Bone weight, defined as the total weight of the bones in all the forequarter and hindquarter joints, can reflect somebody conformation traits and skeletal diseases. To gain a better understanding of the genetic determinants of bone weight, we used a composite strategy including multimarker and rare-marker association to perform genomewide association studies (GWAS) for that character in Simmental cattle. Our strategy consisted of three models: (i) A traditional linear mixed model (LMM) was applied (Q+K-LMM); (ii) single nucleotide polymorphisms (SNPs) with p-values less than .05 from the LMM were selected to undergo the least absolute shrinkage and selector operator (Lasso) in the second stage (LMM-Lasso); (iii) genes containing two or more rare SNPs were examined by performing the sequence kernel association test (gene-based SKAT). A total of 1,225 cattle were genotyped with an Illumina BovineHD BeadChip containing 770,000 SNPs. After the quality-control procedures, 1,217 individuals with 608,696 common SNPs and 105,787 rare SNPs (with 0.001 < minor allele frequency [MAF] <0.05) remained in the sample for analysis. A traditional LMM successfully mapped three genes associated with bone weight, while LMM-Lasso identified nine genes, which included all genes found by traditional LMM. Only a single gene, EPHB3, surpassed the significance threshold after Bonferroni correction in gene-based SKAT. In conclusion, based on functional annotation and results from previous endeavours, we believe that LCORL, RIMS2, LAP3, PRKAR2B, CHSY1, MAP2K6 and EPHB3 are candidate genes for bone weight. In general, such a comprehensive strategy for GWAS may be useful for researchers seeking to probe the full genetic architecture underlying economic traits in livestock.
Sika deer are known to prefer oak leaves, which are rich in tannins and toxic to most mammals; however, the genetic mechanisms underlying their unique ability to adapt to living in the jungle are still unclear. In identifying the mechanism responsible for the tolerance of a highly toxic diet, we have made a major advancement in the elucidation of the genomics of sika deer. We generated the first high-quality, chromosome-level genome assembly of sika deer and measured the correlation between tannin intake and RNA expression in 15 tissues through 180 experiments. Comparative genome analyses showed that the UGT and CYP gene families are functionally involved in the adaptation of sika deer to high-tannin food, especially the expansion of UGT genes in a subfamily. The first chromosome-level assembly and genetic characterization of the tolerance toa highly toxic diet suggest that the sika deer genome will serve as an essential resource for understanding evolutionary events and tannin adaptation. Our study provides a paradigm of comparative expressive genomics that can be applied to the study of unique biological features in non-model animals.
Induced pluripotent stem cell(iPSC) technology promises to be an inexhaustible source of any type of cell needed for therapeutic and research purposes.It is unclear that how distal enhancer-promoter associations/3D chromatin conformation involving in the capacity of self-renewal and pluripotency maintenance. In this study, we have selected a few defined enhancer-promoter associations. After screening of enhancer specificity and activity individually, we design the different combinations and transfect these enhancers into the MEF cells. We simultaneously transfect 7 determined enhancers which represents various specific distal chromatin associations into a GFP tracing MEF cell line. We observe that the MEF cells start generating iPS-like clones at day 22. Importantly, our validations with three germ layer marker genes and in vitro experiments have further confirmed the pluripotency of these clones. Here, our study proposes a potential de novo method of a low-genetic risk iPS generation by introducing spatiotemporal distal chromatin associations. This result also paves out the way on utilizing 3D genomic information to alter cell identity and reprogramming for potential therapeutic strategy.
23Cellulases from glycoside hydrolase (GH) family 5 are key enzymes in the degradation of 24 diverse polysaccharide substrates and are used in industrial enzyme cocktails to break down 25 biomass. The GH5 family shares a canonical (βα) 8 -barrel structure, where each (βα) module 26 is essential for the enzyme stability and activity. Despite their shared topology, the 27 thermostability of GH5 enzymes can vary significantly, and highly thermostable variants are 28 often sought for industrial applications. Based on a previously characterized thermophilic 29 GH5 cellulase from Talaromyces emersonii (TeEgl5A, with an optimal temperature of 90°C), 30we created ten hybrid enzymes with the mesophilic cellulase from Prosthecium opalus 31 (PoCel5) to determine which elements are responsible for enhanced thermostability. Five of 32 the expressed hybrid enzymes exhibit enzyme activity. Two of these hybrids exhibited 33 pronounced increases in the temperature optima (10 and 20°C), T 50 (15 and 19°C), T m (16.5 34 and 22.9°C), and extended half life, t 1/2 (~240-and 650-fold at 55°C) relative to the 35 mesophilic parent enzyme, and demonstrated improved catalytic efficiency on selected 36 substrates. The successful hybridization strategies were validated experimentally in another 37 GH5 cellulase from Aspergillus nidulans (AnCel5), which demonstrated a similar increase in 38 thermostability. Based on molecular dynamics simulations (MD) of both PoCel5 and 39TeEgl5A parent enzymes as well as their hybrids, we hypothesize that improved hydrophobic 40 packing of the interface between α 2 and α 3 is the primary mechanism by which the hybrid 41 enzymes increase their thermostability relative to the mesophilic parent PoCel5. 42Thermal stability is an essential property of enzymes in many industrial biotechnological 45 applications, as high temperatures improve bioreactor throughput. Many protein engineering 46 approaches, such as rational design and directed evolution, have been employed to improve 47 the thermal properties of mesophilic enzymes. Structure-based recombination has also been 48 used to fuse TIM-barrel fragments and even fragments from unrelated folds, to generate new 49 structures. However, there are not many research on GH5 cellulases. In this study, two GH5 50 cellulases, which showed TIM-barrel structure, PoCel5 and TeEgl5A with different thermal 51properties were hybridized to study the roles of different (βα) motifs. This work illustrates the 52 role that structure guided recombination can play in helping to identify sequence function 53 relationships within GH5 enzymes by supplementing natural diversity with synthetic 54 diversity. 55 56 Keywords: GH5 Cellulase; (βα) 8 -barrel structure; structure-based recombination; hybrid 57 enzymes; thermostability; 58 59 5 7 conducting structure-guided protein engineering. The cellulase TeEgl5A from T. emersonii (6) 102 exhibits high thermostability, retaining almost all of the activity after incubation at 70°C for 1 103 h, although the structural underpinning for thermal t...
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