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1. Vocal learning-associated convergent evolution in mammalian proteins and regulatory elements.

Author: Wirthlin, Morgan, Schmid, Tobias, Elie, Julie, Zhang, Xiaomeng, Kowalczyk, Amanda, Redlich, Ruby, Shvareva, Varvara, Rakuljic, Ashley, Ji, Maria, Bhat, Ninad, Kaplow, Irene, Schäffer, Daniel, Lawler, Alyssa, Wang, Andrew, Phan, BaDoi, Annaldasula, Siddharth, Brown, Ashley, Lu, Tianyu, Lim, Byung, Azim, Eiman, Clark, Nathan, Meyer, Wynn, Pond, Sergei, Chikina, Maria, Yartsev, Michael, Pfenning, Andreas, Andrews, Gregory, Armstrong, Joel, Bianchi, Matteo, Birren, Bruce, Bredemeyer, Kevin, Breit, Ana, Christmas, Matthew, Clawson, Hiram, Damas, Joana, Di Palma, Federica, Diekhans, Mark, Dong, Michael, Eizirik, Eduardo, Fan, Kaili, Fanter, Cornelia, Foley, Nicole, Forsberg-Nilsson, Karin, Garcia, Carlos, Gatesy, John, Gazal, Steven, Genereux, Diane, Goodman, Linda, Grimshaw, Jenna, Halsey, Michaela, Harris, Andrew, Hickey, Glenn, Hiller, Michael, Hindle, Allyson, Hubley, Robert, Hughes, Graham, Johnson, Jeremy, Juan, David, Karlsson, Elinor, Keough, Kathleen, Kirilenko, Bogdan, Koepfli, Klaus-Peter, Korstian, Jennifer, Kozyrev, Sergey, Lawless, Colleen, Lehmann, Thomas, Levesque, Danielle, Lewin, Harris, Li, Xue, Lind, Abigail, Lindblad-Toh, Kerstin, Mackay-Smith, Ava, Marinescu, Voichita, Marques-Bonet, Tomas, Mason, Victor, Meadows, Jennifer, Moore, Jill, Moreira, Lucas, Moreno-Santillan, Diana, Morrill, Kathleen, Muntané, Gerard, Murphy, William, Navarro, Arcadi, Nweeia, Martin, Ortmann, Sylvia, Osmanski, Austin, Paten, Benedict, Paulat, Nicole, Pollard, Katherine, Pratt, Henry, Ray, David, Reilly, Steven, Rosen, Jeb, and Ruf, Irina
Subjects: Animals, Chiroptera, Vocalization, Animal, Motor Cortex, Chromatin, Enhancer Elements, Genetic, Motor Neurons, Larynx, Epigenesis, Genetic, Genome, Gene Expression Regulation, Evolution, Molecular, Proteins, Amino Acid Sequence, Eutheria, Machine Learning
Abstract: Vocal production learning (vocal learning) is a convergently evolved trait in vertebrates. To identify brain genomic elements associated with mammalian vocal learning, we integrated genomic, anatomical, and neurophysiological data from the Egyptian fruit bat (Rousettus aegyptiacus) with analyses of the genomes of 215 placental mammals. First, we identified a set of proteins evolving more slowly in vocal learners. Then, we discovered a vocal motor cortical region in the Egyptian fruit bat, an emergent vocal learner, and leveraged that knowledge to identify active cis-regulatory elements in the motor cortex of vocal learners. Machine learning methods applied to motor cortex open chromatin revealed 50 enhancers robustly associated with vocal learning whose activity tended to be lower in vocal learners. Our research implicates convergent losses of motor cortex regulatory elements in mammalian vocal learning evolution.
Published: 2024

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. Effect of an endothelial regulatory module on plasma proteomics in exercising horses

Author: Amiri Roudbar, Mahmoud, Rosengren, Maria K., Mousavi, Seyedeh Fatemeh, Fegraeus, Kim, Naboulsi, Rakan, Meadows, Jennifer R.S., and Lindgren, Gabriella
Published: 2024
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12. Evolution of the ancestral mammalian karyotype and syntenic regions

Author: Damas, Joana, Corbo, Marco, Kim, Jaebum, Turner-Maier, Jason, Farré, Marta, Larkin, Denis M, Ryder, Oliver A, Steiner, Cynthia, Houck, Marlys L, Hall, Shaune, Shiue, Lily, Thomas, Stephen, Swale, Thomas, Daly, Mark, Korlach, Jonas, Uliano-Silva, Marcela, Mazzoni, Camila J, Birren, Bruce W, Genereux, Diane P, Johnson, Jeremy, Lindblad-Toh, Kerstin, Karlsson, Elinor K, Nweeia, Martin T, Johnson, Rebecca N, Lewin, Harris A, Andrews, Gregory, Armstrong, Joel C, Bianchi, Matteo, Bredemeyer, Kevin R, Breit, Ana M, Christmas, Matthew J, Clawson, Hiram, 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, 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, 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, and Ryan, Louise
Subjects: Biological Sciences, Bioinformatics and Computational Biology, Evolutionary Biology, Genetics, Human Genome, Generic health relevance, Animals, Cattle, Chromosomes, Mammalian, Eutheria, Evolution, Molecular, Humans, Karyotype, Mammals, Phylogeny, Sloths, Synteny, chromosome evolution, mammals, synteny conservation, ancestral genome reconstruction, topologically associating domains, Zoonomia Consortium
Abstract: Decrypting the rearrangements that drive mammalian chromosome evolution is critical to understanding the molecular bases of speciation, adaptation, and disease susceptibility. Using 8 scaffolded and 26 chromosome-scale genome assemblies representing 23/26 mammal orders, we computationally reconstructed ancestral karyotypes and syntenic relationships at 16 nodes along the mammalian phylogeny. Three different reference genomes (human, sloth, and cattle) representing phylogenetically distinct mammalian superorders were used to assess reference bias in the reconstructed ancestral karyotypes and to expand the number of clades with reconstructed genomes. The mammalian ancestor likely had 19 pairs of autosomes, with nine of the smallest chromosomes shared with the common ancestor of all amniotes (three still conserved in extant mammals), demonstrating a striking conservation of synteny for ∼320 My of vertebrate evolution. The numbers and types of chromosome rearrangements were classified for transitions between the ancestral mammalian karyotype, descendent ancestors, and extant species. For example, 94 inversions, 16 fissions, and 14 fusions that occurred over 53 My differentiated the therian from the descendent eutherian ancestor. The highest breakpoint rate was observed between the mammalian and therian ancestors (3.9 breakpoints/My). Reconstructed mammalian ancestor chromosomes were found to have distinct evolutionary histories reflected in their rates and types of rearrangements. The distributions of genes, repetitive elements, topologically associating domains, and actively transcribed regions in multispecies homologous synteny blocks and evolutionary breakpoint regions indicate that purifying selection acted over millions of years of vertebrate evolution to maintain syntenic relationships of developmentally important genes and regulatory landscapes of gene-dense chromosomes.
Published: 2022

