collider. A sample of approximately 4 million W boson candidates is used to obtain [Formula: see text], the precision of which exceeds that of all previous measurements combined (stat, statistical uncertainty; syst, systematic uncertainty; MeV, mega-electron volts; c, speed of light in a vacuum). This measurement is in significant tension with the standard model expectation.

Published
2022

24. The complete sequence of a human genome

Author

Nurk, Sergey, Koren, Sergey, Rhie, Arang, Rautiainen, Mikko, Bzikadze, Andrey V, Mikheenko, Alla, Vollger, Mitchell R, Altemose, Nicolas, Uralsky, Lev, Gershman, Ariel, Aganezov, Sergey, Hoyt, Savannah J, Diekhans, Mark, Logsdon, Glennis A, Alonge, Michael, Antonarakis, Stylianos E, Borchers, Matthew, Bouffard, Gerard G, Brooks, Shelise Y, Caldas, Gina V, Chen, Nae-Chyun, Cheng, Haoyu, Chin, Chen-Shan, Chow, William, de Lima, Leonardo G, Dishuck, Philip C, Durbin, Richard, Dvorkina, Tatiana, Fiddes, Ian T, Formenti, Giulio, Fulton, Robert S, Fungtammasan, Arkarachai, Garrison, Erik, Grady, Patrick GS, Graves-Lindsay, Tina A, Hall, Ira M, Hansen, Nancy F, Hartley, Gabrielle A, Haukness, Marina, Howe, Kerstin, Hunkapiller, Michael W, Jain, Chirag, Jain, Miten, Jarvis, Erich D, Kerpedjiev, Peter, Kirsche, Melanie, Kolmogorov, Mikhail, Korlach, Jonas, Kremitzki, Milinn, Li, Heng, Maduro, Valerie V, Marschall, Tobias, McCartney, Ann M, McDaniel, Jennifer, Miller, Danny E, Mullikin, James C, Myers, Eugene W, Olson, Nathan D, Paten, Benedict, Peluso, Paul, Pevzner, Pavel A, Porubsky, David, Potapova, Tamara, Rogaev, Evgeny I, Rosenfeld, Jeffrey A, Salzberg, Steven L, Schneider, Valerie A, Sedlazeck, Fritz J, Shafin, Kishwar, Shew, Colin J, Shumate, Alaina, Sims, Ying, Smit, Arian FA, Soto, Daniela C, Sović, Ivan, Storer, Jessica M, Streets, Aaron, Sullivan, Beth A, Thibaud-Nissen, Françoise, Torrance, James, Wagner, Justin, Walenz, Brian P, Wenger, Aaron, Wood, Jonathan MD, Xiao, Chunlin, Yan, Stephanie M, Young, Alice C, Zarate, Samantha, Surti, Urvashi, McCoy, Rajiv C, Dennis, Megan Y, Alexandrov, Ivan A, Gerton, Jennifer L, O’Neill, Rachel J, Timp, Winston, Zook, Justin M, Schatz, Michael C, Eichler, Evan E, Miga, Karen H, and Phillippy, Adam M

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Cell Line, Chromosomes, Artificial, Bacterial, Chromosomes, Human, Genome, Human, Human Genome Project, Humans, Reference Values, Sequence Analysis, DNA, General Science & Technology
Abstract

Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion-base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.

Published
2022

25. Global urban environmental change drives adaptation in white clover

Author

Santangelo, James S, Ness, Rob W, Cohan, Beata, Fitzpatrick, Connor R, Innes, Simon G, Koch, Sophie, Miles, Lindsay S, Munim, Samreen, Peres-Neto, Pedro R, Prashad, Cindy, Tong, Alex T, Aguirre, Windsor E, Akinwole, Philips O, Alberti, Marina, Álvarez, Jackie, Anderson, Jill T, Anderson, Joseph J, Ando, Yoshino, Andrew, Nigel R, Angeoletto, Fabio, Anstett, Daniel N, Anstett, Julia, Aoki-Gonçalves, Felipe, Arietta, AZ Andis, Arroyo, Mary TK, Austen, Emily J, Baena-Díaz, Fernanda, Barker, Cory A, Baylis, Howard A, Beliz, Julia M, Benitez-Mora, Alfonso, Bickford, David, Biedebach, Gabriela, Blackburn, Gwylim S, Boehm, Mannfred MA, Bonser, Stephen P, Bonte, Dries, Bragger, Jesse R, Branquinho, Cristina, Brans, Kristien I, Bresciano, Jorge C, Brom, Peta D, Bucharova, Anna, Burt, Briana, Cahill, James F, Campbell, Katelyn D, Carlen, Elizabeth J, Carmona, Diego, Castellanos, Maria Clara, Centenaro, Giada, Chalen, Izan, Chaves, Jaime A, Chávez-Pesqueira, Mariana, Chen, Xiao-Yong, Chilton, Angela M, Chomiak, Kristina M, Cisneros-Heredia, Diego F, Cisse, Ibrahim K, Classen, Aimée T, Comerford, Mattheau S, Fradinger, Camila Cordoba, Corney, Hannah, Crawford, Andrew J, Crawford, Kerri M, Dahirel, Maxime, David, Santiago, De Haan, Robert, Deacon, Nicholas J, Dean, Clare, del-Val, Ek, Deligiannis, Eleftherios K, Denney, Derek, Dettlaff, Margarete A, DiLeo, Michelle F, Ding, Yuan-Yuan, Domínguez-López, Moisés E, Dominoni, Davide M, Draud, Savannah L, Dyson, Karen, Ellers, Jacintha, Espinosa, Carlos I, Essi, Liliana, Falahati-Anbaran, Mohsen, Falcão, Jéssica CF, Fargo, Hayden T, Fellowes, Mark DE, Fitzpatrick, Raina M, Flaherty, Leah E, Flood, Pádraic J, Flores, María F, Fornoni, Juan, Foster, Amy G, Frost, Christopher J, Fuentes, Tracy L, Fulkerson, Justin R, Gagnon, Edeline, Garbsch, Frauke, Garroway, Colin J, Gerstein, Aleeza C, and Giasson, Mischa M

Subjects
Adaptation, Physiological, Biological Evolution, Cities, Ecosystem, Genes, Plant, Genome, Plant, Hydrogen Cyanide, Rural Population, Trifolium, Urbanization, General Science & Technology
Abstract

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.

Published
2022

26. Structures of the nitrogenase complex prepared under catalytic turnover conditions

Author

Rutledge, Hannah L, Cook, Brian D, Nguyen, Hoang PM, Herzik, Mark A, and Tezcan, F Akif

Subjects
Generic health relevance, Affordable and Clean Energy, Adenosine Triphosphate, Catalysis, Cryoelectron Microscopy, Hydrolysis, Molybdoferredoxin, Nitrogenase, Oxidation-Reduction, Protein Conformation, General Science & Technology
Abstract

The enzyme nitrogenase couples adenosine triphosphate (ATP) hydrolysis to the multielectron reduction of atmospheric dinitrogen into ammonia. Despite extensive research, the mechanistic details of ATP-dependent energy transduction and dinitrogen reduction by nitrogenase are not well understood, requiring new strategies to monitor its structural dynamics during catalytic action. Here, we report cryo-electron microscopy structures of the nitrogenase complex prepared under enzymatic turnover conditions. We observe that asymmetry governs all aspects of the nitrogenase mechanism, including ATP hydrolysis, protein-protein interactions, and catalysis. Conformational changes near the catalytic iron-molybdenum cofactor are correlated with the nucleotide-hydrolysis state of the enzyme.

