Patients with PSC exhibited a gut microbial signature distinct from both HC and UC without liver disease, but similar in PSC with and without IBD. The genus, which is also associated with other chronic inflammatory and fibrotic conditions, was enriched in PSC.
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by low immunoglobulin (Ig)G and IgA, and/or IgM. In addition to bacterial infections, a large subgroup has noninfectious inflammatory and autoimmune complications. We performed 16S ribosomal RNA-based profiling of stool samples in 44 CVID patients, 45 patients with inflammatory bowel disease (disease controls), and 263 healthy controls. We measured plasma lipopolysaccharide (LPS) and markers of immune cell activation (i.e., soluble (s) CD14 and sCD25) in an expanded cohort of 104 patients with CVID and in 30 healthy controls. We found a large shift in the microbiota of CVID patients characterized by a reduced within-individual bacterial diversity (alpha diversity, P<0.001) without obvious associations to antibiotics use. Plasma levels of both LPS (P=0.001) and sCD25 (P<0.0001) were elevated in CVID, correlating negatively with alpha diversity and positively with a dysbiosis index calculated from the taxonomic profile. Low alpha diversity and high dysbiosis index, LPS, and immune markers were most pronounced in the subgroup with inflammatory and autoimmune complications. Low level of IgA was associated with decreased alpha diversity, but not independently from sCD25 and LPS. Our findings suggest a link between immunodeficiency, systemic immune activation, LPS, and altered gut microbiota.
The human leukocyte antigen (HLA) complex contains the most polymorphic genes in the human genome. The classical HLA class I and II genes define the specificity of adaptive immune responses. Genetic variation at the HLA genes is associated with susceptibility to autoimmune and infectious diseases and plays a major role in transplantation medicine and immunology. Currently, the HLA genes are characterized using Sanger- or next-generation sequencing (NGS) of a limited amplicon repertoire or labeled oligonucleotides for allele-specific sequences. High-quality NGS-based methods are in proprietary use and not publicly available. Here, we introduce the first highly automated open-kit/open-source HLA-typing method for NGS. The method employs in-solution targeted capturing of the classical class I (HLA-A, HLA-B, HLA-C) and class II HLA genes (HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, HLA-DPB1). The calling algorithm allows for highly confident allele-calling to three-field resolution (cDNA nucleotide variants). The method was validated on 357 commercially available DNA samples with known HLA alleles obtained by classical typing. Our results showed on average an accurate allele call rate of 0.99 in a fully automated manner, identifying also errors in the reference data. Finally, our method provides the flexibility to add further enrichment target regions.
Passerine birds show large interspecific variation in extrapair paternity rates. There is accumulating evidence that such promiscuous behavior is driven by indirect, genetic benefits to females. Sexual selection theory distinguishes between two types of genetic benefits, additive and nonadditive effects, mediated by preferences for good and compatible genes, respectively. Good genes preferences should imply directional selection and mating skew among males, and thus reduced genetic diversity in the population.In contrast, compatible genes preferences should give balancing selection that retains genetic diversity. Here, we test how well these predictions fit with patterns of variation in genetic diversity and promiscuity levels among passerine birds. We found that more promiscuous species had higher nucleotide diversity at autosomal introns, but not at Z-chromosome introns. We also found that major histocompatibility complex (MHC) class IIB alleles had higher sequence diversity, and therefore should recognize a broader spectrum of pathogens, in more promiscuous species. Our results suggest that female promiscuity targets a multitude of autosomal genes for their nonadditive, compatibility benefits. Also, as immunity genes seem to be of particular importance, we hypothesize that interspecific variation in female promiscuity among passerine birds has arisen in response to the strength of pathogen-mediated selection. K E Y W O R D S :Balancing selection, compatible genes, extrapair paternity, MHC, pathogen-mediated selection, sperm competition.
