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Studies investigating the influence of toll-like receptor (TLR) polymorphisms and tuberculosis susceptibility have yielded varying and often contradictory results in different ethnic groups. A meta-analysis was conducted to investigate the relationship between TLR variants and susceptibility to tuberculosis, both across and within specific ethnic groups. An extensive database search was performed for studies investigating the relationship between TLR and tuberculosis (TB) susceptibility. Data was subsequently extracted from included studies and statistically analysed. 32 articles involving 18907 individuals were included in this meta-analysis, and data was extracted for 14 TLR polymorphisms. Various genetic models were employed. An increased risk of TB was found for individuals with the TLR2 rs3804100 CC and the TLR9 rs352139 GA and GG genotypes, while decreased risk was identified for those with the AG genotype of TLR1 rs4833095. The T allele of TLR6 rs5743810 conferred protection across all ethnic groups. TLR2 rs5743708 subgroup analysis identified the A allele to increase susceptibility to TB in the Asian ethnic group, while conferring protection in the Hispanic group. The T allele of TLR4 rs4986791 was also found to increase the risk of TB in the Asian subgroup. All other TLR gene variants investigated were not found to be associated with TB in this meta-analysis. Although general associations were identified, most TLR variants showed no significant association with TB, indicating that additional studies investigating a wider range of pattern recognition receptors is required to gain a better understanding of this complex disease.

Assignment of cell types from single-cell RNA sequencing (scRNA-seq) data remains a time-consuming and error-prone process. Current packages for identity assignment use limited types of reference data and often have rigid data structure requirements. We developed the clustifyr R package to leverage several external data types, including gene expression profiles to assign likely cell types using data from scRNA-seq, bulk RNA-seq, microarray expression data, or signature gene lists. We benchmark various parameters of a correlation-based approach and implement gene list enrichment methods. clustifyr is a lightweight and effective cell-type assignment tool developed for compatibility with various scRNA-seq analysis workflows. clustifyr is publicly available at https://github.com/rnabioco/clustifyr

Admixture is a well known confounder in genetic association studies. If genome-wide data is not available, as would be the case for candidate gene studies, ancestry informative markers (AIMs) are required in order to adjust for admixture. The predominant population group in the Western Cape, South Africa, is the admixed group known as the South African Coloured (SAC). A small set of AIMs that is optimized to distinguish between the five source populations of this population (African San, African non-San, European, South Asian, and East Asian) will enable researchers to cost-effectively reduce false-positive findings resulting from ignoring admixture in genetic association studies of the population. Using genome-wide data to find SNPs with large allele frequency differences between the source populations of the SAC, as quantified by Rosenberg et. al's In-statistic, we developed a panel of AIMs by experimenting with various selection strategies. Subsets of different sizes were evaluated by measuring the correlation between ancestry proportions estimated by each AIM subset with ancestry proportions estimated using genome-wide data. We show that a panel of 96 AIMs can be used to assess ancestry proportions and to adjust for the confounding effect of the complex five-way admixture that occurred in the South African Coloured population.

Background. The development of active tuberculosis disease has been shown to be multifactorial. Interactions between host and bacterial genotype may influence disease outcome, with some studies indicating the adaptation of M. tuberculosis strains to specific human populations. Here we investigate the role of the human leukocyte antigen (HLA) class I genes in this biological process. Methods. Three hundred patients with tuberculosis from South Africa were typed for their HLA class I alleles by direct sequencing. Mycobacterium tuberculosis genotype classification was done by IS6110 restriction fragment length polymorphism genotyping and spoligotyping. Results. We showed that Beijing strain occurred more frequently in individuals with multiple disease episodes (P<.001) with the HLA-B27 allele lowering the odds of having an additional episode (odds ratio, 0.21; P = .006). Associations were also identified for specific HLA types and disease caused by the Beijing, LAM, LCC, and Quebec strains. HLA types were also associated with disease caused by strains from the Euro-American or East Asian lineages, and the frequencies of these alleles in their sympatric human populations identified potential revolutionary events between host and pathogen. Conclusions. This is the first report of the association of human HLA types and M. tuberculosis strain genotype, highlighting that both host and pathogen genetics need to be taken into consideration when studying tuberculosis disease development.