Published
2022

27. WTO must ban harmful fisheries subsidies

Author

Sumaila, U Rashid, Skerritt, Daniel J, Schuhbauer, Anna, Villasante, Sebastian, Cisneros-Montemayor, Andrés M, Sinan, Hussain, Burnside, Duncan, Abdallah, Patrízia Raggi, Abe, Keita, Addo, Kwasi A, Adelsheim, Julia, Adewumi, Ibukun J, Adeyemo, Olanike K, Adger, Neil, Adotey, Joshua, Advani, Sahir, Afrin, Zahidah, Aheto, Denis, Akintola, Shehu L, Akpalu, Wisdom, Alam, Lubna, Alava, Juan José, Allison, Edward H, Amon, Diva J, Anderies, John M, Anderson, Christopher M, Andrews, Evan, Angelini, Ronaldo, Anna, Zuzy, Antweiler, Werner, Arizi, Evans K, Armitage, Derek, Arthur, Robert I, Asare, Noble, Asche, Frank, Asiedu, Berchie, Asuquo, Francis, Badmus, Lanre, Bailey, Megan, Ban, Natalie, Barbier, Edward B, Barley, Shanta, Barnes, Colin, Barrett, Scott, Basurto, Xavier, Belhabib, Dyhia, Bennett, Elena, Bennett, Nathan J, Benzaken, Dominique, Blasiak, Robert, Bohorquez, John J, Bordehore, Cesar, Bornarel, Virginie, Boyd, David R, Breitburg, Denise, Brooks, Cassandra, Brotz, Lucas, Campbell, Donovan, Cannon, Sara, Cao, Ling, Cardenas Campo, Juan C, Carpenter, Steve, Carpenter, Griffin, Carson, Richard T, Carvalho, Adriana R, Castrejón, Mauricio, Caveen, Alex J, Chabi, M Nicole, Chan, Kai MA, Chapin, F Stuart, Charles, Tony, Cheung, William, Christensen, Villy, Chuku, Ernest O, Church, Trevor, Clark, Colin, Clarke, Tayler M, Cojocaru, Andreea L, Copeland, Brian, Crawford, Brian, Crépin, Anne-Sophie, Crowder, Larry B, Cury, Philippe, Cutting, Allison N, Daily, Gretchen C, Da-Rocha, Jose Maria, Das, Abhipsita, de la Puente, Santiago, de Zeeuw, Aart, Deikumah, Savior KS, Deith, Mairin, Dewitte, Boris, Doubleday, Nancy, Duarte, Carlos M, Dulvy, Nicholas K, Eddy, Tyler, Efford, Meaghan, Ehrlich, Paul R, Elsler, Laura G, and Fakoya, Kafayat A

Subjects
General Science & Technology
Published
2021

28. Enhanced charge density wave coherence in a light-quenched, high-temperature superconductor

Author

Wandel, S, Boschini, F, da Silva Neto, EH, Shen, L, Na, MX, Zohar, S, Wang, Y, Welch, SB, Seaberg, MH, Koralek, JD, Dakovski, GL, Hettel, W, Lin, M-F, Moeller, SP, Schlotter, WF, Reid, AH, Minitti, MP, Boyle, T, He, F, Sutarto, R, Liang, R, Bonn, D, Hardy, W, Kaindl, RA, Hawthorn, DG, Lee, J-S, Kemper, AF, Damascelli, A, Giannetti, C, Turner, JJ, and Coslovich, G

Subjects
Physical Sciences, Condensed Matter Physics, General Science & Technology
Abstract

Superconductivity and charge density waves (CDWs) are competitive, yet coexisting, orders in cuprate superconductors. To understand their microscopic interdependence, a probe capable of discerning their interaction on its natural length and time scale is necessary. We use ultrafast resonant soft x-ray scattering to track the transient evolution of CDW correlations in YBa2Cu3O6+x after the quench of superconductivity by an infrared laser pulse. We observe a nonthermal response of the CDW order characterized by a near doubling of the correlation length within ≈1 picosecond of the superconducting quench. Our results are consistent with a model in which the interaction between superconductivity and CDWs manifests inhomogeneously through disruption of spatial coherence, with superconductivity playing the dominant role in stabilizing CDW topological defects, such as discommensurations.

Published
2022

29. The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans

Author

Jones, Robert C, Karkanias, Jim, Krasnow, Mark A, Pisco, Angela Oliveira, Quake, Stephen R, Salzman, Julia, Yosef, Nir, Bulthaup, Bryan, Brown, Phillip, Harper, William, Hemenez, Marisa, Ponnusamy, Ravikumar, Salehi, Ahmad, Sanagavarapu, Bhavani A, Spallino, Eileen, Aaron, Ksenia A, Concepcion, Waldo, Gardner, James M, Kelly, Burnett, Neidlinger, Nikole, Wang, Zifa, Crasta, Sheela, Kolluru, Saroja, Morri, Maurizio, Tan, Serena Y, Travaglini, Kyle J, Xu, Chenling, Alcántara-Hernández, Marcela, Almanzar, Nicole, Antony, Jane, Beyersdorf, Benjamin, Burhan, Deviana, Calcuttawala, Kruti, Carter, Matthew M, Chan, Charles KF, Chang, Charles A, Chang, Stephen, Colville, Alex, Culver, Rebecca N, Cvijović, Ivana, D'Amato, Gaetano, Ezran, Camille, Galdos, Francisco X, Gillich, Astrid, Goodyer, William R, Hang, Yan, Hayashi, Alyssa, Houshdaran, Sahar, Huang, Xianxi, Irwin, Juan C, Jang, SoRi, Juanico, Julia Vallve, Kershner, Aaron M, Kim, Soochi, Kiss, Bernhard, Kong, William, Kumar, Maya E, Kuo, Angera H, Li, Baoxiang, Loeb, Gabriel B, Lu, Wan-Jin, Mantri, Sruthi, Markovic, Maxim, McAlpine, Patrick L, de Morree, Antoine, Mrouj, Karim, Mukherjee, Shravani, Muser, Tyler, Neuhöfer, Patrick, Nguyen, Thi D, Perez, Kimberly, Puluca, Nazan, Qi, Zhen, Rao, Poorvi, Raquer-McKay, Hayley, Schaum, Nicholas, Scott, Bronwyn, Seddighzadeh, Bobak, Segal, Joe, Sen, Sushmita, Sikandar, Shaheen, Spencer, Sean P, Steffes, Lea C, Subramaniam, Varun R, Swarup, Aditi, Swift, Michael, Van Treuren, Will, Trimm, Emily, Veizades, Stefan, Vijayakumar, Sivakamasundari, Vo, Kim Chi, Vorperian, Sevahn K, Wang, Wanxin, Weinstein, Hannah NW, Winkler, Juliane, Wu, Timothy TH, Xie, Jamie, Yung, Andrea R, Zhang, Yue, and Detweiler, Angela M

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Generic health relevance, Atlases as Topic, B-Lymphocytes, Cells, Humans, Organ Specificity, RNA Splicing, Single-Cell Analysis, T-Lymphocytes, Transcriptome, Tabula Sapiens Consortium*, General Science & Technology
Abstract

Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.