13. The Fledgling Mindset: Preparing Biology Students to Leave the Academic Nest

Author: Cruz, Laura, Meadows, Jennifer, and Panter, Nikki
Abstract: As Biology students prepare to complete their undergraduate degrees and continue into either a career or to another degree, the scientific skills learned in the classroom are not enough to secure their professional path. In this study, the soft skills such as the ability to work in a team and to communicate effectively were emphasized within the context of a newly designed Biology course. As a required course for majors within the Department of Biology, students represented a wide array of experiences, skill levels, and motivations. By adopting a guided inquiry approach to teaching and learning, instructors designed a student-centered course that focused on four categories of professional skills: problem solving, communication, teamwork, and career management. Data collected from student surveys were analyzed to determine the effectiveness of these interventions in enhancing student's abilities and attitudes towards professional skills. These data suggest that students increased their proficiency in attributes valued by employers regardless of gender or major; became more likely to recognize those traits sought by employers; and gained confidence in their ability to use these skills in the workplace.
Published: 2020

14. Author Correction: Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture

Author: Meadows, Jennifer R. S., Kidd, Jefrey M., Wang, Guo-Dong, Parker, Heidi G., Schall, Peter Z., Bianchi, Matteo, Christmas, Matthew J., Bougiouri, Katia, Buckley, Reuben M., Hitte, Christophe, Nguyen, Anthony K., Wang, Chao, Jagannathan, Vidhya, Niskanen, Julia E., Frantz, Laurent A. F., Arumilli, Meharji, Hundi, Sruthi, Lindblad-Toh, Kerstin, Ginja, Catarina, Agustina, Kadek Karang, André, Catherine, Boyko, Adam R., Davis, Brian W., Drögemüller, Michaela, Feng, Xin-Yao, Gkagkavouzis, Konstantinos, Iliopoulos, Giorgos, Harris, Alexander C., Hytönen, Marjo K., Kalthof, Daniela C., Liu, Yan-Hu, Lymberakis, Petros, Poulakakis, Nikolaos, Pires, Ana Elisabete, Racimo, Fernando, Ramos-Almodovar, Fabian, Savolainen, Peter, Venetsani, Semina, Tammen, Imke, Triantafyllidis, Alexandros, vonHoldt, Bridgett, Wayne, Robert K., Larson, Greger, Nicholas, Frank W., Lohi, Hannes, Leeb, Tosso, Zhang, Ya-Ping, and Ostrander, Elaine A.
Published: 2023
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15. Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture

Author: Meadows, Jennifer R. S., Kidd, Jeffrey M., Wang, Guo-Dong, Parker, Heidi G., Schall, Peter Z., Bianchi, Matteo, Christmas, Matthew J., Bougiouri, Katia, Buckley, Reuben M., Hitte, Christophe, Nguyen, Anthony K., Wang, Chao, Jagannathan, Vidhya, Niskanen, Julia E., Frantz, Laurent A. F., Arumilli, Meharji, Hundi, Sruthi, Lindblad-Toh, Kerstin, Ginja, Catarina, Agustina, Kadek Karang, André, Catherine, Boyko, Adam R., Davis, Brian W., Drögemüller, Michaela, Feng, Xin-Yao, Gkagkavouzis, Konstantinos, Iliopoulos, Giorgos, Harris, Alexander C., Hytönen, Marjo K., Kalthoff, Daniela C., Liu, Yan-Hu, Lymberakis, Petros, Poulakakis, Nikolaos, Pires, Ana Elisabete, Racimo, Fernando, Ramos-Almodovar, Fabian, Savolainen, Peter, Venetsani, Semina, Tammen, Imke, Triantafyllidis, Alexandros, vonHoldt, Bridgett, Wayne, Robert K., Larson, Greger, Nicholas, Frank W., Lohi, Hannes, Leeb, Tosso, Zhang, Ya-Ping, and Ostrander, Elaine A.
Published: 2023
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16. Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies

Author: Bianchi, Matteo, Kozyrev, Sergey V., Sandling, Johanna K., Rönnblom, Lars, Eloranta, Maija-Leena, Syvänen, Ann-Christine, Leonard, Dag, Dahlqvist, Johanna, Lidén, Maria, Mathioudaki, Argyri, Meadows, Jennifer RS., Nordin, Jessika, Nordmark, Gunnel, Lundberg, Ingrid E., Notarnicola, Antonella, Padyukov, Leonid, Tjärnlund, Anna, Dastmalchi, Maryam, Eriksson, Daniel, Molberg, Øyvind, Andersson, Helena, Lindblad-Toh, Kerstin, Farias, Fabiana H.G., Wahren-Herlenius, Marie, Jalal, Awat, Hanna, Balsam, Hellström, Helena, Husmark, Tomas, Häggström, Åsa, Svärd, Anna, Skogh, Thomas, Diederichsen, Louise Pyndt, Lamb, Janine A., Rothwell, Simon, Chinoy, Hector, Cooper, Robert G., Pielberg, Gerli Rosengren, Lobell, Anna, Karlsson, Åsa, Murén, Eva, Ahlgren, Kerstin M., Andersson, Göran, Landegren, Nils, Kämpe, Olle, Söderkvis, Peter, Leclair, Valérie, Galindo-Feria, Angeles S., Kryštůfková, Olga, Zargar, Sepehr Sarrafzadeh, Mann, Herman, Klein, Martin, Tansley, Sarah, McHugh, Neil, Vencovský, Jiri, Holmqvist, Marie, and Diaz-Gallo, Lina-Marcela
Published: 2023
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17. A comparative genomics multitool for scientific discovery and conservation

