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1. 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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2. 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
Full Text: View/download PDF

3. Evolutionary constraint and innovation across hundreds of placental mammals.

Author: Christmas, Matthew J, 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, Zoonomia Consortium§, 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, Christmas, Matthew J, 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, Zoonomia Consortium§, 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, 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 (~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

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

Author: Sullivan, Patrick F, 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, Zoonomia Consortium§, 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, 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, Zoonomia Consortium§, 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

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

Author: Kaplow, Irene M, 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, Zoonomia Consortium**, Karlsson, Elinor K, Lindblad-Toh, Kerstin, Meyer, Wynn K, Pfenning, Andreas R, Kaplow, Irene M, 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, Zoonomia Consortium**, Karlsson, Elinor K, Lindblad-Toh, Kerstin, Meyer, Wynn K, and Pfenning, Andreas R
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

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

Author: National Science Foundation (US), Carnegie Mellon University, Alfred P. Sloan Foundation, Swedish Research Council, 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], 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., Zoonomia Consortium, Juan, David, Marqués-Bonet, Tomàs, Muntané, Gerard, Navarro, Arcadi, Serres-Armero, Aitor, Valenzuela, Alejandro, Karlsson, Elinor K., Lindblad-Toh, Kerstin, Meyer, Wynn K., Pfenning, Andreas R., National Science Foundation (US), Carnegie Mellon University, Alfred P. Sloan Foundation, Swedish Research Council, 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], 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., Zoonomia Consortium, Juan, David, Marqués-Bonet, Tomàs, Muntané, Gerard, Navarro, Arcadi, Serres-Armero, Aitor, Valenzuela, Alejandro, Karlsson, Elinor K., Lindblad-Toh, Kerstin, Meyer, Wynn K., and Pfenning, Andreas R.
Abstract: [INTRODUCTION] Diverse phenotypes, including large brains relative to body size, group living, and vocal learning ability, have evolved multiple times throughout mammalian history. These shared phenotypes may have arisen repeatedly by means of common mechanisms discernible through genome comparisons., [RATIONALE] Protein-coding sequence differences have failed to fully explain the evolution of multiple mammalian phenotypes. This suggests that these phenotypes have evolved at least in part through changes in gene expression, meaning that their differences across species may be caused by differences in genome sequence at enhancer regions that control gene expression in specific tissues and cell types. Yet the enhancers involved in phenotype evolution are largely unknown. Sequence conservation–based approaches for identifying such enhancers are limited because enhancer activity can be conserved even when the individual nucleotides within the sequence are poorly conserved. This is due to an overwhelming number of cases where nucleotides turn over at a high rate, but a similar combination of transcription factor binding sites and other sequence features can be maintained across millions of years of evolution, allowing the function of the enhancer to be conserved in a particular cell type or tissue. Experimentally measuring the function of orthologous enhancers across dozens of species is currently infeasible, but new machine learning methods make it possible to make reliable sequence-based predictions of enhancer function across species in specific tissues and cell types., [RESULTS] To overcome the limits of studying individual nucleotides, we developed the Tissue-Aware Conservation Inference Toolkit (TACIT). Rather than measuring the extent to which individual nucleotides are conserved across a region, TACIT uses machine learning to test whether the function of a given part of the genome is likely to be conserved. More specifically, convolutional neural networks learn the tissue- or cell type–specific regulatory code connecting genome sequence to enhancer activity using candidate enhancers identified from only a few species. This approach allows us to accurately associate differences between species in tissue or cell type–specific enhancer activity with genome sequence differences at enhancer orthologs. We then connect these predictions of enhancer function to phenotypes across hundreds of mammals in a way that accounts for species’ phylogenetic relatedness. We applied TACIT to identify candidate enhancers from motor cortex and parvalbumin neuron open chromatin data that are associated with brain size relative to body size, solitary living, and vocal learning across 222 mammals. Our results include the identification of multiple candidate enhancers associated with brain size relative to body size, several of which are located in linear or three-dimensional proximity to genes whose protein-coding mutations have been implicated in microcephaly or macrocephaly in humans. We also identified candidate enhancers associated with the evolution of solitary living near a gene implicated in separation anxiety and other enhancers associated with the evolution of vocal learning ability. We obtained distinct results for bulk motor cortex and parvalbumin neurons, demonstrating the value in applying TACIT to both bulk tissue and specific minority cell type populations. To facilitate future analyses of our results and applications of TACIT, we released predicted enhancer activity of >400,000 candidate enhancers in each of 222 mammals and their associ, [CONCLUSION] TACIT leverages predicted enhancer activity conservation rather than nucleotide-level conservation to connect genetic sequence differences between species to phenotypes across large numbers of mammals. TACIT can be applied to any phenotype with enhancer activity data available from at least a few species in a relevant tissue or cell type and a whole-genome alignment available across dozens of species with substantial phenotypic variation. Although we developed TACIT for transcriptional enhancers, it could also be applied to genomic regions involved in other components of gene regulation, such as promoters and splicing enhancers and silencers. As the number of sequenced genomes grows, machine learning approaches such as TACIT have the potential to help make sense of how conservation of, or changes in, subtle genome patterns can help explain phenotype evolution.
Published: 2023

7. 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

8. 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

9. scAAVengr, a transcriptome-based pipeline for quantitative ranking of engineered AAVs with single-cell resolution.

Author: Öztürk, Bilge E, Öztürk, Bilge E, Johnson, Molly E, Kleyman, Michael, Turunç, Serhan, He, Jing, Jabalameli, Sara, Xi, Zhouhuan, Visel, Meike, Dufour, Valérie L, Iwabe, Simone, Pompeo Marinho, Luis Felipe L, Aguirre, Gustavo D, Sahel, José-Alain, Schaffer, David V, Pfenning, Andreas R, Flannery, John G, Beltran, William A, Stauffer, William R, Byrne, Leah C, Öztürk, Bilge E, Öztürk, Bilge E, Johnson, Molly E, Kleyman, Michael, Turunç, Serhan, He, Jing, Jabalameli, Sara, Xi, Zhouhuan, Visel, Meike, Dufour, Valérie L, Iwabe, Simone, Pompeo Marinho, Luis Felipe L, Aguirre, Gustavo D, Sahel, José-Alain, Schaffer, David V, Pfenning, Andreas R, Flannery, John G, Beltran, William A, Stauffer, William R, and Byrne, Leah C
Abstract: BackgroundAdeno-associated virus (AAV)-mediated gene therapies are rapidly advancing to the clinic, and AAV engineering has resulted in vectors with increased ability to deliver therapeutic genes. Although the choice of vector is critical, quantitative comparison of AAVs, especially in large animals, remains challenging.MethodsHere, we developed an efficient single-cell AAV engineering pipeline (scAAVengr) to simultaneously quantify and rank efficiency of competing AAV vectors across all cell types in the same animal.ResultsTo demonstrate proof-of-concept for the scAAVengr workflow, we quantified - with cell-type resolution - the abilities of naturally occurring and newly engineered AAVs to mediate gene expression in primate retina following intravitreal injection. A top performing variant identified using this pipeline, K912, was used to deliver SaCas9 and edit the rhodopsin gene in macaque retina, resulting in editing efficiency similar to infection rates detected by the scAAVengr workflow. scAAVengr was then used to identify top-performing AAV variants in mouse brain, heart, and liver following systemic injection.ConclusionsThese results validate scAAVengr as a powerful method for development of AAV vectors.FundingThis work was supported by funding from the Ford Foundation, NEI/NIH, Research to Prevent Blindness, Foundation Fighting Blindness, UPMC Immune Transplant and Therapy Center, and the Van Sloun fund for canine genetic research.
Published: 2021

10. scAAVengr, a transcriptome-based pipeline for quantitative ranking of engineered AAVs with single-cell resolution.

Author: Öztürk, Bilge E, Öztürk, Bilge E, Johnson, Molly E, Kleyman, Michael, Turunç, Serhan, He, Jing, Jabalameli, Sara, Xi, Zhouhuan, Visel, Meike, Dufour, Valérie L, Iwabe, Simone, Pompeo Marinho, Luis Felipe L, Aguirre, Gustavo D, Sahel, José-Alain, Schaffer, David V, Pfenning, Andreas R, Flannery, John G, Beltran, William A, Stauffer, William R, Byrne, Leah C, Öztürk, Bilge E, Öztürk, Bilge E, Johnson, Molly E, Kleyman, Michael, Turunç, Serhan, He, Jing, Jabalameli, Sara, Xi, Zhouhuan, Visel, Meike, Dufour, Valérie L, Iwabe, Simone, Pompeo Marinho, Luis Felipe L, Aguirre, Gustavo D, Sahel, José-Alain, Schaffer, David V, Pfenning, Andreas R, Flannery, John G, Beltran, William A, Stauffer, William R, and Byrne, Leah C
Abstract: BackgroundAdeno-associated virus (AAV)-mediated gene therapies are rapidly advancing to the clinic, and AAV engineering has resulted in vectors with increased ability to deliver therapeutic genes. Although the choice of vector is critical, quantitative comparison of AAVs, especially in large animals, remains challenging.MethodsHere, we developed an efficient single-cell AAV engineering pipeline (scAAVengr) to simultaneously quantify and rank efficiency of competing AAV vectors across all cell types in the same animal.ResultsTo demonstrate proof-of-concept for the scAAVengr workflow, we quantified - with cell-type resolution - the abilities of naturally occurring and newly engineered AAVs to mediate gene expression in primate retina following intravitreal injection. A top performing variant identified using this pipeline, K912, was used to deliver SaCas9 and edit the rhodopsin gene in macaque retina, resulting in editing efficiency similar to infection rates detected by the scAAVengr workflow. scAAVengr was then used to identify top-performing AAV variants in mouse brain, heart, and liver following systemic injection.ConclusionsThese results validate scAAVengr as a powerful method for development of AAV vectors.FundingThis work was supported by funding from the Ford Foundation, NEI/NIH, Research to Prevent Blindness, Foundation Fighting Blindness, UPMC Immune Transplant and Therapy Center, and the Van Sloun fund for canine genetic research.
Published: 2021

