The Tibetan cashmere goat (Capra hircus), one of the most ancient breeds in China, has historically been a critical source of meat and cashmere production for local farmers. To adapt to the high-altitude area, extremely harsh climate, and hypoxic environment that the Tibetan cashmere goat lives in, this goat has developed distinct phenotypic traits compared to lowland breeds. However, the genetic components underlying this phenotypic adaptation remain largely unknown. We obtained 118,700 autosomal SNPs through exome sequencing of 330 cashmere goats located at a wide geographic range, including the Tibetan Plateau and low-altitude regions in China. The great majority of SNPs showed low genetic differentiation among populations; however, approximately 2-3 % of the loci showed more genetic differentiation than expected under a selectively neutral model. Together with a combined analysis of high- and low-altitude breeds, we revealed 339 genes potentially under high-altitude selection. Genes associated with cardiovascular system development were significantly enriched in our study. Among these genes, the most evident one was endothelial PAS domain protein 1 (EPAS1), which has been previously reported to be involved in complex oxygen sensing and significantly associated with high-altitude adaptation of human, dog, and grey wolf. The missense mutation Q579L that we identified in EPAS1, which occurs next to the Hypoxia-Inducible Factor-1 (HIF-1) domain, was exclusively enriched in the high-altitude populations. Our study provides insights concerning the population variation in six different cashmere goat populations in China. The variants in cardiovascular system-related genes may explain the observed phenotypic adaptation of the Tibetan cashmere goat.

In contrast to most animal genomes, mitochondrial genomes in species belonging to the phylum Cnidaria show distinct variations in genome structure, including the mtDNA structure (linear or circular) and the presence or absence of introns in protein-coding genes. Therefore, the analysis of nuclear insertions of mitochondrial sequences (NUMTs) in cnidarians allows us to compare the NUMT content in animals with different mitochondrial genome structures. NUMT identification in the Hydra magnipapillata, Nematostella vectensis and Acropora digitifera genomes showed that the NUMT density in the H. magnipapillata genome clearly exceeds that in other two cnidarians with circular mitochondrial genomes. We found that H. magnipapillata is an exceptional ancestral metazoan with a high NUMT cumulative percentage but a large genome, and its mitochondrial genome linearisation might be responsible for the NUMT enrichment. We also detected the co-transposition of exonic and intronic fragments within NUMTs in N. vectensis and provided direct evidence that mitochondrial sequences can be transposed into the nuclear genome through DNA-mediated fragment transfer. In addition, NUMT expression analyses showed that NUMTs are co-expressed with adjacent protein-coding genes, suggesting the relevance of their biological function. Taken together, our results provide valuable information for understanding the impact of mitochondrial genome structure on the interaction of mitochondrial molecules and nuclear genomes.

Long intergenic noncoding RNAs (lincRNAs) have been recognized in recent years as key regulators of biological processes. However, lincRNAs in goat remain poorly characterized both across various tissues and during different developmental stages in goat (Capra hircus). We performed the genome-wide discovery of the lincRNAs in goat by combining the RNA-seq dataset that were generated from 28 cashmere goat skin samples and the 12 datasets of goat tissues downloaded from the NCBI database. We identified a total of 5546 potential lincRNA transcripts that overlapped 3641 lincRNA genes. These lincRNAs exhibited a tissue-specific pattern. Specifically, there are 584 lincRNAs expressed exclusively in only one tissue, and 91 were highly expressed in hair follicle (HF). In addition, 2350 protein-coding genes and 492 lincRNAs were differentially expressed in the skin of goat. The majority exhibited the remarkable differential expression during the transition of the goat skin from the May–June to August–October time point, which covered the different seasons. Fundamental biological processes, such as skin development, were significantly enriched in these genes. Furthermore, we identified several lincRNAs highly expressed in the HF, which exhibited not only the co-expression pattern with the key factors to the HF development but also the activated expression in the August to October time point. Intriguingly, one of spatiotemporal lincRNAs, linc-chig1598 could be a potential regulator of distal-less homeobox 3 expression during the secondary hair follicle growth. This study will facilitate future studies aimed at unravelling the function of lincRNAs in hair follicle development.