Published
2022

30. The critically endangered vaquita is not doomed to extinction by inbreeding depression

Author

Robinson, Jacqueline A, Kyriazis, Christopher C, Nigenda-Morales, Sergio F, Beichman, Annabel C, Rojas-Bracho, Lorenzo, Robertson, Kelly M, Fontaine, Michael C, Wayne, Robert K, Lohmueller, Kirk E, Taylor, Barbara L, and Morin, Phillip A

Subjects
Brain Disorders, Biotechnology, Mental Health, Genetics, Depression, Human Genome, Life on Land, Animals, Conservation of Natural Resources, Endangered Species, Genetic Variation, Genome, Inbreeding, Inbreeding Depression, Phocoena, General Science & Technology
Abstract

In cases of severe wildlife population decline, a key question is whether recovery efforts will be impeded by genetic factors, such as inbreeding depression. Decades of excess mortality from gillnet fishing have driven Mexico's vaquita porpoise (Phocoena sinus) to ~10 remaining individuals. We analyzed whole-genome sequences from 20 vaquitas and integrated genomic and demographic information into stochastic, individual-based simulations to quantify the species' recovery potential. Our analysis suggests that the vaquita's historical rarity has resulted in a low burden of segregating deleterious variation, reducing the risk of inbreeding depression. Similarly, genome-informed simulations suggest that the vaquita can recover if bycatch mortality is immediately halted. This study provides hope for vaquitas and other naturally rare endangered species and highlights the utility of genomics in predicting extinction risk.

Published
2022

31. From telomere to telomere: The transcriptional and epigenetic state of human repeat elements

Author

Hoyt, Savannah J, Storer, Jessica M, Hartley, Gabrielle A, Grady, Patrick GS, Gershman, Ariel, de Lima, Leonardo G, Limouse, Charles, Halabian, Reza, Wojenski, Luke, Rodriguez, Matias, Altemose, Nicolas, Rhie, Arang, Core, Leighton J, Gerton, Jennifer L, Makalowski, Wojciech, Olson, Daniel, Rosen, Jeb, Smit, Arian FA, Straight, Aaron F, Vollger, Mitchell R, Wheeler, Travis J, Schatz, Michael C, Eichler, Evan E, Phillippy, Adam M, Timp, Winston, Miga, Karen H, and O'Neill, Rachel J

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Generic health relevance, Epigenesis, Genetic, Genome, Human, Humans, Repetitive Sequences, Nucleic Acid, Telomere, Transcription, Genetic, General Science & Technology
Abstract

Mobile elements and repetitive genomic regions are sources of lineage-specific genomic innovation and uniquely fingerprint individual genomes. Comprehensive analyses of such repeat elements, including those found in more complex regions of the genome, require a complete, linear genome assembly. We present a de novo repeat discovery and annotation of the T2T-CHM13 human reference genome. We identified previously unknown satellite arrays, expanded the catalog of variants and families for repeats and mobile elements, characterized classes of complex composite repeats, and located retroelement transduction events. We detected nascent transcription and delineated CpG methylation profiles to define the structure of transcriptionally active retroelements in humans, including those in centromeres. These data expand our insight into the diversity, distribution, and evolution of repetitive regions that have shaped the human genome.

Published
2022

32. Complete genomic and epigenetic maps of human centromeres

Author

Altemose, Nicolas, Logsdon, Glennis A, Bzikadze, Andrey V, Sidhwani, Pragya, Langley, Sasha A, Caldas, Gina V, Hoyt, Savannah J, Uralsky, Lev, Ryabov, Fedor D, Shew, Colin J, Sauria, Michael EG, Borchers, Matthew, Gershman, Ariel, Mikheenko, Alla, Shepelev, Valery A, Dvorkina, Tatiana, Kunyavskaya, Olga, Vollger, Mitchell R, Rhie, Arang, McCartney, Ann M, Asri, Mobin, Lorig-Roach, Ryan, Shafin, Kishwar, Lucas, Julian K, Aganezov, Sergey, Olson, Daniel, de Lima, Leonardo Gomes, Potapova, Tamara, Hartley, Gabrielle A, Haukness, Marina, Kerpedjiev, Peter, Gusev, Fedor, Tigyi, Kristof, Brooks, Shelise, Young, Alice, Nurk, Sergey, Koren, Sergey, Salama, Sofie R, Paten, Benedict, Rogaev, Evgeny I, Streets, Aaron, Karpen, Gary H, Dernburg, Abby F, Sullivan, Beth A, Straight, Aaron F, Wheeler, Travis J, Gerton, Jennifer L, Eichler, Evan E, Phillippy, Adam M, Timp, Winston, Dennis, Megan Y, O'Neill, Rachel J, Zook, Justin M, Schatz, Michael C, Pevzner, Pavel A, Diekhans, Mark, Langley, Charles H, Alexandrov, Ivan A, and Miga, Karen H

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Generic health relevance, Centromere, Chromosome Mapping, Epigenesis, Genetic, Evolution, Molecular, Genome, Human, Genomics, Humans, Repetitive Sequences, Nucleic Acid, General Science & Technology
Abstract

Existing human genome assemblies have almost entirely excluded repetitive sequences within and near centromeres, limiting our understanding of their organization, evolution, and functions, which include facilitating proper chromosome segregation. Now, a complete, telomere-to-telomere human genome assembly (T2T-CHM13) has enabled us to comprehensively characterize pericentromeric and centromeric repeats, which constitute 6.2% of the genome (189.9 megabases). Detailed maps of these regions revealed multimegabase structural rearrangements, including in active centromeric repeat arrays. Analysis of centromere-associated sequences uncovered a strong relationship between the position of the centromere and the evolution of the surrounding DNA through layered repeat expansions. Furthermore, comparisons of chromosome X centromeres across a diverse panel of individuals illuminated high degrees of structural, epigenetic, and sequence variation in these complex and rapidly evolving regions.

Published
2022

33. A single-cell atlas of the normal and malformed human brain vasculature

Author

Winkler, Ethan A, Kim, Chang N, Ross, Jayden M, Garcia, Joseph H, Gil, Eugene, Oh, Irene, Chen, Lindsay Q, Wu, David, Catapano, Joshua S, Raygor, Kunal, Narsinh, Kazim, Kim, Helen, Weinsheimer, Shantel, Cooke, Daniel L, Walcott, Brian P, Lawton, Michael T, Gupta, Nalin, Zlokovic, Berislav V, Chang, Edward F, Abla, Adib A, Lim, Daniel A, and Nowakowski, Tomasz J

Subjects
Biomedical and Clinical Sciences, Immunology, Stem Cell Research, Stem Cell Research - Nonembryonic - Human, Neurosciences, Brain Disorders, Stroke, 1.1 Normal biological development and functioning, Aetiology, 2.1 Biological and endogenous factors, Underpinning research, Adult, Blood Vessels, Brain, Cells, Cultured, Cerebral Cortex, Cerebral Hemorrhage, Cerebrovascular Circulation, Endothelial Cells, Fibroblasts, Humans, Inflammation, Intracranial Arteriovenous Malformations, Monocytes, Muscle, Smooth, Vascular, Pericytes, RNA-Seq, Single-Cell Analysis, Transcriptome, General Science & Technology
Abstract

Cerebrovascular diseases are a leading cause of death and neurologic disability. Further understanding of disease mechanisms and therapeutic strategies requires a deeper knowledge of cerebrovascular cells in humans. We profiled transcriptomes of 181,388 cells to define a cell atlas of the adult human cerebrovasculature, including endothelial cell molecular signatures with arteriovenous segmentation and expanded perivascular cell diversity. By leveraging this reference, we investigated cellular and molecular perturbations in brain arteriovenous malformations, which are a leading cause of stroke in young people, and identified pathologic endothelial transformations with abnormal vascular patterning and the ontology of vascularly derived inflammation. We illustrate the interplay between vascular and immune cells that contributes to brain hemorrhage and catalog opportunities for targeting angiogenic and inflammatory programs in vascular malformations.

