Genome-Wide Gene-Environment Interaction Analysis Identifies Novel Candidate Variants for Growth Traits in Beef Cattle.

Complex traits are widely considered to be the result of a compound regulation of genes, environmental factors, and genotype-by-environment interaction (G × E). The inclusion of G × E in genome-wide association analyses is essential to understand animal environmental adaptations and improve the efficiency of breeding decisions. Here, we systematically investigated the G × E of growth traits (including weaning weight, yearling weight, 18-month body weight, and 24-month body weight) with environmental factors (farm and temperature) using genome-wide genotype-by-environment interaction association studies (GWEIS) with a dataset of 1350 cattle. We validated the robust estimator's effectiveness in GWEIS and detected 29 independent interacting SNPs with a significance threshold of 1.67 × 10-6, indicating that these SNPs, which do not show main effects in traditional genome-wide association studies (GWAS), may have non-additive effects across genotypes but are obliterated by environmental means. The gene-based analysis using MAGMA identified three genes that overlapped with the GEWIS results exhibiting G × E, namely SMAD2, PALMD, and MECOM. Further, the results of functional exploration in gene-set analysis revealed the bio-mechanisms of how cattle growth responds to environmental changes, such as mitotic or cytokinesis, fatty acid ß-oxidation, neurotransmitter activity, gap junction, and keratan sulfate degradation. This study not only reveals novel genetic loci and underlying mechanisms influencing growth traits but also transforms our understanding of environmental adaptation in beef cattle, thereby paving the way for more targeted and efficient breeding strategies.

Genome-Wide Detection of Copy Number Variations and Their Potential Association with Carcass and Meat Quality Traits in Pingliang Red Cattle.

Copy number variation (CNV) serves as a significant source of genetic diversity in mammals and exerts substantial effects on various complex traits. Pingliang red cattle, an outstanding indigenous resource in China, possess remarkable breeding value attributed to their tender meat and superior marbling quality. However, the genetic mechanisms influencing carcass and meat quality traits in Pingliang red cattle are not well understood. We generated a comprehensive genome-wide CNV map for Pingliang red cattle using the GGP Bovine 100K SNP chip. A total of 755 copy number variable regions (CNVRs) spanning 81.03 Mb were identified, accounting for approximately 3.24% of the bovine autosomal genome. Among these, we discovered 270 potentially breed-specific CNVRs in Pingliang red cattle, including 143 gains, 73 losses, and 54 mixed events. Functional annotation analysis revealed significant associations between these specific CNVRs and important traits such as carcass and meat quality, reproduction, exterior traits, growth traits, and health traits. Additionally, our network and transcriptome analysis highlighted CACNA2D1, CYLD, UBXN2B, TG, NADK, and ITGA9 as promising candidate genes associated with carcass weight and intramuscular fat deposition. The current study presents a genome-wide CNV map in Pingliang red cattle, highlighting breed-specific CNVRs, and transcriptome findings provide valuable insights into the underlying genetic characteristics of Pingliang red cattle. These results offer potential avenues for enhancing meat quality through a targeted breeding program.

A clinical nomogram for predicting occult lymph node metastasis in patients with non-small-cell lung cancer ≤2 cm.

OBJECTIVES: Sublobar resection has been shown to be feasible for non-small-cell lung cancers (NSCLC) <2 cm in size based on several prospective studies. However, the prognosis of clinical N0 patients who experience an N-stage upgrade after surgery [known as occult lymph node metastasis (OLM)] may be worse. The ability of predict OLM in patients eligible for sublobar resection remains a controversial issue. METHODS: Patients with NSCLC ≤2 cm in diameter and containing a solid component who underwent surgical treatment at the Affiliated Hospital of Qingdao University were retrospectively enrolled, and 1:1 case matching was performed. The risk factors were identified through logistic regression analyses and theoretical criteria, followed by the development of a nomogram that was evaluated using 200 iterations of 10-fold cross-validation. RESULTS: After case matching, 130 pairs of patients were selected for modelling. According to the multivariable logistic regression analysis, the carcinoembryonic antigen level, consolidation tumour ratio, mean computed tomography number and tumour margin were included in the nomogram. The cross-validated average area under the receiver operating characteristic curve was found to be 0.86. Furthermore, calibration curve and decision curve analyses demonstrated the excellent predictive accuracy and clinical utility of the nomogram respectively. CONCLUSIONS: By utilizing accessible characteristics, we developed a nomogram that predicts the probability of OLM in patients with NSCLC ≤2 cm with a solid component. Risk stratification with this nomogram could aid in surgical method decision-making. CLINICAL REGISTRATION NUMBER: Not applicable.