11. A comparative genomics multitool for scientific discovery and conservation

Author: Genereux, Diane P., Serres, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita, Murén, 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 F. K., Lander, Eric S., Meadows, Jennifer, Murphy, William J., Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R., Pollard, Katherine S., Ray, David A., Shapiro, Beth, Smit, Arian F. A., 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, Karlsson, Elinor K., Genereux, Diane P., Serres, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita, Murén, 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 F. K., Lander, Eric S., Meadows, Jennifer, Murphy, William J., Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R., Pollard, Katherine S., Ray, David A., Shapiro, Beth, Smit, Arian F. A., 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.
Abstract: A whole-genome alignment of 240 phylogenetically diverse species of eutherian mammal-including 131 previously uncharacterized species-from the Zoonomia Project provides data that support biological discovery, medical research and conservation. 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., Group Authors: Zoonomia Consortium
Published: 2020
Full Text: View/download PDF

12. Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates

Author: Damas, Joana, Hughes, Graham M., Keough, Kathleen C., Painter, Corrie A., Persky, Nicole S., Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R., Zhao, Huabin, Genereux, Diane P., Swofford, Ross, Pollard, Katherine S., Ryder, Oliver A., Nweeia, Martin T., Lindblad-Toh, Kerstin, Teeling, Emma C., Karlsson, Elinor K., Lewin, Harris A., Damas, Joana, Hughes, Graham M., Keough, Kathleen C., Painter, Corrie A., Persky, Nicole S., Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R., Zhao, Huabin, Genereux, Diane P., Swofford, Ross, Pollard, Katherine S., Ryder, Oliver A., Nweeia, Martin T., Lindblad-Toh, Kerstin, Teeling, Emma C., Karlsson, Elinor K., and Lewin, Harris A.
Abstract: The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.
Published: 2020
Full Text: View/download PDF

13. A comparative genomics multitool for scientific discovery and conservation

Author: Genereux, Diane P., Serres, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita, Murén, 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 F. K., Lander, Eric S., Meadows, Jennifer, Murphy, William J., Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R., Pollard, Katherine S., Ray, David A., Shapiro, Beth, Smit, Arian F. A., 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, Karlsson, Elinor K., Genereux, Diane P., Serres, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita, Murén, 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 F. K., Lander, Eric S., Meadows, Jennifer, Murphy, William J., Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R., Pollard, Katherine S., Ray, David A., Shapiro, Beth, Smit, Arian F. A., 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.
Abstract: A whole-genome alignment of 240 phylogenetically diverse species of eutherian mammal-including 131 previously uncharacterized species-from the Zoonomia Project provides data that support biological discovery, medical research and conservation. 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., Group Authors: Zoonomia Consortium
Published: 2020
Full Text: View/download PDF

14. A comparative genomics multitool for scientific discovery and conservation

Author: Genereux, Diane P., Serres, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita, Murén, 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 F. K., Lander, Eric S., Meadows, Jennifer, Murphy, William J., Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R., Pollard, Katherine S., Ray, David A., Shapiro, Beth, Smit, Arian F. A., 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, Karlsson, Elinor K., Genereux, Diane P., Serres, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita, Murén, 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 F. K., Lander, Eric S., Meadows, Jennifer, Murphy, William J., Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R., Pollard, Katherine S., Ray, David A., Shapiro, Beth, Smit, Arian F. A., 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.
Abstract: A whole-genome alignment of 240 phylogenetically diverse species of eutherian mammal-including 131 previously uncharacterized species-from the Zoonomia Project provides data that support biological discovery, medical research and conservation. 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., Group Authors: Zoonomia Consortium
Published: 2020
Full Text: View/download PDF

15. Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates

Author: Damas, Joana, Hughes, Graham M., Keough, Kathleen C., Painter, Corrie A., Persky, Nicole S., Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R., Zhao, Huabin, Genereux, Diane P., Swofford, Ross, Pollard, Katherine S., Ryder, Oliver A., Nweeia, Martin T., Lindblad-Toh, Kerstin, Teeling, Emma C., Karlsson, Elinor K., Lewin, Harris A., Damas, Joana, Hughes, Graham M., Keough, Kathleen C., Painter, Corrie A., Persky, Nicole S., Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R., Zhao, Huabin, Genereux, Diane P., Swofford, Ross, Pollard, Katherine S., Ryder, Oliver A., Nweeia, Martin T., Lindblad-Toh, Kerstin, Teeling, Emma C., Karlsson, Elinor K., and Lewin, Harris A.
Abstract: The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.
Published: 2020
Full Text: View/download PDF

16. Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates

Author: Damas, Joana, Hughes, Graham M., Keough, Kathleen C., Painter, Corrie A., Persky, Nicole S., Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R., Zhao, Huabin, Genereux, Diane P., Swofford, Ross, Pollard, Katherine S., Ryder, Oliver A., Nweeia, Martin T., Lindblad-Toh, Kerstin, Teeling, Emma C., Karlsson, Elinor K., Lewin, Harris A., Damas, Joana, Hughes, Graham M., Keough, Kathleen C., Painter, Corrie A., Persky, Nicole S., Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R., Zhao, Huabin, Genereux, Diane P., Swofford, Ross, Pollard, Katherine S., Ryder, Oliver A., Nweeia, Martin T., Lindblad-Toh, Kerstin, Teeling, Emma C., Karlsson, Elinor K., and Lewin, Harris A.
Abstract: The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.
Published: 2020
Full Text: View/download PDF

17. Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates.

Author: Damas, Joana, Damas, Joana, Hughes, Graham M, Keough, Kathleen C, Painter, Corrie A, Persky, Nicole S, Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R, Zhao, Huabin, Genereux, Diane P, Swofford, Ross, Pollard, Katherine S, Ryder, Oliver A, Nweeia, Martin T, Lindblad-Toh, Kerstin, Teeling, Emma C, Karlsson, Elinor K, Lewin, Harris A, Damas, Joana, Damas, Joana, Hughes, Graham M, Keough, Kathleen C, Painter, Corrie A, Persky, Nicole S, Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R, Zhao, Huabin, Genereux, Diane P, Swofford, Ross, Pollard, Katherine S, Ryder, Oliver A, Nweeia, Martin T, Lindblad-Toh, Kerstin, Teeling, Emma C, Karlsson, Elinor K, and Lewin, Harris A
Abstract: The novel coronavirus SARS-CoV-2 is the cause of Coronavirus Disease-2019 (COVID-19). The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of 410 vertebrates, including 252 mammals, to study cross-species conservation of ACE2 and its likelihood to function as a SARS-CoV-2 receptor. We designed a five-category ranking score based on the conservation properties of 25 amino acids important for the binding between receptor and virus, classifying all species from very high to very low. Only mammals fell into the medium to very high categories, and only catarrhine primates in the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 binding, and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (<0.1%) variants in 10/25 binding sites. In addition, we observed evidence of positive selection in ACE2 in multiple species, including bats. Utilized appropriately, our results may lead to the identification of intermediate host species for SARS-CoV-2, justify the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.
Published: 2020

18. Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates.

Author: Damas, Joana, Damas, Joana, Hughes, Graham M, Keough, Kathleen C, Painter, Corrie A, Persky, Nicole S, Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R, Zhao, Huabin, Genereux, Diane P, Swofford, Ross, Pollard, Katherine S, Ryder, Oliver A, Nweeia, Martin T, Lindblad-Toh, Kerstin, Teeling, Emma C, Karlsson, Elinor K, Lewin, Harris A, Damas, Joana, Damas, Joana, Hughes, Graham M, Keough, Kathleen C, Painter, Corrie A, Persky, Nicole S, Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R, Zhao, Huabin, Genereux, Diane P, Swofford, Ross, Pollard, Katherine S, Ryder, Oliver A, Nweeia, Martin T, Lindblad-Toh, Kerstin, Teeling, Emma C, Karlsson, Elinor K, and Lewin, Harris A
Abstract: The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.
Published: 2020

19. Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates

Author: Damas, Joana, Hughes, Graham M., Keough, Kathleen C., Painter, Corrie A., Persky, Nicole S., Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R., Zhao, Huabin, Genereux, Diane P., Swofford, Ross, Pollard, Katherine S., Ryder, Oliver A., Nweeia, Martin T., Lindblad-Toh, Kerstin, Teeling, Emma C., Karlsson, Elinor K., Lewin, Harris A., Damas, Joana, Hughes, Graham M., Keough, Kathleen C., Painter, Corrie A., Persky, Nicole S., Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R., Zhao, Huabin, Genereux, Diane P., Swofford, Ross, Pollard, Katherine S., Ryder, Oliver A., Nweeia, Martin T., Lindblad-Toh, Kerstin, Teeling, Emma C., Karlsson, Elinor K., and Lewin, Harris A.
Abstract: The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.
Published: 2020
Full Text: View/download PDF

20. Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates.

Author: Damas, Joana, Damas, Joana, Hughes, Graham M, Keough, Kathleen C, Painter, Corrie A, Persky, Nicole S, Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R, Zhao, Huabin, Genereux, Diane P, Swofford, Ross, Pollard, Katherine S, Ryder, Oliver A, Nweeia, Martin T, Lindblad-Toh, Kerstin, Teeling, Emma C, Karlsson, Elinor K, Lewin, Harris A, Damas, Joana, Damas, Joana, Hughes, Graham M, Keough, Kathleen C, Painter, Corrie A, Persky, Nicole S, Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R, Zhao, Huabin, Genereux, Diane P, Swofford, Ross, Pollard, Katherine S, Ryder, Oliver A, Nweeia, Martin T, Lindblad-Toh, Kerstin, Teeling, Emma C, Karlsson, Elinor K, and Lewin, Harris A
Abstract: The novel coronavirus SARS-CoV-2 is the cause of Coronavirus Disease-2019 (COVID-19). The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of 410 vertebrates, including 252 mammals, to study cross-species conservation of ACE2 and its likelihood to function as a SARS-CoV-2 receptor. We designed a five-category ranking score based on the conservation properties of 25 amino acids important for the binding between receptor and virus, classifying all species from very high to very low. Only mammals fell into the medium to very high categories, and only catarrhine primates in the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 binding, and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (<0.1%) variants in 10/25 binding sites. In addition, we observed evidence of positive selection in ACE2 in multiple species, including bats. Utilized appropriately, our results may lead to the identification of intermediate host species for SARS-CoV-2, justify the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.
Published: 2020

21. Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates.