Published
2022

34. Daily energy expenditure through the human life course

Author

Pontzer, Herman, Yamada, Yosuke, Sagayama, Hiroyuki, Ainslie, Philip N, Andersen, Lene F, Anderson, Liam J, Arab, Lenore, Baddou, Issaad, Bedu-Addo, Kweku, Blaak, Ellen E, Blanc, Stephane, Bonomi, Alberto G, Bouten, Carlijn VC, Bovet, Pascal, Buchowski, Maciej S, Butte, Nancy F, Camps, Stefan G, Close, Graeme L, Cooper, Jamie A, Cooper, Richard, Das, Sai Krupa, Dugas, Lara R, Ekelund, Ulf, Entringer, Sonja, Forrester, Terrence, Fudge, Barry W, Goris, Annelies H, Gurven, Michael, Hambly, Catherine, Hamdouchi, Asmaa El, Hoos, Marjije B, Hu, Sumei, Joonas, Noorjehan, Joosen, Annemiek M, Katzmarzyk, Peter, Kempen, Kitty P, Kimura, Misaka, Kraus, William E, Kushner, Robert F, Lambert, Estelle V, Leonard, William R, Lessan, Nader, Martin, Corby, Medin, Anine C, Meijer, Erwin P, Morehen, James C, Morton, James P, Neuhouser, Marian L, Nicklas, Teresa A, Ojiambo, Robert M, Pietiläinen, Kirsi H, Pitsiladis, Yannis P, Plange-Rhule, Jacob, Plasqui, Guy, Prentice, Ross L, Rabinovich, Roberto A, Racette, Susan B, Raichlen, David A, Ravussin, Eric, Reynolds, Rebecca M, Roberts, Susan B, Schuit, Albertine J, Sjödin, Anders M, Stice, Eric, Urlacher, Samuel S, Valenti, Giulio, Van Etten, Ludo M, Van Mil, Edgar A, Wells, Jonathan CK, Wilson, George, Wood, Brian M, Yanovski, Jack, Yoshida, Tsukasa, Zhang, Xueying, Murphy-Alford, Alexia J, Loechl, Cornelia, Luke, Amy H, Rood, Jennifer, Schoeller, Dale A, Westerterp, Klaas R, Wong, William W, Speakman, John R, and Consortium§, IAEA DLW Database

Subjects
Aging, Nutrition, Adolescent, Adult, Aged, Aged, 80 and over, Basal Metabolism, Body Composition, Body Weight, Child, Child, Preschool, Energy Metabolism, Exercise, Female, Humans, Infant, Infant, Newborn, Male, Middle Aged, Pregnancy, Young Adult, IAEA DLW Database Consortium, General Science & Technology
Abstract

Total daily energy expenditure ("total expenditure") reflects daily energy needs and is a critical variable in human health and physiology, but its trajectory over the life course is poorly studied. We analyzed a large, diverse database of total expenditure measured by the doubly labeled water method for males and females aged 8 days to 95 years. Total expenditure increased with fat-free mass in a power-law manner, with four distinct life stages. Fat-free mass-adjusted expenditure accelerates rapidly in neonates to ~50% above adult values at ~1 year; declines slowly to adult levels by ~20 years; remains stable in adulthood (20 to 60 years), even during pregnancy; then declines in older adults. These changes shed light on human development and aging and should help shape nutrition and health strategies across the life span.

Published
2021

35. De novo assembly, annotation, and comparative analysis of 26 diverse maize genomes

Author

Hufford, Matthew B, Seetharam, Arun S, Woodhouse, Margaret R, Chougule, Kapeel M, Ou, Shujun, Liu, Jianing, Ricci, William A, Guo, Tingting, Olson, Andrew, Qiu, Yinjie, Della Coletta, Rafael, Tittes, Silas, Hudson, Asher I, Marand, Alexandre P, Wei, Sharon, Lu, Zhenyuan, Wang, Bo, Tello-Ruiz, Marcela K, Piri, Rebecca D, Wang, Na, Kim, Dong Won, Zeng, Yibing, O'Connor, Christine H, Li, Xianran, Gilbert, Amanda M, Baggs, Erin, Krasileva, Ksenia V, Portwood, John L, Cannon, Ethalinda KS, Andorf, Carson M, Manchanda, Nancy, Snodgrass, Samantha J, Hufnagel, David E, Jiang, Qiuhan, Pedersen, Sarah, Syring, Michael L, Kudrna, David A, Llaca, Victor, Fengler, Kevin, Schmitz, Robert J, Ross-Ibarra, Jeffrey, Yu, Jianming, Gent, Jonathan I, Hirsch, Candice N, Ware, Doreen, and Dawe, R Kelly

Subjects
Genetics, Human Genome, Centromere, Chromosome Mapping, Chromosomes, Plant, DNA Methylation, Disease Resistance, Genes, Plant, Genetic Variation, Genome, Plant, Genotype, High-Throughput Nucleotide Sequencing, Molecular Sequence Annotation, Multifactorial Inheritance, Phenotype, Plant Diseases, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid, Sequence Analysis, DNA, Tetraploidy, Transcriptome, Whole Genome Sequencing, Zea mays, General Science & Technology
Abstract

We report de novo genome assemblies, transcriptomes, annotations, and methylomes for the 26 inbreds that serve as the founders for the maize nested association mapping population. The number of pan-genes in these diverse genomes exceeds 103,000, with approximately a third found across all genotypes. The results demonstrate that the ancient tetraploid character of maize continues to degrade by fractionation to the present day. Excellent contiguity over repeat arrays and complete annotation of centromeres revealed additional variation in major cytological landmarks. We show that combining structural variation with single-nucleotide polymorphisms can improve the power of quantitative mapping studies. We also document variation at the level of DNA methylation and demonstrate that unmethylated regions are enriched for cis-regulatory elements that contribute to phenotypic variation.

Published
2021

36. Total synthesis of himastatin

Author

D'Angelo, Kyan A, Schissel, Carly K, Pentelute, Bradley L, and Movassaghi, Mohammad

Subjects
Organic Chemistry, Chemical Sciences, Anti-Bacterial Agents, Bacillus subtilis, Cell Membrane, Chemistry Techniques, Synthetic, Dimerization, Molecular Structure, Peptides, Cyclic, Stereoisomerism, General Science & Technology
Abstract

The natural product himastatin has an unusual homodimeric structure that presents a substantial synthetic challenge. We report the concise total synthesis of himastatin from readily accessible precursors, incorporating a final-stage dimerization strategy that was inspired by a detailed consideration of the compound's biogenesis. Combining this approach with a modular synthesis enabled expedient access to more than a dozen designed derivatives of himastatin, including synthetic probes that provide insight into its antibiotic activity.