Canine atopic dermatitis (CAD) is a common inflammatory skin condition in dogs. It is a lifelong issue that poses a significant welfare concern due to the chronic skin discomfort and pruritus (itching) experienced by affected animals. Excessive scratching, licking, and chewing cause self-inflicted injuries to the skin and increase the risk of secondary infections. Several dog breeds, including Labrador Retriever, Boxer, and French Bulldog, are known to be predisposed to these issues, suggesting a genetic link to the condition. Access to a large population of dogs genotyped on a medium-density single-nucleotide polymorphism (SNP) array through commercial Wisdom Panel testing, along with their linked clinical records, allowed a large-scale, highly powered genome-wide association study (GWAS) to be performed. In this study, over 28,000 dogs were examined to identify genetic changes associated with CAD. A statistically significant signal on canine chromosome 38 was identified, with a particularly strong signal in French Bulldogs. Whole-genome resequencing revealed a compelling splice donor variant in the signaling lymphocytic activation molecule 1 ( ), a transmembrane receptor with important functions in immune cells. Further analysis of additional genome sequences and RNA samples from the MARS PETCARE BIOBANK confirmed that the splice variant is a strong potential contributor to an increased risk of atopic dermatitis. The discovery represents the first compelling genetic variant associated with CAD to be validated in more than one breed of dog. The study identifies as a potential pharmaceutical target and the associated variant as a biomarker to enable dog breeders to make informed breeding decisions to reduce risk of CAD in future generations. The presence of the variant in many dog breeds and free-roaming dogs worldwide, indicates its potential role in contributing to the global risk of CAD.

Admixed populations can make an important contribution to the discovery of disease susceptibility genes if the parental populations exhibit substantial variation in susceptibility. Admixture mapping has been used successfully, but is not designed to cope with populations that have more than two or three ancestral populations. The inference of admixture proportions and local ancestry and the imputation of missing genotypes in admixed populations are crucial in both understanding variation in disease and identifying novel disease loci. These inferences make use of reference populations, and accuracy depends on the choice of ancestral populations. Using an insufficient or inaccurate ancestral panel can result in erroneously inferred ancestry and affect the detection power of GWAS and meta-analysis when using imputation. Current algorithms are inadequate for multi-way admixed populations. To address these challenges we developed PROXYANC, an approach to select the best proxy ancestral populations. From the simulation of a multi-way admixed population we demonstrate the capability and accuracy of PROXYANC and illustrate the importance of the choice of ancestry in both estimating admixture proportions and imputing missing genotypes. We applied this approach to a complex, uniquely admixed South African population. Using genome-wide SNP data from over 764 individuals, we accurately estimate the genetic contributions from the best ancestral populations: isiXhosa [Formula: see text], ‡Khomani SAN [Formula: see text], European [Formula: see text], Indian [Formula: see text], and Chinese [Formula: see text]. We also demonstrate that the ancestral allele frequency differences correlate with increased linkage disequilibrium in the South African population, which originates from admixture events rather than population bottlenecks. The collective term for people of mixed ancestry in southern Africa is \"Coloured,\" and this is officially recognized in South Africa as a census term, and for self-classification. Whilst we acknowledge that some cultures may use this term in a derogatory manner, these connotations are not present in South Africa, and are certainly not intended here.