Author: Damas, Joana, Damas, Joana, Hughes, Graham M, Keough, Kathleen C, Painter, Corrie A, Persky, Nicole S, Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R, Zhao, Huabin, Genereux, Diane P, Swofford, Ross, Pollard, Katherine S, Ryder, Oliver A, Nweeia, Martin T, Lindblad-Toh, Kerstin, Teeling, Emma C, Karlsson, Elinor K, Lewin, Harris A, Damas, Joana, Damas, Joana, Hughes, Graham M, Keough, Kathleen C, Painter, Corrie A, Persky, Nicole S, Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R, Zhao, Huabin, Genereux, Diane P, Swofford, Ross, Pollard, Katherine S, Ryder, Oliver A, Nweeia, Martin T, Lindblad-Toh, Kerstin, Teeling, Emma C, Karlsson, Elinor K, and Lewin, Harris A
Abstract: The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.
Published: 2020

22. A comparative genomics multitool for scientific discovery and conservation

Author: Genereux, Diane P., Serres, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita, Murén, 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 F. K., Lander, Eric S., Meadows, Jennifer, Murphy, William J., Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R., Pollard, Katherine S., Ray, David A., Shapiro, Beth, Smit, Arian F. A., 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, Karlsson, Elinor K., Genereux, Diane P., Serres, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita, Murén, 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 F. K., Lander, Eric S., Meadows, Jennifer, Murphy, William J., Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R., Pollard, Katherine S., Ray, David A., Shapiro, Beth, Smit, Arian F. A., 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.
Abstract: A whole-genome alignment of 240 phylogenetically diverse species of eutherian mammal-including 131 previously uncharacterized species-from the Zoonomia Project provides data that support biological discovery, medical research and conservation. 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., Group Authors: Zoonomia Consortium
Published: 2020
Full Text: View/download PDF

23. Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates

Author: Damas, Joana, Hughes, Graham M., Keough, Kathleen C., Painter, Corrie A., Persky, Nicole S., Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R., Zhao, Huabin, Genereux, Diane P., Swofford, Ross, Pollard, Katherine S., Ryder, Oliver A., Nweeia, Martin T., Lindblad-Toh, Kerstin, Teeling, Emma C., Karlsson, Elinor K., Lewin, Harris A., Damas, Joana, Hughes, Graham M., Keough, Kathleen C., Painter, Corrie A., Persky, Nicole S., Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R., Zhao, Huabin, Genereux, Diane P., Swofford, Ross, Pollard, Katherine S., Ryder, Oliver A., Nweeia, Martin T., Lindblad-Toh, Kerstin, Teeling, Emma C., Karlsson, Elinor K., and Lewin, Harris A.
Abstract: The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.
Published: 2020
Full Text: View/download PDF

24. A comparative genomics multitool for scientific discovery and conservation

Author: National Institutes of Health (US), Swedish Research Council, Knut and Alice Wallenberg Foundation, Uppsala University, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Howard Hughes Medical Institute, European Research Council, Fundación la Caixa, Wellcome Trust, Royal Society (UK), Ministerio de Economía y Competitividad (España), Fondation Prince Albert II de Monaco, Smithsonian Institution, Irish Research Council, Medical Research Council (UK), National Science Foundation (US), Academy of Finland, Genereux, Diane P., Serres-Armero, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita D., Murén, 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 F. K., Lander, Eric S., Meadows, Jennifer R.S., Murphy, William J., Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R., Pollard, Katherine S., Ray, David A., Shapiro, Beth, Smit, Arian F. A., 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, Marqués-Bonet, Tomàs, Lindblad-Toh, Kerstin, Karlsson, Elinor K., National Institutes of Health (US), Swedish Research Council, Knut and Alice Wallenberg Foundation, Uppsala University, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, Howard Hughes Medical Institute, European Research Council, Fundación la Caixa, Wellcome Trust, Royal Society (UK), Ministerio de Economía y Competitividad (España), Fondation Prince Albert II de Monaco, Smithsonian Institution, Irish Research Council, Medical Research Council (UK), National Science Foundation (US), Academy of Finland, Genereux, Diane P., Serres-Armero, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita D., Murén, 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 F. K., Lander, Eric S., Meadows, Jennifer R.S., Murphy, William J., Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R., Pollard, Katherine S., Ray, David A., Shapiro, Beth, Smit, Arian F. A., 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, Marqués-Bonet, Tomàs, Lindblad-Toh, Kerstin, and Karlsson, Elinor K.
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

25. A comparative genomics multitool for scientific discovery and conservation

Author: Genereux, Diane P., Serres, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita, Murén, 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 F. K., Lander, Eric S., Meadows, Jennifer, Murphy, William J., Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R., Pollard, Katherine S., Ray, David A., Shapiro, Beth, Smit, Arian F. A., 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, Karlsson, Elinor K., Genereux, Diane P., Serres, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita, Murén, 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 F. K., Lander, Eric S., Meadows, Jennifer, Murphy, William J., Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R., Pollard, Katherine S., Ray, David A., Shapiro, Beth, Smit, Arian F. A., 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.
Abstract: A whole-genome alignment of 240 phylogenetically diverse species of eutherian mammal-including 131 previously uncharacterized species-from the Zoonomia Project provides data that support biological discovery, medical research and conservation. 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., Group Authors: Zoonomia Consortium
Published: 2020
Full Text: View/download PDF

26. Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates

Author: Damas, Joana, Hughes, Graham M., Keough, Kathleen C., Painter, Corrie A., Persky, Nicole S., Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R., Zhao, Huabin, Genereux, Diane P., Swofford, Ross, Pollard, Katherine S., Ryder, Oliver A., Nweeia, Martin T., Lindblad-Toh, Kerstin, Teeling, Emma C., Karlsson, Elinor K., Lewin, Harris A., Damas, Joana, Hughes, Graham M., Keough, Kathleen C., Painter, Corrie A., Persky, Nicole S., Corbo, Marco, Hiller, Michael, Koepfli, Klaus-Peter, Pfenning, Andreas R., Zhao, Huabin, Genereux, Diane P., Swofford, Ross, Pollard, Katherine S., Ryder, Oliver A., Nweeia, Martin T., Lindblad-Toh, Kerstin, Teeling, Emma C., Karlsson, Elinor K., and Lewin, Harris A.
Abstract: The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.
Published: 2020
Full Text: View/download PDF

27. A Modular Approach to Vocal Learning: Disentangling the Diversity of a Complex Behavioral Trait.

Author: Wirthlin, Morgan, Wirthlin, Morgan, Chang, Edward F, Knörnschild, Mirjam, Krubitzer, Leah A, Mello, Claudio V, Miller, Cory T, Pfenning, Andreas R, Vernes, Sonja C, Tchernichovski, Ofer, Yartsev, Michael M, Wirthlin, Morgan, Wirthlin, Morgan, Chang, Edward F, Knörnschild, Mirjam, Krubitzer, Leah A, Mello, Claudio V, Miller, Cory T, Pfenning, Andreas R, Vernes, Sonja C, Tchernichovski, Ofer, and Yartsev, Michael M
Abstract: Vocal learning is a behavioral trait in which the social and acoustic environment shapes the vocal repertoire of individuals. Over the past century, the study of vocal learning has progressed at the intersection of ecology, physiology, neuroscience, molecular biology, genomics, and evolution. Yet, despite the complexity of this trait, vocal learning is frequently described as a binary trait, with species being classified as either vocal learners or vocal non-learners. As a result, studies have largely focused on a handful of species for which strong evidence for vocal learning exists. Recent studies, however, suggest a continuum in vocal learning capacity across taxa. Here, we further suggest that vocal learning is a multi-component behavioral phenotype comprised of distinct yet interconnected modules. Discretizing the vocal learning phenotype into its constituent modules would facilitate integration of findings across a wider diversity of species, taking advantage of the ways in which each excels in a particular module, or in a specific combination of features. Such comparative studies can improve understanding of the mechanisms and evolutionary origins of vocal learning. We propose an initial set of vocal learning modules supported by behavioral and neurobiological data and highlight the need for diversifying the field in order to disentangle the complexity of the vocal learning phenotype.
Published: 2019

28. Quantum dots in micropillar cavities for scalable photonic applications

Author: Moczała-Dusanowska, Magdalena, Huber, Tobias, Dusanowski, Łukasz, Gerhardt, Stefan, Jurkat, Jonathan, Pfenning, Andreas, Trotta, Rinaldo, Rastelli, Armando, Gregersen, Niels, Schneider, Christian, Hofling, Sven, Moczała-Dusanowska, Magdalena, Huber, Tobias, Dusanowski, Łukasz, Gerhardt, Stefan, Jurkat, Jonathan, Pfenning, Andreas, Trotta, Rinaldo, Rastelli, Armando, Gregersen, Niels, Schneider, Christian, and Hofling, Sven
Abstract: Scalable quantum photonic applications require wavelength reproducibility and high quality of the emitted photons. To address these issues, we investigate strain-tuning of self-assembled semiconductor quantum dots embedded into micropillar cavities
Published: 2019

29. High-throughput functional comparison of promoter and enhancer activities

Author: Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Pfenning, Andreas R., Nguyen, Thomas A., Jones, Richard D., Snavely, Andrew R., Kirchner, Rory, Hemberg, Martin, Gray, Jesse M., Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Pfenning, Andreas R., Nguyen, Thomas A., Jones, Richard D., Snavely, Andrew R., Kirchner, Rory, Hemberg, Martin, and Gray, Jesse M.
Abstract: Promoters initiate RNA synthesis, and enhancers stimulate promoter activity. Whether promoter and enhancer activities are encoded distinctly in DNA sequences is unknown. We measured the enhancer and promoter activities of thousands of DNA fragments transduced into mouse neurons. We focused on genomic loci bound by the neuronal activity-regulated coactivator CREBBP, and we measured enhancer and promoter activities both before and after neuronal activation. We find that the same sequences typically encode both enhancer and promoter activities. However, gene promoters generate more promoter activity than distal enhancers, despite generating similar enhancer activity. Surprisingly, the greater promoter activity of gene promoters is not due to conventional core promoter elements or splicing signals. Instead, we find that particular transcription factor binding motifs are intrinsically biased toward the generation of promoter activity, whereas others are not. Although the specific biases we observe may be dependent on experimental or cellular context, our results suggest that gene promoters are distinguished from distal enhancers by specific complements of transcriptional activators., National Institute of Mental Health (U.S.) (Grant R01 MH101528-01)
Published: 2017