Abnormal performance of peroral endoscopic myotomy (POEM): a case misdiagnosed as achalasia of cardia.

BACKGROUND: Pseudoachalasia is a rare disease that behaves similarly to achalasia (AC), making it sometimes difficult to differentiate. CASE PRESENTATION: We report a case of 49-year-old male with adenocarcinoma of the gastroesophageal junction misdiagnosed as achalasia. No obvious abnormalities were found in his initial examinations including upper digestive endoscopy, upper gastrointestinal imaging and chest computed tomography (CT). During the subsequent introduced-peroral endoscopic myotomy (POEM), it was found that the mucosal layer and the muscular layer had severe adhesion, which did not receive much attention, delayed the clear diagnosis and effect treatment, and ultimately led to a poor prognosis for the patient. CONCLUSIONS: This case suggests that when patients with AC found mucosal and muscular adhesions during POEM surgery, the possibility should be considered that the lesion may be caused by a malignant lesion.

Transcriptome Analysis of Compensatory Growth and Meat Quality Alteration after Varied Restricted Feeding Conditions in Beef Cattle.

Compensatory growth (CG) is a physiological response that accelerates growth following a period of nutrient limitation, with the potential to improve growth efficiency and meat quality in cattle. However, the underlying molecular mechanisms remain poorly understood. In this study, 60 Huaxi cattle were divided into one ad libitum feeding (ALF) group and two restricted feeding groups (75% restricted, RF75; 50% restricted, RF50) undergoing a short-term restriction period followed by evaluation of CG. Detailed comparisons of growth performance during the experimental period, as well as carcass and meat quality traits, were conducted, complemented by a comprehensive transcriptome analysis of the longissimus dorsi muscle using differential expression analysis, gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and weighted correlation network analysis (WGCNA). The results showed that irrespective of the restriction degree, the restricted animals exhibited CG, achieving final body weights comparable to the ALF group. Compensating animals showed differences in meat quality traits, such as pH, cooking loss, and fat content, compared to the ALF group. Transcriptomic analysis revealed 57 genes and 31 pathways differentially regulated during CG, covering immune response, acid-lipid metabolism, and protein synthesis. Notably, complement-coagulation-fibrinolytic system synergy was identified as potentially responsible for meat quality optimization in RF75. This study provides novel and valuable genetic insights into the regulatory mechanisms of CG in beef cattle.

Improving Genomic Predictions in Multi-Breed Cattle Populations: A Comparative Analysis of BayesR and GBLUP Models.