Published
2022

37. Discovery of genomic loci of the human cerebral cortex using genetically informed brain atlases

Author

Makowski, Carolina, van der Meer, Dennis, Dong, Weixiu, Wang, Hao, Wu, Yan, Zou, Jingjing, Liu, Cin, Rosenthal, Sara B, Hagler, Donald J, Fan, Chun Chieh, Kremen, William S, Andreassen, Ole A, Jernigan, Terry L, Dale, Anders M, Zhang, Kun, Visscher, Peter M, Yang, Jian, and Chen, Chi-Hua

Subjects
Biological Psychology, Biological Sciences, Genetics, Psychology, Brain Disorders, Human Genome, Clinical Research, Neurosciences, Mental Health, Pediatric, Prevention, 2.1 Biological and endogenous factors, Neurological, Adult, Aged, Aged, 80 and over, Cerebral Cortex, Child, Chromatin, Cohort Studies, Female, Gene Ontology, Genetic Association Studies, Genetic Loci, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Mental Disorders, Middle Aged, Molecular Sequence Annotation, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid, General Science & Technology
Abstract

To determine the impact of genetic variants on the brain, we used genetically informed brain atlases in genome-wide association studies of regional cortical surface area and thickness in 39,898 adults and 9136 children. We uncovered 440 genome-wide significant loci in the discovery cohort and 800 from a post hoc combined meta-analysis. Loci in adulthood were largely captured in childhood, showing signatures of negative selection, and were linked to early neurodevelopment and pathways associated with neuropsychiatric risk. Opposing gradations of decreased surface area and increased thickness were associated with common inversion polymorphisms. Inferior frontal regions, encompassing Broca's area, which is important for speech, were enriched for human-specific genomic elements. Thus, a mixed genetic landscape of conserved and human-specific features is concordant with brain hierarchy and morphogenetic gradients.

Published
2022

38. Amplification of human interneuron progenitors promotes brain tumors and neurological defects

Author

Eichmüller, Oliver L, Corsini, Nina S, Vértesy, Ábel, Morassut, Ilaria, Scholl, Theresa, Gruber, Victoria-Elisabeth, Peer, Angela M, Chu, Julia, Novatchkova, Maria, Hainfellner, Johannes A, Paredes, Mercedes F, Feucht, Martha, and Knoblich, Jürgen A

Subjects
Cancer, Pediatric, Neurodegenerative, Rare Diseases, Stem Cell Research - Nonembryonic - Human, Tuberous Sclerosis, Epilepsy, Congenital Structural Anomalies, Stem Cell Research, Stem Cell Research - Nonembryonic - Non-Human, Neurosciences, Brain Disorders, Underpinning research, 2.1 Biological and endogenous factors, Aetiology, 1.1 Normal biological development and functioning, Neurological, Brain, Brain Neoplasms, Carcinogenesis, Cell Lineage, Cell Proliferation, Disease Progression, ErbB Receptors, Gene Expression Profiling, Humans, Induced Pluripotent Stem Cells, Interneurons, Loss of Heterozygosity, Neural Stem Cells, Organoids, RNA-Seq, TOR Serine-Threonine Kinases, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, General Science & Technology
Abstract

Evolutionary development of the human brain is characterized by the expansion of various brain regions. Here, we show that developmental processes specific to humans are responsible for malformations of cortical development (MCDs), which result in developmental delay and epilepsy in children. We generated a human cerebral organoid model for tuberous sclerosis complex (TSC) and identified a specific neural stem cell type, caudal late interneuron progenitor (CLIP) cells. In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors, and cortical malformations. Epidermal growth factor receptor inhibition reduces tumor burden, identifying potential treatment options for TSC and related disorders. The identification of CLIP cells reveals the extended interneuron generation in the human brain as a vulnerability for disease. In addition, this work demonstrates that analyzing MCDs can reveal fundamental insights into human-specific aspects of brain development.

Published
2022

39. Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production

Author

Orecchioni, Marco, Kobiyama, Kouji, Winkels, Holger, Ghosheh, Yanal, McArdle, Sara, Mikulski, Zbigniew, Kiosses, William B, Fan, Zhichao, Wen, Lai, Jung, Yunmin, Roy, Payel, Ali, Amal J, Miyamoto, Yukiko, Mangan, Matthew, Makings, Jeffrey, Wang, Zhihao, Denn, Angela, Vallejo, Jenifer, Owens, Michaela, Durant, Christopher P, Braumann, Simon, Mader, Navid, Li, Lin, Matsunami, Hiroaki, Eckmann, Lars, Latz, Eicke, Wang, Zeneng, Hazen, Stanley L, and Ley, Klaus

Subjects
Atherosclerosis, Cardiovascular, Neurosciences, Aging, 2.1 Biological and endogenous factors, Aetiology, Adult, Aldehydes, Animals, Aorta, Humans, Inflammasomes, Interleukin-1, Interleukin-1alpha, Interleukin-1beta, Lipid Peroxidation, Macrophages, Mice, Mice, Inbred C57BL, Middle Aged, NLR Family, Pyrin Domain-Containing 3 Protein, Oxidative Stress, Receptors, Odorant, Signal Transduction, General Science & Technology
Abstract

Atherosclerosis is an inflammatory disease of the artery walls and involves immune cells such as macrophages. Olfactory receptors (OLFRs) are G protein–coupled chemoreceptors that have a central role in detecting odorants and the sense of smell. We found that mouse vascular macrophages express the olfactory receptor Olfr2 and all associated trafficking and signaling molecules. Olfr2 detects the compound octanal, which activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome and induces interleukin-1β secretion in human and mouse macrophages. We found that human and mouse blood plasma contains octanal, a product of lipid peroxidation, at concentrations sufficient to activate Olfr2 and the human ortholog olfactory receptor 6A2 (OR6A2). Boosting octanal levels exacerbated atherosclerosis, whereas genetic targeting of Olfr2 in mice significantly reduced atherosclerotic plaques. Our findings suggest that inhibiting OR6A2 may provide a promising strategy to prevent and treat atherosclerosis.

