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      Genetic Analyses Confirm SNPs in HSPA8 and ERBB2 are Associated with Milk Protein Concentration in Chinese Holstein Cattle

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          Abstract

          Heat shock 70 kDa protein 8 ( HSPA8) and erb-b2 receptor tyrosine kinase 2 ( ERBB2) were the promising candidates for milk protein concentration in dairy cattle revealed through previous RNA sequencing (RNA-Seq) study. The objective of this post-RNA-Seq study was to confirm genetic effects of HSPA8 and ERBB2 on milk protein concentration in a large Chinese Holstein population and to evaluate the genetic effects of both genes on other milk production traits. There were 2 single-nucleotide polymorphisms (SNPs) identified for HSPA8 and 11 SNPs for ERBB2 by sequencing 17 unrelated Chinese Holstein sires. The SNP-rs136632043 in HSPA8 had significant associations with all five milk production traits ( p = 0.0086 to p < 0.0001), whereas SNP-rs132976221 was remarkably associated with three yield traits ( p < 0.0001). Nine (ss1996900615, rs109017161, rs109122971, ss1996900614, rs110133654, rs109941438, rs110552983, rs133031530, and rs109763505) of 11 SNPs in ERBB2 were significantly associated with milk protein percentage ( p = 0.0177 to p < 0.0001). A 12 Kb haplotype block was formed in ERBB2 and haplotype associations revealed similar effects on milk protein traits. Our findings confirmed the significant genetic effects of HSPA8 and ERBB2 on milk protein concentration and other milk production traits and SNP phenotypic variances above 1% may serve as genetic markers in dairy cattle breeding programs.

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          Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure.

          Catechol-O-methyltransferase (COMT) is a key regulator of pain perception, cognitive function, and affective mood. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous position, code for differences in COMT enzymatic activity and are associated with pain sensitivity. Haplotypes divergent in synonymous changes exhibited the largest difference in COMT enzymatic activity, due to a reduced amount of translated protein. The major COMT haplotypes varied with respect to messenger RNA local stem-loop structures, such that the most stable structure was associated with the lowest protein levels and enzymatic activity. Site-directed mutagenesis that eliminated the stable structure restored the amount of translated protein. These data highlight the functional significance of synonymous variations and suggest the importance of haplotypes over single-nucleotide polymorphisms for analysis of genetic variations.
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            Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene.

            A novel potential cell surface receptor of the tyrosine kinase gene family has been identified and characterized by molecular cloning. Its primary sequence is very similar to that of the human epidermal growth factor receptor and the v-erbB oncogene product; the chromosomal location of the gene for this protein is coincident with the neu oncogene, which suggests that the two genes may be identical.
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              Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction.

              By means of a large-scale, case-control association study using 92,788 gene-based single-nucleotide polymorphism (SNP) markers, we identified a candidate locus on chromosome 6p21 associated with susceptibility to myocardial infarction. Subsequent linkage-disequilibrium (LD) mapping and analyses of haplotype structure showed significant associations between myocardial infarction and a single 50 kb halpotype comprised of five SNPs in LTA (encoding lymphotoxin-alpha), NFKBIL1 (encoding nuclear factor of kappa light polypeptide gene enhancer in B cells, inhibitor-like 1) and BAT1 (encoding HLA-B associated transcript 1). Homozygosity with respect to each of the two SNPs in LTA was significantly associated with increased risk for myocardial infarction (odds ratio = 1.78, chi(2) = 21.6, P = 0.00000033; 1,133 affected individuals versus 1,006 controls). In vitro functional analyses indicated that one SNP in the coding region of LTA, which changed an amino-acid residue from threonine to asparagine (Thr26Asn), effected a twofold increase in induction of several cell-adhesion molecules, including VCAM1, in vascular smooth-muscle cells of human coronary artery. Moreover, the SNP, in intron 1 of LTA, enhanced the transcriptional level of LTA. These results indicate that variants in the LTA are risk factors for myocardial infraction and implicate LTA in the pathogenesis of the disorder.
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                Author and article information

                Journal
                Genes (Basel)
                Genes (Basel)
                genes
                Genes
                MDPI
                2073-4425
                30 January 2019
                February 2019
                : 10
                : 2
                : 104
                Affiliations
                [1 ]Shaanxi Key Laboratory of Molecular Biology for Agriculture, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China; congl@ 123456nwafu.edu.cn (C.L.); wangmiao9254@ 123456gmail.com (M.W.)
                [2 ]Department of Animal Genetics and Breeding, College of Animal Science and Technology, Key Laboratory of Animal Genetics and Breeding of Ministry of Agriculture, National Engineering Laboratory for Animal Breeding, China Agricultural University, Beijing 100193, China; wtaocai@ 123456163.com (W.C.); shuliliu1991@ 123456cau.edu.cn (S.L.); reddsbhj3@ 123456163.com (C.Z.); yinhongwei@ 123456cau.edu.cn (H.Y.); sundx@ 123456cau.edu.cn (D.S.)
                Author notes
                [* ]Correspondence: zhangslcau@ 123456cau.edu.cn ; Tel.: +86-13901194331; Fax: +86-01062733697
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-2588-4781
                https://orcid.org/0000-0002-5639-1755
                Article
                genes-10-00104
                10.3390/genes10020104
                6409942
                30704154
                a2ea6d3d-ad95-4bb6-bfba-90238d5dd318
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 November 2018
                : 28 January 2019
                Categories
                Article

                candidate genes,milk protein traits,association analyses,haplotypes,dairy cows

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