Numerous studies have shown that combining populations from similar or closely related genetic breeds improves the accuracy of genomic predictions (GP). Extensive experimentation with diverse Bayesian and genomic best linear unbiased prediction (GBLUP) models have been developed to explore multi-breed genomic selection (GS) in livestock, ultimately establishing them as successful approaches for predicting genomic estimated breeding value (GEBV). This study aimed to assess the effectiveness of using BayesR and GBLUP models with linkage disequilibrium (LD)-weighted genomic relationship matrices (GRMs) for genomic prediction in three different beef cattle breeds to identify the best approach for enhancing the accuracy of multi-breed genomic selection in beef cattle. Additionally, a comparison was conducted to evaluate the predictive precision of different marker densities and genetic correlations among the three breeds of beef cattle. The GRM between Yunling cattle (YL) and other breeds demonstrated modest affinity and highlighted a notable genetic concordance of 0.87 between Chinese Wagyu (WG) and Huaxi (HX) cattle. In the within-breed GS, BayesR demonstrated an advantage over GBLUP. The prediction accuracies for HX cattle using the BayesR model were 0.52 with BovineHD BeadChip data (HD) and 0.46 with whole-genome sequencing data (WGS). In comparison to the GBLUP model, the accuracy increased by 26.8% for HD data and 9.5% for WGS data. For WG and YL, BayesR doubled the within-breed prediction accuracy to 14.3% from 7.1%, outperforming GBLUP across both HD and WGS datasets. Moreover, analyzing multiple breeds using genomic selection showed that BayesR consistently outperformed GBLUP in terms of predictive accuracy, especially when using WGS. For instance, in a mixed reference population of HX and WG, BayesR achieved a significant accuracy of 0.53 using WGS for HX, which was a substantial enhancement over the accuracies obtained with GBLUP models. The research further highlights the benefit of including various breeds in the reference group, leading to enhanced accuracy in predictions and emphasizing the importance of comprehensive genomic selection methods. Our research findings indicate that BayesR exhibits superior performance compared to GBLUP in multi-breed genomic prediction accuracy, achieving a maximum improvement of 33.3%, especially in genetically diverse breeds. The improvement can be attributed to the effective utilization of higher single nucleotide polymorphism (SNP) marker density by BayesR, resulting in enhanced prediction accuracy. This evidence conclusively demonstrates the significant impact of BayesR on enhancing genomic predictions in diverse cattle populations, underscoring the crucial role of genetic relatedness in selection methodologies. In parallel, subsequent studies should focus on refining GRM and exploring alternative models for GP.

Genetic Origin and Introgression Pattern of Pingliang Red Cattle Revealed Using Genome-Wide SNP Analyses.

The Pingliang red cattle, an outstanding indigenous resource in China, possesses an exceptional breeding value attributed to its tender meat and superior marbling quality. Currently, research efforts have predominantly concentrated on exploring its maternal origin and conducting conventional phenotypic studies. However, there remains a lack of comprehensive understanding regarding its genetic basis. To address this gap, we conducted a thorough whole-genome analysis to investigate the population structure, phylogenetic relationships, and gene flows of this breed using genomic SNP chip data from 17 bovine breeds. The results demonstrate that Pingliang red cattle have evolved distinct genetic characteristics unique to this breed, clearly distinguishing it from other breeds. Based on the analysis of the population structure and phylogenetic tree, it can be classified as a hybrid lineage between Bos taurus and Bos indicus. Furthermore, Pingliang red cattle display a more prominent B. taurus pedigree in comparison with Jinnan, Qinchuan, Zaosheng, Nanyang, and Luxi cattle. Moreover, this study also revealed closer genetic proximity within the Chinese indigenous cattle breed, particularly Qinchuan cattle, which shares the longest identical by descent (IBD) fragment with Pingliang red cattle. Gene introgression analysis shows that Pingliang red cattle have undergone gene exchange with South Devon and Red Angus cattle from Europe. Admixture analysis revealed that the proportions of East Asian taurine and Chinese indicine in the ancestry of Pingliang red cattle are approximately 52.44% and 21.00%, respectively, while Eurasian taurine, European taurine, and Indian indicine account for approximately 17.55%, 7.27%, and 1.74%. Our findings unveil distinct genetic characteristics in Pingliang red cattle and attribute their origin to B. taurus and B. indicus ancestry, as well as contributions from Qinchuan cattle, South Devon, and Red Angus.

Genome-Wide Association Analysis Identifies the PMEL Gene Affecting Coat Color and Birth Weight in Simmental × Holstein.

