The immunoglobulin (IG) loci consist of repeated and highly homologous sets of genes of different types, variable (V), diversity (D) and junction (J), that rearrange in developing B cells to produce an individual’s highly variable repertoire of expressed antibodies, designed to bind to a vast array of pathogens. This repeated structure makes these loci susceptible to a high frequency of insertion and deletion events through evolutionary time, and also makes them difficult to characterize at the genomic level or assay with high-throughput techniques. Given the central role of antibodies in the adaptive immune system, it is not surprising that early candidate gene approaches showed that germline polymorphisms in these regions correlated with susceptibility to both infectious and autoimmune diseases. However, more recent studies, particularly those using high-throughput genome-wide arrays, have failed to implicate these loci in disease. In this review of the IG heavy chain variable gene cluster (IGHV), we examine how poorly we understand the distribution of haplotype variation in this genomic region, and we argue that this lack of information may mask candidate loci in the IGHV gene cluster as causative factors for infectious and autoimmune diseases.

The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease

The immunoglobulin heavy variable (IGHV) and T cell beta variable (TRBV) loci are among the most complex and variable regions in the human genome. Generated through a process of gene duplication/deletion and diversification, these loci can vary extensively between individuals in copy number and contain genes that are highly similar, making their analysis technically challenging. Here, we present a comprehensive study of the functional gene segments in the IGHV and TRBV loci, quantifying their copy number and single-nucleotide variation in a globally diverse sample of 109 (IGHV) and 286 (TRBV) humans from over a 100 populations. We find that the IGHV and TRBV gene families exhibit starkly different patterns of variation. In addition to providing insight into the different evolutionary paths of the IGHV and TRBV loci, our results are also important to the adaptive immune repertoire sequencing community, where the lack of frequencies of common alleles and copy number variants is hampering existing analytical pipelines.

https://www.life-science-alliance.org/content/lsa/2/2/e201800221.full.pdf

Worldwide genetic variation of the IGHV and TRBV immune receptor gene families in humans.

To investigate whether deletion of the Humhv3005 and the homologous VH3-30.3 (both share an identical amino acid sequence) genes is associated with susceptibility and/or certain clinical manifestations of systemic lupus erythematosus(SLE), DNA from 108 Korean SLE patients and 102 healthy subjects were analysed for the status of hv3005 gene by polymerase chain reaction-enzyme-linked immunosorbent assay. This method consists of amplification of selected germline VH3 genes with biotinylated primers, efficient capture of amplicons onto streptavidin-coated wells, and quantitative typing of bound VH3 gene with diagnostic oligonucleotides. We found that deletion of the hv3005 gene (including VH3-30.3) was more frequent in SLE patients than in healthy controls (26.9 versus 11.8%, P 0.006, odds ratio 2.75). When clinical features were examined, patients with hv3005 deletion have a higher frequency of lupus nephritis (LN) (75.9 versus 44.3% for those without, P 0.004), and higher activity index [median (range), 6 (...

Association of homozygous deletion of the Humhv3005 and the VH3-30.3 genes with renal involvement in systemic lupus erythematosus

IGHV4-39 deletion polymorphism does not associate with risk or outcome of multiple sclerosis

The antibody response to SARS-CoV-2 shows biased immunoglobulin heavy chain variable (IGHV) gene usage, allowing definition of genetic signatures for some classes of neutralizing antibodies. We investigated IGHV gene usage frequencies by sorting spike-specific single memory B cells from individuals infected with SARS-CoV-2 early in the pandemic. From two study participants and 703 spike-specific B cells, the most used genes were IGHV1-69, IGHV3-30-3, and IGHV3-30. Here, we focused on the IGHV3-30 group of genes and an IGHV3-30-3-using ultrapotent neutralizing monoclonal antibody, CAB-F52, which displayed broad neutralizing activity also in its germline-reverted form. IGHV3-30-3 is encoded by a region of the IGH locus that is highly variable at both the allelic and structural levels. Using personalized IG genotyping, we found that 4 of 14 study participants lacked the IGHV3-30-3 gene on both chromosomes, raising the question if other, highly similar IGHV genes could substitute for IGHV3-30-3 in persons lacking this gene. In the context of CAB-F52, we found that none of the tested IGHV3-33 alleles, but several IGHV3-30 alleles could substitute for IGHV3-30-3, suggesting functional redundancy between the highly homologous IGHV3-30 and IGHV3-30-3 genes for this antibody.