Published
2022

40. Structural basis for antibody inhibition of flavivirus NS1–triggered endothelial dysfunction

Author

Biering, Scott B, Akey, David L, Wong, Marcus P, Brown, W Clay, Lo, Nicholas TN, Puerta-Guardo, Henry, Tramontini Gomes de Sousa, Francielle, Wang, Chunling, Konwerski, Jamie R, Espinosa, Diego A, Bockhaus, Nicholas J, Glasner, Dustin R, Li, Jeffrey, Blanc, Sophie F, Juan, Evan Y, Elledge, Stephen J, Mina, Michael J, Beatty, P Robert, Smith, Janet L, and Harris, Eva

Subjects
Vaccine Related, Prevention, Immunization, Vector-Borne Diseases, Rare Diseases, Emerging Infectious Diseases, Biodefense, Infectious Diseases, West Nile Virus, Aetiology, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Cross Reactions, Crystallography, X-Ray, Dengue, Dengue Virus, Endothelium, Glycocalyx, Humans, Mice, Protein Conformation, beta-Strand, Protein Domains, Viral Nonstructural Proteins, West Nile Fever, West Nile virus, Zika Virus, Zika Virus Infection, General Science & Technology
Abstract

Medically important flaviviruses cause diverse disease pathologies and collectively are responsible for a major global disease burden. A contributing factor to pathogenesis is secreted flavivirus nonstructural protein 1 (NS1). Despite demonstrated protection by NS1-specific antibodies against lethal flavivirus challenge, the structural and mechanistic basis remains unknown. Here, we present three crystal structures of full-length dengue virus NS1 complexed with a flavivirus-cross-reactive, NS1-specific monoclonal antibody, 2B7, at resolutions between 2.89 and 3.96 angstroms. These structures reveal a protective mechanism by which two domains of NS1 are antagonized simultaneously. The NS1 wing domain mediates cell binding, whereas the β-ladder triggers downstream events, both of which are required for dengue, Zika, and West Nile virus NS1-mediated endothelial dysfunction. These observations provide a mechanistic explanation for 2B7 protection against NS1-induced pathology and demonstrate the potential of one antibody to treat infections by multiple flaviviruses.

Published
2021

41. Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms

Author

Gordon, David E, Hiatt, Joseph, Bouhaddou, Mehdi, Rezelj, Veronica V, Ulferts, Svenja, Braberg, Hannes, Jureka, Alexander S, Obernier, Kirsten, Guo, Jeffrey Z, Batra, Jyoti, Kaake, Robyn M, Weckstein, Andrew R, Owens, Tristan W, Gupta, Meghna, Pourmal, Sergei, Titus, Erron W, Cakir, Merve, Soucheray, Margaret, McGregor, Michael, Cakir, Zeynep, Jang, Gwendolyn, O’Meara, Matthew J, Tummino, Tia A, Zhang, Ziyang, Foussard, Helene, Rojc, Ajda, Zhou, Yuan, Kuchenov, Dmitry, Hüttenhain, Ruth, Xu, Jiewei, Eckhardt, Manon, Swaney, Danielle L, Fabius, Jacqueline M, Ummadi, Manisha, Tutuncuoglu, Beril, Rathore, Ujjwal, Modak, Maya, Haas, Paige, Haas, Kelsey M, Naing, Zun Zar Chi, Pulido, Ernst H, Shi, Ying, Barrio-Hernandez, Inigo, Memon, Danish, Petsalaki, Eirini, Dunham, Alistair, Marrero, Miguel Correa, Burke, David, Koh, Cassandra, Vallet, Thomas, Silvas, Jesus A, Azumaya, Caleigh M, Billesbølle, Christian, Brilot, Axel F, Campbell, Melody G, Diallo, Amy, Dickinson, Miles Sasha, Diwanji, Devan, Herrera, Nadia, Hoppe, Nick, Kratochvil, Huong T, Liu, Yanxin, Merz, Gregory E, Moritz, Michelle, Nguyen, Henry C, Nowotny, Carlos, Puchades, Cristina, Rizo, Alexandrea N, Schulze-Gahmen, Ursula, Smith, Amber M, Sun, Ming, Young, Iris D, Zhao, Jianhua, Asarnow, Daniel, Biel, Justin, Bowen, Alisa, Braxton, Julian R, Chen, Jen, Chio, Cynthia M, Chio, Un Seng, Deshpande, Ishan, Doan, Loan, Faust, Bryan, Flores, Sebastian, Jin, Mingliang, Kim, Kate, Lam, Victor L, Li, Fei, Li, Junrui, Li, Yen-Li, Li, Yang, Liu, Xi, Lo, Megan, Lopez, Kyle E, Melo, Arthur A, Moss, Frank R, Nguyen, Phuong, Paulino, Joana, Pawar, Komal Ishwar, and Peters, Jessica K

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Infectious Diseases, Coronaviruses Therapeutics and Interventions, Lung, Coronaviruses, Pneumonia, Emerging Infectious Diseases, Genetics, Biodefense, Pneumonia & Influenza, Generic health relevance, Infection, Good Health and Well Being, COVID-19, Conserved Sequence, Coronavirus Nucleocapsid Proteins, Cryoelectron Microscopy, Host Microbial Interactions, Humans, Mitochondrial Membrane Transport Proteins, Mitochondrial Precursor Protein Import Complex Proteins, Phosphoproteins, Protein Conformation, Protein Interaction Maps, Severe acute respiratory syndrome-related coronavirus, SARS-CoV-2, Severe Acute Respiratory Syndrome, QCRG Structural Biology Consortium, Zoonomia Consortium, General Science & Technology
Abstract

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo-electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study.

Published
2020

42. Biosynthesis of fluopsin C, a copper-containing antibiotic from Pseudomonas aeruginosa

Author

Patteson, Jon B, Putz, Andrew T, Tao, Lizhi, Simke, William C, Bryant, L Henry, Britt, R David, and Li, Bo

Subjects
Microbiology, Medical Microbiology, Biomedical and Clinical Sciences, Biological Sciences, Infectious Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 2.2 Factors relating to the physical environment, Aetiology, Infection, Anti-Bacterial Agents, Bacteria, Biosynthetic Pathways, Copper, Drug Resistance, Bacterial, Electron Spin Resonance Spectroscopy, Genes, Bacterial, Microbial Sensitivity Tests, Molecular Structure, Operon, Pseudomonas aeruginosa, General Science & Technology
Abstract

Metal-binding natural products contribute to metal acquisition and bacterial virulence, but their roles in metal stress response are underexplored. We show that a five-enzyme pathway in Pseudomonas aeruginosa synthesizes a small-molecule copper complex, fluopsin C, in response to elevated copper concentrations. Fluopsin C is a broad-spectrum antibiotic that contains a copper ion chelated by two minimal thiohydroxamates. Biosynthesis of the thiohydroxamate begins with cysteine and requires two lyases, two iron-dependent enzymes, and a methyltransferase. The iron-dependent enzymes remove the carboxyl group and the α carbon from cysteine through decarboxylation, N-hydroxylation, and methylene excision. Conservation of the pathway in P. aeruginosa and other bacteria suggests a common role for fluopsin C in the copper stress response, which involves fusing copper into an antibiotic against other microbes.

Published
2021

43. Reconstitution of an intact clock reveals mechanisms of circadian timekeeping

Author

Chavan, Archana G, Swan, Jeffrey A, Heisler, Joel, Sancar, Cigdem, Ernst, Dustin C, Fang, Mingxu, Palacios, Joseph G, Spangler, Rebecca K, Bagshaw, Clive R, Tripathi, Sarvind, Crosby, Priya, Golden, Susan S, Partch, Carrie L, and LiWang, Andy

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Sleep Research, Bacterial Proteins, Circadian Rhythm, Circadian Rhythm Signaling Peptides and Proteins, Gene Expression Regulation, Bacterial, Molecular Mimicry, Mutation, Phosphotransferases, Promoter Regions, Genetic, Protein Domains, Protein Folding, Protein Kinases, Protein Multimerization, Synechococcus, Transcription, Genetic, General Science & Technology
Abstract

Circadian clocks control gene expression to provide an internal representation of local time. We report reconstitution of a complete cyanobacterial circadian clock in vitro, including the central oscillator, signal transduction pathways, downstream transcription factor, and promoter DNA. The entire system oscillates autonomously and remains phase coherent for many days with a fluorescence-based readout that enables real-time observation of each component simultaneously without user intervention. We identified the molecular basis for loss of cycling in an arrhythmic mutant and explored fundamental mechanisms of timekeeping in the cyanobacterial clock. We find that SasA, a circadian sensor histidine kinase associated with clock output, engages directly with KaiB on the KaiC hexamer to regulate period and amplitude of the central oscillator. SasA uses structural mimicry to cooperatively recruit the rare, fold-switched conformation of KaiB to the KaiC hexamer to form the nighttime repressive complex and enhance rhythmicity of the oscillator, particularly under limiting concentrations of KaiB. Thus, the expanded in vitro clock reveals previously unknown mechanisms by which the circadian system of cyanobacteria maintains the pace and rhythmicity under variable protein concentrations.

