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1. Index

Author

Ryan, Louise

Published
2023

3. Notes

Author

Ryan, Louise

Published
2023

4. References

Author

Ryan, Louise

Published
2023

18. Cover

Author

Ryan, Louise

Published
2023

19. Semi-parametric Benchmark Dose Analysis with Monotone Additive Models

Author

Stringer, Alex, Hocagil, Tugba Akkaya, Cook, Richard, Ryan, Louise, Jacobson, Sandra W., and Jacobson, Joseph L.

Subjects
Statistics - Methodology
Abstract

Benchmark dose analysis aims to estimate the level of exposure to a toxin that results in a clinically-significant adverse outcome and quantifies uncertainty using the lower limit of a confidence interval for this level. We develop a novel framework for benchmark dose analysis based on monotone additive dose-response models. We first introduce a flexible approach for fitting monotone additive models via penalized B-splines and Laplace-approximate marginal likelihood. A reflective Newton method is then developed that employs de Boor's algorithm for computing splines and their derivatives for efficient estimation of the benchmark dose. Finally, we develop and assess three approaches for calculating benchmark dose lower limits: a naive one based on asymptotic normality of the estimator, one based on an approximate pivot, and one using a Bayesian parametric bootstrap. The latter approaches improve upon the naive method in terms of accuracy and are guaranteed to return a positive lower limit; the approach based on an approximate pivot is typically an order of magnitude faster than the bootstrap, although they are both practically feasible to compute. We apply the new methods to make inferences about the level of prenatal alcohol exposure associated with clinically significant cognitive defects in children using data from an NIH-funded longitudinal study. Software to reproduce the results in this paper is available at https://github.com/awstringer1/bmd-paper-code.

Published
2023

22. A genomic timescale for placental mammal evolution

Author

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

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

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

Published
2023

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

Author

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

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

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

Published
2023

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

Author

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

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

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

Published
2023

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

Author

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

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

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

Published
2023

26. Integrating gene annotation with orthology inference at scale

Author

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

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

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

Published
2023

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

Author

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

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

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

Published
2023

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

Author

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

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

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

Published
2023

29. Evolutionary constraint and innovation across hundreds of placental mammals

Author

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

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

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

Published
2023

30. Bayesian outcome selection modelling

Author

Dang, Khue-Dung, Ryan, Louise M., Cook, Richard J., Akkaya-Hocagil, Tugba, Jacobson, Sandra W., and Jacobson, Joseph L.

Subjects
Statistics - Methodology
Abstract

Psychiatric and social epidemiology often involves assessing the effects of environmental exposure on outcomes that are difficult to measure directly. To address this problem, it is common to measure outcomes using a comprehensive battery of different tests thought to be related to a common, underlying construct of interest. In the application that motivates our work, for example, researchers wanted to assess the impact of in utero alcohol exposure on child cognition and neuropsychological development, which were evaluated using a range of different tests. Statistical analysis of the resulting multiple outcomes data can be challenging, not only because of the need to account for the correlation between outcomes measured on the same individual, but because it is often unclear, a priori, which outcomes are impacted by the exposure under study. While researchers will generally have some hypotheses about which outcomes are important, a framework is needed to help identify outcomes that are sensitive to the exposure and to quantify the associated treatment or exposure effects of interest. We propose such a framework using a modification of stochastic search variable selection (SSVS), a popular Bayesian variable selection model and use it to quantify an overall effect of the exposure on the affected outcomes. We investigate the performance of the method via simulation and illustrate its application to data from a study involving the effects of prenatal alcohol exposure on child cognition.

