Urochordates, the closest relatives of vertebrates, lack adaptive immunity. However, some taxa, such as the colonial species Botryllus schlosseri, provide a unique model for studying innate self/non-self recognition through natural allogeneic transplantation responses. In this species, interactions between colonies are controlled by a highly polymorphic locus, with the Botryllus histocompatibility factor (BHF) being the only gene known to predict tissue fusion or rejection outcomes with complete accuracy. Here, we analyzed full-length BHF alleles from 19 laboratory-born and wild colonies and found that highly divergent alleles tend to coexist within individuals, whereas identical alleles can be shared across continental-scale distances. Despite extensive length variation, evidence of intragenic recombination, and pronounced nucleotide diversity, BHF exhibits limited protein divergence, with 33 alleles encoding only 17 distinct protein variants. Contrary to expectations for polymorphic recognition genes, no evidence of balancing or directional selection was detected. Instead, signatures of purifying selection were observed. We propose that this contrast between nucleotide and protein diversity arises from the combined effects of recombination, human-mediated gene flow, and linkage to nearby loci under balancing selection, while functional constraints maintain protein stability. These findings suggest that extensive protein diversification may not be a universal driver of allorecognition gene evolution.
Breast cancer (BC) is closely linked to coronary heart disease (CHD), yet the genetic causal relationship and common driving mechanism between the two have not been fully elucidated. The purpose of this study is to infer the causal relationship between BC and CHD at the genetic level and identify the cross-omic molecular characteristics of them through the integrated analysis of multiple genomics. Firstly, large-scale Genome Wide Association Study (GWAS) data were used for bidirectional Mendelian randomization (MR) analysis. Secondly, multi-center transcriptome data were integrated and combined with differential expression analysis (DEGs) and weighted gene co-expression network analysis (WGCNA) to screen for key comorbidity genes. Univariate, Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses were used to construct a prognostic model. The Benjamin Hochberg method was used for False Discovery Rate (FDR) correction. Finally, molecular pathways were explored through Gene Set Enrichment Analysis (GSEA), and key genes were validated using quantitative real-time polymerase chain reaction (qRT-PCR) in independent clinical samples. MR analysis revealed a significant positive correlation between BC and CHD in Asian populations (OR = 1.095, 95
Defensins are key innate immune proteins exhibiting pleiotropic functions such as antibacterial activity, antiviral activity, anti-inflammatory activity, immunomodulatory functions, and roles in reproduction. Genomic information inadequately explains the whole gamut of the landscape of β-defensin in Bubalus bubalis and Ovis aries genomes. This study investigates the sequence evaluation and evolutionary relationships of β-defensin with 131 complete sequences in buffalo, sheep, and human. Sequence and domain-based analyses revealed diverse patterns of disulfide bridges and multiple signature patterns, including N- and O-glycosylation sites, N-myristoylation sites, and protein kinase C phosphorylation sites, indicating extensive post-translational regulation involved in various antimicrobial activities, signaling pathways, and reproduction. Phyre2-based 3D structural modeling, followed by PyMOL visualization, revealed β-strands stabilized by cysteine disulfide bonds and a short N-terminal α-helix. Variation analysis of β-defensin sequences identified unique allelic variants with several conserved amino acid positions. All sequences shared the characteristic six conserved cysteine residues, along with conserved glycine (G) in the GXC motif and glutamic acid (E), which contribute to structural stability and proper protein folding. We report sixteen amino acid sites depicting 9 distinct types of mutations within the cysteine residues, with most frequent substitutions of C→S (5/16) and C→P (3/16) amino acids. Phylogenetic and domain-based analyses across humans, sheep, and buffalo revealed eight major clusters, of which cluster I was found to be most diverse (36/131). Altogether, we provide a comprehensive analysis of β-defensin protein sequences revealing conserved features, functional motifs, and evolutionary relationships underpinning the functional role of β-defensins.
TAPBP is a key chaperone of the peptide-loading complex that facilitates peptide loading onto major histocompatibility complex class I (MHC I) molecules. This study characterized TAPBP alleles in Korean Native Chickens (KNCs), identified novel variants, and evaluated allelic associations with BF2. Thirty-six samples representing six KNC lines were genotyped using LEI0258 and the MHC-B SNP panel, and individuals homozygous at both markers were classified into 16 groups. The same samples were subjected to Sanger sequencing of TAPBP exons 3-8. Sequences were assembled and aligned against MHC-B reference alleles of the TAPBP gene and the Red Junglefowl reference. Additional comparisons with “tapasin allele” datasets enabled the identification of novel variants. Six novel nucleotide variants were detected across exons 3-6, including one nonsynonymous substitution in exon 4 (D251H). This residue corresponds to position Q265 in human TAPBP and lies adjacent to residues involved in MHC I interaction, suggesting potential functional relevance. Furthermore, TAPBP exhibited high haplotype diversity (Hd = 0.93) and moderate nucleotide diversity (π = 0.00892), with exon 5 showing the highest diversity (π = 0.01). B9 was the most frequent allele at the nucleotide level, whereas B6/B24 predominated at the amino acid level. Comparison with BF2 data revealed allele-dependent pairing patterns: BF2-B9 consistently matched TAPBP-B9, whereas BF2-B6 was associated with distinct TAPBP nucleotide variants, indicating allelic diversification. Homozygosity at LEI0258 and the SNP panel corresponded with TAPBP homozygosity, supporting marker-based prediction. These findings highlight potential BF2-TAPBP associations and provide a foundation for understanding variation in MHC I peptide loading.
Understanding how environmental heterogeneity drives spatially varying selection is key to deciphering adaptive evolution. The Major Histocompatibility Complex (MHC) provides an ideal model to study this process. We investigated the MHC class II DQA gene across seven subspecies of wild argali sheep (Ovis ammon) in China. High-throughput sequencing of 98 individuals revealed high diversity (25 alleles), with balancing selection maintaining allelic richness and trans-species polymorphism indicating long-term balancing selection. Molecular evolutionary analyses uncovered heterogeneous positive selection on antigen-binding sites among subspecies (ω = 1.181-3.000), mirroring variable pathogen-driven pressures. Mantel tests detected no significant isolation-by-distance or isolation-by-environment. However, Spearman correlations identified significant associations between specific alleles (e.g., Ovam-DQA*08) and climatic variables, as well as between allele frequencies and MaxEnt-predicted suitability. Redundancy analysis showed that temperature and precipitation explained 54.7