Coat color and birth weight, as easily selected traits in cattle, play important roles in cattle breeding. Therefore, we carried out a genome-wide association study on birth weight and coat color to identify loci or potential linkage regions in 233 Simmental × Holstein crossbred beef cattle. The results revealed that nine SNPs were significantly associated with coat color (rs137169378, rs110022687, rs136002689, Hypotrichosis_PMel17, PMEL_1, rs134930689, rs383170073, rs109924971, and rs109146332), and these were in RNF41, ZC3H10, ERBB3, PMEL, and OR10A7 on BTA5. Interestingly, rs137169378, rs110022687, rs136002689, Hypotrichosis_PMel17, and PMEL_1 showed strong linkage disequilibrium (r2 > 0.8) and were significantly associated with coat color. Notably, Hypotrichosis_PMel17 and PMEL_1 were located in the gene PMEL (p = 2.22 × 10-18). Among the five significant SNPs associated with coat color, the birth weight of heterozygous individuals (AB) was greater than that of homozygous individuals (AA). Notably, the birth weight of heterozygous individuals with Hypotrichosis_PMel17 and PMEL_1 genotypes was significantly greater than that of homozygous individuals (0.01 < p < 0.05). Interestingly, the two loci were homozygous in black/white individuals and heterozygous in gray/white individuals, and the birth weight of heterozygous brown/white individuals (43.82 ± 5.25 kg) was greater than that of homozygous individuals (42.58 ± 3.09 kg). The birth weight of calves with the parental color (41.95 ± 3.53 kg) was significantly lower than that of calves with a non-parental color (43.54 ± 4.78 kg) (p < 0.05), and the birth weight of gray/white individuals (49.40 ± 7.11 kg) was the highest. Overall, PMEL appears to be a candidate gene affecting coat color in cattle, and coat color may have a selective effect on birth weight. This study provides a foundation for the breeding of beef cattle through GWAS for coat color and birth weight.

Genetic Association Analysis of Copy Number Variations for Meat Quality in Beef Cattle.

Meat quality is an economically important trait for global food production. Copy number variations (CNVs) have been previously implicated in elucidating the genetic basis of complex traits. In this article, we detected a total of 112,198 CNVs and 10,102 CNV regions (CNVRs) based on the Bovine HD SNP array. Next, we performed a CNV-based genome-wide association analysis (GWAS) of six meat quality traits and identified 12 significant CNV segments corresponding to eight candidate genes, including PCDH15, CSMD3, etc. Using region-based association analysis, we further identified six CNV segments relevant to meat quality in beef cattle. Among these, TRIM77 and TRIM64 within CNVR4 on BTA29 were detected as candidate genes for backfat thickness (BFT). Notably, we identified a 34 kb duplication for meat color (MC) which was supported by read-depth signals, and this duplication was embedded within the keratin gene family including KRT4, KRT78, and KRT79. Our findings will help to dissect the genetic architecture of meat quality traits from the aspects of CNVs, and subsequently improve the selection process in breeding programs.

Characterization of Chromatin Accessibility in Fetal Bovine Chondrocytes.

Despite significant advances of the bovine epigenome investigation, new evidence for the epigenetic basis of fetal cartilage development remains lacking. In this study, the chondrocytes were isolated from long bone tissues of bovine fetuses at 90 days. The Assay for Transposase-Accessible Chromatin with high throughput sequencing (ATAC-seq) and transcriptome sequencing (RNA-seq) were used to characterize gene expression and chromatin accessibility profile in bovine chondrocytes. A total of 9686 open chromatin regions in bovine fetal chondrocytes were identified and 45% of the peaks were enriched in the promoter regions. Then, all peaks were annotated to the nearest gene for Gene Ontology (GO) and Kyoto Encylopaedia of Genes and Genomes (KEGG) analysis. Growth and development-related processes such as amide biosynthesis process (GO: 0043604) and translation regulation (GO: 006417) were enriched in the GO analysis. The KEGG analysis enriched endoplasmic reticulum protein processing signal pathway, TGF-ß signaling pathway and cell cycle pathway, which are closely related to protein synthesis and processing during cell proliferation. Active transcription factors (TFs) were enriched by ATAC-seq, and were fully verified with gene expression levels obtained by RNA-seq. Among the top50 TFs from footprint analysis, known or potential cartilage development-related transcription factors FOS, FOSL2 and NFY were found. Overall, our data provide a theoretical basis for further determining the regulatory mechanism of cartilage development in bovine.