Author: Genereux, Diane P, Serres, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita D, Muren, Eva, Juan, David, Bejerano, Gill, Casewell, Nicholas R, Chemnick, Leona G, Damas, Joana, Di Palma, Federica, Diekhans, Mark, Fiddes, Ian T, Garber, Manuel, Gladyshev, Vadim N, Goodman, Linda, Haerty, Wilfried, Houck, Marlys L, Hubley, Robert, Kivioja, Teemu, Koepfli, Klaus-Peter, Kuderna, Lukas FK, Lander, Eric S, Meadows, Jennifer RS, Murphy, William J, Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R, Pollard, Katherine S, Ray, David A, Shapiro, Beth, Smit, Arian FA, Springer, Mark S, Steiner, Cynthia C, Swofford, Ross, Taipale, Jussi, Teeling, Emma C, Turner-Maier, Jason, Alfoldi, Jessica, Birren, Bruce, Ryder, Oliver A, Lewin, Harris A, Paten, Benedict, Marques-Bonet, Tomas, Lindblad-Toh, Kerstin, and Karlsson, Elinor K
Subjects: Human Genome, Genetics, Biotechnology, Life on Land, Animals, Biodiversity, Biomedical Research, Conservation of Natural Resources, Eutheria, Evolution, Molecular, Extinction, Biological, Genetic Speciation, Genetic Variation, Genomics, Humans, Infections, Knowledge Discovery, Loss of Heterozygosity, Neoplasms, Phylogeny, Risk Assessment, Selection, Genetic, Sequence Alignment, Species Specificity, Venoms, Zoonomia Consortium, General Science & Technology
Abstract: The Zoonomia Project is investigating the genomics of shared and specialized traits in eutherian mammals. Here we provide genome assemblies for 131 species, of which all but 9 are previously uncharacterized, and describe a whole-genome alignment of 240 species of considerable phylogenetic diversity, comprising representatives from more than 80% of mammalian families. We find that regions of reduced genetic diversity are more abundant in species at a high risk of extinction, discern signals of evolutionary selection at high resolution and provide insights from individual reference genomes. By prioritizing phylogenetic diversity and making data available quickly and without restriction, the Zoonomia Project aims to support biological discovery, medical research and the conservation of biodiversity.
Published: 2020

18. Interpretable machine learning identifies paediatric Systemic Lupus Erythematosus subtypes based on gene expression data

Author: Yones, Sara A., Annett, Alva, Stoll, Patricia, Diamanti, Klev, Holmfeldt, Linda, Barrenäs, Carl Fredrik, Meadows, Jennifer R. S., and Komorowski, Jan
Published: 2022
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19. Bayesian model and selection signature analyses reveal risk factors for canine atopic dermatitis

Author: Tengvall, Katarina, Sundström, Elisabeth, Wang, Chao, Bergvall, Kerstin, Wallerman, Ola, Pederson, Eric, Karlsson, Åsa, Harvey, Naomi D., Blott, Sarah C., Olby, Natasha, Olivry, Thierry, Brander, Gustaf, Meadows, Jennifer R. S., Roosje, Petra, Leeb, Tosso, Hedhammar, Åke, Andersson, Göran, and Lindblad-Toh, Kerstin
Published: 2022
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20. Effect of an endothelial regulatory module on plasma proteomics in exercising horses

Author: Roudbar, Mahmoud Amiri, primary, Rosengren, Maria K., additional, Mousavi, Seyedeh Fatemeh, additional, Fegraeus, Kim, additional, Naboulsi, Rakan, additional, Meadows, Jennifer R.S., additional, and Lindgren, Gabriella, additional
Published: 2024
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21. Sheep: Domestication

Author: Meadows, Jennifer R. S. and Smith, Claire, editor
Published: 2020
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22. An endothelial regulatory module links blood pressure regulation with elite athletic performance

Author: Fegraeus, Kim, Rosengren, Maria K., Naboulsi, Rakan, Orlando, Ludovic, Åbrink, Magnus, Jouni, Ahmad, Velie, Brandon D., Raine, Amanda, Egner, Beate, Mattsson, C. Mikael, Lång, Karin, Zhigulev, Artemy, Björck, Hanna M., Franco-Cereceda, Anders, Eriksson, Per, Andersson, Göran, Sahlén, Pelin, Meadows, Jennifer R. S., Lindgren, Gabriella, Fegraeus, Kim, Rosengren, Maria K., Naboulsi, Rakan, Orlando, Ludovic, Åbrink, Magnus, Jouni, Ahmad, Velie, Brandon D., Raine, Amanda, Egner, Beate, Mattsson, C. Mikael, Lång, Karin, Zhigulev, Artemy, Björck, Hanna M., Franco-Cereceda, Anders, Eriksson, Per, Andersson, Göran, Sahlén, Pelin, Meadows, Jennifer R. S., and Lindgren, Gabriella
Abstract: The control of transcription is crucial for homeostasis in mammals. A previous selective sweep analysis of horse racing performance revealed a 19.6 kb candidate regulatory region 50 kb downstream of the Endothelin3 (EDN3) gene. Here, the region was narrowed to a 5.5 kb span of 14 SNVs, with elite and sub-elite haplotypes analyzed for association to racing performance, blood pressure and plasma levels of EDN3 in Coldblooded trotters and Standardbreds. Comparative analysis of human HiCap data identified the span as an enhancer cluster active in endothelial cells, interacting with genes relevant to blood pressure regulation. Coldblooded trotters with the sub-elite haplotype had significantly higher blood pressure compared to horses with the elite performing haplotype during exercise. Alleles within the elite haplotype were part of the standing variation in pre-domestication horses, and have risen in frequency during the era of breed development and selection. These results advance our understanding of the molecular genetics of athletic performance and vascular traits in both horses and humans., De två första författarna delar förstaförfattarskapetDe två sista författarna delar sistaförfattarskapet
Published: 2024
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23. The HLA region in ANCA-associated vasculitis : characterisation of genetic associations in a Scandinavian patient population

