Associations between the K232A polymorphism in the diacylglycerol-O-transferase 1 (DGAT1) gene and performance in Irish Holstein-Friesian dairy cattle

peer-reviewedSelection based on genetic polymorphisms requires accurate quantification of the effect or association of the polymorphisms with all traits of economic importance. The objective of this study was to estimate, using progeny performance data on 848 Holstein-Friesian bulls, the association between a non-conservative alanine to lysine amino acid change (K232A) in exon 8 of the diacylglycerol-O-transferase 1 (DGAT1) gene and milk production and functionality in the Irish Holstein-Friesian population. The DGAT1 gene encodes the diacylglycerol-O-transferase microsomal enzyme necessary to catalyze the final step in triglyceride synthesis. Weighted mixed model methodology, accounting for the additive genetic relationships among animals, was used to evaluate the association between performance and the K232A polymorphism. The minor allele frequency (K allele) was 0.32. One copy of the K allele was associated (P < 0.001) with 77 kg less milk yield, 4.22 kg more fat yield, 0.99 kg less protein yield, and 1.30 and 0.28 g/kg greater milk fat and protein concentration, respectively; all traits were based on predicted 305-day production across the first five lactations. The K232A polymorphism explained 4.8%, 10.3% and 1.0% of the genetic variance in milk yield, fat yield and protein yield, respectively. There was no association between the K232A polymorphism and fertility, functional survival, calving performance, carcass traits, or any conformation trait with the exception of rump width and carcass conformation. Using the current economic values for the milk production traits in the Irish total merit index, one copy of the K allele is worth €5.43 in expected profitability of progeny. Results from this study will be useful in quantifying the cost-benefit of including the K232A polymorphism in the Irish national breeding programme

Allelic Frequency of Kappa-Casein Locus (Asp148/Ala) in F1: Simmental (Bos Taurus) X Ongole Grade (Bos Indicus)

This study was conducted to detect the genetic variants (single nucleotide polymorphism) of kappa-casein locus (Asp148/Ala) in F1: Simmental (Bos taurus) x Ongole grade (Bos indicus), SIMPO. Genomic DNA was isolated from blood sample of 40 SIMPO (21 males and 19 females). A 780 bp specific fragment of kappa-casein gene spanning from the forth exon region (517 bp) to forth intron (263 bp) was successfully amplified. The result of the PCR-RFLP (Polymerase Chain Reaction - Restriction Fragment Length Polymorphisms) analysis using HindIII enzyme showed that two genotypes (AA and AB) were found at this locus in SIMPO. The frequencies of A and B alleles in SIMPO were 0.79 and 0.21, respectively. The frequency lies between B. taurus (Simmental) and B. indicus group

Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis

The finding of TDP-43 as a major component of ubiquitinated protein inclusions in amyotrophic lateral sclerosis (ALS) has led to the identification of 30 mutations in the transactive response-DNA binding protein (TARDBP) gene, encoding TDP-43. All but one are in exon 6, which encodes the glycine-rich domain. The aim of this study was to determine the frequency of TARDBP mutations in a large cohort of motor neurone disease patients from Northern England (42 non-superoxide dismutase 1 (SOD1) familial ALS (FALS), nine ALS-frontotemporal dementia, 474 sporadic ALS (SALS), 45 progressive muscular atrophy cases). We identified four mutations, two of which were novel, in two familial (FALS) and two sporadic (SALS) cases, giving a frequency of TARDBP mutations in non-SOD1 FALS of 5% and SALS of 0.4%. Analysis of clinical data identified that patients had typical ALS, with limb or bulbar onset, and showed considerable variation in age of onset and rapidity of disease course. However, all cases had an absence of clinically overt cognitive dysfunction

Association of Calpastatin (CAST) Gene with Growth Traits and Carcass Characteristics in Bali Cattle

Calpastatin (CAST) gene is well known as an inhibitor of muscle protein degradation and relates to muscle growth and meat tenderness. The objective of this study was to determine the association of CAST gene with growth traits and carcass characteristics in Bali cattle. A number of data from 35 Bali bulls were collected from BPTU Bali Cattle to obtain growth traits, carcass characteristics, and blood samples. Polymorphism of CAST gene in Bali bulls was analyzed by using PCR-RFLP and DNA sequencing. The association of CAST gene with growth traits and carcass characteristics were analyzed by using General Linear Model (GLM). The result showed that there were two genotypes (GG and AG) of CAST gene with allele frequencies of 0.857 and 0.143, respectively, for G and A. Notably, mutation A to G occurred in 253 bp CAST fragment gene in Bali Cattle. Genotypes GG and AG of CAST gene significantly affected (P&lt;0.05) the back-fat thickness and longissimus dorsi without a significant effect on the growth traits. It could be concluded that CAST gene had a potency as a marker gene for carcass quality in Bali cattle