Evaluation of Linear Programming and Optimal Contribution Selection Approaches for Long-Term Selection on Beef Cattle Breeding.

The optimized selection method can maximize the genetic gain in offspring under the premise of controlling the inbreeding level of the population. At present, genetic gain has been largely improved by using genomic selection in multiple farm animals. However, the design of the optimal selection method and assessment of its effects during long-term selection in beef cattle breeding are yet to be fully explored. In this study, a simulated beef cattle population was constructed, and 15 generations of simulated breeding were carried out using the linear programming breeding strategy (LP) and optimal contribution selection strategy (OCS), respectively. The truncation selection strategy (TS-I and TS-II) was used as the control. During the breeding process, genetic parameters including genetic gain, average kinship coefficient, QTL effect variance, and average observed heterozygosity were calculated and compared across generations. Our results showed that the LP method can significantly improve the genetic gain in the population, especially the genetic performance of the traits with high heritability and the traits with high weight in the breeding process, but the inbreeding level of the population is higher under LP strategy. Although the genetic gain in the population under the OCS strategy is lower than the TS-II strategy, this method can effectively control the inbreeding level of the population. Our findings also suggest that the LP and OCS method can be used as an effective means to improve genetic gain, while the OCS method is a more ideal method to obtain sustainable genetic gain during long-term selection.

The eQTL colocalization and transcriptome-wide association study identify potentially causal genes responsible for economic traits in Simmental beef cattle.

BACKGROUND: A detailed understanding of genetic variants that affect beef merit helps maximize the efficiency of breeding for improved production merit in beef cattle. To prioritize the putative variants and genes, we ran a comprehensive genome-wide association studies (GWAS) analysis for 21 agronomic traits using imputed whole-genome variants in Simmental beef cattle. Then, we applied expression quantitative trait loci (eQTL) mapping between the genotype variants and transcriptome of three tissues (longissimus dorsi muscle, backfat, and liver) in 120 cattle. RESULTS: We identified 1,580 association signals for 21 beef agronomic traits using GWAS. We then illuminated 854,498 cis-eQTLs for 6,017 genes and 46,970 trans-eQTLs for 1,903 genes in three tissues and built a synergistic network by integrating transcriptomics with agronomic traits. These cis-eQTLs were preferentially close to the transcription start site and enriched in functional regulatory regions. We observed an average of 43.5% improvement in cis-eQTL discovery using multi-tissue eQTL mapping. Fine-mapping analysis revealed that 111, 192, and 194 variants were most likely to be causative to regulate gene expression in backfat, liver, and muscle, respectively. The transcriptome-wide association studies identified 722 genes significantly associated with 11 agronomic traits. Via the colocalization and Mendelian randomization analyses, we found that eQTLs of several genes were associated with the GWAS signals of agronomic traits in three tissues, which included genes, such as NADSYN1, NDUFS3, LTF and KIFC2 in liver, GRAMD1C, TMTC2 and ZNF613 in backfat, as well as TIGAR, NDUFS3 and L3HYPDH in muscle that could serve as the candidate genes for economic traits. CONCLUSIONS: The extensive atlas of GWAS, eQTL, fine-mapping, and transcriptome-wide association studies aid in the suggestion of potentially functional variants and genes in cattle agronomic traits and will be an invaluable source for genomics and breeding in beef cattle.

Association of survival with adjuvant radiotherapy for pN0 esophageal cancer.