30. Integrative analysis of 111 reference human epigenomes

Author: Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Picower Institute for Learning and Memory, Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Yen, Angela, Kheradpour, Pouya, Zhang, Zhizhuo, Wang, Jianrong, Ward, Lucas D., Sarkar, Abhishek Kulshreshtha, Quon, Gerald, Eaton, Matthew Lucas, Wu, Yi-Chieh, Pfenning, Andreas R., Wang, Xinchen, Claussnitzer, Melina, Liu, Yaping, Bansal, Mukul S., Feizi-Khankandi, Soheil, Kim, Ah Ram, Cowper Sal-lari, Richard, Sinnott-Armstrong, Nicholas A., Kellis, Manolis, Boyer, Laurie, Gjoneska, Elizabeta, Tsai, Li-Huei, Feizi- Khankandi, Soheil, Boyer, Laurie Ann, Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Picower Institute for Learning and Memory, Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Yen, Angela, Kheradpour, Pouya, Zhang, Zhizhuo, Wang, Jianrong, Ward, Lucas D., Sarkar, Abhishek Kulshreshtha, Quon, Gerald, Eaton, Matthew Lucas, Wu, Yi-Chieh, Pfenning, Andreas R., Wang, Xinchen, Claussnitzer, Melina, Liu, Yaping, Bansal, Mukul S., Feizi-Khankandi, Soheil, Kim, Ah Ram, Cowper Sal-lari, Richard, Sinnott-Armstrong, Nicholas A., Kellis, Manolis, Boyer, Laurie, Gjoneska, Elizabeta, Tsai, Li-Huei, Feizi- Khankandi, Soheil, and Boyer, Laurie Ann
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease., National Human Genome Research Institute (U.S.) (RC1HG005334), National Human Genome Research Institute (U.S.) (R01HG004037), National Human Genome Research Institute (U.S.) (R01HG004037-S1), National Human Genome Research Institute (U.S.) (RO1NS078839), National Science Foundation (U.S.) (CAREER Award 1254200)
Published: 2016

31. Core and region-enriched networks of behaviorally regulated genes and the singing genome

Author: Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Pfenning, Andreas R., Kellis, Manolis, Whitney, Osceola, Howard, Jason T., Blatti, Charles A., Liu, Fang, Ward, James M., Wang, Rui, Audet, Jean-Nicolas, Mukherjee, Sayan, Sinha, Saurabh, Hartemink, Alexander J., West, Anne E., Jarvis, Erich D., Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Pfenning, Andreas R., Kellis, Manolis, Whitney, Osceola, Howard, Jason T., Blatti, Charles A., Liu, Fang, Ward, James M., Wang, Rui, Audet, Jean-Nicolas, Mukherjee, Sayan, Sinha, Saurabh, Hartemink, Alexander J., West, Anne E., and Jarvis, Erich D.
Abstract: Songbirds represent an important model organism for elucidating molecular mechanisms that link genes with complex behaviors, in part because they have discrete vocal learning circuits that have parallels with those that mediate human speech. We found that ~10% of the genes in the avian genome were regulated by singing, and we found a striking regional diversity of both basal and singing-induced programs in the four key song nuclei of the zebra finch, a vocal learning songbird. The region-enriched patterns were a result of distinct combinations of region-enriched transcription factors (TFs), their binding motifs, and presinging acetylation of histone 3 at lysine 27 (H3K27ac) enhancer activity in the regulatory regions of the associated genes. RNA interference manipulations validated the role of the calcium-response transcription factor (CaRF) in regulating genes preferentially expressed in specific song nuclei in response to singing. Thus, differential combinatorial binding of a small group of activity-regulated TFs and predefined epigenetic enhancer activity influences the anatomical diversity of behaviorally regulated gene networks.
Published: 2016

32. Integrative analysis of 111 reference human epigenomes

Author: Roadmap Epigenomics Consortium, Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Bilenky, Misha, Yen, Angela, Heravi-Moussavi, Alireza, Kheradpour, Pouya, Zhang, Zhizhuo, Wang, Jianrong, Ziller, Michael J., Amin, Viren, Whitaker, John W., Schultz, Matthew D., Ward, Lucas D., Sarkar, Abhishek, Quon, Gerald, Sandstrom, Richard S., Eaton, Matthew L., Wu, Yi-Chieh, Pfenning, Andreas R., Wang, Xinchen, Claussnitzer, Melina, Liu, Yaping, Coarfa, Cristian, Harris, R. Alan, Shoresh, Noam, Epstein, Charles B., Gjoneska, Elizabeta, Leung, Danny, Xie, Wei, Hawkins, R. David, Lister, Ryan, Hong, Chibo, Gascard, Philippe, Mungall, Andrew J., Moore, Richard, Chuah, Eric, Tam, Angela, Canfield, Theresa K., Hansen, R. Scott, Kaul, Rajinder, Sabo, Peter J., Bansal, Mukul S., Carles, Annaick, Dixon, Jesse R., Farh, Kai-How, Feizi, Soheil, Karlic, Rosa, Kim, Ah-Ram, Kulkarni, Ashwinikumar, Li, Daofeng, Lowdon, Rebecca, Elliott, GiNell, Mercer, Tim R., Neph, Shane J., Onuchic, Vitor, Polak, Paz, Rajagopal, Nisha, Ray, Pradipta, Sallari, Richard C., Siebenthall, Kyle T., Sinnott-Armstrong, Nicholas A., Stevens, Michael, Thurman, Robert E., Wu, Jie, Zhang, Bo, Zhou, Xin, Beaudet, Arthur E., Boyer, Laurie A., De Jager, Philip L., Farnham, Peggy J., Fisher, Susan J., Haussler, David, Jones, Steven J.M., Li, Wei, Marra, Marco A., McManus, Michael T., Sunyaev, Shamil, Thomson, James A., Tlsty, Thea D., Tsai, Li-Huei, Wang, Wei, Waterland, Robert A., Zhang, Michael Q., Chadwick, Lisa H., Bernstein, Bradley E., Costello, Joseph F., Ecker, Joseph R., Hirst, Martin, Meissner, Alexander, Milosavljevic, Aleksandar, Ren, Bing, Stamatoyannopoulos, John A., Wang, Ting, Kellis, Manolis, Roadmap Epigenomics Consortium, Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Bilenky, Misha, Yen, Angela, Heravi-Moussavi, Alireza, Kheradpour, Pouya, Zhang, Zhizhuo, Wang, Jianrong, Ziller, Michael J., Amin, Viren, Whitaker, John W., Schultz, Matthew D., Ward, Lucas D., Sarkar, Abhishek, Quon, Gerald, Sandstrom, Richard S., Eaton, Matthew L., Wu, Yi-Chieh, Pfenning, Andreas R., Wang, Xinchen, Claussnitzer, Melina, Liu, Yaping, Coarfa, Cristian, Harris, R. Alan, Shoresh, Noam, Epstein, Charles B., Gjoneska, Elizabeta, Leung, Danny, Xie, Wei, Hawkins, R. David, Lister, Ryan, Hong, Chibo, Gascard, Philippe, Mungall, Andrew J., Moore, Richard, Chuah, Eric, Tam, Angela, Canfield, Theresa K., Hansen, R. Scott, Kaul, Rajinder, Sabo, Peter J., Bansal, Mukul S., Carles, Annaick, Dixon, Jesse R., Farh, Kai-How, Feizi, Soheil, Karlic, Rosa, Kim, Ah-Ram, Kulkarni, Ashwinikumar, Li, Daofeng, Lowdon, Rebecca, Elliott, GiNell, Mercer, Tim R., Neph, Shane J., Onuchic, Vitor, Polak, Paz, Rajagopal, Nisha, Ray, Pradipta, Sallari, Richard C., Siebenthall, Kyle T., Sinnott-Armstrong, Nicholas A., Stevens, Michael, Thurman, Robert E., Wu, Jie, Zhang, Bo, Zhou, Xin, Beaudet, Arthur E., Boyer, Laurie A., De Jager, Philip L., Farnham, Peggy J., Fisher, Susan J., Haussler, David, Jones, Steven J.M., Li, Wei, Marra, Marco A., McManus, Michael T., Sunyaev, Shamil, Thomson, James A., Tlsty, Thea D., Tsai, Li-Huei, Wang, Wei, Waterland, Robert A., Zhang, Michael Q., Chadwick, Lisa H., Bernstein, Bradley E., Costello, Joseph F., Ecker, Joseph R., Hirst, Martin, Meissner, Alexander, Milosavljevic, Aleksandar, Ren, Bing, Stamatoyannopoulos, John A., Wang, Ting, and Kellis, Manolis
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease-and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease. © 2015 Macmillan Publishers Limited.
Published: 2015