Author: Lundtoft, Christian, Knight, Ann, Meadows, Jennifer, Karlsson, Åsa, Rantapää-Dahlqvist, Solbritt, Berglin, Ewa, Palm, Øyvind, Haukeland, Hilde, Gunnarsson, Iva, Bruchfeld, Annette, Segelmark, Mårten, Ohlsson, Sophie, Mohammad, Aladdin J., Eriksson, Per, Söderkvist, Peter, Rönnblom, Lars, Omdal, Roald, Jonsson, Roland, Lindblad-Toh, Kerstin, Dahlqvist, Johanna, Lundtoft, Christian, Knight, Ann, Meadows, Jennifer, Karlsson, Åsa, Rantapää-Dahlqvist, Solbritt, Berglin, Ewa, Palm, Øyvind, Haukeland, Hilde, Gunnarsson, Iva, Bruchfeld, Annette, Segelmark, Mårten, Ohlsson, Sophie, Mohammad, Aladdin J., Eriksson, Per, Söderkvist, Peter, Rönnblom, Lars, Omdal, Roald, Jonsson, Roland, Lindblad-Toh, Kerstin, and Dahlqvist, Johanna
Abstract: Objective: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV. Methods: Genotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were extracted from a targeted exome-sequencing dataset comprising Scandinavian AAV cases and controls. Classical HLA alleles were called using xHLA. After quality control, association analyses were performed of a joint SNP/classical HLA allele dataset for cases with PR3-AAV (n=411) and MPO-AAV (n=162) versus controls (n=1595). Disease-associated genetic variants were analysed for association with organ involvement, age at diagnosis and relapse, respectively. Results: PR3-AAV was significantly associated with both HLA-DPB1*04:01 and rs1042335 at the HLA-DPB1 locus, also after stepwise conditional analysis. MPO-AAV was significantly associated with HLA-DRB1*04:04. Neither carriage of HLA-DPB1*04:01 alleles in PR3-AAV nor of HLA-DRB1*04:04 alleles in MPO-AAV were associated with organ involvement, age at diagnosis or relapse. Conclusions: The association to the HLA region was distinct in Scandinavian cases with MPO-AAV compared with cases of East Asian descent. In PR3-AAV, the two separate signals of association to the HLD-DPB1 region mediate potentially different functional effects.
Published: 2024
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24. Effect of an Endothelial Regulatory Module on Plasma Proteomics in Exercising Horses

Author: Amiri Roudbar, Mahmoud, primary, Rosengren, Maria K., additional, Mousavi, Seyedeh Fatemeh, additional, Fegraeus, Kim, additional, Naboulsi, Rakan, additional, Meadows, Jennifer R. S., additional, and Lindgren, Gabriella, additional
Published: 2024
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25. SweHLA: the high confidence HLA typing bio-resource drawn from 1000 Swedish genomes

Author: Nordin, Jessika, Ameur, Adam, Lindblad-Toh, Kerstin, Gyllensten, Ulf, and Meadows, Jennifer R. S.
Published: 2020
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26. Author Correction: Targeted sequencing reveals the somatic mutation landscape in a Swedish breast cancer cohort

Author: Mathioudaki, Argyri, Ljungström, Viktor, Melin, Malin, Arendt, Maja Louise, Nordin, Jessika, Karlsson, Åsa, Murén, Eva, Saksena, Pushpa, Meadows, Jennifer R. S., Marinescu, Voichita D., Sjöblom, Tobias, and Lindblad-Toh, Kerstin
Published: 2021
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27. The ABCC4 gene is associated with pyometra in golden retriever dogs

Author: Arendt, Maja, Ambrosen, Aime, Fall, Tove, Kierczak, Marcin, Tengvall, Katarina, Meadows, Jennifer R. S., Karlsson, Åsa, Lagerstedt, Anne-Sofie, Bergström, Tomas, Andersson, Göran, Lindblad-Toh, Kerstin, and Hagman, Ragnvi
Published: 2021
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28. A novel canine reference genome resolves genomic architecture and uncovers transcript complexity

Author: Wang, Chao, Wallerman, Ola, Arendt, Maja-Louise, Sundström, Elisabeth, Karlsson, Åsa, Nordin, Jessika, Mäkeläinen, Suvi, Pielberg, Gerli Rosengren, Hanson, Jeanette, Ohlsson, Åsa, Saellström, Sara, Rönnberg, Henrik, Ljungvall, Ingrid, Häggström, Jens, Bergström, Tomas F., Hedhammar, Åke, Meadows, Jennifer R. S., and Lindblad-Toh, Kerstin
Published: 2021
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29. Planning an Informal STEM Event? Try the Assets-based Approach to Planning and Research for Informal STEM Events

Author: Meadows, Jennifer, primary, Baker, Jane, additional, Dzenga, Nyasha, additional, Hinkel, Shawn, additional, and Wilson, Carey Ann, additional
Published: 2023
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30. Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies

Author: Leclair, Valérie, primary, Galindo-Feria, Angeles S., additional, Rothwell, Simon, additional, Kryštůfková, Olga, additional, Zargar, Sepehr Sarrafzadeh, additional, Mann, Herman, additional, Diederichsen, Louise Pyndt, additional, Andersson, Helena, additional, Klein, Martin, additional, Tansley, Sarah, additional, Rönnblom, Lars, additional, Lindblad-Toh, Kerstin, additional, Syvänen, Ann-Christine, additional, Wahren-Herlenius, Marie, additional, Sandling, Johanna K., additional, McHugh, Neil, additional, Lamb, Janine A., additional, Vencovský, Jiri, additional, Chinoy, Hector, additional, Holmqvist, Marie, additional, Bianchi, Matteo, additional, Padyukov, Leonid, additional, Lundberg, Ingrid E., additional, Diaz-Gallo, Lina-Marcela, additional, Kozyrev, Sergey V., additional, Eloranta, Maija-Leena, additional, Leonard, Dag, additional, Dahlqvist, Johanna, additional, Lidén, Maria, additional, Mathioudaki, Argyri, additional, Meadows, Jennifer RS., additional, Nordin, Jessika, additional, Nordmark, Gunnel, additional, Notarnicola, Antonella, additional, Tjärnlund, Anna, additional, Dastmalchi, Maryam, additional, Eriksson, Daniel, additional, Molberg, Øyvind, additional, Farias, Fabiana H.G., additional, Jalal, Awat, additional, Hanna, Balsam, additional, Hellström, Helena, additional, Husmark, Tomas, additional, Häggström, Åsa, additional, Svärd, Anna, additional, Skogh, Thomas, additional, Cooper, Robert G., additional, Pielberg, Gerli Rosengren, additional, Lobell, Anna, additional, Karlsson, Åsa, additional, Murén, Eva, additional, Ahlgren, Kerstin M., additional, Andersson, Göran, additional, Landegren, Nils, additional, Kämpe, Olle, additional, and Söderkvis, Peter, additional
Published: 2023
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31. Digital Signage

