Goals and Objectives The Genomics and Computational Biology Core (GCBC) provides genomic analysis support for NIDCD and NIDCR intramural investigators. We maintain and operate massively parallel sequencers (Illumina HiSeq, NextSeq, and MiSeq), a 96-capillary sequencer (AB3730xl), a microarray scanner (Illumina iScan), a LifeTech Vii7a realtime PCR machine, a Fluidigm BioMarkHD and a 10xGenomics single-cell controller. We provide library preparation for massively parallel (nextgen) sequencing, perform sequencing reactions, and analyze the resulting data. Our efforts fall in to two major categoreis: variant detection by whole-exome (WE) sequencing of DNA samples from subjects who stutter or who are deaf, and transcriptional profiling (RNA-Seq) from tissues or single cells of interest. Summary Whole Exome Sequencing In collaboration with Principal Investigator Dennis Drayna, PhD (project DC000046 Genetic Studies of Human Communications Disorders), the GCBC sequenced and analyzed > 800 whole-exome samples of subjects who stutter or are neurologically normal. Most of the samples were from single individuals and comprise a portion of a large case-control study. A few samples were from families in which stuttering is segregating as a Mendelian trait. In addition, more than 1,400 whole-exome samples are being re-mapped and re-analyzed to take advantage of more recent improvements in variant and copy number detection algorithms, and in improvements in the human reference genome sequence. The data is uploaded to a custom relational database designed in collaboration with the Data Management Section. This relational database will aid in the identification of shared genes with predicted pathological sequence variants and be a valuable resource to other researchers. In collaboration with Principal Investigator Thomas B. Friedman, PhD (project DC000039 Identification of Genes Causing Syndromic and Nonsyndromic Hearing Impairment), the GCBC sequenced and analyzed 96 whole-exome samples of subjects who are deaf. Most of the samples were from subjects in families segregating nonsyndromic deafness. There are over 100 different genes known to cause nonsyndromic deafness, so the families are usually prescreened to remove those that are segregating a gene that has already been identified. In this way, new deafness genes are identified by the sharing of predicted pathological variants among affected siblings. In this way, mutant alleles of the gene S1PR2 were found to cause nonsyndromic hearing loss (DFNB68). We also surveyed the genetic causes of moderate hearing loss in the Pakistani population. RNA-Seq The GCBC is participating in multiple tissue-level RNA-seq projects comparing heat shock treated versus untreated mouse utricles (collaboration with Lisa Cunningham, NIDCD); and mutant versus wild-type transcriptomes in mouse inner ear (collaboration with Thomas Friedman, NIDCD), wounded bone (collaboration with Marian Young, NIDCR) and salivary glands (collaborations with Matt Hoffman, NIDCR and James Melvin, NIDCR). We have also characterized the transcriptomes thousands of single cells isolated from inner ear (collaborations with Matt Kelley, NIDCD and Michael Hoa, NIDCD) and salivary glands (collaboration with Matt Hoffman, NIDCR).
| Imtiaz, Ayesha; Belyantseva, Inna A; Beirl, Alisha J et al. (2018) CDC14A phosphatase is essential for hearing and male fertility in mouse and human. Hum Mol Genet 27:780-798 |
| Nakano, Yoko; Kelly, Michael C; Rehman, Atteeq U et al. (2018) Defects in the Alternative Splicing-Dependent Regulation of REST Cause Deafness. Cell 174:536-548.e21 |
| Fan, Jianguo; Jia, Li; Li, Yan et al. (2017) Maturation arrest in early postnatal sensory receptors by deletion of the miR-183/96/182 cluster in mouse. Proc Natl Acad Sci U S A 114:E4271-E4280 |
| Faridi, R; Rehman, A U; Morell, R J et al. (2017) Mutations of SGO2 and CLDN14 collectively cause coincidental Perrault syndrome. Clin Genet 91:328-332 |
| Chattaraj, Parna; Munjal, Tina; Honda, Keiji et al. (2017) A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct. J Med Genet 54:665-673 |
| Honda, Keiji; Kim, Sung Huhn; Kelly, Michael C et al. (2017) Molecular architecture underlying fluid absorption by the developing inner ear. Elife 6: |
| Naz, Sadaf; Imtiaz, Ayesha; Mujtaba, Ghulam et al. (2017) Genetic causes of moderate to severe hearing loss point to modifiers. Clin Genet 91:589-598 |
| Brewer, Carmen C; Zalewski, Christopher K; King, Kelly A et al. (2016) Heritability of non-speech auditory processing skills. Eur J Hum Genet 24:1137-44 |
| Imtiaz, Ayesha; Maqsood, Azra; Rehman, Atteeq U et al. (2016) Recessive mutations of TMC1 associated with moderate to severe hearing loss. Neurogenetics 17:115-123 |
| Santos-Cortez, Regie Lyn P; Faridi, Rabia; Rehman, Atteeq U et al. (2016) Autosomal-Recessive Hearing Impairment Due to Rare Missense Variants within S1PR2. Am J Hum Genet 98:331-8 |
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