The genes of the major histocompatibility complex (MHC) are important model genes for understanding selective forces in evolution. Here, we document, using a cloning and sequencing approach, high polymorphism at the exon 2 of the MHC class II B (MHCIIB) genes in the bluethroat (Luscinia svecica); a minimum of 61 unique alleles were detected in 20 individuals, and at least 11 functional loci. In addition, several pseudogenes were revealed. The specimens originated from three different bluethroat subspecies (azuricollis, cyanecula and svecica), and we also analysed four specimens of the closely related thrush nightingale (L. luscinia) for comparison. Phylogenetic analyses of the functional alleles revealed 258 equally parsimonious trees with poor statistical support for the majority of nodes. The distribution of the sequences in the trees point to an ancestral origin of the polymorphism in MHC class II B genes, a portion of which predated the phylogenetic split between the bluethroat and the thrush nightingale. Strong signatures of balancing selection were uncovered for the codons coding for the peptide‐binding residues of the functional MHCIIB exon 2 alleles. Our results highlight the importance of duplication and recombination events for shaping passerine MHC and give insights in the evolutionary dynamics of MHC variation among closely related taxa.
Genes of the major histocompatibility complex (MHC) are essential in vertebrate adaptive immunity, and they are highly diverse and duplicated in many lineages. While it is widely established that pathogen‐mediated selection maintains MHC diversity through balancing selection, the role of mate choice in shaping MHC diversity is debated. Here, we investigate female mating preferences for MHC class II (MHCII) in the bluethroat (Luscinia svecica), a passerine bird with high levels of extra‐pair paternity and extremely duplicated MHCII. We genotyped family samples with mixed brood paternity and categorized their MHCII alleles according to their functional properties in peptide binding. Our results strongly indicate that females select extra‐pair males in a nonrandom, self‐matching manner that provides offspring with an allelic repertoire size closer to the population mean, as compared to offspring sired by the social male. This is consistent with a compatible genes model for extra‐pair mate choice where the optimal allelic diversity is intermediate, not maximal. This golden mean presumably reflects a trade‐off between maximizing pathogen recognition benefits and minimizing autoimmunity costs. Our study exemplifies how mate choice can reduce the population variance in individual MHC diversity and exert strong stabilizing selection on the trait. It also supports the hypothesis that extra‐pair mating is adaptive through altered genetic constitution in offspring.
BackgroundMicrosatellites are frequently used genetic markers in a wide range of applications, primarily due to their high length polymorphism levels that can easily be genotyped by fragment length analysis. However, the mode of microsatellite evolution is yet not fully understood, and the role of interrupting motifs for the stability of microsatellites remains to be explored in more detail. Here we present a sequence analysis of mutation events and a description of the structure of repeated regions in the hypervariable, pentanucleotide microsatellite locus HrU10 in barn swallows (Hirundo rustica) and tree swallows (Tachycineta bicolor).ResultsIn a large-scale parentage analysis in barn swallows and tree swallows, broods were screened for mutations at the HrU10 locus. In 41 cases in the barn swallows and 15 cases in the tree swallows, mutations corresponding to the loss or gain of one or two repeat units were detected. The parent and mutant offspring alleles were sequenced for 33 of these instances (26 in barn swallows and 7 in tree swallows). Replication slippage was considered the most likely mutational process. We tested the hypothesis that HrU10, a microsatellite with a wide allele size range, has an increased probability of introductions of interruptive motifs (IMs) with increasing length of the repeated region. Indeed, the number and length of the IMs was strongly positively correlated with the total length of the microsatellite. However, there was no significant correlation with the length of the longest stretch of perfectly repeated units, indicating a threshold level for the maximum length of perfectly repeated pentanucleotide motifs in stable HrU10 alleles. The combination of sequence and pedigree data revealed that 15 barn swallow mutations (58%) produced alleles that were size homoplasic to other alleles in the data set.ConclusionOur results give further insights into the mode of microsatellite evolution, and support the assumption of increased slippage rate with increased microsatellite length and a stabilizing effect of interrupting motifs for microsatellite regions consisting of perfect repeats. In addition, the observed extent of size homoplasy may impose a general caution against using hypervariable microsatellites in genetic diversity measures when alleles are identified by fragment length analysis only.
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