BACKGROUND: Inflammation is a key component in the development of abdominal aortic aneurysm (AAA), yet insights into the roles of immune cells and their interactions in this process are limited. METHODS: Using single-cell RNA transcriptomic analysis, we deconstructed the CD45 ⁺ cell population in elastase-induced murine AAA at the single-cell level. We isolated each group of immune cells from murine AAA tissue at different time points and divided them into several subtypes, listed the remarkable differentially expressed genes, explored the developmental trajectories of immune cells, and demonstrated the interactions among them. RESULTS: Our findings reveal significant differences in several immune cell subsets, including macrophages, dendritic cells, and T cells, within the AAA microenvironment compared with the normal aorta. Especially, conventional dendritic cell type 1 exclusively existed in the AAA tissue rather than the normal aortas. Via CellChat analysis, we identified several intercellular communication pathways like visfatin, which targets monocyte differentiation and neutrophil extracellular trap–mediated interaction between neutrophils and dendritic cells, which might contribute to AAA development. Some of these pathways were validated in human AAA. CONCLUSIONS: Despite the absence of external pathogenic stimuli, AAA tissues develop a complex inflammatory microenvironment involving numerous immune cells. In-depth studies of the inflammatory network shall provide new strategies for patients with AAA.

Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease characterized by the expansion of the aortic wall. One of the most significant features is the infiltration of macrophages in the adventitia, which drives vasculature remodeling. The role of macrophage-derived interferon regulatory factor 5 (IRF5) in macrophage infiltration and AAA formation remains unknown. RNA sequencing of AAA adventitia identified Irf5 as the top significantly increased transcription factor that is predominantly expressed in macrophages. Global and myeloid cell–specific deficiency of Irf5 reduced AAA progression, with a marked reduction in macrophage infiltration. Further cellular investigations indicated that IRF5 promotes macrophage migration by direct regulation of downstream phosphoinositide 3-kinase γ (PI3Kγ, Pik3cg ). Pik3cg ablation hindered AAA progression, and myeloid cell–specific salvage of Pik3cg restored AAA progression and macrophage infiltration derived from Irf5 deficiency. Finally, we found that IRF5 and PI3Kγ expression in the adventitia is significantly increased in patients with AAA. These findings reveal that the IRF5-dependent regulation of PI3Kγ is essential for AAA formation.

Background: Dilated cardiomyopathy (DCM) is one of the most frequent causes of heart failure and heart transplantation (HTx). The genetic basis of DCM among patients undergoing HTx remains to be further studied. This study aimed to characterize the genetic basis of DCM HTx in the Chinese population. Methods: In total, 208 unrelated DCM patients who underwent HTx at Fuwai Hospital between June 2004 and June 2017 were included in this study. Whole-exome sequencing (WES) was performed for all patients. Gene burden analysis, variant classification, and genotype–phenotype correlation analysis were subsequently performed. Results: After completing the bioinformatics analysis, gene burden analysis suggested that titin (TTN), filamin C (FLNC) and lamin A/C (LMNA) were significantly enriched with rare protein-altering variants. The frequencies of TTN and FLNC truncating variants in our cohort were 18.8% and 8.7%, respectively. Among the 165 rare variants in high evidence DCM-related genes, 27 (16.4%) and 59 (35.8%) were interpreted as pathogenic (P) and likely pathogenic (LP), respectively. In addition, 41 (47.7%) and 16 (18.6%) of these 86 P/LP variants are located in TTN and FLNC, respectively. The FLNC group contained more patients with NYHA class IV than the P/LP-negative group (FLNC, 16/18 vs. P/LP-negative, 81/123, P = 0.049). Conclusions: Based on WES, we provided a primary genetic spectrum of DCM patients undergoing HTx in the Chinese population. TTN and FLNC harbour the most P/LP variants. FLNC truncation may lead to severe clinical symptoms in DCM patients.