Author: Meadows, Jennifer H., primary
Published: 2020
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32. Other New Technologies

Author: Meadows, Jennifer H., primary
Published: 2020
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33. Understanding Communication Technologies

Author: Meadows, Jennifer H., primary
Published: 2020
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34. Targeted sequencing reveals the somatic mutation landscape in a Swedish breast cancer cohort

Author: Mathioudaki, Argyri, Ljungström, Viktor, Melin, Malin, Arendt, Maja Louise, Nordin, Jessika, Karlsson, Åsa, Murén, Eva, Saksena, Pushpa, Meadows, Jennifer R. S., Marinescu, Voichita D., Sjöblom, Tobias, and Lindblad-Toh, Kerstin
Published: 2020
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35. Mutations in the CYP27B1 gene cause vitamin D dependent rickets in pugs

Author: Rohdin, Cecilia, primary, Wang, Chao, additional, Brander, Gustaf, additional, Rondahl, Veronica, additional, Karlsson, Åsa, additional, Friling, Lisa, additional, Fischetti, Anthony, additional, Meadows, Jennifer, additional, Häggström, Jens, additional, Jäderlund, Karin Hultin, additional, Ljungvall, Ingrid, additional, and Lindblad‐Toh, Kerstin, additional
Published: 2023
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36. Mutations in the CYP27B1 gene cause vitamin D dependent rickets in pugs

Author: Rohdin, Cecilia, Wang, Chao, Brander, Gustaf, Rondahl, Veronica, Karlsson, Åsa, Friling, Lisa, Fischetti, Anthony, Meadows, Jennifer, Häggström, Jens, Jäderlund, Karin Hultin, Ljungvall, Ingrid, Lindblad‐Toh, Kerstin, Rohdin, Cecilia, Wang, Chao, Brander, Gustaf, Rondahl, Veronica, Karlsson, Åsa, Friling, Lisa, Fischetti, Anthony, Meadows, Jennifer, Häggström, Jens, Jäderlund, Karin Hultin, Ljungvall, Ingrid, and Lindblad‐Toh, Kerstin
Published: 2023
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37. Relation between HLA and copy number variation of steroid 21-hydroxylase in a Swedish cohort of patients with autoimmune Addison's disease

Author: Lundtoft, Christian, Eriksson, Daniel, Bianchi, Matteo, Aranda-Guillén, Maribel, Landegren, Nils, Rantapää-Dahlqvist, Solbritt, Söderkvist, Peter, Meadows, Jennifer R.S., Bensing, Sophie, Pielberg, Gerli Rosengren, Lindblad-Toh, Kerstin, Rönnblom, Lars, Kämpe, Olle, Lundtoft, Christian, Eriksson, Daniel, Bianchi, Matteo, Aranda-Guillén, Maribel, Landegren, Nils, Rantapää-Dahlqvist, Solbritt, Söderkvist, Peter, Meadows, Jennifer R.S., Bensing, Sophie, Pielberg, Gerli Rosengren, Lindblad-Toh, Kerstin, Rönnblom, Lars, and Kämpe, Olle
Abstract: Objective: Autoantibodies against the adrenal enzyme 21-hydroxylase is a hallmark manifestation in autoimmune Addison's disease (AAD). Steroid 21-hydroxylase is encoded by CYP21A2, which is located in the human leucocyte antigen (HLA) region together with the highly similar pseudogene CYP21A1P. A high level of copy number variation is seen for the 2 genes, and therefore, we asked whether genetic variation of the CYP21 genes is associated with AAD. Design: Case-control study on patients with AAD and healthy controls. Methods: Using next-generation DNA sequencing, we estimated the copy number of CYP21A2 and CYP21A1P, together with HLA alleles, in 479 Swedish patients with AAD and autoantibodies against 21-hydroxylase and in 1393 healthy controls. Results: With 95% of individuals carrying 2 functional 21-hydroxylase genes, no difference in CYP21A2 copy number was found when comparing patients and controls. In contrast, we discovered a lower copy number of the pseudogene CYP21A1P among AAD patients (P = 5 × 10-44), together with associations of additional nucleotide variants, in the CYP21 region. However, the strongest association was found for HLADQB1*02:01 (P = 9 × 10-63), which, in combination with the DRB1*04:04-DQB1*03:02 haplotype, imposed the greatest risk of AAD. Conclusions: We identified strong associations between copy number variants in the CYP21 region and risk of AAD, although these associations most likely are due to linkage disequilibrium with disease-associated HLA class II alleles.
Published: 2023
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38. Bayesian mixed model analysis uncovered 21 risk loci for chronic kidney disease in boxer dogs