Published
2021

44. A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity

Author

Swaney, Danielle L, Ramms, Dana J, Wang, Zhiyong, Park, Jisoo, Goto, Yusuke, Soucheray, Margaret, Bhola, Neil, Kim, Kyumin, Zheng, Fan, Zeng, Yan, McGregor, Michael, Herrington, Kari A, O'Keefe, Rachel, Jin, Nan, VanLandingham, Nathan K, Foussard, Helene, Von Dollen, John, Bouhaddou, Mehdi, Jimenez-Morales, David, Obernier, Kirsten, Kreisberg, Jason F, Kim, Minkyu, Johnson, Daniel E, Jura, Natalia, Grandis, Jennifer R, Gutkind, J Silvio, Ideker, Trey, and Krogan, Nevan J

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Cancer, Genetics, Rare Diseases, Dental/Oral and Craniofacial Disease, 2.1 Biological and endogenous factors, Aetiology, Animals, Carcinoma, Squamous Cell, Cell Line, Tumor, Cell Movement, Class I Phosphatidylinositol 3-Kinases, Drug Resistance, Neoplasm, Female, Head and Neck Neoplasms, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Nude, Microfilament Proteins, Mutation, Protein Interaction Maps, Receptor, Fibroblast Growth Factor, Type 3, Xenograft Model Antitumor Assays, General Science & Technology
Abstract

We outline a framework for elucidating tumor genetic complexity through multidimensional protein-protein interaction maps and apply it to enhancing our understanding of head and neck squamous cell carcinoma. This network uncovers 771 interactions from cancer and noncancerous cell states, including WT and mutant protein isoforms. Prioritization of cancer-enriched interactions reveals a previously unidentified association of the fibroblast growth factor receptor tyrosine kinase 3 with Daple, a guanine-nucleotide exchange factor, resulting in activation of Gαi- and p21-activated protein kinase 1/2 to promote cancer cell migration. Additionally, we observe mutation-enriched interactions between the human epidermal growth factor receptor 3 (HER3) receptor tyrosine kinase and PIK3CA (the alpha catalytic subunit of phosphatidylinositol 3-kinase) that can inform the response to HER3 inhibition in vivo. We anticipate that the application of this framework will be valuable for translating genetic alterations into a molecular and clinical understanding of the underlying biology of many disease areas.

Published
2021

45. A protein interaction landscape of breast cancer

Author

Kim, Minkyu, Park, Jisoo, Bouhaddou, Mehdi, Kim, Kyumin, Rojc, Ajda, Modak, Maya, Soucheray, Margaret, McGregor, Michael J, O'Leary, Patrick, Wolf, Denise, Stevenson, Erica, Foo, Tzeh Keong, Mitchell, Dominique, Herrington, Kari A, Muñoz, Denise P, Tutuncuoglu, Beril, Chen, Kuei-Ho, Zheng, Fan, Kreisberg, Jason F, Diolaiti, Morgan E, Gordan, John D, Coppé, Jean-Philippe, Swaney, Danielle L, Xia, Bing, van 't Veer, Laura, Ashworth, Alan, Ideker, Trey, and Krogan, Nevan J

Subjects
Biotechnology, Breast Cancer, Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Cell Line, Tumor, Female, Humans, Mass Spectrometry, Mutation, Neoplasm Proteins, Protein Interaction Maps, Tandem Affinity Purification, General Science & Technology
Abstract

Cancers have been associated with a diverse array of genomic alterations. To help mechanistically understand such alterations in breast-invasive carcinoma, we applied affinity purification–mass spectrometry to delineate comprehensive biophysical interaction networks for 40 frequently altered breast cancer (BC) proteins, with and without relevant mutations, across three human breast cell lines. These networks identify cancer-specific protein-protein interactions (PPIs), interconnected and enriched for common and rare cancer mutations, that are substantially rewired by the introduction of key BC mutations. Our analysis identified BPIFA1 and SCGB2A1 as PIK3CA-interacting proteins, which repress PI3K-AKT signaling, and uncovered USP28 and UBE2N as functionally relevant interactors of BRCA1. We also show that the protein phosphatase 1 regulatory subunit spinophilin interacts with and regulates dephosphorylation of BRCA1 to promote DNA double-strand break repair. Thus, PPI landscapes provide a powerful framework for mechanistically interpreting disease genomic data and can identify valuable therapeutic targets.

Published
2021

46. Response to Comments on “Aberrant type 1 immunity drives susceptibility to mucosal fungal infections”

Author

Break, Timothy J, Oikonomou, Vasileios, Dutzan, Nicolas, Desai, Jigar V, Swidergall, Marc, Freiwald, Tilo, Chauss, Daniel, Harrison, Oliver J, Alejo, Julie, Williams, Drake W, Pittaluga, Stefania, Lee, Chyi-Chia R, Bouladoux, Nicolas, Swamydas, Muthulekha, Hoffman, Kevin W, Greenwell-Wild, Teresa, Bruno, Vincent M, Rosen, Lindsey B, Lwin, Wint, Renteria, Andy, Pontejo, Sergio M, Shannon, John P, Myles, Ian A, Olbrich, Peter, Ferré, Elise MN, Schmitt, Monica, Martin, Daniel, Core16, Genomics and Computational Biology, Barber, Daniel L, Solis, Norma V, Notarangelo, Luigi D, Serreze, David V, Matsumoto, Mitsuru, Hickman, Heather D, Murphy, Philip M, Anderson, Mark S, Lim, Jean K, Holland, Steven M, Filler, Scott G, Afzali, Behdad, Belkaid, Yasmine, Moutsopoulos, Niki M, and Lionakis, Michail S

Subjects
Autoimmune Disease, Clinical Research, Infectious Diseases, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Humans, Immunity, Mucosal, Mucous Membrane, Mycoses, Genomics and Computational Biology Core16, General Science & Technology
Abstract

Puel and Casanova and Kisand et al. challenge our conclusions that interferonopathy and not IL-17/IL-22 autoantibodies promote candidiasis in autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy. We acknowledge that conclusive evidence for causation is difficult to obtain in complex human diseases. However, our studies clearly document interferonopathy driving mucosal candidiasis with intact IL-17/IL-22 responses in Aire-deficient mice, with strong corroborative evidence in patients.