Central role for the XRCC1 BRCT I domain in mammalian DNA single-strand break repair

The DNA single-strand break repair (SSBR) protein XRCC1 is required for genetic stability and for embryonic viability. XRCC1 possesses two BRCA1 carboxyl-terminal (BRCT) protein interaction domains, denoted BRCT I and II. BRCT II is required for SSBR during G1 but is dispensable for this process during S/G2 and consequently for cell survival following DNA alkylation. Little is known about BRCT I, but this domain has attracted considerable interest because it is the site of a genetic polymorphism that epidemiological studies have associated with altered cancer risk. We report that the BRCT I domain comprises the evolutionarily conserved core of XRCC1 and that this domain is required for efficient SSBR during both G1 and S/G2 cell cycle phases and for cell survival following treatment with methyl methanesulfonate. However, the naturally occurring human polymorphism in BRCT I supported XRCC1-dependent SSBR and cell survival after DNA alkylation equally well. We conclude that while the BRCT I domain is critical for XRCC1 to maintain genetic integrity and cell survival, the polymorphism does not impact significantly on this function and therefore is unlikely to impact significantly on susceptibility to cancer

Pharmacogenetics of ophthalmic topical β-blockers

Glaucoma is the second leading cause of blindness worldwide. The primary glaucoma risk factor is elevated intraocular pressure. Topical β-blockers are affordable and widely used to lower intraocular pressure. Genetic variability has been postulated to contribute to interpersonal differences in efficacy and safety of topical β-blockers. This review summarizes clinically significant polymorphisms that have been identified in the β-adrenergic receptors (ADRB1, ADRB2 and ADRB3). The implications of polymorphisms in CYP2D6 are also discussed. Although the candidate-gene approach has facilitated significant progress in our understanding of the genetic basis of glaucoma treatment response, most drug responses involve a large number of genes, each containing multiple polymorphisms. Genome-wide association studies may yield a more comprehensive set of polymorphisms associated with glaucoma outcomes. An understanding of the genetic mechanisms associated with variability in individual responses to topical β-blockers may advance individualized treatment at a lower cost

FABP-2 and PPAR-γ Haplotype as Risk Factors for Dyslipidemia in a Type 2 Diabetes Mellitus Population of Santa Rosa del Conlara, San Luis, Argentina

Introduction: Type 2 Diabetes Mellitus (T2DM) is a complex disorder caused by the interaction between genetic predisposition and environmental factors. Genetics plays an important role on lipid homeostasis. Many genes are involved in the lipid metabolism, such as FABP-2 and PPAR-γ. Aim: To evaluate the association between specific SNPs and haplotypes of the FABP-2 and PPAR-γ genes with T2DM and lipid profile in an Argentinean population. Methods: The FABP-2 (rs1799883) and PPAR-γ (rs1801282) polymorphisms were genotyped and analyzed in association with lipid profile and T2DM, separately and also combined in haplotypes. Results: The frequency of the rare Thr54 allele of the FABP-2 polymorphism in control (0.33) was not different from the frequency in T2DM (0.27), whereas the frequency of the rare Ala12 allele of the PPAR-γ polymorphism in control was different from the frequency in T2DM (0.26 and 0.14, respectively; p = 0.0031). Frequencies of haplotypes for these two single-nucleotide polymorphisms differed significantly in control and T2DM. Haplotype association analysis showed the associations between ThrPro haplotype and TG levels (OR = 2.520; 95% CI = 1.139 - 5.575; p = 0.027) and between ThrPro haplotype and TC and LDL-c levels when compared to AlaPro haplotype (difference = 0.175, 95% CI = 0068 - 0.499, p < 0.0001; difference = 0.052, 95% CI = 0.017 - 0.158, p < 0.0001, respectively). Conclusions: These results from a haplotype analysis show for the first time that genetic combinations of alleles of the FABP-2 and PPAR-γ gene could play a role in the susceptibility to develop dyslipemia in T2DM.Fil: Siewert, Susana Elfrida. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Bioquímica y Ciencias Biológicas. Laboratorio de Diabetes; ArgentinaFil: Olmos Nicotra, Maria Florencia. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Bioquímica y Ciencias Biológicas. Laboratorio de Diabetes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gonzalez, Irma Ines. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Bioquímica y Ciencias Biológicas. Laboratorio de Diabetes; ArgentinaFil: Fernandez, Gustavo. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Bioquímica y Ciencias Biológicas. Laboratorio de Diabetes; ArgentinaFil: Ojeda, Marta Susana. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Departamento de Bioquímica y Ciencias Biológicas. Laboratorio de Diabetes; Argentin