Author: Lingaas, Frode, Tengvall, Katarina, Jansen, Johan Hogset, Pelander, Lena, Hurst, Maria H., Meuwissen, Theo, Karlsson, Åsa, Meadows, Jennifer, Sundström, Elisabeth, Thoresen, Stein Istre, Arnet, Ellen Froysadal, Guttersrud, Ole Albert, Kierczak, Marcin, Hytonen, Marjo K., Lohi, Hannes, Hedhammar, Ake, Lindblad-Toh, Kerstin, Wang, Chao, Lingaas, Frode, Tengvall, Katarina, Jansen, Johan Hogset, Pelander, Lena, Hurst, Maria H., Meuwissen, Theo, Karlsson, Åsa, Meadows, Jennifer, Sundström, Elisabeth, Thoresen, Stein Istre, Arnet, Ellen Froysadal, Guttersrud, Ole Albert, Kierczak, Marcin, Hytonen, Marjo K., Lohi, Hannes, Hedhammar, Ake, Lindblad-Toh, Kerstin, and Wang, Chao
Abstract: Author summaryChronic kidney disease (CKD) is described as a set of heterogeneous disorders affecting kidney structure and function. CKD is common in dogs and has been diagnosed in nearly all breeds. In this study, we identified 21 genetic regions associated with CKD in a boxer population and investigated the relevant genes and putative regulatory variants in these regions. Studies of canine CKD may help to better understand the pathology of kidney disease in both dogs and humans, and shows an important potential for early identification of high-risk individuals. Chronic kidney disease (CKD) affects 10% of the human population, with only a small fraction genetically defined. CKD is also common in dogs and has been diagnosed in nearly all breeds, but its genetic basis remains unclear. Here, we performed a Bayesian mixed model genome-wide association analysis for canine CKD in a boxer population of 117 canine cases and 137 controls, and identified 21 genetic regions associated with the disease. At the top markers from each CKD region, the cases carried an average of 20.2 risk alleles, significantly higher than controls (15.6 risk alleles). An ANOVA test showed that the 21 CKD regions together explained 57% of CKD phenotypic variation in the population. Based on whole genome sequencing data of 20 boxers, we identified 5,206 variants in LD with the top 50 BayesR markers. Following comparative analysis with human regulatory data, 17 putative regulatory variants were identified and tested with electrophoretic mobility shift assays. In total four variants, three intronic variants from the MAGI2 and GALNT18 genes, and one variant in an intergenic region on chr28, showed alternative binding ability for the risk and protective alleles in kidney cell lines. Many genes from the 21 CKD regions, RELN, MAGI2, FGFR2 and others, have been implicated in human kidney development or disease. The results from this study provide new information that may enlighten the etiology of CKD in b
Published: 2023
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39. Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture

Author: Meadows, Jennifer, Kidd, Jeffrey M., Wang, Guo-Dong, Parker, Heidi G., Schall, Peter Z., Bianchi, Matteo, Christmas, Matthew, Bougiouri, Katia, Buckley, Reuben M., Hitte, Christophe, Nguyen, Anthony K., Wang, Chao, Jagannathan, Vidhya, Niskanen, Julia E., Frantz, Laurent A. F., Arumilli, Meharji, Hundi, Sruthi, Lindblad-Toh, Kerstin, Ginja, Catarina, Agustina, Kadek Karang, Andre, Catherine, Boyko, Adam R., Davis, Brian W., Drögemüller, Michaela, Feng, Xin-Yao, Gkagkavouzis, Konstantinos, Iliopoulos, Giorgos, Harris, Alexander C., Hytonen, Marjo K., Kalthoff, Daniela C., Liu, Yan-Hu, Lymberakis, Petros, Poulakakis, Nikolaos, Pires, Ana Elisabete, Racimo, Fernando, Ramos-Almodovar, Fabian, Savolainen, Peter, Venetsani, Semina, Tammen, Imke, Triantafyllidis, Alexandros, vonHoldt, Bridgett, Wayne, Robert K., Larson, Greger, Nicholas, Frank W., Lohi, Hannes, Leeb, Tosso, Zhang, Ya-Ping, Ostrander, Elaine A., Meadows, Jennifer, Kidd, Jeffrey M., Wang, Guo-Dong, Parker, Heidi G., Schall, Peter Z., Bianchi, Matteo, Christmas, Matthew, Bougiouri, Katia, Buckley, Reuben M., Hitte, Christophe, Nguyen, Anthony K., Wang, Chao, Jagannathan, Vidhya, Niskanen, Julia E., Frantz, Laurent A. F., Arumilli, Meharji, Hundi, Sruthi, Lindblad-Toh, Kerstin, Ginja, Catarina, Agustina, Kadek Karang, Andre, Catherine, Boyko, Adam R., Davis, Brian W., Drögemüller, Michaela, Feng, Xin-Yao, Gkagkavouzis, Konstantinos, Iliopoulos, Giorgos, Harris, Alexander C., Hytonen, Marjo K., Kalthoff, Daniela C., Liu, Yan-Hu, Lymberakis, Petros, Poulakakis, Nikolaos, Pires, Ana Elisabete, Racimo, Fernando, Ramos-Almodovar, Fabian, Savolainen, Peter, Venetsani, Semina, Tammen, Imke, Triantafyllidis, Alexandros, vonHoldt, Bridgett, Wayne, Robert K., Larson, Greger, Nicholas, Frank W., Lohi, Hannes, Leeb, Tosso, Zhang, Ya-Ping, and Ostrander, Elaine A.
Abstract: Background: The international Dog10K project aims to sequence and analyze several thousand canine genomes. Incorporating 20 x data from 1987 individuals, including 1611 dogs (321 breeds), 309 village dogs, 63 wolves, and four coyotes, we identify genomic variation across the canid family, setting the stage for detailed studies of domestication, behavior, morphology, disease susceptibility, and genome architecture and function. Results: We report the analysis of > 48 M single-nucleotide, indel, and structural variants spanning the autosomes, X chromosome, and mitochondria. We discover more than 75% of variation for 239 sampled breeds. Allele sharing analysis indicates that 94.9% of breeds form monophyletic clusters and 25 major clades. German Shepherd Dogs and related breeds show the highest allele sharing with independent breeds from multiple clades. On average, each breed dog differs from the UU_Cfam_GSD_1.0 reference at 26,960 deletions and 14,034 insertions greater than 50 bp, with wolves having 14% more variants. Discovered variants include retrogene insertions from 926 parent genes. To aid functional prioritization, single-nucleotide variants were annotated with SnpEff and Zoonomia phyloP constraint scores. Constrained positions were negatively correlated with allele frequency. Finally, the utility of the Dog10K data as an imputation reference panel is assessed, generating high-confidence calls across varied genotyping platform densities including for breeds not included in the Dog10K collection. Conclusions: We have developed a dense dataset of 1987 sequenced canids that reveals patterns of allele sharing, identifies likely functional variants, informs breed structure, and enables accurate imputation. Dog10K data are publicly available., Correction in: Genome Biology volume 24, Article number: 255 (2023)DOI: 10.1186/s13059-023-03101-w
Published: 2023
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40. Leveraging base-pair mammalian constraint to understand genetic variation and human disease