INTRODUCTION: This study was conducted to elucidate the link between adjuvant radiotherapy and survival in pathologic node-negative (pN0) esophageal cancer patients with upfront esophagectomy. METHODS: From 2000 to 2016, patients with pN0 esophageal cancer who underwent upfront esophagectomy were selected from the Surveillance, Epidemiology, and End Results (SEER) database. The association of high-risk covariates with survival after adjuvant radiotherapy was evaluated using propensity score matching and multivariate analysis. RESULTS: We identified 3197 patients, 321 (10.0%) underwent postoperative radiotherapy and 2876 (90.0%) underwent esophagectomy alone. In the unmatched cohort, postoperative radiotherapy was associated with a statistically significant but modest absolute decrease in survival outcomes (P < 0.001). In the matched cohort, the survival differences disappeared. Additionally, adjuvant radiotherapy was linked to a 5-year overall survival (OS) benefit for patients with the pT3-4N0 disease (34.8% vs. 27.7%; P = 0.008). Adjuvant radiotherapy for pT3-4N0 disease with tumor length ≥3 cm, adenocarcinoma, and evaluated lymph node count <12 was shown to independently function as a risk factor for improved OS, as per a multivariate analysis (P < 0.01). CONCLUSIONS: This population-based trial showed that high-risk patients with pT3-4N0 esophageal cancer had better OS following upfront esophagectomy followed by radiotherapy therapy. This discovery may have major significance in the use of adjuvant radiotherapy following upfront esophagectomy in patients with pN0 esophageal cancer.

Development a m6A regulators characterized by the immune cell infiltration in stomach adenocarcinoma for predicting the prognosis and immunotherapy response.

N6-Methyladenosine (m6A) has attracted growing interest among scholars as an important regulator of mRNA expression. Although the significant role of m6A in multiple biological processes (like proliferation and growth of cancers) has been comprehensively described, an analysis of its possible role in stomach adenocarcinoma (STAD) of tumor immune microenvironment (TIME) remains lacking. The data for RNA expression, single nucleotide polymorphism (SNP), and copy number variation (CNV) were downloaded from The Cancer Genome Atlas (TCGA). Subsequently, 23 m6A regulators were curated, with patients being clustered into three m6A subtypes and m6A-related gene subtypes. Furthermore, they were compared based on overall survival (OS). This study also evaluates the association between m6A regulators and immune as well as response to the treatment. According to the TCGA-STAD cohort, three m6A clusters conformed to three phenotypes, immune-inflamed, immune-dessert, and immune-excluded, respectively. Patients who displayed lower m6A scores presented better overall survival outcomes. The GEO cohort demonstrated that those with a low m6A score had obvious general survival benefits and clinical advantages. Low m6A scores can carry the enhanced neoantigen loads, triggering an immune response. Meanwhile, three anti-PD-1 cohorts have confirmed the value of predicting survival outcomes. The results of this study indicate that m6A regulators are associated with TIME, and the m6A score is an efficient prognostic biomarker and predictive indicator for immunotherapy and chemotherapeutics. Moreover, comprehensive evaluations of m6A regulators in tumors will broaden our comprehension of TIME, efficiently guiding enhancing explorations on immunotherapy and chemotherapy strategies for STAD.

Short-term outcome of totally minimally invasive versus hybrid minimally invasive Ivor-Lewis esophagectomy.

OBJECTIVES: For resectable esophageal cancer, the choice of total minimally invasive esophagectomy (TMIE) or hybrid minimally invasive esophagectomy (HMIE) remains controversial. The purpose of this study was to evaluate the short-term clinical outcomes of TMIE and HMIE under the Ivor-Lewis procedure. METHODS: The data of 145 patients diagnosed with middle or lower esophageal cancer who underwent radical Ivor-Lewis esophagectomy in the Affiliated Hospital of Qingdao University between January 2018 and December 2019 were retrospectively analyzed. The short-term outcomes such as complications during surgery or within 30 days after surgery and postoperative pain were analyzed. RESULTS: All patients were divided into TMIE group (75 patients) and HMIE group (70 patients). No significant difference was observed in the baseline characteristics of the two groups. TMIE was associated with less blood loss than the HMIE group (p < 0.05). A total of 54 (37.2%) patients had postoperative complications. Although the two groups were statistically similar in the incidence of major complications, patients in the HMIE group were more likely to have pneumonia compared with those in the TMIE group. The numeric rating scale for pain was significantly higher in the HMIE group (p = 0.002) and more patients required an additional opioid analgesia after esophagectomy (p = 0.282). CONCLUSIONS: In conclusion, according to perioperative outcomes, TMIE can benefit patients better than HMIE.