33. Integrative analysis of 111 reference human epigenomes

Author: Roadmap Epigenomics Consortium, Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Bilenky, Misha, Yen, Angela, Heravi-Moussavi, Alireza, Kheradpour, Pouya, Zhang, Zhizhuo, Wang, Jianrong, Ziller, Michael J., Amin, Viren, Whitaker, John W., Schultz, Matthew D., Ward, Lucas D., Sarkar, Abhishek, Quon, Gerald, Sandstrom, Richard S., Eaton, Matthew L., Wu, Yi-Chieh, Pfenning, Andreas R., Wang, Xinchen, Claussnitzer, Melina, Liu, Yaping, Coarfa, Cristian, Harris, R. Alan, Shoresh, Noam, Epstein, Charles B., Gjoneska, Elizabeta, Leung, Danny, Xie, Wei, Hawkins, R. David, Lister, Ryan, Hong, Chibo, Gascard, Philippe, Mungall, Andrew J., Moore, Richard, Chuah, Eric, Tam, Angela, Canfield, Theresa K., Hansen, R. Scott, Kaul, Rajinder, Sabo, Peter J., Bansal, Mukul S., Carles, Annaick, Dixon, Jesse R., Farh, Kai-How, Feizi, Soheil, Karlic, Rosa, Kim, Ah-Ram, Kulkarni, Ashwinikumar, Li, Daofeng, Lowdon, Rebecca, Elliott, GiNell, Mercer, Tim R., Neph, Shane J., Onuchic, Vitor, Polak, Paz, Rajagopal, Nisha, Ray, Pradipta, Sallari, Richard C., Siebenthall, Kyle T., Sinnott-Armstrong, Nicholas A., Stevens, Michael, Thurman, Robert E., Wu, Jie, Zhang, Bo, Zhou, Xin, Beaudet, Arthur E., Boyer, Laurie A., De Jager, Philip L., Farnham, Peggy J., Fisher, Susan J., Haussler, David, Jones, Steven J.M., Li, Wei, Marra, Marco A., McManus, Michael T., Sunyaev, Shamil, Thomson, James A., Tlsty, Thea D., Tsai, Li-Huei, Wang, Wei, Waterland, Robert A., Zhang, Michael Q., Chadwick, Lisa H., Bernstein, Bradley E., Costello, Joseph F., Ecker, Joseph R., Hirst, Martin, Meissner, Alexander, Milosavljevic, Aleksandar, Ren, Bing, Stamatoyannopoulos, John A., Wang, Ting, Kellis, Manolis, Roadmap Epigenomics Consortium, Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Bilenky, Misha, Yen, Angela, Heravi-Moussavi, Alireza, Kheradpour, Pouya, Zhang, Zhizhuo, Wang, Jianrong, Ziller, Michael J., Amin, Viren, Whitaker, John W., Schultz, Matthew D., Ward, Lucas D., Sarkar, Abhishek, Quon, Gerald, Sandstrom, Richard S., Eaton, Matthew L., Wu, Yi-Chieh, Pfenning, Andreas R., Wang, Xinchen, Claussnitzer, Melina, Liu, Yaping, Coarfa, Cristian, Harris, R. Alan, Shoresh, Noam, Epstein, Charles B., Gjoneska, Elizabeta, Leung, Danny, Xie, Wei, Hawkins, R. David, Lister, Ryan, Hong, Chibo, Gascard, Philippe, Mungall, Andrew J., Moore, Richard, Chuah, Eric, Tam, Angela, Canfield, Theresa K., Hansen, R. Scott, Kaul, Rajinder, Sabo, Peter J., Bansal, Mukul S., Carles, Annaick, Dixon, Jesse R., Farh, Kai-How, Feizi, Soheil, Karlic, Rosa, Kim, Ah-Ram, Kulkarni, Ashwinikumar, Li, Daofeng, Lowdon, Rebecca, Elliott, GiNell, Mercer, Tim R., Neph, Shane J., Onuchic, Vitor, Polak, Paz, Rajagopal, Nisha, Ray, Pradipta, Sallari, Richard C., Siebenthall, Kyle T., Sinnott-Armstrong, Nicholas A., Stevens, Michael, Thurman, Robert E., Wu, Jie, Zhang, Bo, Zhou, Xin, Beaudet, Arthur E., Boyer, Laurie A., De Jager, Philip L., Farnham, Peggy J., Fisher, Susan J., Haussler, David, Jones, Steven J.M., Li, Wei, Marra, Marco A., McManus, Michael T., Sunyaev, Shamil, Thomson, James A., Tlsty, Thea D., Tsai, Li-Huei, Wang, Wei, Waterland, Robert A., Zhang, Michael Q., Chadwick, Lisa H., Bernstein, Bradley E., Costello, Joseph F., Ecker, Joseph R., Hirst, Martin, Meissner, Alexander, Milosavljevic, Aleksandar, Ren, Bing, Stamatoyannopoulos, John A., Wang, Ting, and Kellis, Manolis
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease-and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease. © 2015 Macmillan Publishers Limited.
Published: 2015

34. Integrative analysis of 111 reference human epigenomes

Author: Roadmap Epigenomics Consortium, Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Bilenky, Misha, Yen, Angela, Heravi-Moussavi, Alireza, Kheradpour, Pouya, Zhang, Zhizhuo, Wang, Jianrong, Ziller, Michael J., Amin, Viren, Whitaker, John W., Schultz, Matthew D., Ward, Lucas D., Sarkar, Abhishek, Quon, Gerald, Sandstrom, Richard S., Eaton, Matthew L., Wu, Yi-Chieh, Pfenning, Andreas R., Wang, Xinchen, Claussnitzer, Melina, Liu, Yaping, Coarfa, Cristian, Harris, R. Alan, Shoresh, Noam, Epstein, Charles B., Gjoneska, Elizabeta, Leung, Danny, Xie, Wei, Hawkins, R. David, Lister, Ryan, Hong, Chibo, Gascard, Philippe, Mungall, Andrew J., Moore, Richard, Chuah, Eric, Tam, Angela, Canfield, Theresa K., Hansen, R. Scott, Kaul, Rajinder, Sabo, Peter J., Bansal, Mukul S., Carles, Annaick, Dixon, Jesse R., Farh, Kai-How, Feizi, Soheil, Karlic, Rosa, Kim, Ah-Ram, Kulkarni, Ashwinikumar, Li, Daofeng, Lowdon, Rebecca, Elliott, GiNell, Mercer, Tim R., Neph, Shane J., Onuchic, Vitor, Polak, Paz, Rajagopal, Nisha, Ray, Pradipta, Sallari, Richard C., Siebenthall, Kyle T., Sinnott-Armstrong, Nicholas A., Stevens, Michael, Thurman, Robert E., Wu, Jie, Zhang, Bo, Zhou, Xin, Beaudet, Arthur E., Boyer, Laurie A., De Jager, Philip L., Farnham, Peggy J., Fisher, Susan J., Haussler, David, Jones, Steven J.M., Li, Wei, Marra, Marco A., McManus, Michael T., Sunyaev, Shamil, Thomson, James A., Tlsty, Thea D., Tsai, Li-Huei, Wang, Wei, Waterland, Robert A., Zhang, Michael Q., Chadwick, Lisa H., Bernstein, Bradley E., Costello, Joseph F., Ecker, Joseph R., Hirst, Martin, Meissner, Alexander, Milosavljevic, Aleksandar, Ren, Bing, Stamatoyannopoulos, John A., Wang, Ting, Kellis, Manolis, Roadmap Epigenomics Consortium, Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Bilenky, Misha, Yen, Angela, Heravi-Moussavi, Alireza, Kheradpour, Pouya, Zhang, Zhizhuo, Wang, Jianrong, Ziller, Michael J., Amin, Viren, Whitaker, John W., Schultz, Matthew D., Ward, Lucas D., Sarkar, Abhishek, Quon, Gerald, Sandstrom, Richard S., Eaton, Matthew L., Wu, Yi-Chieh, Pfenning, Andreas R., Wang, Xinchen, Claussnitzer, Melina, Liu, Yaping, Coarfa, Cristian, Harris, R. Alan, Shoresh, Noam, Epstein, Charles B., Gjoneska, Elizabeta, Leung, Danny, Xie, Wei, Hawkins, R. David, Lister, Ryan, Hong, Chibo, Gascard, Philippe, Mungall, Andrew J., Moore, Richard, Chuah, Eric, Tam, Angela, Canfield, Theresa K., Hansen, R. Scott, Kaul, Rajinder, Sabo, Peter J., Bansal, Mukul S., Carles, Annaick, Dixon, Jesse R., Farh, Kai-How, Feizi, Soheil, Karlic, Rosa, Kim, Ah-Ram, Kulkarni, Ashwinikumar, Li, Daofeng, Lowdon, Rebecca, Elliott, GiNell, Mercer, Tim R., Neph, Shane J., Onuchic, Vitor, Polak, Paz, Rajagopal, Nisha, Ray, Pradipta, Sallari, Richard C., Siebenthall, Kyle T., Sinnott-Armstrong, Nicholas A., Stevens, Michael, Thurman, Robert E., Wu, Jie, Zhang, Bo, Zhou, Xin, Beaudet, Arthur E., Boyer, Laurie A., De Jager, Philip L., Farnham, Peggy J., Fisher, Susan J., Haussler, David, Jones, Steven J.M., Li, Wei, Marra, Marco A., McManus, Michael T., Sunyaev, Shamil, Thomson, James A., Tlsty, Thea D., Tsai, Li-Huei, Wang, Wei, Waterland, Robert A., Zhang, Michael Q., Chadwick, Lisa H., Bernstein, Bradley E., Costello, Joseph F., Ecker, Joseph R., Hirst, Martin, Meissner, Alexander, Milosavljevic, Aleksandar, Ren, Bing, Stamatoyannopoulos, John A., Wang, Ting, and Kellis, Manolis
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease-and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease. © 2015 Macmillan Publishers Limited.
Published: 2015

35. Comparative genomics reveals insights into avian genome evolution and adaptation

Author: Zhang, Guojie, Li, Cai, Li, Qiye, Li, Bo, Larkin, Denis M., Lee, Chul, Storz, Jay F., Antunes, Agostinho, Greenwold, Matthew J., Meredith, Robert W., Ödeen, Anders, Cui, Jie, Zhou, Qi, Xu, Luohao, Pan, Hailin, Wang, Zongji, Jin, Lijun, Zhang, Pei, Hu, Haofu, Yang, Wei, Hu, Jiang, Xiao, Jin, Yang, Zhikai, Liu, Yang, Xie, Qiaolin, Yu, Hao, Lian, Jinmin, Wen, Ping, Zhang, Fang, Li, Hui, Zeng, Yongli, Xiong, Zijun, Liu, Shiping, Zhou, Long, Huang, Zhiyong, An, Na, Wang, Jie, Zheng, Qiumei, Xiong, Yingqi, Wang, Guangbiao, Wang, Bo, Wang, Jingjing, Fan, Yu, da Fonseca, Rute R., Alfaro-Nunez, Alonzo, Schubert, Mikkel, Orlando, Ludovic, Mourier, Tobias, Howard, Jason T., Ganapathy, Ganeshkumar, Pfenning, Andreas, Whitney, Osceola, Rivas, Miriam V., Hara, Erina, Smith, Julia, Farre, Marta, Narayan, Jitendra, Slavov, Gancho, Romanov, Michael N., Borges, Rui, Machado, Joao Paulo, Khan, Imran, Springer, Mark S., Gatesy, John, Hoffmann, Federico G., Opazo, Juan C., Hastad, Olle, Sawyer, Roger H., Kim, Heebal, Kim, Kyu-Won, Kim, Hyeon Jeong, Cho, Seoae, Li, Ning, Huang, Yinhua, Bruford, Michael W., Zhan, Xiangjiang, Dixon, Andrew, Bertelsen, Mads F., Derryberry, Elizabeth, Warren, Wesley, Wilson, Richard K., Li, Shengbin, Ray, David A., Green, Richard E., O'Brien, Stephen J., Griffin, Darren, Johnson, Warren E., Haussler, David, Ryder, Oliver A., Willerslev, Eske, Graves, Gary R., Alstroem, Per, Fjeldsa, Jon, Mindell, David P., Edwards, Scott V., Braun, Edward L., Rahbek, Carsten, Burt, David W., Houde, Peter, Zhang, Yong, Yang, Huanming, Wang, Jian, Jarvis, Erich D., Gilbert, M. Thomas P., Wang, Jun, Zhang, Guojie, Li, Cai, Li, Qiye, Li, Bo, Larkin, Denis M., Lee, Chul, Storz, Jay F., Antunes, Agostinho, Greenwold, Matthew J., Meredith, Robert W., Ödeen, Anders, Cui, Jie, Zhou, Qi, Xu, Luohao, Pan, Hailin, Wang, Zongji, Jin, Lijun, Zhang, Pei, Hu, Haofu, Yang, Wei, Hu, Jiang, Xiao, Jin, Yang, Zhikai, Liu, Yang, Xie, Qiaolin, Yu, Hao, Lian, Jinmin, Wen, Ping, Zhang, Fang, Li, Hui, Zeng, Yongli, Xiong, Zijun, Liu, Shiping, Zhou, Long, Huang, Zhiyong, An, Na, Wang, Jie, Zheng, Qiumei, Xiong, Yingqi, Wang, Guangbiao, Wang, Bo, Wang, Jingjing, Fan, Yu, da Fonseca, Rute R., Alfaro-Nunez, Alonzo, Schubert, Mikkel, Orlando, Ludovic, Mourier, Tobias, Howard, Jason T., Ganapathy, Ganeshkumar, Pfenning, Andreas, Whitney, Osceola, Rivas, Miriam V., Hara, Erina, Smith, Julia, Farre, Marta, Narayan, Jitendra, Slavov, Gancho, Romanov, Michael N., Borges, Rui, Machado, Joao Paulo, Khan, Imran, Springer, Mark S., Gatesy, John, Hoffmann, Federico G., Opazo, Juan C., Hastad, Olle, Sawyer, Roger H., Kim, Heebal, Kim, Kyu-Won, Kim, Hyeon Jeong, Cho, Seoae, Li, Ning, Huang, Yinhua, Bruford, Michael W., Zhan, Xiangjiang, Dixon, Andrew, Bertelsen, Mads F., Derryberry, Elizabeth, Warren, Wesley, Wilson, Richard K., Li, Shengbin, Ray, David A., Green, Richard E., O'Brien, Stephen J., Griffin, Darren, Johnson, Warren E., Haussler, David, Ryder, Oliver A., Willerslev, Eske, Graves, Gary R., Alstroem, Per, Fjeldsa, Jon, Mindell, David P., Edwards, Scott V., Braun, Edward L., Rahbek, Carsten, Burt, David W., Houde, Peter, Zhang, Yong, Yang, Huanming, Wang, Jian, Jarvis, Erich D., Gilbert, M. Thomas P., and Wang, Jun
Abstract: Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits.
Published: 2014
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36. Comparative genomics reveals insights into avian genome evolution and adaptation.