Published
2022

32. Evolution of the ancestral mammalian karyotype and syntenic regions

Author

Damas, Joana, Corbo, Marco, Kim, Jaebum, Turner-Maier, Jason, Farré, Marta, Larkin, Denis M, Ryder, Oliver A, Steiner, Cynthia, Houck, Marlys L, Hall, Shaune, Shiue, Lily, Thomas, Stephen, Swale, Thomas, Daly, Mark, Korlach, Jonas, Uliano-Silva, Marcela, Mazzoni, Camila J, Birren, Bruce W, Genereux, Diane P, Johnson, Jeremy, Lindblad-Toh, Kerstin, Karlsson, Elinor K, Nweeia, Martin T, Johnson, Rebecca N, Lewin, Harris A, Andrews, Gregory, Armstrong, Joel C, Bianchi, Matteo, Bredemeyer, Kevin R, Breit, Ana M, Christmas, Matthew J, Clawson, Hiram, Di Palma, Federica, Diekhans, Mark, Dong, Michael X, Eizirik, Eduardo, Fan, Kaili, Fanter, Cornelia, Foley, Nicole M, Forsberg-Nilsson, Karin, Garcia, Carlos J, Gatesy, John, Gazal, Steven, Goodman, Linda, Grimshaw, Jenna, Halsey, Michaela K, Harris, Andrew J, Hickey, Glenn, Hiller, Michael, Hindle, Allyson G, Hubley, Robert M, Hughes, Graham M, Juan, David, Kaplow, Irene M, Keough, Kathleen C, Kirilenko, Bogdan, Koepfli, Klaus-Peter, Korstian, Jennifer M, Kowalczyk, Amanda, Kozyrev, Sergey V, Lawler, Alyssa J, Lawless, Colleen, Lehmann, Thomas, Levesque, Danielle L, Li, Xue, Lind, Abigail, Mackay-Smith, Ava, Marinescu, Voichita D, Marques-Bonet, Tomas, Mason, Victor C, Meadows, Jennifer RS, Meyer, Wynn K, Moore, Jill E, Moreira, Lucas R, Moreno-Santillan, Diana D, Morrill, Kathleen M, Muntané, Gerard, Murphy, William J, Navarro, Arcadi, Nweeia, Martin, Ortmann, Sylvia, Osmanski, Austin, Paten, Benedict, Paulat, Nicole S, Pfenning, Andreas R, Phan, BaDoi N, Pollard, Katherine S, Pratt, Henry E, Ray, David A, Reilly, Steven K, Rosen, Jeb R, Ruf, Irina, and Ryan, Louise

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Evolutionary Biology, Genetics, Human Genome, Generic health relevance, Animals, Cattle, Chromosomes, Mammalian, Eutheria, Evolution, Molecular, Humans, Karyotype, Mammals, Phylogeny, Sloths, Synteny, chromosome evolution, mammals, synteny conservation, ancestral genome reconstruction, topologically associating domains, Zoonomia Consortium
Abstract

Decrypting the rearrangements that drive mammalian chromosome evolution is critical to understanding the molecular bases of speciation, adaptation, and disease susceptibility. Using 8 scaffolded and 26 chromosome-scale genome assemblies representing 23/26 mammal orders, we computationally reconstructed ancestral karyotypes and syntenic relationships at 16 nodes along the mammalian phylogeny. Three different reference genomes (human, sloth, and cattle) representing phylogenetically distinct mammalian superorders were used to assess reference bias in the reconstructed ancestral karyotypes and to expand the number of clades with reconstructed genomes. The mammalian ancestor likely had 19 pairs of autosomes, with nine of the smallest chromosomes shared with the common ancestor of all amniotes (three still conserved in extant mammals), demonstrating a striking conservation of synteny for ∼320 My of vertebrate evolution. The numbers and types of chromosome rearrangements were classified for transitions between the ancestral mammalian karyotype, descendent ancestors, and extant species. For example, 94 inversions, 16 fissions, and 14 fusions that occurred over 53 My differentiated the therian from the descendent eutherian ancestor. The highest breakpoint rate was observed between the mammalian and therian ancestors (3.9 breakpoints/My). Reconstructed mammalian ancestor chromosomes were found to have distinct evolutionary histories reflected in their rates and types of rearrangements. The distributions of genes, repetitive elements, topologically associating domains, and actively transcribed regions in multispecies homologous synteny blocks and evolutionary breakpoint regions indicate that purifying selection acted over millions of years of vertebrate evolution to maintain syntenic relationships of developmentally important genes and regulatory landscapes of gene-dense chromosomes.

Published
2022

35. Modelling age-related changes in executive functions of soccer players

Author

Chin, Vincent, Beavan, Adam, Fransen, Job, Mayer, Jan, Kohn, Robert, Ryan, Louise M., and Sisson, Scott A.

Subjects
Statistics - Applications
Abstract

The widespread popularity of soccer across the globe has turned it into a multi-billion dollar industry. As a result, most professional clubs actively engage in talent identification and development programmes. Contemporary research has generally supported the use of executive functions - a class of neuropsychological processes responsible for cognitive behaviours - in predicting a soccer player's future success. However, studies on the developmental evolution of executive functions have yielded differing results in their structural form (such as inverted U-shapes, or otherwise). This article presents the first analysis of changes in the domain-generic and domain-specific executive functions based on longitudinal data measured on elite German soccer players. Results obtained from a latent variable model show that these executive functions experience noticeable growth from late childhood until pre-adolescence, but remain fairly stable in later growth stages. As a consequence, our results suggest that the role of executive functions in facilitating talent identification may have been overly emphasised.