A 1.1 Mb duplication CNV on chromosome 17 contributes to skeletal muscle development in Boer goats.

The Boer goat is one of the top meat breeds in modern animal husbandry and has attracted widespread attention for its unique growth performance. However, the genetic basis of muscle development in the Boer goat remains obscure. In this study, we identified specific structural variants in the Boer goat based on genome-wide selection signals and analyzed the basis of the molecular heredity of related candidate genes in muscle development. A total of 9 959 autosomal copy number variations (CNVs) were identified through selection signal analysis in 127 goat genomes. Specifically, we confirmed that the highest signal CNV (HSV) was a chromosomal arrangement containing an approximately 1.11 Mb (CHIR17: 60062304-61171840 bp) duplicated fragment inserted in reverse orientation and a 5 362 bp deleted region (CHIR17:60145940-60151302 bp) with overlapping genes (e.g., ARHGAP10, NR3C2, EDNRA, PRMT9, and TMEM184C). The homozygous duplicated HSV genotype (+/+) was found in 96% of Boer goats but was not detected in Eurasian goats and was only detected in 4% of indigenous African goats. The expression network of three candidate genes ( ARHGAP10, NR3C2, and EDNRA) regulating dose transcription was constructed by RNA sequencing. Results indicated that these genes were involved in the proliferation and differentiation of skeletal muscle satellite cells (SMSCs) and their overexpression significantly increased the expression of SAA3. The HSV of the Boer goat contributed to superior skeletal muscle growth via the dose effects of overlapping genes.

MAK: a machine learning framework improved genomic prediction via multi-target ensemble regressor chains and automatic selection of assistant traits.

Incorporating the genotypic and phenotypic of the correlated traits into the multi-trait model can significantly improve the prediction accuracy of the target trait in animal and plant breeding, as well as human genetics. However, in most cases, the phenotypic information of the correlated and target trait of the individual to be evaluated was null simultaneously, particularly for the newborn. Therefore, we propose a machine learning framework, MAK, to improve the prediction accuracy of the target trait by constructing the multi-target ensemble regression chains and selecting the assistant trait automatically, which predicted the genomic estimated breeding values of the target trait using genotypic information only. The prediction ability of MAK was significantly more robust than the genomic best linear unbiased prediction, BayesB, BayesRR and the multi trait Bayesian method in the four real animal and plant datasets, and the computational efficiency of MAK was roughly 100 times faster than BayesB and BayesRR.

Cis-eQTL Analysis and Functional Validation of Candidate Genes for Carcass Yield Traits in Beef Cattle.

Carcass yield traits are of considerable economic importance for farm animals, which act as a major contributor to the world's food supply. Genome-wide association studies (GWASs) have identified many genetic variants associated with carcass yield traits in beef cattle. However, their functions are not effectively illustrated. In this study, we performed an integrative analysis of gene-based GWAS with expression quantitative trait locus (eQTL) analysis to detect candidate genes for carcass yield traits and validate their effects on bovine skeletal muscle satellite cells (BSCs). The gene-based GWAS and cis-eQTL analysis revealed 1780 GWAS and 1538 cis-expression genes. Among them, we identified 153 shared genes that may play important roles in carcass yield traits. Notably, the identified cis-eQTLs of PON3 and PRIM2 were significantly (p < 0.001) enriched in previous GWAS loci for carcass traits. Furthermore, overexpression of PON3 and PRIM2 promoted the BSCs' proliferation, increased the expression of MYOD and downregulated the expression of MYOG, which indicated that these genes may inhibit myogenic differentiation. In contrast, PON3 and PRIM2 were significantly downregulated during the differentiation of BSCs. These findings suggested that PON3 and PRIM2 may promote the proliferation of BSCs and inhibit them in the pre-differentiation stage. Our results further contribute to the understanding of the molecular mechanisms of carcass yield traits in beef cattle.