Author: Zhang, Guojie, Zhang, Guojie, Li, Cai, Li, Qiye, Li, Bo, Larkin, Denis M, Lee, Chul, Storz, Jay F, Antunes, Agostinho, Greenwold, Matthew J, Meredith, Robert W, Ödeen, Anders, Cui, Jie, Zhou, Qi, Xu, Luohao, Pan, Hailin, Wang, Zongji, Jin, Lijun, Zhang, Pei, Hu, Haofu, Yang, Wei, Hu, Jiang, Xiao, Jin, Yang, Zhikai, Liu, Yang, Xie, Qiaolin, Yu, Hao, Lian, Jinmin, Wen, Ping, Zhang, Fang, Li, Hui, Zeng, Yongli, Xiong, Zijun, Liu, Shiping, Zhou, Long, Huang, Zhiyong, An, Na, Wang, Jie, Zheng, Qiumei, Xiong, Yingqi, Wang, Guangbiao, Wang, Bo, Wang, Jingjing, Fan, Yu, da Fonseca, Rute R, Alfaro-Núñez, Alonzo, Schubert, Mikkel, Orlando, Ludovic, Mourier, Tobias, Howard, Jason T, Ganapathy, Ganeshkumar, Pfenning, Andreas, Whitney, Osceola, Rivas, Miriam V, Hara, Erina, Smith, Julia, Farré, Marta, Narayan, Jitendra, Slavov, Gancho, Romanov, Michael N, Borges, Rui, Machado, João Paulo, Khan, Imran, Springer, Mark S, Gatesy, John, Hoffmann, Federico G, Opazo, Juan C, Håstad, Olle, Sawyer, Roger H, Kim, Heebal, Kim, Kyu-Won, Kim, Hyeon Jeong, Cho, Seoae, Li, Ning, Huang, Yinhua, Bruford, Michael W, Zhan, Xiangjiang, Dixon, Andrew, Bertelsen, Mads F, Derryberry, Elizabeth, Warren, Wesley, Wilson, Richard K, Li, Shengbin, Ray, David A, Green, Richard E, O'Brien, Stephen J, Griffin, Darren, Johnson, Warren E, Haussler, David, Ryder, Oliver A, Willerslev, Eske, Graves, Gary R, Alström, Per, Fjeldså, Jon, Mindell, David P, Edwards, Scott V, Braun, Edward L, Rahbek, Carsten, Burt, David W, Houde, Peter, Zhang, Guojie, Zhang, Guojie, Li, Cai, Li, Qiye, Li, Bo, Larkin, Denis M, Lee, Chul, Storz, Jay F, Antunes, Agostinho, Greenwold, Matthew J, Meredith, Robert W, Ödeen, Anders, Cui, Jie, Zhou, Qi, Xu, Luohao, Pan, Hailin, Wang, Zongji, Jin, Lijun, Zhang, Pei, Hu, Haofu, Yang, Wei, Hu, Jiang, Xiao, Jin, Yang, Zhikai, Liu, Yang, Xie, Qiaolin, Yu, Hao, Lian, Jinmin, Wen, Ping, Zhang, Fang, Li, Hui, Zeng, Yongli, Xiong, Zijun, Liu, Shiping, Zhou, Long, Huang, Zhiyong, An, Na, Wang, Jie, Zheng, Qiumei, Xiong, Yingqi, Wang, Guangbiao, Wang, Bo, Wang, Jingjing, Fan, Yu, da Fonseca, Rute R, Alfaro-Núñez, Alonzo, Schubert, Mikkel, Orlando, Ludovic, Mourier, Tobias, Howard, Jason T, Ganapathy, Ganeshkumar, Pfenning, Andreas, Whitney, Osceola, Rivas, Miriam V, Hara, Erina, Smith, Julia, Farré, Marta, Narayan, Jitendra, Slavov, Gancho, Romanov, Michael N, Borges, Rui, Machado, João Paulo, Khan, Imran, Springer, Mark S, Gatesy, John, Hoffmann, Federico G, Opazo, Juan C, Håstad, Olle, Sawyer, Roger H, Kim, Heebal, Kim, Kyu-Won, Kim, Hyeon Jeong, Cho, Seoae, Li, Ning, Huang, Yinhua, Bruford, Michael W, Zhan, Xiangjiang, Dixon, Andrew, Bertelsen, Mads F, Derryberry, Elizabeth, Warren, Wesley, Wilson, Richard K, Li, Shengbin, Ray, David A, Green, Richard E, O'Brien, Stephen J, Griffin, Darren, Johnson, Warren E, Haussler, David, Ryder, Oliver A, Willerslev, Eske, Graves, Gary R, Alström, Per, Fjeldså, Jon, Mindell, David P, Edwards, Scott V, Braun, Edward L, Rahbek, Carsten, Burt, David W, and Houde, Peter
Abstract: Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits.
Published: 2014

37. Comparative genomics reveals insights into avian genome evolution and adaptation

Author: Zhang, Guojie, Li, Cai, Li, Qiye, Li, Bo, Larkin, Denis M., Lee, Chul, Storz, Jay F., Antunes, Agostinho, Greenwold, Matthew J., Meredith, Robert W., Ödeen, Anders, Cui, Jie, Zhou, Qi, Xu, Luohao, Pan, Hailin, Wang, Zongji, Jin, Lijun, Zhang, Pei, Hu, Haofu, Yang, Wei, Hu, Jiang, Xiao, Jin, Yang, Zhikai, Liu, Yang, Xie, Qiaolin, Yu, Hao, Lian, Jinmin, Wen, Ping, Zhang, Fang, Li, Hui, Zeng, Yongli, Xiong, Zijun, Liu, Shiping, Zhou, Long, Huang, Zhiyong, An, Na, Wang, Jie, Zheng, Qiumei, Xiong, Yingqi, Wang, Guangbiao, Wang, Bo, Wang, Jingjing, Fan, Yu, Rodrigues da Fonseca, Rute Andreia, Alfaro Nuñez, Luis Alonso, Schubert, Mikkel, Orlando, Ludovic Antoine Alexandre, Mourier, Tobias, Howard, Jason T., Ganapathy, Ganeshkumar, Pfenning, Andreas, Whitney, Osceola, Rivas, Miriam V., Hara, Erina, Smith, Julia, Farré, Marta, Narayan, Jitendra, Slavov, Gancho, Romanov, Michael N., Borges, Rui, MacHado, João Paulo, Khan, Imran, Springer, Mark S., Gatesy, John, Hoffmann, Federico G., Opazo, Juan C., Håstad, Olle, Sawyer, Roger H., Kim, Heebal, Kim, Kyu Won, Kim, Hyeon Jeong, Cho, Seoae, Li, Ning, Huang, Yinhua, Bruford, Michael W., Zhan, Xiangjiang, Dixon, Andrew, Bertelsen, Mads F., Derryberry, Elizabeth, Warren, Wesley, Wilson, Richard K., Li, Shengbin, Ray, David A., Green, Richard E., O'Brien, Stephen J., Griffin, Darren, Johnson, Warren E., Haussler, David, Ryder, Oliver A., Willerslev, Eske, Graves, Gary R., Alström, Per, Fjeldså, Jon, Mindell, David P., Edwards, Scott V., Braun, Edward L., Rahbek, Carsten, Burt, David W., Houde, Peter, Zhang, Yong, Yang, Huanming, Wang, Jian, Jarvis, Erich D., Gilbert, M Thomas P, Wang, Jun, Zhang, Guojie, Li, Cai, Li, Qiye, Li, Bo, Larkin, Denis M., Lee, Chul, Storz, Jay F., Antunes, Agostinho, Greenwold, Matthew J., Meredith, Robert W., Ödeen, Anders, Cui, Jie, Zhou, Qi, Xu, Luohao, Pan, Hailin, Wang, Zongji, Jin, Lijun, Zhang, Pei, Hu, Haofu, Yang, Wei, Hu, Jiang, Xiao, Jin, Yang, Zhikai, Liu, Yang, Xie, Qiaolin, Yu, Hao, Lian, Jinmin, Wen, Ping, Zhang, Fang, Li, Hui, Zeng, Yongli, Xiong, Zijun, Liu, Shiping, Zhou, Long, Huang, Zhiyong, An, Na, Wang, Jie, Zheng, Qiumei, Xiong, Yingqi, Wang, Guangbiao, Wang, Bo, Wang, Jingjing, Fan, Yu, Rodrigues da Fonseca, Rute Andreia, Alfaro Nuñez, Luis Alonso, Schubert, Mikkel, Orlando, Ludovic Antoine Alexandre, Mourier, Tobias, Howard, Jason T., Ganapathy, Ganeshkumar, Pfenning, Andreas, Whitney, Osceola, Rivas, Miriam V., Hara, Erina, Smith, Julia, Farré, Marta, Narayan, Jitendra, Slavov, Gancho, Romanov, Michael N., Borges, Rui, MacHado, João Paulo, Khan, Imran, Springer, Mark S., Gatesy, John, Hoffmann, Federico G., Opazo, Juan C., Håstad, Olle, Sawyer, Roger H., Kim, Heebal, Kim, Kyu Won, Kim, Hyeon Jeong, Cho, Seoae, Li, Ning, Huang, Yinhua, Bruford, Michael W., Zhan, Xiangjiang, Dixon, Andrew, Bertelsen, Mads F., Derryberry, Elizabeth, Warren, Wesley, Wilson, Richard K., Li, Shengbin, Ray, David A., Green, Richard E., O'Brien, Stephen J., Griffin, Darren, Johnson, Warren E., Haussler, David, Ryder, Oliver A., Willerslev, Eske, Graves, Gary R., Alström, Per, Fjeldså, Jon, Mindell, David P., Edwards, Scott V., Braun, Edward L., Rahbek, Carsten, Burt, David W., Houde, Peter, Zhang, Yong, Yang, Huanming, Wang, Jian, Jarvis, Erich D., Gilbert, M Thomas P, and Wang, Jun
Abstract: Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits.
Published: 2014