Published
2021

47. Fisheries rely on threatened salt marshes

Author

Baker, Ronald, Taylor, Matthew D, Able, Kenneth W, Beck, Michael W, Cebrian, Just, Colombano, Denise D, Connolly, Rod M, Currin, Carolyn, Deegan, Linda A, Feller, Ilka C, Gilby, Ben L, Kimball, Matthew E, Minello, Thomas J, Rozas, Lawrence P, Simenstad, Charles, Turner, R Eugene, Waltham, Nathan J, Weinstein, Michael P, Ziegler, Shelby L, Zu Ermgassen, Philine SE, Alcott, Caitlin, Alford, Scott B, Barbeau, Myriam A, Crosby, Sarah C, Dodds, Kate, Frank, Alyssa, Goeke, Janelle, Goodridge Gaines, Lucy A, Hardcastle, Felicity E, Henderson, Christopher J, James, W Ryan, Kenworthy, Matthew D, Lesser, Justin, Mallick, Debbrota, Martin, Charles W, McDonald, Ashley E, McLuckie, Catherine, Morrison, Blair H, Nelson, James A, Norris, Gregory S, Ollerhead, Jeff, Pahl, James W, Ramsden, Sarah, Rehage, Jennifer S, Reinhardt, James F, Rezek, Ryan J, Risse, L Mark, Smith, Joseph AM, Sparks, Eric L, and Staver, Lorie W

Subjects
Environmental Restoration and Remediation, Fisheries, United States, Wetlands, General Science & Technology
Published
2020

48. Cryptic transmission of SARS-CoV-2 in Washington state

Author

Bedford, Trevor, Greninger, Alexander L, Roychoudhury, Pavitra, Starita, Lea M, Famulare, Michael, Huang, Meei-Li, Nalla, Arun, Pepper, Gregory, Reinhardt, Adam, Xie, Hong, Shrestha, Lasata, Nguyen, Truong N, Adler, Amanda, Brandstetter, Elisabeth, Cho, Shari, Giroux, Danielle, Han, Peter D, Fay, Kairsten, Frazar, Chris D, Ilcisin, Misja, Lacombe, Kirsten, Lee, Jover, Kiavand, Anahita, Richardson, Matthew, Sibley, Thomas R, Truong, Melissa, Wolf, Caitlin R, Nickerson, Deborah A, Rieder, Mark J, Englund, Janet A, Hadfield, James, Hodcroft, Emma B, Huddleston, John, Moncla, Louise H, Müller, Nicola F, Neher, Richard A, Deng, Xianding, Gu, Wei, Federman, Scot, Chiu, Charles, Duchin, Jeffrey S, Gautom, Romesh, Melly, Geoff, Hiatt, Brian, Dykema, Philip, Lindquist, Scott, Queen, Krista, Tao, Ying, Uehara, Anna, Tong, Suxiang, MacCannell, Duncan, Armstrong, Gregory L, Baird, Geoffrey S, Chu, Helen Y, Shendure, Jay, Jerome, Keith R, Boeckh, Michael, Lutz, Barry R, Thompson, Matthew, Huang, Shichu, Jackson, Michael L, Kimball, Louise E, Logue, Jennifer, Lyon, Victoria, Newman, Kira L, and Suchsland, Monica L Zigman

Subjects
Infectious Diseases, Pneumonia & Influenza, Lung, Prevention, Emerging Infectious Diseases, Biodefense, Vaccine Related, Pneumonia, Infection, Good Health and Well Being, Bayes Theorem, Betacoronavirus, COVID-19, Coronavirus Infections, Genome, Viral, Humans, Likelihood Functions, Pandemics, Phylogeny, Pneumonia, Viral, SARS-CoV-2, Washington, Seattle Flu Study Investigators, General Science & Technology
Abstract

After its emergence in Wuhan, China, in late November or early December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus rapidly spread globally. Genome sequencing of SARS-CoV-2 allows the reconstruction of its transmission history, although this is contingent on sampling. We analyzed 453 SARS-CoV-2 genomes collected between 20 February and 15 March 2020 from infected patients in Washington state in the United States. We find that most SARS-CoV-2 infections sampled during this time derive from a single introduction in late January or early February 2020, which subsequently spread locally before active community surveillance was implemented.

Published
2020

49. Proximal colon–derived O-glycosylated mucus encapsulates and modulates the microbiota

Author

Bergstrom, Kirk, Shan, Xindi, Casero, David, Batushansky, Albert, Lagishetty, Venu, Jacobs, Jonathan P, Hoover, Christopher, Kondo, Yuji, Shao, Bojing, Gao, Liang, Zandberg, Wesley, Noyovitz, Benjamin, McDaniel, J Michael, Gibson, Deanna L, Pakpour, Sepideh, Kazemian, Negin, McGee, Samuel, Houchen, Courtney W, Rao, Chinthalapally V, Griffin, Timothy M, Sonnenburg, Justin L, McEver, Rodger P, Braun, Jonathan, and Xia, Lijun

Subjects
Digestive Diseases, Cancer, Colo-Rectal Cancer, Animals, Colon, Feces, Gastrointestinal Microbiome, Glycosylation, Mice, Mice, Knockout, Mucin-2, Mucus, Transcription, Genetic, General Science & Technology
Abstract

Colon mucus segregates the intestinal microbiota from host tissues, but how it organizes to function throughout the colon is unclear. In mice, we found that colon mucus consists of two distinct O-glycosylated entities of Muc2: a major form produced by the proximal colon, which encapsulates the fecal material including the microbiota, and a minor form derived from the distal colon, which adheres to the major form. The microbiota directs its own encapsulation by inducing Muc2 production from proximal colon goblet cells. In turn, O-glycans on proximal colon-derived Muc2 modulate the structure and function of the microbiota as well as transcription in the colon mucosa. Our work shows how proximal colon control of mucin production is an important element in the regulation of host-microbiota symbiosis.

Published
2020

50. The activities of drug inactive ingredients on biological targets

Author

Pottel, Joshua, Armstrong, Duncan, Zou, Ling, Fekete, Alexander, Huang, Xi-Ping, Torosyan, Hayarpi, Bednarczyk, Dallas, Whitebread, Steven, Bhhatarai, Barun, Liang, Guiqing, Jin, Hong, Ghaemi, S Nassir, Slocum, Samuel, Lukacs, Katalin V, Irwin, John J, Berg, Ellen L, Giacomini, Kathleen M, Roth, Bryan L, Shoichet, Brian K, and Urban, Laszlo

Subjects
5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Animals, Drug Compounding, Drug Evaluation, Preclinical, Excipients, Humans, Molecular Targeted Therapy, General Science & Technology
Abstract

Excipients, considered "inactive ingredients," are a major component of formulated drugs and play key roles in their pharmacokinetics. Despite their pervasiveness, whether they are active on any targets has not been systematically explored. We computed the likelihood that approved excipients would bind to molecular targets. Testing in vitro revealed 25 excipient activities, ranging from low-nanomolar to high-micromolar concentration. Another 109 activities were identified by testing against clinical safety targets. In cellular models, five excipients had fingerprints predictive of system-level toxicity. Exposures of seven excipients were investigated, and in certain populations, two of these may reach levels of in vitro target potency, including brain and gut exposure of thimerosal and its major metabolite, which had dopamine D3 receptor dissociation constant K d values of 320 and 210 nM, respectively. Although most excipients deserve their status as inert, many approved excipients may directly modulate physiologically relevant targets.

Published
2020

Catalog

Books, media, physical & digital resources
See catalog results