Author: Sullivan, Patrick F., Meadows, Jennifer, 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, Marinescu, Voichita, 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, Sullivan, Patrick F., Meadows, Jennifer, 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, Marinescu, Voichita, 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., and Lindblad-Toh, Kerstin
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
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41. Evolutionary constraint and innovation across hundreds of placental mammals

Author: Christmas, Matthew, 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 R.S., 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, 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., Nweela, Martin, Sabeti, Pardis C., Shapiro, Beth, Smit, Arian F. A., 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., Christmas, Matthew, 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 R.S., 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, 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., Nweela, Martin, Sabeti, Pardis C., Shapiro, Beth, Smit, Arian F. A., 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, and Karlsson, Elinor K.
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 (similar to 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
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42. Leveraging base-pair mammalian constraint to understand genetic variation and human disease

Author: Swedish Research Council, Knut and Alice Wallenberg Foundation, Swedish Cancer Society, Swedish Childhood Cancer Foundation, National Institute of Mental Health (US), Gladstone Institutes, National Institute on Drug Abuse (US), University College Dublin, National Human Genome Research Institute (US), National Institutes of Health (US), National Health and Medical Research Council (Australia), Juan, David [0000-0003-1912-9667], Marqués-Bonet, Tomàs [0000-0002-5597-3075], Muntané, Gerard [0000-0003-1541-8365], Navarro, Arcadi [0000-0003-2162-8246], Valenzuela, Alejandro [0000-0001-6120-6246], Sullivan, Patrick F., Meadows, Jennifer R. S., 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, Zoonomia Consortium, Juan, David, Marqués-Bonet, Tomàs, Muntané, Gerard, Navarro, Arcadi, Serres-Armero, Aitor, Valenzuela, Alejandro, 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, Swedish Research Council, Knut and Alice Wallenberg Foundation, Swedish Cancer Society, Swedish Childhood Cancer Foundation, National Institute of Mental Health (US), Gladstone Institutes, National Institute on Drug Abuse (US), University College Dublin, National Human Genome Research Institute (US), National Institutes of Health (US), National Health and Medical Research Council (Australia), Juan, David [0000-0003-1912-9667], Marqués-Bonet, Tomàs [0000-0002-5597-3075], Muntané, Gerard [0000-0003-1541-8365], Navarro, Arcadi [0000-0003-2162-8246], Valenzuela, Alejandro [0000-0001-6120-6246], Sullivan, Patrick F., Meadows, Jennifer R. S., 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, Zoonomia Consortium, Juan, David, Marqués-Bonet, Tomàs, Muntané, Gerard, Navarro, Arcadi, Serres-Armero, Aitor, Valenzuela, Alejandro, Paten, Benedict, Reilly, Steven K., Hughes, Graham M., Weng, Zhiping, Pollard, Katherine S., Pfenning, Andreas R., Forsberg-Nilsson, Karin, Karlsson, Elinor K., and Lindblad-Toh, Kerstin
Abstract: [INTRODUCTION] Thousands of genetic variants have been associated with human diseases and traits through genome-wide association studies (GWASs). Translating these discoveries into improved therapeutics requires discerning which variants among hundreds of candidates are causally related to disease risk. To date, only a handful of causal variants have been confirmed. Here, we leverage 100 million years of mammalian evolution to address this major challenge., [RATIONALE] We compared genomes from hundreds of mammals and identified bases with unusually few variants (evolutionarily constrained). Constraint is a measure of functional importance that is agnostic to cell type or developmental stage. It can be applied to investigate any heritable disease or trait and is complementary to resources using cell type– and time point–specific functional assays like Encyclopedia of DNA Elements (ENCODE) and Genotype-Tissue Expression (GTEx)., [RESULTS] Using constraint calculated across placental mammals, 3.3% of bases in the human genome are significantly constrained, including 57.6% of coding bases. Most constrained bases (80.7%) are noncoding. Common variants (allele frequency ≥ 5%) and low-frequency variants (0.5% ≤ allele frequency < 5%) are depleted for constrained bases (1.85 versus 3.26% expected by chance, P < 2.2 × 10−308). Pathogenic ClinVar variants are more constrained than benign variants (P < 2.2 × 10−16). The most constrained common variants are more enriched for disease single-nucleotide polymorphism (SNP)–heritability in 63 independent GWASs. The enrichment of SNP-heritability in constrained regions is greater (7.8-fold) than previously reported in mammals and is even higher in primates (11.1-fold). It exceeds the enrichment of SNP-heritability in nonsynonymous coding variants (7.2-fold) and fine-mapped expression quantitative trait loci (eQTL)–SNPs (4.8-fold). The enrichment peaks near constrained bases, with a log-linear decrease of SNP-heritability enrichment as a function of the distance to a constrained base. Zoonomia constraint scores improve functionally informed fine-mapping. Variants at sites constrained in mammals and primates have greater posterior inclusion probabilities and higher per-SNP contributions. In addition, using both constraint and functional annotations improves polygenic risk score accuracy across a range of traits. Finally, incorporating constraint information into the analysis of noncoding somatic variants in medulloblastomas identifies new candidate driver genes., [CONCLUSION] Genome-wide measures of evolutionary constraint can help discern which variants are functionally important. This information may accelerate the translation of genomic discoveries into the biological, clinical, and therapeutic knowledge that is required to understand and treat human disease.
Published: 2023