Published
2021

36. Contradictory Phylogenetic Signals in the Laurasiatheria Anomaly Zone

Author

Doronina, Liliya, Hughes, Graham M, Moreno-Santillan, Diana, Lawless, Colleen, Lonergan, Tadhg, Ryan, Louise, Jebb, David, Kirilenko, Bogdan M, Korstian, Jennifer M, Dávalos, Liliana M, Vernes, Sonja C, Myers, Eugene W, Teeling, Emma C, Hiller, Michael, Jermiin, Lars S, Schmitz, Jürgen, Springer, Mark S, and Ray, David A

Subjects
Biological Sciences, Ecology, Evolutionary Biology, Genetics, Human Genome, Animals, Eutheria, Genome, Mammals, Phylogeny, Retroelements, retrophylogenomics, exon concatenation, exon coalescence, Laurasiatheria, Scrotifera, anomaly zone
Abstract

Relationships among laurasiatherian clades represent one of the most highly disputed topics in mammalian phylogeny. In this study, we attempt to disentangle laurasiatherian interordinal relationships using two independent genome-level approaches: (1) quantifying retrotransposon presence/absence patterns, and (2) comparisons of exon datasets at the levels of nucleotides and amino acids. The two approaches revealed contradictory phylogenetic signals, possibly due to a high level of ancestral incomplete lineage sorting. The positions of Eulipotyphla and Chiroptera as the first and second earliest divergences were consistent across the approaches. However, the phylogenetic relationships of Perissodactyla, Cetartiodactyla, and Ferae, were contradictory. While retrotransposon insertion analyses suggest a clade with Cetartiodactyla and Ferae, the exon dataset favoured Cetartiodactyla and Perissodactyla. Future analyses of hitherto unsampled laurasiatherian lineages and synergistic analyses of retrotransposon insertions, exon and conserved intron/intergenic sequences might unravel the conflicting patterns of relationships in this major mammalian clade.

Published
2022

38. Bayesian structural equation modeling for data from multiple cohorts

Author

Dang, Khue-Dung, Ryan, Louise M., Akkaya-Hocagil, Tugba, Cook, Richard J., Richardson, Gale A., Day, Nancy L., Coles, Claire D., Olson, Heather Carmichael, Jacobson, Sandra W., and Jacobson, Joseph L.

Subjects
Statistics - Applications
Abstract

While it is well known that high levels of prenatal alcohol exposure (PAE) result in significant cognitive deficits in children, the exact nature of the dose response is less well understood. In particular, there is a pressing need to identify the levels of PAE associated with an increased risk of clinically significant adverse effects. To address this issue, data have been combined from six longitudinal birth cohort studies in the United States that assessed the effects of PAE on cognitive outcomes measured from early school age through adolescence. Structural equation models (SEMs) are commonly used to capture the association among multiple observed outcomes in order to characterise the underlying variable of interest (in this case, cognition) and then relate it to PAE. However, it was not possible to apply classic SEM software in our context because different outcomes were measured in the six studies. In this paper we show how a Bayesian approach can be used to fit a multi-group multi-level structural model that maps cognition to a broad range of observed variables measured at multiple ages. These variables map to several different cognitive subdomains and are examined in relation to PAE after adjusting for confounding using propensity scores. The model also tests the possibility of a change point in the dose-response function.

Published
2020

41. Modern strategies for time series regression

Author

Clark, Stephanie, Hyndman, Rob J, Pagendam, Dan, and Ryan, Louise M

Subjects
Statistics - Methodology, Statistics - Machine Learning
Abstract

This paper discusses several modern approaches to regression analysis involving time series data where some of the predictor variables are also indexed by time. We discuss classical statistical approaches as well as methods that have been proposed recently in the machine learning literature. The approaches are compared and contrasted, and it will be seen that there are advantages and disadvantages to most currently available approaches. There is ample room for methodological developments in this area. The work is motivated by an application involving the prediction of water levels as a function of rainfall and other climate variables in an aquifer in eastern Australia.

Published
2020

42. A Hierarchical Meta-Analysis for Settings Involving Multiple Outcomes across Multiple Cohorts

Author

Hocagil, Tugba Akkaya, Ryan, Louise M., Cook, Richard J., Richardson, Gale A., Day, Nancy L., Coles, Claire D., Olson, Heather Carmichael, Jacobson, Sandra W., and Jacobson, Joseph L.

