%0 Journal Article %J Nat Genet %D 2014 %T A framework for the interpretation of de novo mutation in human disease. %A Samocha, Kaitlin E %A Robinson, Elise B %A Sanders, Stephan J %A Stevens, Christine %A Sabo, Aniko %A McGrath, Lauren M %A Kosmicki, Jack A %A Rehnström, Karola %A Mallick, Swapan %A Kirby, Andrew %A Wall, Dennis P %A MacArthur, Daniel G %A Gabriel, Stacey B %A DePristo, Mark %A Purcell, Shaun M %A Palotie, Aarno %A Boerwinkle, Eric %A Buxbaum, Joseph D %A Cook, Edwin H %A Gibbs, Richard A %A Schellenberg, Gerard D %A Sutcliffe, James S %A Devlin, Bernie %A Roeder, Kathryn %A Neale, Benjamin M %A Daly, Mark J %K Child Development Disorders, Pervasive %K Exome %K Female %K Genetic Code %K Genetic Predisposition to Disease %K Genetics, Medical %K Humans %K Male %K Mutation %X

Spontaneously arising (de novo) mutations have an important role in medical genetics. For diseases with extensive locus heterogeneity, such as autism spectrum disorders (ASDs), the signal from de novo mutations is distributed across many genes, making it difficult to distinguish disease-relevant mutations from background variation. Here we provide a statistical framework for the analysis of excesses in de novo mutation per gene and gene set by calibrating a model of de novo mutation. We applied this framework to de novo mutations collected from 1,078 ASD family trios, and, whereas we affirmed a significant role for loss-of-function mutations, we found no excess of de novo loss-of-function mutations in cases with IQ above 100, suggesting that the role of de novo mutations in ASDs might reside in fundamental neurodevelopmental processes. We also used our model to identify ∼1,000 genes that are significantly lacking in functional coding variation in non-ASD samples and are enriched for de novo loss-of-function mutations identified in ASD cases.

%B Nat Genet %V 46 %P 944-50 %8 2014 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/25086666?dopt=Abstract %R 10.1038/ng.3050 %0 Journal Article %J Nature %D 2014 %T Gibbon genome and the fast karyotype evolution of small apes. %A Carbone, Lucia %A Harris, R Alan %A Gnerre, Sante %A Veeramah, Krishna R %A Lorente-Galdos, Belen %A Huddleston, John %A Meyer, Thomas J %A Herrero, Javier %A Roos, Christian %A Aken, Bronwen %A Anaclerio, Fabio %A Archidiacono, Nicoletta %A Baker, Carl %A Barrell, Daniel %A Batzer, Mark A %A Beal, Kathryn %A Blancher, Antoine %A Bohrson, Craig L %A Brameier, Markus %A Campbell, Michael S %A Capozzi, Oronzo %A Casola, Claudio %A Chiatante, Giorgia %A Cree, Andrew %A Damert, Annette %A De Jong, Pieter J %A Dumas, Laura %A Fernandez-Callejo, Marcos %A Flicek, Paul %A Fuchs, Nina V %A Gut, Ivo %A Gut, Marta %A Hahn, Matthew W %A Hernandez-Rodriguez, Jessica %A Hillier, LaDeana W %A Hubley, Robert %A Ianc, Bianca %A Izsvák, Zsuzsanna %A Jablonski, Nina G %A Johnstone, Laurel M %A Karimpour-Fard, Anis %A Konkel, Miriam K %A Kostka, Dennis %A Lazar, Nathan H %A Lee, Sandra L %A Lewis, Lora R %A Liu, Yue %A Locke, Devin P %A Mallick, Swapan %A Mendez, Fernando L %A Muffato, Matthieu %A Nazareth, Lynne V %A Nevonen, Kimberly A %A O'Bleness, Majesta %A Ochis, Cornelia %A Odom, Duncan T %A Pollard, Katherine S %A Quilez, Javier %A Reich, David %A Rocchi, Mariano %A Schumann, Gerald G %A Searle, Stephen %A Sikela, James M %A Skollar, Gabriella %A Smit, Arian %A Sonmez, Kemal %A ten Hallers, Boudewijn %A Terhune, Elizabeth %A Thomas, Gregg W C %A Ullmer, Brygg %A Ventura, Mario %A Walker, Jerilyn A %A Wall, Jeffrey D %A Walter, Lutz %A Ward, Michelle C %A Wheelan, Sarah J %A Whelan, Christopher W %A White, Simon %A Wilhelm, Larry J %A Woerner, August E %A Yandell, Mark %A Zhu, Baoli %A Hammer, Michael F %A Marques-Bonet, Tomas %A Eichler, Evan E %A Fulton, Lucinda %A Fronick, Catrina %A Muzny, Donna M %A Warren, Wesley C %A Worley, Kim C %A Rogers, Jeffrey %A Wilson, Richard K %A Gibbs, Richard A %K Animals %K Evolution, Molecular %K Genome %K Hominidae %K Humans %K Hylobates %K Karyotype %K Molecular Sequence Data %K Phylogeny %K Retroelements %K Selection, Genetic %K Transcription Termination, Genetic %X

Gibbons are small arboreal apes that display an accelerated rate of evolutionary chromosomal rearrangement and occupy a key node in the primate phylogeny between Old World monkeys and great apes. Here we present the assembly and analysis of a northern white-cheeked gibbon (Nomascus leucogenys) genome. We describe the propensity for a gibbon-specific retrotransposon (LAVA) to insert into chromosome segregation genes and alter transcription by providing a premature termination site, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage. We further show that the gibbon genera (Nomascus, Hylobates, Hoolock and Symphalangus) experienced a near-instantaneous radiation ∼5 million years ago, coincident with major geographical changes in southeast Asia that caused cycles of habitat compression and expansion. Finally, we identify signatures of positive selection in genes important for forelimb development (TBX5) and connective tissues (COL1A1) that may have been involved in the adaptation of gibbons to their arboreal habitat.

%B Nature %V 513 %P 195-201 %8 2014 Sep 11 %G eng %N 7517 %1 https://www.ncbi.nlm.nih.gov/pubmed/25209798?dopt=Abstract %R 10.1038/nature13679