/pdf/frequent-use-of-ighv3-30-3-in-sars-cov-2-neutralizing-3ezftgec.pdf

Frequent use of IGHV3-30-3 in SARS-CoV-2 neutralizing antibody responses

The Humhv3005 human VH gene is located in an intricate locus that encompasses for each haplotype a combination of one to four copies of six highly homologous VH3 genes. To assess the complexity of this region, we developed a polymerase chain reaction-enzyme-derived immunosorbent assay (PCR-ELISA) method capable of detecting each of the VH3 genes. The method consisted of amplification of selected germline VH3 genes with a biotinylated primer, covalent capture of the amplicons onto streptavidin-coated wells, and quantitative typing of the bound VH3 genes with diagnostic oligonucleotides. Pilot studies of two DNA samples with known presence or absence of hv3005 [according to a characteristic BamH1 restriction fragment-length polymorphism (RFLP)] yielded the expected results. Subsequent analysis of 100 additional DNA samples with the known EcoR1 RFLP of hv3005 showed a complete match between the absence of the 9.4-kb hybridizing band and lack of hv3005-like genes, as determined by PCR-ELISA. Importantly, the PCR-ELISA analyses of these 102 genomic DNA samples revealed two new haplotypes in the complex hv3005 region. Combined, these data demonstrate the usefulness and efficiency of this new technique to ascertain the presence or absence of six highly homologous genes in an unusually heterogeneous duplication-insertion-deletion region. In the future, a similar strategy may be used to dissect other similarly complex VH genetic loci.

Genotyping by PCR-ELISA of a complex polymorphic region that contains one to four copies of six highly homologous human VH3 genes.

Abstract. Indoor point cloud data is easy to obtain and contains a large amount of data, but there is no connectivity, no structural attributes, and no semantic information between point clouds. It is very difficult to extract interior components. In order to solve the problem that it is difficult to extract the closed door in the indoor point cloud, and the indoor scanning point cloud data is noisy and redundant, a point cloud segmentation method is proposed to reduce the amount of data and the impact of noise. Because most of the indoor components are not on the same horizontal plane, different component information can be obtained by slicing the point cloud at different heights. In these slices, the component that always exists is the wall. By comparing other data with the point cloud data with a more complete wall, the required component can be extracted. The experimental results show that this method can accurately extract the indoor door component information and beam component information, providing a data basis for building model refinement.


/pdf/point-cloud-slicing-based-extraction-of-indoor-components-2gbhw6x4.pdf

Point cloud slicing-based extraction of indoor components

This article uses the analysis framework of the macro model of the health system to analyze the influenza vaccine policy documents issued by the state and governments at all levels from three perspectives: structure, process and results, and provides a scientific basis for improving the application strategy of influenza vaccine. It is suggested that on the basis of continuing to strengthen publicity, mobilization and organizational guarantee, measures to promote the application of influenza vaccine in China by exploring multi-channel financing mechanisms, combining the experience of new crown vaccination to improve the convenience of influenza vaccination, and scientifically setting vaccination rate targets, improve preparedness for an influenza pandemic.

[Analysis of China's influenza vaccine application policy based on the macro model of the health system].

RWD51 Do the Characteristics of the Site of Care Influence Outcomes? Associations between Community Practice-Level Characteristics and Real-World Overall Survival Among Patients with Multiple Myeloma

Effects of Light Intensity on Morphological Structure and Physiological Characteristics of Gleditsia sinensis Seedlings

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