A fundamental question is how enzymes can accelerate chemical reactions. Catalysis is not only defined by actual chemical steps, but also by enzyme structure and dynamics. To investigate the role of protein dynamics in enzymatic turnover, we measured residue-specific protein dynamics in hyperthermophilic and mesophilic homologs of adenylate kinase during catalysis. A dynamic process, the opening of the nucleotide-binding lids, was found to be rate-limiting for both enzymes as measured by NMR relaxation. Moreover, we found that the reduced catalytic activity of the hyperthermophilic enzyme at ambient temperatures is caused solely by a slower lid-opening rate. This comparative and quantitative study of activity, structure and dynamics revealed a close link between protein dynamics and catalytic turnover.
To assess whether the same mutation(s) were responsible for similar phenotypes attributed to ovine chromosome 2 (OAR2) quantitative trait loci (QTL) in different sheep breeds, Suffolk, Texel and Charollais rams from British commercial flocks were genotyped for two single nucleotide polymorphisms (SNPs) located in the myostatin (GDF8) region of OAR2, previously detected in progeny of Belgian Texel rams exhibiting muscular hypertrophy. The first SNP (g.-2449G>C) was located upstream from the transcription start site and the second SNP (g.+6723G>A) in the 3' UTR of GDF8. The g.-2449C and g.+6723A alleles were absent in the Suffolk sires sampled, almost fixed in the Texel and segregating in the Charollais sires. Mixed model association analyses using SNP data on 338 Charollais lambs from 17 paternal half-sib families and phenotype and pedigree data on 56 500 lambs revealed that both SNPs had a significant association with muscle depth (P < 0.001). The SNPs were segregating at intermediate frequencies (p = 0.3) and exhibited strong linkage disequilibrium (r(2) = 0.90). Animals with the g.+6723AA genotype had significantly greater muscle depth than those with either the g.+6723GG or the g.+6723AG genotypes (P < 0.002), with the g.+6723A allele, the likely causative mutation, having an additive effect of 1.20 (+/-0.30) mm and a dominance effect of -0.73 (+/-0.36) mm. Based on estimated allelic effects and sample allele frequencies, the g.+6723G>A SNP explained 14% of the additive genetic variance of muscle depth. The maximum genetic variance for the trait (38%) attributed to the SNP would be attained at a g.+6723A allele frequency of 0.7. Our findings indicate that marker-assisted selection using these two GDF8 SNPs would be beneficial for the Charollais breed.
Domestic species such as cattle (Bos taurus taurus and B. t. indicus) represent attractive biological models to characterize the genetic basis of short‐term evolutionary response to climate pressure induced by their post‐domestication history. Here, using newly generated dense SNP genotyping data, we assessed the structuring of genetic diversity of 21 autochtonous cattle breeds from the whole Mediterranean basin and performed genome‐wide association analyses with covariables discriminating the different Mediterranean climate subtypes. This provided insights into both the demographic and adaptive histories of Mediterranean cattle. In particular, a detailed functional annotation of genes surrounding variants associated with climate variations highlighted several biological functions involved in Mediterranean climate adaptation such as thermotolerance, UV protection, pathogen resistance or metabolism with strong candidate genes identified (e.g., NDUFB3, FBN1, METTL3, LEF1, ANTXR2 and TCF7). Accordingly, our results suggest that main selective pressures affecting cattle in Mediterranean area may have been related to variation in heat and UV exposure, in food resources availability and in exposure to pathogens, such as anthrax bacteria (Bacillus anthracis). Furthermore, the observed contribution of the three main bovine ancestries (indicine, European and African taurine) in these different populations suggested that adaptation to local climate conditions may have either relied on standing genomic variation of taurine origin, or adaptive introgression from indicine origin, depending on the local breed origins. Taken together, our results highlight the genetic uniqueness of local Mediterranean cattle breeds and strongly support conservation of these populations.
The objective of this work was to identify single nucleotide polymorphisms (SNP) in the ovine acetyl-coenzyme A acyltransferase 2 (ACAA2) gene and investigate their association with milk production traits. Molecular characterization was accomplished by sequencing the entire coding region and the 3' and 5' untranslated regions (UTR) of the ACAA2 gene from individuals of the Chios sheep bred in Cyprus. All exons appeared to be monomorphic except for the last exon, for which a single SNP located in the 3' UTR of the gene (HM537015:g.2982T>C) was detected. Mixed model association analysis, using SNP data from 318 animals from 104 paternal half-sib families and first-lactation phenotype and pedigree information on 2,405 ewes revealed that this SNP was significantly associated with milk yield. The significance of the SNP effect persisted when milk yield information up to the third lactation was analyzed. Both alleles at the locus segregated at similar frequencies. The T allele was associated with increased milk yield and exhibited partial dominant action. Animals with the g.2982TT or g.2982CT genotype had significantly higher milk yield than those with the g.2982CC genotype, with the g.2982T allele having an additive effect of 13.4 (± 4.7) kg and a dominance effect of 7.9 (± 6.1) kg. Based on estimated allelic effects and sample allele frequencies, the g.2982T>C SNP explained 10% of the additive genetic variance for milk yield. A putative mode of action through nutrient metabolism is discussed.
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