Evidence of widespread degradation of gene control regions in hominid genomes

Although sequences containing regulatory elements located close to protein-coding genes are often only weakly conserved during evolution, comparisons of rodent genomes have implied that these sequences are subject to some selective constraints. Evolutionary conservation is particularly apparent upstream of coding sequences and in first introns, regions that are enriched for regulatory elements. By comparing the human and chimpanzee genomes, we show here that there is almost no evidence for conservation in these regions in hominids. Furthermore, we show that gene expression is diverging more rapidly in hominids than in murids per unit of neutral sequence divergence. By combining data on polymorphism levels in human noncoding DNA and the corresponding human¿chimpanzee divergence, we show that the proportion of adaptive substitutions in these regions in hominids is very low. It therefore seems likely that the lack of conservation and increased rate of gene expression divergence are caused by a reduction in the effectiveness of natural selection against deleterious mutations because of the low effective population sizes of hominids. This has resulted in the accumulation of a large number of deleterious mutations in sequences containing gene control elements and hence a widespread degradation of the genome during the evolution of humans and chimpanzees

A new common functional coding variant at the DDC gene change renal enzyme activity and modify renal dopamine function.

The intra-renal dopamine (DA) system is highly expressed in the proximal tubule and contributes to Na+ and blood pressure homeostasis, as well as to the development of nephropathy. In the kidney, the enzyme DOPA Decarboxylase (DDC) originating from the circulation. We used a twin/family study design, followed by polymorphism association analysis at DDC locus to elucidate heritable influences on renal DA production. Dense single nucleotide polymorphism (SNP) genotyping across the DDC locus on chromosome 7p12 was analyzed by re-sequencing guided by trait-associated genetic markers to discover the responsible genetic variation. We also characterized kinetics of the expressed DDC mutant enzyme. Systematic polymorphism screening across the 15-Exon DDC locus revealed a single coding variant in Exon-14 that was associated with DA excretion and multiple other renal traits indicating pleiotropy. When expressed and characterized in eukaryotic cells, the 462Gln variant displayed lower Vmax (maximal rate of product formation by an enzyme) (21.3 versus 44.9 nmol/min/mg) and lower Km (substrate concentration at which half-maximal product formation is achieved by an enzyme.)(36.2 versus 46.8 μM) than the wild-type (Arg462) allele. The highly heritable DA excretion trait is substantially influenced by a previously uncharacterized common coding variant (Arg462Gln) at the DDC gene that affects multiple renal tubular and glomerular traits, and predicts accelerated functional decline in chronic kidney disease

Ala54Thr Fatty Acid-Binding Protein 2 (FABP2) Polymorphism in Recurrent Depression: Associations with Fatty Acid Concentrations and Waist Circumference

BACKGROUND: Fatty acid (FA)-alterations may mediate the mutual association between Major Depressive Disorder (MDD) and cardiovascular disease (CVD). However, etiology of observed FA-alterations in MDD and CVD remains largely unclear. An interesting candidate may be a mutation in the fatty acid-binding protein 2 (FABP2)-gene, because it regulates dietary FA-uptake. Therefore, we aimed to test the hypotheses that in MDD-patients the FABP2 Ala54Thr-polymorphism would be (I) more prevalent than in sex- and age-matched controls, (II) associated with observed alterations in FA-metabolism, and (III) associated with CVD-risk factor waist circumference. METHODS: We measured concentrations of 29 different erythrocyte FAs, FABP2-genotype, and waist circumference in recurrent MDD-patients and matched never-depressed controls. RESULTS: FABP2-genotype distribution did not significantly differ between the 137 MDD-patients and 73 matched controls. However, patients with the Ala54Thr-polymorphism had (I) higher concentrations of especially eicosadienoic acid (C20:2ω6; P=.009) and other 20-carbon FAs, and associated (II) lower waist circumference (P=.019). In addition, FABP2-genotype effects on waist circumference in patients seemed (I) mediated by its effect on C20:2ω6, and (II) different from controls. CONCLUSIONS: Although Ala54Thr-polymorphism distribution was not associated with recurrent MDD, our results indicate that FABP2 may play a role in the explanation of observed FA-alterations in MDD. For Ala54Thr-polymorphism patients, potentially adaptive conversion of increased bioavailable dietary precursors into eicosadienoic acid instead of arachidonic acid might be related to a low waist circumference. Because this is the first investigation of these associations, replication is warranted, preferably by nutrigenetic studies applying lipidomics and detailed dietary assessment