38. Convergent transcriptional specializations in the brains of humans and song-learning birds

Author: Pfenning, Andreas R., Hara, Erina, Whitney, Osceola, Rivas, Miriam V., Wang, Rui, Roulhac, Petra L., Howard, Jason T., Wirthlin, Morgan, Lovell, Peter V., Ganapathy, Ganeshkumar, Mouncastle, Jacquelyn, Moseley, M. Arthur, Thompson, J. Will, Soderblom, Erik J., Iriki, Atsushi, Kato, Masaki, Gilbert, M. Thomas P., Zhang, Guojie, Bakken, Trygve, Bongaarts, Angie, Bernard, Amy, Lein, Ed, Mello, Claudio V., Hartemink, Alexander J., Jarvis, Erich D., Pfenning, Andreas R., Hara, Erina, Whitney, Osceola, Rivas, Miriam V., Wang, Rui, Roulhac, Petra L., Howard, Jason T., Wirthlin, Morgan, Lovell, Peter V., Ganapathy, Ganeshkumar, Mouncastle, Jacquelyn, Moseley, M. Arthur, Thompson, J. Will, Soderblom, Erik J., Iriki, Atsushi, Kato, Masaki, Gilbert, M. Thomas P., Zhang, Guojie, Bakken, Trygve, Bongaarts, Angie, Bernard, Amy, Lein, Ed, Mello, Claudio V., Hartemink, Alexander J., and Jarvis, Erich D.
Abstract: Song-learning birds and humans share independently evolved similarities in brain pathways for vocal learning that are essential for song and speech and are not found in most other species. Comparisons of brain transcriptomes of song-learning birds and humans relative to vocal nonlearners identified convergent gene expression specializations in specific song and speech brain regions of avian vocal learners and humans. The strongest shared profiles relate bird motor and striatal song-learning nuclei, respectively, with human laryngeal motor cortex and parts of the striatum that control speech production and learning. Most of the associated genes function in motor control and brain connectivity. Thus, convergent behavior and neural connectivity for a complex trait are associated with convergent specialized expression of multiple genes.
Published: 2014

39. Convergent transcriptional specializations in the brains of humans and song-learning birds

Author: Pfenning, Andreas R., Hara, Erina, Whitney, Osceola, Rivas, Miriam V., Wang, Rui, Roulhac, Petra L., Howard, Jason T., Wirthlin, Morgan, Lovell, Peter V., Ganapathy, Ganeshkumar, Mouncastle, Jacquelyn, Moseley, M. Arthur, Thompson, J. Will, Soderblom, Erik J., Iriki, Atsushi, Kato, Masaki, Gilbert, M. Thomas P., Zhang, Guojie, Bakken, Trygve, Bongaarts, Angie, Bernard, Amy, Lein, Ed, Mello, Claudio V., Hartemink, Alexander J., Jarvis, Erich D., Pfenning, Andreas R., Hara, Erina, Whitney, Osceola, Rivas, Miriam V., Wang, Rui, Roulhac, Petra L., Howard, Jason T., Wirthlin, Morgan, Lovell, Peter V., Ganapathy, Ganeshkumar, Mouncastle, Jacquelyn, Moseley, M. Arthur, Thompson, J. Will, Soderblom, Erik J., Iriki, Atsushi, Kato, Masaki, Gilbert, M. Thomas P., Zhang, Guojie, Bakken, Trygve, Bongaarts, Angie, Bernard, Amy, Lein, Ed, Mello, Claudio V., Hartemink, Alexander J., and Jarvis, Erich D.
Abstract: Song-learning birds and humans share independently evolved similarities in brain pathways for vocal learning that are essential for song and speech and are not found in most other species. Comparisons of brain transcriptomes of song-learning birds and humans relative to vocal nonlearners identified convergent gene expression specializations in specific song and speech brain regions of avian vocal learners and humans. The strongest shared profiles relate bird motor and striatal song-learning nuclei, respectively, with human laryngeal motor cortex and parts of the striatum that control speech production and learning. Most of the associated genes function in motor control and brain connectivity. Thus, convergent behavior and neural connectivity for a complex trait are associated with convergent specialized expression of multiple genes.
Published: 2014

40. Comparative genomics reveals insights into avian genome evolution and adaptation

Author: Zhang, Guojie, Li, Cai, Li, Qiye, Li, Bo, Larkin, Denis M., Lee, Chul, Storz, Jay F., Antunes, Agostinho, Greenwold, Matthew J., Meredith, Robert W., Ödeen, Anders, Cui, Jie, Zhou, Qi, Xu, Luohao, Pan, Hailin, Wang, Zongji, Jin, Lijun, Zhang, Pei, Hu, Haofu, Yang, Wei, Hu, Jiang, Xiao, Jin, Yang, Zhikai, Liu, Yang, Xie, Qiaolin, Yu, Hao, Lian, Jinmin, Wen, Ping, Zhang, Fang, Li, Hui, Zeng, Yongli, Xiong, Zijun, Liu, Shiping, Zhou, Long, Huang, Zhiyong, An, Na, Wang, Jie, Zheng, Qiumei, Xiong, Yingqi, Wang, Guangbiao, Wang, Bo, Wang, Jingjing, Fan, Yu, Rodrigues da Fonseca, Rute Andreia, Alfaro Nuñez, Luis Alonso, Schubert, Mikkel, Orlando, Ludovic Antoine Alexandre, Mourier, Tobias, Howard, Jason T., Ganapathy, Ganeshkumar, Pfenning, Andreas, Whitney, Osceola, Rivas, Miriam V., Hara, Erina, Smith, Julia, Farré, Marta, Narayan, Jitendra, Slavov, Gancho, Romanov, Michael N., Borges, Rui, MacHado, João Paulo, Khan, Imran, Springer, Mark S., Gatesy, John, Hoffmann, Federico G., Opazo, Juan C., Håstad, Olle, Sawyer, Roger H., Kim, Heebal, Kim, Kyu Won, Kim, Hyeon Jeong, Cho, Seoae, Li, Ning, Huang, Yinhua, Bruford, Michael W., Zhan, Xiangjiang, Dixon, Andrew, Bertelsen, Mads F., Derryberry, Elizabeth, Warren, Wesley, Wilson, Richard K., Li, Shengbin, Ray, David A., Green, Richard E., O'Brien, Stephen J., Griffin, Darren, Johnson, Warren E., Haussler, David, Ryder, Oliver A., Willerslev, Eske, Graves, Gary R., Alström, Per, Fjeldså, Jon, Mindell, David P., Edwards, Scott V., Braun, Edward L., Rahbek, Carsten, Burt, David W., Houde, Peter, Zhang, Yong, Yang, Huanming, Wang, Jian, Jarvis, Erich D., Gilbert, M Thomas P, Wang, Jun, Zhang, Guojie, Li, Cai, Li, Qiye, Li, Bo, Larkin, Denis M., Lee, Chul, Storz, Jay F., Antunes, Agostinho, Greenwold, Matthew J., Meredith, Robert W., Ödeen, Anders, Cui, Jie, Zhou, Qi, Xu, Luohao, Pan, Hailin, Wang, Zongji, Jin, Lijun, Zhang, Pei, Hu, Haofu, Yang, Wei, Hu, Jiang, Xiao, Jin, Yang, Zhikai, Liu, Yang, Xie, Qiaolin, Yu, Hao, Lian, Jinmin, Wen, Ping, Zhang, Fang, Li, Hui, Zeng, Yongli, Xiong, Zijun, Liu, Shiping, Zhou, Long, Huang, Zhiyong, An, Na, Wang, Jie, Zheng, Qiumei, Xiong, Yingqi, Wang, Guangbiao, Wang, Bo, Wang, Jingjing, Fan, Yu, Rodrigues da Fonseca, Rute Andreia, Alfaro Nuñez, Luis Alonso, Schubert, Mikkel, Orlando, Ludovic Antoine Alexandre, Mourier, Tobias, Howard, Jason T., Ganapathy, Ganeshkumar, Pfenning, Andreas, Whitney, Osceola, Rivas, Miriam V., Hara, Erina, Smith, Julia, Farré, Marta, Narayan, Jitendra, Slavov, Gancho, Romanov, Michael N., Borges, Rui, MacHado, João Paulo, Khan, Imran, Springer, Mark S., Gatesy, John, Hoffmann, Federico G., Opazo, Juan C., Håstad, Olle, Sawyer, Roger H., Kim, Heebal, Kim, Kyu Won, Kim, Hyeon Jeong, Cho, Seoae, Li, Ning, Huang, Yinhua, Bruford, Michael W., Zhan, Xiangjiang, Dixon, Andrew, Bertelsen, Mads F., Derryberry, Elizabeth, Warren, Wesley, Wilson, Richard K., Li, Shengbin, Ray, David A., Green, Richard E., O'Brien, Stephen J., Griffin, Darren, Johnson, Warren E., Haussler, David, Ryder, Oliver A., Willerslev, Eske, Graves, Gary R., Alström, Per, Fjeldså, Jon, Mindell, David P., Edwards, Scott V., Braun, Edward L., Rahbek, Carsten, Burt, David W., Houde, Peter, Zhang, Yong, Yang, Huanming, Wang, Jian, Jarvis, Erich D., Gilbert, M Thomas P, and Wang, Jun
Abstract: Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits.
Published: 2014