Tuberculosis (TB) is the second leading cause of mortality from infectious disease worldwide. One of the factors involved in developing disease is the genetics of the host, yet the field of TB susceptibility genetics has not yielded the answers that were expected. A commonly posited explanation for the missing heritability of complex disease is gene-gene interactions, also referred to as epistasis. In this study we investigate the role of gene-gene interactions in genetic susceptibility to TB using a cohort recruited from a high TB incidence community from Cape Town, South Africa. Our discovery data set incorporates genotypes from a large a number of candidate gene studies as well as genome-wide data. After limiting our search space to pairs of putative TB susceptibility genes, as well as pairs of genes that have been curated in online databases as potential interactors, we use statistical modelling to identify pairs of interacting SNPs. We attempt to validate the top models identified in our discovery data set using an independent genome-wide TB case-control data set from The Gambia. A number of models were successfully validated, indicating that interplay between the NRG1 - NRG3, GRIK1 - GRIK3 and IL23R - ATG4C gene pairs may modify susceptibility to TB. Gene pairs involved in the NF-κB pathway were also identified in the discovery data set (SFTPD - NOD2, ISG15 - TLR8 and NLRC5 - IL12RB1), but could not be tested in the Gambian study group due to lack of overlapping data.

We used a deeply sequenced dataset of 910 individuals, all of African descent, to construct a set of DNA sequences that is present in these individuals but missing from the reference human genome. We aligned 1.19 trillion reads from the 910 individuals to the reference genome (GRCh38), collected all reads that failed to align, and assembled these reads into contiguous sequences (contigs). We then compared all contigs to one another to identify a set of unique sequences representing regions of the African pan-genome missing from the reference genome. Our analysis revealed 296,485,284 bp in 125,715 distinct contigs present in the populations of African descent, demonstrating that the African pan-genome contains ~10% more DNA than the current human reference genome. Although the functional significance of nearly all of this sequence is unknown, 387 of the novel contigs fall within 315 distinct protein-coding genes, and the rest appear to be intergenic. Assembly of a pan-genome from 910 humans of African descent identifies 296.5 Mb of novel DNA mapping to 125,715 distinct contigs. This African pan-genome contains ~10% more DNA than the current human reference genome.

The prevalence of APOL1 variants that confer a risk of chronic kidney disease in numerous American populations who share Western African genetic ancestry varies from 1% to 22%.

The molecular mechanisms that regulate tuberculosis susceptibility and bacillus Calmette-Guérin (BCG)-induced immunity are mostly unknown. However, induction of the adaptive immune response is a critical step in host control of Mycobacterium tuberculosis. Toll-interacting protein (TOLLIP) is a ubiquitin-binding protein that regulates innate immune responses, including Toll-like receptor signaling, which initiate adaptive immunity. TOLLIP variation is associated with susceptibility to tuberculosis, but the mechanism by which it regulates tuberculosis immunity is poorly understood. To identify functional TOLLIP variants and evaluate the role of TOLLIP variation on innate and adaptive immune responses to mycobacteria and susceptibility to tuberculosis. We used human cellular immunology approaches to characterize the role of a functional TOLLIP variant on monocyte mRNA expression and M. tuberculosis-induced monocyte immune functions. We also examined the association of TOLLIP variation with BCG-induced T-cell responses and susceptibility to latent tuberculosis infection. We identified a functional TOLLIP promoter region single-nucleotide polymorphism, rs5743854, which was associated with decreased TOLLIP mRNA expression in infant monocytes. After M. tuberculosis infection, TOLLIP-deficient monocytes demonstrated increased IL-6, increased nitrite, and decreased bacterial replication. The TOLLIP-deficiency G/G genotype was associated with decreased BCG-specific IL-2 CD4 T-cell frequency and proliferation. This genotype was also associated with increased susceptibility to latent tuberculosis infection. TOLLIP deficiency is associated with decreased BCG-specific T-cell responses and increased susceptibility to tuberculosis. We hypothesize that the heightened antibacterial monocyte responses after vaccination of TOLLIP-deficient infants are responsible for decreased BCG-specific T-cell responses. Activating TOLLIP may provide a novel adjuvant strategy for BCG vaccination.