Biology subjects

Gholson J Lyon

Publications and source records attributed to Gholson J Lyon.

3 recordsLinked to original sources

bioRxiv2016

Proteomic and genomic characterization of a yeast model for Ogden syndrome

Naa10 is a N-terminal acetyltransferase that, in a complex with its auxiliary subunit Naa15, co-translationally acetylates the -amino group of newly synthetized proteins as they emerge from the ribosome. Roughly 40-50% of the human proteome is acetylated by Naa10, rendering this an enzyme with one of the most broad substrate ranges known. Recently, we reported an X-linked disorder of infancy, Ogden syndrome, in two families harboring a c.109T>C (p.Ser37Pro) variant in NAA10. In the present study we performed in-depth characterization of a yeast model of Ogden syndrome. Stress tests and proteomic analyses suggest that the S37P mutation disrupts Naa10 function thereby reducing cellular fitness, possibly due to an impaired functionality of molecular chaperones, Hsp104, Hsp40 and the Hsp70 family. Microarray and RNA-seq revealed a pseudo-diploid gene expression profile in {Delta}Naa10 cells, likely responsible for a mating defect. In conclusion, the data presented here further support the disruptive nature of the S37P/Ogden mutation and identify affected cellular processes potentially contributing to the severe phenotype seen in Ogden syndrome.

Genomics↗

bioRxiv2013

Accurate detection of de novo and transmitted INDELs within exome-capture data using micro-assembly

We present a new open-source algorithm, Scalpel, for sensitive and specific discovery of INDELs in exome-capture data. By combining the power of mapping and assembly, Scalpel searches the de Bruijn graph for sequence paths (contigs) that span each exon. The algorithm creates a single path for exons with no INDEL, two paths for an exon with a heterozygous mutation, and multiple paths for more exotic variations. A detailed repeat composition analysis coupled with a self-tuning k-mer strategy allows Scalpel to outperform other state-of-the-art approaches for INDEL discovery. We extensively compared Scalpel with a battery of >10000 simulated and >1000 experimentally validated INDELs between 1 and 100bp against two recent algorithms for INDEL discovery: GATK HaplotypeCaller and SOAPindel. We report anomalies for these tools in their ability to detect INDELs, especially in regions containing near-perfect repeats which contribute to high false positive rates. In contrast, Scalpel demonstrates superior specificity while maintaining high sensitivity. We also present a large-scale application of Scalpel for detecting de novo and transmitted INDELs in 593 families with autistic children from the Simons Simplex Collection. Scalpel demonstrates enhanced power to detect long ([≥]20bp) transmitted events, and strengthens previous reports of enrichment for de novo likely gene-disrupting INDEL mutations in children with autism with many new candidate genes. The source code and documentation for the algorithm is available at http://scalpel.sourceforge.net.

Bioinformatics↗

bioRxiv2013

Human genetics and clinical aspects of neurodevelopmental disorders

Introduction Introduction Clinical classifications and the... De novo mutations, germline... Rare and compensatory mutations Current ability / approaches Prenatal diagnosis,... Implications for acceptance,... Conclusions References \"our incomplete studies do not permit actual classification; but it is better to leave things by themselves rather than to force them into classes which have their foundation only on paper\" -- Edouard Seguin (Seguin, 1866)\n\n\"The fundamental mistake which vitiates all work based upon Mendels method is the neglect of ancestry, and the attempt to regard the whole effect upon offspring, produced by a particular parent, as due to the existence in the parent of particular structural c ...

Genetics↗