43. Evolutionary constraint and innovation across hundreds of placental mammals

Author: National Institutes of Health (US), National Science Foundation (US), European Research Council, European Commission, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Science Foundation Ireland, Irish Research Council, Swedish Research Council, Carnegie Mellon University, Roddenberry Foundation, Gladstone Institutes, LOEWE Center for Insect Biotechnology & Bioresources, Robert and Rosabel Osborne Endowment, SFI Research Centre in Applied Geosciences (Ireland), Alfred P. Sloan Foundation, UMaine Institute of Medicine, University College Dublin, Knut and Alice Wallenberg Foundation, Lehigh University, Valenzuela, Alejandro [0000-0001-6120-6246], Marqués-Bonet, Tomàs [0000-0002-5597-3075], Navarro, Arcadi [0000-0003-2162-8246], 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 R. S., 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., Zoonomia Consortium, Birren, Bruce W., Gazal, Steven, Hubley, Robert M., Koepfli, Klaus-Peter, Marqués-Bonet, Tomàs, Meyer, Wynn K., Nweeia, Martin, Sabeti, Pardis C., Shapiro, Beth, Smit, Arian F. A., 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., National Institutes of Health (US), National Science Foundation (US), European Research Council, European Commission, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Science Foundation Ireland, Irish Research Council, Swedish Research Council, Carnegie Mellon University, Roddenberry Foundation, Gladstone Institutes, LOEWE Center for Insect Biotechnology & Bioresources, Robert and Rosabel Osborne Endowment, SFI Research Centre in Applied Geosciences (Ireland), Alfred P. Sloan Foundation, UMaine Institute of Medicine, University College Dublin, Knut and Alice Wallenberg Foundation, Lehigh University, Valenzuela, Alejandro [0000-0001-6120-6246], Marqués-Bonet, Tomàs [0000-0002-5597-3075], Navarro, Arcadi [0000-0003-2162-8246], 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 R. S., 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., Zoonomia Consortium, Birren, Bruce W., Gazal, Steven, Hubley, Robert M., Koepfli, Klaus-Peter, Marqués-Bonet, Tomàs, Meyer, Wynn K., Nweeia, Martin, Sabeti, Pardis C., Shapiro, Beth, Smit, Arian F. A., 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, and Karlsson, Elinor K.
Abstract: [INTRODUCTION] A major challenge in genomics is discerning which bases among billions alter organismal phenotypes and affect health and disease risk. Evidence of past selective pressure on a base, whether highly conserved or fast evolving, is a marker of functional importance. Bases that are unchanged in all mammals may shape phenotypes that are essential for organismal health. Bases that are evolving quickly in some species, or changed only in species that share an adaptive trait, may shape phenotypes that support survival in specific niches. Identifying bases associated with exceptional capacity for cellular recovery, such as in species that hibernate, could inform therapeutic discovery., [RATIONALE] The power and resolution of evolutionary analyses scale with the number and diversity of species compared. By analyzing genomes for hundreds of placental mammals, we can detect which individual bases in the genome are exceptionally conserved (constrained) and likely to be functionally important in both coding and noncoding regions. By including species that represent all orders of placental mammals and aligning genomes using a method that does not require designating humans as the reference species, we explore unusual traits in other species., [RESULTS] Zoonomia’s mammalian comparative genomics resources are the most comprehensive and statistically well-powered produced to date, with a protein-coding alignment of 427 mammals and a whole-genome alignment of 240 placental mammals representing all orders. We estimate that at least 10.7% of the human genome is evolutionarily conserved relative to neutrally evolving repeats and identify about 101 million significantly constrained single bases (false discovery rate < 0.05). We cataloged 4552 ultraconserved elements at least 20 bases long that are identical in more than 98% of the 240 placental mammals. Many constrained bases have no known function, illustrating the potential for discovery using evolutionary measures. Eighty percent are outside protein-coding exons, and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Constrained bases tend to vary less within human populations, which is consistent with purifying selection. Species threatened with extinction have few substitutions at constrained sites, possibly because severely deleterious alleles have been purged from their small populations. By pairing Zoonomia’s genomic resources with phenotype annotations, we find genomic elements associated with phenotypes that differ between species, including olfaction, hibernation, brain size, and vocal learning. We associate genomic traits, such as the number of olfactory receptor genes, with physical phenotypes, such as the number of olfactory turbinals. By comparing hibernators and nonhibernators, we implicate genes involved in mitochondrial disorders, protection against heat stress, and longevity in this physiologically intriguing phenotype. Using a machine learning–based approach that predicts tissue-specific cis-regulatory activity in hundreds of species using data from just a few, we associate changes in noncoding sequence with traits for which humans are exceptional: brain size and vocal learning., [CONCLUSION] Large-scale comparative genomics opens new opportunities to explore how genomes evolved as mammals adapted to a wide range of ecological niches and to discover what is shared across species and what is distinctively human. High-quality data for consistently defined phenotypes are necessary to realize this potential. Through partnerships with researchers in other fields, comparative genomics can address questions in human health and basic biology while guiding efforts to protect the biodiversity that is essential to these discoveries.
Published: 2023

44. 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 R. S., 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 F. A., 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, and Karlsson, Elinor K.
Subjects: Article
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

45. Sheep: Domestication

Author: Meadows, Jennifer R. S. and Smith, Claire, editor
Published: 2014
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46. Other New Technologies

Author: Meadows, Jennifer H., primary
Published: 2018
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47. Digital Signage

Author: Meadows, Jennifer, primary
Published: 2018
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48. Esports

Author: Meadows, Jennifer H., primary and Grubb, Max, additional
Published: 2018
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49. Understanding Communication Technologies

Author: Meadows, Jennifer H., primary
Published: 2018
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50. Supplementary Figures 1-8 from SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma

Author: Sakthikumar, Sharadha, primary, Elvers, Ingegerd, primary, Kim, Jaegil, primary, Arendt, Maja L., primary, Thomas, Rachael, primary, Turner-Maier, Jason, primary, Swofford, Ross, primary, Johnson, Jeremy, primary, Schumacher, Steven E., primary, Alföldi, Jessica, primary, Axelsson, Erik, primary, Couto, C. Guillermo, primary, Kisseberth, William C., primary, Pettersson, Mats E., primary, Getz, Gad, primary, Meadows, Jennifer R.S., primary, Modiano, Jaime F., primary, Breen, Matthew, primary, Kierczak, Marcin, primary, Forsberg-Nilsson, Karin, primary, Marinescu, Voichita D., primary, and Lindblad-Toh, Kerstin, primary
Published: 2023
Full Text: View/download PDF

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