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Mark Gosink

Publications and source records attributed to Mark Gosink.

2 recordsLinked to original sources

A comprehensive mouse IBD database for the efficient localization of quantitative trait loci.

Traditional fine-mapping approaches in mouse genetics that go from a linkage region to a candidate gene are very costly and time consuming. Shared ancestry regions, along with the combination of genetics and genomics approaches, provide a powerful tool to shorten the time and effort required to identify a causative gene. In this article we present a novel methodology that predicts IBD (identical by descent) regions between pairs of inbred strains using single nucleotide polymorphism (SNP) maps. We have validated this approach by comparing the IBD regions, estimated using different algorithms, to the results derived using the sequence information in the strains present in the Celera Mouse Database. We showed that based on the current publicly available SNP genotypes, large IBD regions (>1 Mb) can be identified successfully. By assembling a list of 21,514 SNPs in 61 common inbred strains, we inferred IBD regions between all pairs of strains and confirmed, for the first time, that existing quantitative trait genes (QTG) and susceptibility genes all lie outside of IBD regions. We also illustrated how knowledge of IBD structures can be applied to strain selection for future crosses. We have made our results available for data mining and download through a public website ( http://www.mouseibd.florida.scripps.edu ).

Algorithms↗

Histone deacetylase 5 is not a p53 target gene, but its overexpression inhibits tumor cell growth and induces apoptosis.

p53 tumor suppressor is activated by phosphorylation and acetylation on DNA damage. One of unknown p53 early transcripts was identified to be histone deacetylase-5 (HDAC5). We tested a hypothesis that HDAC5 is a p53 down-stream target gene that on induction by p53 inactivates p53 by removal of acetyl group in p53 molecule, thus functioning as an auto-regulatory negative feedback loop in analogue to p53-murine double minute 2 interaction. Six p53 binding consensus sites were identified in the promoter of HDAC5. p53 binds to one of the sites weakly. However, luciferase constructs driven by the HDAC5 promoter containing three to six potential binding sites were not activated by p53, nor was the expression of HDAC5 mRNA induced by p53-activating agents. Furthermore, HDAC5 does not bind to p53 nor reduces etoposide-induced p53 acetylation. Thus, HDAC5 is not a p53 target gene and may act in a p53-independent manner. We next studied the effect of HDAC5 on tumor cell growth and apoptosis. Transfection of HDAC5 inhibited growth of multiple tumor cell lines including U2OS osteogenic sarcoma cells, SY5Y neuroblastoma cells, and MCF breast carcinoma cells. The growth suppression seen in HDAC5-overexpressing cells appears to be attributable partly to a reduced growth rate as revealed by cell growth assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and mainly to spontaneous apoptosis as shown by DNA fragmentation ELISA and morphological appearance. Mechanistically, repression of three cell proliferation genes in mitogen-activated protein kinase pathway and induction of seven apoptosis-related genes were identified by microarray profiling in HDAC5-overexpressed cells. Among induced genes, four (TNFR1, TNFSF7, caspase-8, and DAPK1) were associated with the tumor necrosis factor ligand-receptor death pathway. Induction of TNFR1, TNFSF7, and caspase-8 were confirmed by Northern and Western analyses. Thus, activation of tumor necrosis factor death receptor pathway appears to be associated with HDAC5-induced spontaneous apoptosis.

Apoptosis↗