Genomic prediction of carcass traits using different haplotype block partitioning methods in beef cattle.

Genomic prediction (GP) based on haplotype alleles can capture quantitative trait loci (QTL) effects and increase predictive ability because the haplotypes are expected to be in linkage disequilibrium (LD) with QTL. In this study, we constructed haploblocks using LD-based and the fixed number of single nucleotide polymorphisms (fixed-SNP) methods with Illumina BovineHD chip in beef cattle. To evaluate the performance of different haplotype block partitioning methods, we constructed haploblocks based on LD thresholds (from r 2 > 0.2 to r 2 > 0.8) and the number of fixed-SNPs (5, 10, 20). The performance of predictive methods for three carcass traits including liveweight (LW), dressing percentage (DP), and longissimus dorsi muscle weight (LDMW) was evaluated using three approaches (GBLUP and BayesB model based on the SNP, GHBLUP, and BayesBH models based on the haploblock, and GHBLUP+GBLUP and BayesBH+BayesB models based on the combined haploblock and the nonblocked SNPs, which were located between blocks). In this study, we found the accuracies of LD-based and fixed-SNP haplotype Bayesian methods outperformed the Bayesian models (up to 8.54 ± 7.44% and 5.74 ± 2.95%, respectively). GHBLUP showed a high improvement (up to 11.29 ± 9.87%) compared with GBLUP. The Bayesian models have higher accuracies than BLUP models in most scenarios. The average computing time of the BayesBH+BayesB model can reduce by 29.3% compared with the BayesB model. The prediction accuracies using the LD-based haplotype method showed higher improvements than the fixed-SNP haplotype method. In addition, to avoid the influence of rare haplotypes generated from haplotype construction, we compared the performance of GP by filtering four types of minor haplotype allele frequency (MHAF) (0.01, 0.025, 0.05, and 0.1) under different conditions (LD levels were set at r 2 > 0.3, and the fixed number of SNPs was 5). We found the optimal MHAF threshold for LW was 0.01, and the optimal MHAF threshold for DP and LDMW was 0.025.

Improving Genomic Prediction with Machine Learning Incorporating TPE for Hyperparameters Optimization.

Depending on excellent prediction ability, machine learning has been considered the most powerful implement to analyze high-throughput sequencing genome data. However, the sophisticated process of tuning hyperparameters tremendously impedes the wider application of machine learning in animal and plant breeding programs. Therefore, we integrated an automatic tuning hyperparameters algorithm, tree-structured Parzen estimator (TPE), with machine learning to simplify the process of using machine learning for genomic prediction. In this study, we applied TPE to optimize the hyperparameters of Kernel ridge regression (KRR) and support vector regression (SVR). To evaluate the performance of TPE, we compared the prediction accuracy of KRR-TPE and SVR-TPE with the genomic best linear unbiased prediction (GBLUP) and KRR-RS, KRR-Grid, SVR-RS, and SVR-Grid, which tuned the hyperparameters of KRR and SVR by using random search (RS) and grid search (Gird) in a simulation dataset and the real datasets. The results indicated that KRR-TPE achieved the most powerful prediction ability considering all populations and was the most convenient. Especially for the Chinese Simmental beef cattle and Loblolly pine populations, the prediction accuracy of KRR-TPE had an 8.73% and 6.08% average improvement compared with GBLUP, respectively. Our study will greatly promote the application of machine learning in GP and further accelerate breeding progress.