RESUMO
While haplotype-specific genetic load shapes the evolutionary trajectory of natural and captive populations, mixed-haplotype assembly and genotyping hindered its characterization in diploids. Herein, we produced two phased genome assemblies of the critically endangered fish Chinese Bahaba (Bahaba taipingensis, Sciaenidae, Teleostei) and resequenced 20 whole genomes to quantify population genetic load at a haplotype level. We identified frame-shifting variants as the most deleterious type, followed by mutations in the 5'-UTR, 3'-UTR and missense mutations at conserved amino acids. Phased haplotypes revealed gene deletions and high-impact deleterious variants. We estimated ~1.12% of genes missing or interrupted per haplotype, with a significant overlap of disrupted genes (30.35%) between haplotype sets. Relative proportions of deleterious variant categories differed significantly between haplotypes. Simulations suggested that purifying selection struggled to purge slightly deleterious genetic load in captive breeding compared to genotyping interventions, and that higher inter-haplotypic variance of genetic load predicted more efficient purging by artificial selection. Combining the knowledge of haplotype-resolved genetic load with predictive modelling will be immensely useful for understanding the evolution of deleterious variants and guiding conservation planning.
Assuntos
Variação Genética , Perciformes , Animais , Haplótipos/genética , Carga Genética , Mutação , Perciformes/genética , ChinaRESUMO
The low survival rates, poor responses, and drug resistance of patients with melanoma make it urgent to find new therapeutic targets. This study investigated whether the circ_0084043-miR-134-5p axis regulates the antitumor effect of protocadherin 9 (PCDH9) in melanoma. Ectopic expression or knock down (KD) of PCDH9 with a lentivirus vector, we explored its effects on the proliferation, invasion, and apoptosis of melanoma and verified its regulatory effect on ras-related C3 botulinum toxin substrate 1 (RAC1), proline-rich tyrosine kinase 2 (Pyk2), Cyclin D1, matrix metalloproteinase 2 (MMP2), and MMP9. We further observed the effect of KD circ_0084043 on the malignant behavior of melanoma and studied whether circ_0084043 sponged miR-134-5p and regulated PCDH9. We found that circ_0084043 was overexpressed in melanoma and associated with the malignant phenotype. PCDH9 was poorly expressed in human melanoma tissues, and overexpression of PCDH9 inhibited melanoma progression. Quantitative real-time PCR and Western blotting results showed that overexpression of PCDH9 could downregulate RAC1, MMP2, and MMP9 and upregulate Pyk2 and Cyclin D1. Circ_0084043 KD inhibited invasion and promoted apoptosis in melanoma cells. Circ_0084043 could sponge miR-134-5p and thus indirectly regulate PCDH9. Furthermore, we discovered that inhibiting circ_0084043 had an anti-PD-Ll effect. In vivo, PCDH9 overexpression inhibited melanoma tumor growth, but PCDH9 KD promoted it. In conclusion, PCDH9, which is regulated by the circ 0084043-miR-134-5p axis, can suppress malignant biological behavior in melanoma and influence the expression levels of Pyk2, RAC1, Cyclin D1, MMP2, and MMP9.