Uncovering genetic variation through resequencing is limited by the fact that only sequences with similarity to the reference genome are examined. Reference genomes are often incomplete and cannot represent the full range of genetic diversity as a result of geographical divergence and independent demographic events. To more comprehensively characterize genetic variation of pigs (Sus scrofa), we generated de novo assemblies of nine geographically and phenotypically representative pigs from Eurasia. By comparing them to the reference pig assembly, we uncovered a substantial number of novel SNPs and structural variants, as well as 137.02-Mb sequences harboring 1737 protein-coding genes that were absent in the reference assembly, revealing variants left by selection. Our results illustrate the power of whole-genome de novo sequencing relative to resequencing and provide valuable genetic resources that enable effective use of pigs in both agricultural production and biomedical research.

There are hundreds of phenotypically distinguishable domestic chicken breeds or lines with highly specialized traits worldwide, which provide a unique opportunity to illustrate how selection shapes patterns of genetic variation. There are many local chicken breeds in China. Here, we provide a population genome landscape of genetic variations in 86 domestic chickens representing 10 phenotypically diverse breeds. Genome-wide analysis indicated that sex chromosomes have less genetic diversity and are under stronger selection than autosomes during domestication and local adaptation. We found an evidence of admixture between Tibetan chickens and other domestic population. We further identified strong signatures of selection affecting genomic regions that harbor genes underlying economic traits (typically related to feathers, skin color, growth, reproduction and aggressiveness) and local adaptation (to high altitude). By comparing the genomes of the Tibetan and lowland fowls, we identified genes associated with high-altitude adaptation in Tibetan chickens were mainly involved in energy metabolism, body size maintenance and available food sources. The work provides crucial insights into the distinct evolutionary scenarios occurring under artificial selection for agricultural production and under natural selection for success at high altitudes in chicken. Several genes were identified as candidates for chicken economic traits and other phenotypic traits.

Recent studies have shown that copy number variation (CNV) in mammalian genomes contributes to phenotypic diversity, including health and disease status. In domestic pigs, CNV has been catalogued by several reports, but the extent of CNV and the phenotypic effects are far from clear. The goal of this study was to identify CNV regions (CNVRs) in pigs based on array comparative genome hybridization (aCGH).

Genetic variants in the asialoglycoprotein receptor 1 (ASGR1) are associated with a reduced risk of cardiovascular disease (CVD) in humans. However, the underlying molecular mechanism remains elusive. Given the cardiovascular similarities between pigs and humans, we generated ASGR1-deficient pigs using the CRISPR/Cas9 system. These pigs show age-dependent low levels of non-HDL-C under standard diet. When received an atherogenic diet for 6 months, ASGR1-deficient pigs show lower levels of non-HDL-C and less atherosclerotic lesions than that of controls. Furthermore, by analysis of hepatic transcriptome and in vivo cholesterol metabolism, we show that ASGR1 deficiency reduces hepatic de novo cholesterol synthesis by downregulating 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and increases cholesterol clearance by upregulating the hepatic low-density lipoprotein receptor (LDLR), which together contribute to the low levels of non-HDL-C. Despite the cardioprotective effect, we unexpectedly observed mild to moderate hepatic injury in ASGR1-deficient pigs, which has not been documented in humans with ASGR1 variants. Thus, targeting ASGR1 might be an effective strategy to reduce hypercholesterolemia and atherosclerosis, whereas further clinical evidence is required to assess its hepatic impact.

Evidence supports prophylactic use of olanzapine for the treatment of chemotherapy-induced nausea and vomiting (CINV). However, most studies to date have focused on patients with single-day highly emetogenic chemotherapy (HEC). Currently, administration of antiemetic therapies for nausea and vomiting induced by multiday chemotherapy regimens remains a challenge. In this study, we evaluated the efficacy of olanzapine combined with triple antiemetic therapy for the prevention of CINV in patients receiving multiday chemotherapy. We performed a randomized, double-blind, placebo-controlled phase 3 trial in 22 hospitals. Eligible patients were between 18 and 75 years old, were diagnosed with malignant solid tumors, and they had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. All the study participants were scheduled to be treated with chemotherapy regimens containing 3-day cisplatin (3-day total dose ≥75 mg/m²). Randomization was computer generated and stratified by gender and chemotherapy treatment history. Allocation was done via an interactive web response system. Enrolled patients were randomly assigned 1:1 to receive either 5 mg olanzapine or placebo orally before bedtime for 5 days combined with intravenous fosaprepitant (150 mg) 1 h before the administration of cisplatin on day 1, ondansetron hydrochloride intravenously, and dexamethasone orally 30 min before cisplatin from days 1 to 3. Dexamethasone was also administered at the same time on days 4 and 5. The primary endpoint was the proportion of subjects with complete response (no vomiting and no rescue therapy) within the overall phase (days 1-8) after starting chemotherapy. Baseline plasma concentrations of P-substance and 5-HT were measured for exploratory analysis. This study was registered at ClinicalTrials.gov, number NCT04536558. Between December 2020 and September 2021, 349 patients with malignant solid tumors were enrolled in the study, with 175 participants randomly assigned to receive olanzapine and 174 participants assigned to receive placebo. The proportion of patients who achieved a complete response in the overall phase was significantly higher in the olanzapine group than in the placebo group (69% vs. 58%, P = 0.031). A complete response benefit was observed in the olanzapine group versus the placebo group in almost all the subgroups. Four factors were considered significantly associated with complete response in multivariable analysis: treatment group, gender, baseline plasma concentration of 5-HT, and prior radiotherapy. All the reported adverse events associated with olanzapine administration were grades 1 and 2. Olanzapine (5 mg) combined with fosaprepitant, ondansetron, and dexamethasone was better than triple antiemetic therapy alone for patients receiving multiday chemotherapy regimens. Based on these results, the four-drug combination should be recommended as the best antiemetic regimen given to patients receiving multiday cisplatin-based chemotherapy and baseline plasma concentration of 5-HT may be used to identify individuals who are prone to CINV. However, all these findings need to be further validated in future studies. Jiangsu Hansoh Pharmaceutical Group Co., Ltd. provided research grant and study drugs for this investigator-initiated study.