Browsing by Author "Kellis, Manolis"

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    A high-resolution map of human evolutionary constraint using 29 mammals.
    (Nature, 2011-10-12) Lindblad-Toh, Kerstin; Garber, Manuel; Zuk, Or; Lin, Michael F; Parker, Brian J; Washietl, Stefan; Kheradpour, Pouya; Ernst, Jason; Jordan, Gregory; Mauceli, Evan; Ward, Lucas D; Lowe, Craig B; Holloway, Alisha K; Clamp, Michele; Gnerre, Sante; Alföldi, Jessica; Beal, Kathryn; Chang, Jean; Clawson, Hiram; Cuff, James; Di Palma, Federica; Fitzgerald, Stephen; Flicek, Paul; Guttman, Mitchell; Hubisz, Melissa J; Jaffe, David B; Jungreis, Irwin; Kent, W James; Kostka, Dennis; Lara, Marcia; Martins, Andre L; Massingham, Tim; Moltke, Ida; Raney, Brian J; Rasmussen, Matthew D; Robinson, Jim; Stark, Alexander; Vilella, Albert J; Wen, Jiayu; Xie, Xiaohui; Zody, Michael C; Broad Institute Sequencing Platform and Whole Genome Assembly Team; Baldwin, Jen; Bloom, Toby; Chin, Chee Whye; Heiman, Dave; Nicol, Robert; Nusbaum, Chad; Young, Sarah; Wilkinson, Jane; Worley, Kim C; Kovar, Christie L; Muzny, Donna M; Gibbs, Richard A; Baylor College of Medicine Human Genome Sequencing Center Sequencing Team; Cree, Andrew; Dihn, Huyen H; Fowler, Gerald; Jhangiani, Shalili; Joshi, Vandita; Lee, Sandra; Lewis, Lora R; Nazareth, Lynne V; Okwuonu, Geoffrey; Santibanez, Jireh; Warren, Wesley C; Mardis, Elaine R; Weinstock, George M; Wilson, Richard K; Genome Institute at Washington University; Delehaunty, Kim; Dooling, David; Fronik, Catrina; Fulton, Lucinda; Fulton, Bob; Graves, Tina; Minx, Patrick; Sodergren, Erica; Birney, Ewan; Margulies, Elliott H; Herrero, Javier; Green, Eric D; Haussler, David; Siepel, Adam; Goldman, Nick; Pollard, Katherine S; Pedersen, Jakob S; Lander, Eric S; Kellis, Manolis
    The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.
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    Core and region-enriched networks of behaviorally regulated genes and the singing genome.
    (Science, 2014-12-12) Whitney, Osceola; Pfenning, Andreas R; Howard, Jason T; Blatti, Charles A; Liu, Fang; Ward, James M; Wang, Rui; Audet, Jean-Nicoles; Kellis, Manolis; Mukherjee, Sayan; Sinha, Saurabh; Hartemink, Alexander J; West, Anne E; Jarvis, Erich D
    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.
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    Loss of LDAH associated with prostate cancer and hearing loss.
    (Human molecular genetics, 2018-12) Currall, Benjamin B; Chen, Ming; Sallari, Richard C; Cotter, Maura; Wong, Kristen E; Robertson, Nahid G; Penney, Kathryn L; Lunardi, Andrea; Reschke, Markus; Hickox, Ann E; Yin, Yanbo; Wong, Garrett T; Fung, Jacqueline; Brown, Kerry K; Williamson, Robin E; Sinnott-Armstrong, Nicholas A; Kammin, Tammy; Ivanov, Andrew; Zepeda-Mendoza, Cinthya J; Shen, Jun; Quade, Bradley J; Signoretti, Sabina; Arnos, Kathleen S; Banks, Alexander S; Patsopoulos, Nikolaos; Liberman, M Charles; Kellis, Manolis; Pandolfi, Pier Paolo; Morton, Cynthia C
    Great strides in gene discovery have been made using a multitude of methods to associate phenotypes with genetic variants, but there still remains a substantial gap between observed symptoms and identified genetic defects. Herein, we use the convergence of various genetic and genomic techniques to investigate the underpinnings of a constellation of phenotypes that include prostate cancer (PCa) and sensorineural hearing loss (SNHL) in a human subject. Through interrogation of the subject's de novo, germline, balanced chromosomal translocation, we first identify a correlation between his disorders and a poorly annotated gene known as lipid droplet associated hydrolase (LDAH). Using data repositories of both germline and somatic variants, we identify convergent genomic evidence that substantiates a correlation between loss of LDAH and PCa. This correlation is validated through both in vitro and in vivo models that show loss of LDAH results in increased risk of PCa and, to a lesser extent, SNHL. By leveraging convergent evidence in emerging genomic data, we hypothesize that loss of LDAH is involved in PCa and other phenotypes observed in support of a genotype-phenotype association in an n-of-one human subject.
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    Three periods of regulatory innovation during vertebrate evolution.
    (Science (New York, N.Y.), 2011-08) Lowe, Craig B; Kellis, Manolis; Siepel, Adam; Raney, Brian J; Clamp, Michele; Salama, Sofie R; Kingsley, David M; Lindblad-Toh, Kerstin; Haussler, David
    The gain, loss, and modification of gene regulatory elements may underlie a substantial proportion of phenotypic changes on animal lineages. To investigate the gain of regulatory elements throughout vertebrate evolution, we identified genome-wide sets of putative regulatory regions for five vertebrates, including humans. These putative regulatory regions are conserved nonexonic elements (CNEEs), which are evolutionarily conserved yet do not overlap any coding or noncoding mature transcript. We then inferred the branch on which each CNEE came under selective constraint. Our analysis identified three extended periods in the evolution of gene regulatory elements. Early vertebrate evolution was characterized by regulatory gains near transcription factors and developmental genes, but this trend was replaced by innovations near extracellular signaling genes, and then innovations near posttranslational protein modifiers.