Subjects
Statistics - Methodology
Abstract

Evidence from animal models and epidemiological studies has linked prenatal alcohol exposure (PAE) to a broad range of long-term cognitive and behavioral deficits. However, there is virtually no information in the scientific literature regarding the levels of PAE associated with an increased risk of clinically significant adverse effects. During the period from 1975-1993, several prospective longitudinal cohort studies were conducted in the U.S., in which maternal reports regarding alcohol use were obtained during pregnancy and the cognitive development of the offspring was assessed from early childhood through early adulthood. The sample sizes in these cohorts did not provide sufficient power to examine effects associated with different levels and patterns of PAE. To address this critical public health issue, we have developed a hierarchical meta-analysis to synthesize information regarding the effects of PAE on cognition, integrating data on multiple endpoints from six U.S. longitudinal cohort studies. Our approach involves estimating the dose-response coefficients for each endpoint and then pooling these correlated dose-response coefficients to obtain an estimated `global' effect of exposure on cognition. In the first stage, we use individual participant data to derive estimates of the effects of PAE by fitting regression models that adjust for potential confounding variables using propensity scores. The correlation matrix characterizing the dependence between the endpoint-specific dose-response coefficients estimated within each cohort is then run, while accommodating incomplete information on some endpoints. We also compare and discuss inferences based on the proposed approach to inferences based on a full multivariate analysis

Published
2020

48. Constructing Identity in the Time of Coronavirus: Reading as Recovery

Author

Torres-Ryan, Louise

Abstract

How does a beginning teacher go about constructing a teacherly identity in a pandemic? How does one reconcile what might be with what is, as dictated by the rhetoric of a neoliberal government, which prizes the individual mind over the collective one, the product over the process, and results over relationships? This essay explores these questions through the experience of reading "Jane Eyre" with a Year 9 English class. Personal and professional stories form the core of this investigation that explores the complexities of finding a teacherly identity; this is a discussion about aims and values and relationships, rather than just 'effective' teaching strategies.

Published
2022
Full Text
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49. Multiclass classification of growth curves using random change points and heterogeneous random effects

Author

Chin, Vincent, Lee, Jarod Y. L., Ryan, Louise M., Kohn, Robert, and Sisson, Scott A.

Subjects
Statistics - Methodology, Statistics - Applications
Abstract

Faltering growth among children is a nutritional problem prevalent in low to medium income countries; it is generally defined as a slower rate of growth compared to a reference healthy population of the same age and gender. As faltering is closely associated with reduced physical, intellectual and economic productivity potential, it is important to identify faltered children and be able to characterise different growth patterns so that targeted treatments can be designed and administered. We introduce a multiclass classification model for growth trajectory that flexibly extends a current classification approach called the broken stick model, which is a piecewise linear model with breaks at fixed knot locations. Heterogeneity in growth patterns among children is captured using mixture distributed random effects, whereby the mixture components determine the classification of children into subgroups. The mixture distribution is modelled using a Dirichlet process prior, which avoids the need to choose the "true" number of mixture components, and allows this to be driven by the complexity of the data. Because children have individual differences in the onset of growth stages, we introduce child-specific random change points. Simulation results show that the random change point model outperforms the broken stick model because it has fewer restrictions on knot locations. We illustrate our model on a longitudinal birth cohort from the Healthy Birth, Growth and Development knowledge integration project funded by the Bill and Melinda Gates Foundation. Analysis reveals 9 subgroups of children within the population which exhibit varying faltering trends between birth and age one.

Published
2019

50. Detecting Faltering Growth in Children via Minimum Random Slopes

Author

Lee, Jarod Y. L., Anderson, Craig, Hung, Wai T., Hwang, Hon, and Ryan, Louise M.

Subjects
Statistics - Applications
Abstract

A child is considered to have faltered growth when increases in their height or weight starts to decline relative to a suitable comparison population. However, there is currently a lack of consensus on both the choice of anthropometric indexes for characterizing growth over time and the operational definition of faltering. Cole's classic conditional standard deviation scores is a popular metric but can be problematic, since it only utilizes two data points and relies on having complete data. In the existing literature, arbitrary thresholds are often used to define faltering, which may not be appropriate for all populations. In this article, we propose to assess faltering via minimum random slopes (MRS) derived from a piecewise linear mixed model. When used in conjunction with mixture model-based classification, MRS provides a viable method for identifying children that have faltered, without being dependent upon arbitrary standards. We illustrate our work via a simulation study and apply it to a case study based on a birth cohort within the Healthy Birth, Growth and Development knowledge integration (HBGDki) project funded by the Bill and Melinda Gates Foundation.

Published
2018

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