41. Comparative genomics reveals insights into avian genome evolution and adaptation

Author: Zhang, Guojie, Li, Cai, Li, Qiye, Li, Bo, Larkin, Denis M., Lee, Chul, Storz, Jay F, Antunes, Agostinho, Greenwold, Matthew J, Meredith, Robert W, Ödeen, Anders, Cui, Jie, Zhou, Qi, Xu, Luohao, Pan, Hailin, Wang, Zongji, Jin, Lijun, Zhang, Pei, Hu, Haofu, Yang, Wei, Hu, Jiang, Xiao, Jin, Yang, Zhikai, Liu, Yang, Xie, Qiaolin, Yu, Hao, Lian, Jinmin, Wen, Ping, Zhang, Fang, Li, Hui, Zeng, Yongli, Xiong, Zijun, Liu, Shiping, Zhou, Long, Huang, Zhiyong, An, Na, Wang, Jie, Zheng, Qiumei, Xiong, Yingqi, Wang, Guangbiao, Wang, Bo, Wang, Jingjing, Fan, Yu, da Fonseca, Rute R, Alfaro-Núñez, Alonzo, Schubert, Mikkel, Orlando, Ludovic, Mourier, Tobias, Howard, Jason T, Ganapathy, Ganeshkumar, Pfenning, Andreas, Whitney, Osceola, Rivas, Miriam V, Hara, Erina, Smith, Julia, Farré, Marta, Narayan, Jitendra, Slavov, Gancho, Romanov, Michael N, Borges, Rui, Machado, João Paulo, Khan, Imran, Springer, Mark S, Gatesy, John, Hoffmann, Federico G, Opazo, Juan C, Håstad, Olle, Sawyer, Roger H, Kim, Heebal, Kim, Kyu-Won, Kim, Hyeon Jeong, Cho, Seoae, Li, Ning, Huang, Yinhua, Bruford, Michael W, Zhan, Xiangjiang, Dixon, Andrew, Bertelsen, Mads F, Derryberry, Elizabeth, Warren, Wesley, Wilson, Richard K, Li, Shengbin, Ray, David A, Green, Richard E, O'Brien, Stephen J, Griffin, Darren K., Johnson, Warren E, Haussler, David, Ryder, Oliver A, Willerslev, Eske, Graves, Gary R, Alström, Per, Fjeldså, Jon, Mindell, David P, Edwards, Scott V, Braun, Edward L, Rahbek, Carsten, Burt, David W, Houde, Peter, Zhang, Yong, Yang, Huanming, Wang, Jian, Avian Genome Consortium, Jarvis, Erich D, Gilbert, M Thomas P, Wang, Jun, Zhang, Guojie, Li, Cai, Li, Qiye, Li, Bo, Larkin, Denis M., Lee, Chul, Storz, Jay F, Antunes, Agostinho, Greenwold, Matthew J, Meredith, Robert W, Ödeen, Anders, Cui, Jie, Zhou, Qi, Xu, Luohao, Pan, Hailin, Wang, Zongji, Jin, Lijun, Zhang, Pei, Hu, Haofu, Yang, Wei, Hu, Jiang, Xiao, Jin, Yang, Zhikai, Liu, Yang, Xie, Qiaolin, Yu, Hao, Lian, Jinmin, Wen, Ping, Zhang, Fang, Li, Hui, Zeng, Yongli, Xiong, Zijun, Liu, Shiping, Zhou, Long, Huang, Zhiyong, An, Na, Wang, Jie, Zheng, Qiumei, Xiong, Yingqi, Wang, Guangbiao, Wang, Bo, Wang, Jingjing, Fan, Yu, da Fonseca, Rute R, Alfaro-Núñez, Alonzo, Schubert, Mikkel, Orlando, Ludovic, Mourier, Tobias, Howard, Jason T, Ganapathy, Ganeshkumar, Pfenning, Andreas, Whitney, Osceola, Rivas, Miriam V, Hara, Erina, Smith, Julia, Farré, Marta, Narayan, Jitendra, Slavov, Gancho, Romanov, Michael N, Borges, Rui, Machado, João Paulo, Khan, Imran, Springer, Mark S, Gatesy, John, Hoffmann, Federico G, Opazo, Juan C, Håstad, Olle, Sawyer, Roger H, Kim, Heebal, Kim, Kyu-Won, Kim, Hyeon Jeong, Cho, Seoae, Li, Ning, Huang, Yinhua, Bruford, Michael W, Zhan, Xiangjiang, Dixon, Andrew, Bertelsen, Mads F, Derryberry, Elizabeth, Warren, Wesley, Wilson, Richard K, Li, Shengbin, Ray, David A, Green, Richard E, O'Brien, Stephen J, Griffin, Darren K., Johnson, Warren E, Haussler, David, Ryder, Oliver A, Willerslev, Eske, Graves, Gary R, Alström, Per, Fjeldså, Jon, Mindell, David P, Edwards, Scott V, Braun, Edward L, Rahbek, Carsten, Burt, David W, Houde, Peter, Zhang, Yong, Yang, Huanming, Wang, Jian, Avian Genome Consortium, Jarvis, Erich D, Gilbert, M Thomas P, and Wang, Jun
Abstract: Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits.
Published: 2014

42. The genome of a songbird

Author: Warren, Wesley C, Clayton, David F, Ellegren, Hans, Arnold, Arthur P, Hillier, Ladeana W, Künstner, Axel, Searle, Steve, White, Simon, Vilella, Albert J, Fairley, Susan, Heger, Andreas, Kong, Lesheng, Ponting, Chris P, Jarvis, Erich D, Mello, Claudio V, Minx, Pat, Lovell, Peter, Velho, Tarciso A F, Ferris, Margaret, Balakrishnan, Christopher N, Sinha, Saurabh, Blatti, Charles, London, Sarah E, Li, Yun, Lin, Ya-Chi, George, Julia, Sweedler, Jonathan, Southey, Bruce, Gunaratne, Preethi, Watson, Michael, Nam, Kiwoong, Backström, Niclas, Smeds, Linnea, Nabholz, Benoit, Itoh, Yuichiro, Whitney, Osceola, Pfenning, Andreas R, Howard, Jason, Völker, Martin, Skinner, Bejamin M, Griffin, Darren K, Ye, Liang, McLaren, William M, Flicek, Paul, Quesada, Victor, Velasco, Gloria, Lopez-Otin, Carlos, Puente, Xose S, Olender, Tsviya, Lancet, Doron, Smit, Arian F A, Hubley, Robert, Konkel, Miriam K, Walker, Jerilyn A, Batzer, Mark A, Gu, Wanjun, Pollock, David D, Chen, Lin, Cheng, Ze, Eichler, Evan E, Stapley, Jessica, Slate, Jon, Ekblom, Robert, Birkhead, Tim, Burke, Terry, Burt, David, Scharff, Constance, Adam, Iris, Richard, Hugues, Sultan, Marc, Soldatov, Alexey, Lehrach, Hans, Edwards, Scott V, Yang, Shiaw-Pyng, Li, Xiaoching, Graves, Tina, Fulton, Lucinda, Nelson, Joanne, Chinwalla, Asif, Hou, Shunfeng, Mardis, Elaine R, Wilson, Richard K, Warren, Wesley C, Clayton, David F, Ellegren, Hans, Arnold, Arthur P, Hillier, Ladeana W, Künstner, Axel, Searle, Steve, White, Simon, Vilella, Albert J, Fairley, Susan, Heger, Andreas, Kong, Lesheng, Ponting, Chris P, Jarvis, Erich D, Mello, Claudio V, Minx, Pat, Lovell, Peter, Velho, Tarciso A F, Ferris, Margaret, Balakrishnan, Christopher N, Sinha, Saurabh, Blatti, Charles, London, Sarah E, Li, Yun, Lin, Ya-Chi, George, Julia, Sweedler, Jonathan, Southey, Bruce, Gunaratne, Preethi, Watson, Michael, Nam, Kiwoong, Backström, Niclas, Smeds, Linnea, Nabholz, Benoit, Itoh, Yuichiro, Whitney, Osceola, Pfenning, Andreas R, Howard, Jason, Völker, Martin, Skinner, Bejamin M, Griffin, Darren K, Ye, Liang, McLaren, William M, Flicek, Paul, Quesada, Victor, Velasco, Gloria, Lopez-Otin, Carlos, Puente, Xose S, Olender, Tsviya, Lancet, Doron, Smit, Arian F A, Hubley, Robert, Konkel, Miriam K, Walker, Jerilyn A, Batzer, Mark A, Gu, Wanjun, Pollock, David D, Chen, Lin, Cheng, Ze, Eichler, Evan E, Stapley, Jessica, Slate, Jon, Ekblom, Robert, Birkhead, Tim, Burke, Terry, Burt, David, Scharff, Constance, Adam, Iris, Richard, Hugues, Sultan, Marc, Soldatov, Alexey, Lehrach, Hans, Edwards, Scott V, Yang, Shiaw-Pyng, Li, Xiaoching, Graves, Tina, Fulton, Lucinda, Nelson, Joanne, Chinwalla, Asif, Hou, Shunfeng, Mardis, Elaine R, and Wilson, Richard K
Abstract: The zebra finch is an important model organism in several fields with unique relevance to human neuroscience. Like other songbirds, the zebra finch communicates through learned vocalizations, an ability otherwise documented only in humans and a few other animals and lacking in the chicken-the only bird with a sequenced genome until now. Here we present a structural, functional and comparative analysis of the genome sequence of the zebra finch (Taeniopygia guttata), which is a songbird belonging to the large avian order Passeriformes. We find that the overall structures of the genomes are similar in zebra finch and chicken, but they differ in many intrachromosomal rearrangements, lineage-specific gene family expansions, the number of long-terminal-repeat-based retrotransposons, and mechanisms of sex chromosome dosage compensation. We show that song behaviour engages gene regulatory networks in the zebra finch brain, altering the expression of long non-coding RNAs, microRNAs, transcription factors and their targets. We also show evidence for rapid molecular evolution in the songbird lineage of genes that are regulated during song experience. These results indicate an active involvement of the genome in neural processes underlying vocal communication and identify potential genetic substrates for the evolution and regulation of this behaviour.
Published: 2010
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