Genus Oncology (United States)

Abstract The objective of this study was to identify genomic makers associated with age at puberty in a composite beef cattle breed. The data used consisted of 3,902 Composite Gene Combination animals (CGC; 1/2 Red Angus, 1/4 Charolais, 1/4 Tarentaise) born from 2002 to 2015 genotyped with Illumina BovineSNP50. Phenotypic records of age at puberty were analyzed for 1,365 heifers. Pedigree information tracing back up to 4 generations consisted of 4,983 records. A single-step GBLUP approach was applied to identify candidate regions and markers associated with the age at puberty. SNP markers were weighted based on three iterations, the variance of which was used to emphasize genomic regions in each iteration. Genomic regions explaining more than 0.5% were assumed to be significantly associated with the age at puberty based on visual inspection of the Manhattan plots. The results indicated that peaks on chromosomes 1, 3, 14, and 24 were associated with age at puberty in CGC cows. The largest peak was observed in BTA14, and multiple protein-coding candidate genes in that region could explain such relationships. The enriched genes list includes CHD7, CLVS1, RAB2A, EMILIN2, among others. Additionally, this window contains regions annotated as long noncoding RNAs, which could also be modulating target genes associated with age at puberty. Similar features were identified for other windows associated with the trait. Given the complexity and multifactorial basis of fertility traits, such as age at puberty, further work on genome annotation, including functional and pathway analysis of enriched regions, is planned. The findings from this study provide insights for enhancing the detection of genomic variants influencing complex traits in livestock and that using weighted approaches may help emphasize important regions.

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Mucin 1 (MUC1) is a heterodimeric protein that is aberrantly expressed in diverse human carcinomas and certain hematologic malignancies. The oncogenic MUC1 transmembrane C-terminal subunit (MUC1-C) functions in part by transducing growth and survival signals from cell surface receptors. However, little is known about the structure of the MUC1-C cytoplasmic domain as a potential drug target. Using methods for structural predictions, our results indicate that a highly conserved CQCRRK sequence, which is adjacent to the cell membrane, forms a small pocket that exposes the two cysteine residues for forming disulfide bonds. By contrast, the remainder of the MUC1-C cytoplasmic domain has no apparent structure, consistent with an intrinsically disordered protein. Our studies thus focused on targeting the MUC1 CQCRRK region. The results show that L- and D-amino acid CQCRRK-containing peptides bind directly to the CQC motif. We further show that the D-amino acid peptide, designated GO-203, blocks homodimerization of the MUC1-C cytoplasmic domain in vitro and in transfected cells. Moreover, GO-203 binds directly to endogenous MUC1-C in breast and lung cancer cells. Colocalization studies further demonstrate that GO-203 predominantly binds to MUC1-C at the cell membrane. These findings support the further development of agents that target the MUC1-C cytoplasmic domain CQC motif and thereby MUC1-C function in cancer cells.

Lactation is an economically important phase in the lifecycle of sows, and events that happen during that period have a big impact on longevity of the sow and therefore profitability of the operation. The difficulty in collecting accurate phenotypes that are required to assess lactation performance, and the inability to evaluate longevity of sows in nucleus herds, highlight the importance of using genomic tools to examine the underlying genetics of these traits. The goal of this project was to conduct genome wide association studies (GWAS) of traits related to lactation in Yorkshire sows using 60k SNP marker information. A 1 Mb region on chromosome 2 (SCC2), which showed strong evidence of linkage disequilibrium, explained around 50% of genetic variation for total weaning weight of litter and litter weight gain for sows in parity 2 and also affected parity 3 phenotypes. These results are extremely encouraging and may be useful in marker assisted or genomic selection to improve lactation performance, especially litter weaning weight of sows in parity 2 and higher.

NLRP12 is a member of the intracellular Nod-like receptor (NLR) family that has been suggested to downregulate the production of inflammatory cytokines, but its physiological role in regulating inflammation has not been characterized. We analyzed mice deficient in Nlrp12 to study its role in inflammatory diseases such as colitis and colorectal tumorigenesis. We show that Nlrp12-deficient mice are highly susceptible to colon inflammation and tumorigenesis, which is associated with increased production of inflammatory cytokines, chemokines, and tumorigenic factors. Enhanced colon inflammation and colorectal tumor development in Nlrp12-deficient mice are due to a failure to dampen NF-κB and ERK activation in macrophages. These results reveal a critical role for NLRP12 in maintaining intestinal homeostasis and providing protection against colorectal tumorigenesis.2011 Elsevier Inc. All rights reserved. PMID: 22094258 Funding information This work was supported by: NIAID NIH HHS, United States Grant ID: AI088177 NIAMS NIH HHS, United States Grant ID: R01AR056296 NIAID NIH HHS, United States Grant ID: R21 AI088177 NIAMS NIH HHS, United States Grant ID: R01 AR056296