The amazing advances brought forward by the completion of the Human Genome Project, new sequencing technologies and new methodologies to extract specific fragments of genomic DNA (gDNA), have now made it possible to sequence the "exome" in an individual patient in a relatively short time-frame (whole exome sequencing, WES). The Core PI and Co-PI of are thoroughly expert in the design and implementation of next-generation sequencing (NGS) experiments, and will establish and operate the NGS Core B to generate WES data across each ofthe proposed Projects, involving human, mouse and zebrafish. It has long been appreciated that the vast majority of alleles with strong effect are located in the exome, which constitutes just 1% of most vertebrate genomes. The methodologies to capture and sequence the exome in humans was the first to emerge and is transforming the way scientists approach genetic disease. Methodologies to capture and sequence the mouse and zebrafish exomes will be available shortly. In this Core, we will bring these technologies to bear on structural brain diseases (SBDs) across the evolutionary spectrum. We have been successful at generating WES data that produces 95% target bases at >10X coverage. For dominant disease, the ability to systematically identify heterozygous variants is limited by this coverage, but for recessive disease, this hurdle is easily overcome. Because recessive disease due to homozygous mutations in humans, mouse and zebrafish is the focus of this application, we will be extraordinarily well-powered to identify causative mutations in these species using this approach. An important aspect of Core B is the close ties that will develop not just to the Scientific Projects but also with Core C (Bioinformatics Core) and Core A (Administrative Core). Core C will develop and utilize new software that is specifically devised for identifying homozygous potentially deleterious sequence variants (PDSVs) in the data from Core B. Core A will support the technological infrastructure of both Core B and Core C. Projects I, II and III will be well-positioned to uncover new mechanisms of SBDs, and translate these into new discoveries about underlying mechanisms.
Almost 5% of all births in the US, and an even higher percent in other world populations, are affected by birth defects, and of these, structural brain defects make a major contribution. We will develop and optimize methodology to increase sensitivity and specificity of detecting genetic causes, which can be translated into improved diagnostic strategies for the population in general.
|Marin-Valencia, Isaac; Guerrini, Renzo; Gleeson, Joseph G (2014) Pathogenetic mechanisms of focal cortical dysplasia. Epilepsia 55:970-8|
|Schaffer, Ashleigh E; Eggens, Veerle R C; Caglayan, Ahmet Okay et al. (2014) CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration. Cell 157:651-63|
|Marín, Oscar; Müller, Ulrich (2014) Lineage origins of GABAergic versus glutamatergic neurons in the neocortex. Curr Opin Neurobiol 26:132-41|
|Novarino, Gaia; Fenstermaker, Ali G; Zaki, Maha S et al. (2014) Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343:506-11|
|Thomas, Sophie; Wright, Kevin J; Le Corre, Stéphanie et al. (2014) A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium. Hum Mutat 35:137-46|
|Kinsella, Marcus; Patel, Anand; Bafna, Vineet (2014) The elusive evidence for chromothripsis. Nucleic Acids Res 42:8231-42|
|Ronen, Roy; Zhou, Dan; Bafna, Vineet et al. (2014) The genetic basis of chronic mountain sickness. Physiology (Bethesda) 29:403-12|
|Kramer, Michael; Dutkowski, Janusz; Yu, Michael et al. (2014) Inferring gene ontologies from pairwise similarity data. Bioinformatics 30:i34-42|
|Akizu, Naiara; Silhavy, Jennifer L; Rosti, Rasim Ozgur et al. (2014) Mutations in CSPP1 lead to classical Joubert syndrome. Am J Hum Genet 94:80-6|
|Gil-Sanz, Cristina; Landeira, Bruna; Ramos, Cynthia et al. (2014) Proliferative defects and formation of a double cortex in mice lacking Mltt4 and Cdh2 in the dorsal telencephalon. J Neurosci 34:10475-87|
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