The X chromosome and X-linked variants have largely been ignored in genome-wide and candidate association studies of infectious diseases due to the complexity of statistical analysis of the X ...chromosome. This exclusion is significant, since the X chromosome contains a high density of immune-related genes and regulatory elements that are extensively involved in both the innate and adaptive immune responses. Many diseases present with a clear sex bias, and apart from the influence of sex hormones and socioeconomic and behavioural factors, the X chromosome, X-linked genes and X chromosome inactivation mechanisms contribute to this difference. Females are functional mosaics for X-linked genes due to X chromosome inactivation and this, combined with other X chromosome inactivation mechanisms such as genes that escape silencing and skewed inactivation, could contribute to an immunological advantage for females in many infections. In this review, we discuss the involvement of the X chromosome and X inactivation in immunity and address its role in sexual dimorphism of infectious diseases using tuberculosis susceptibility as an example, in which male sex bias is clear, yet not fully explored.
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.
Summary The evidence for a human genetic component in susceptibility to tuberculosis (TB) is incontrovertible. Quite apart from studies of rare disease events illustrating the importance of key genes ...in humans and animals, TB at the population level is also influenced by the genetics of the host. Heritability of disease concordance and immune responses to mycobacterial antigens has been clearly shown, and ranges up to 71%. Linkage studies, designed to identify major susceptibility genes in a disease, have produced a number of candidate loci but few, except for regions on chromosome 5p15, 20p and 20q, have been replicated. The region on 5p15 regulates the intensity of the response to the tuberculin skin test, and another locus on 11p14 appears to control resistance to the bacterium. In addition, numerous genes and pathways have been implicated in candidate gene association studies, with validation of polymorphisms in IFNG , NRAMP1 , and NOS2A and equivocal results for IL10 , CCL2 , DC-SIGN , P2RX7 , VDR , TLR2 , TLR9 and SP110 . Other more recently researched candidate genes such as TNFRSF1B remain to be validated, preferably in meta-analyses. New approaches have provided early evidence for the importance of gene–gene interactions in regulating resistance to disease, and also the prospect that applying host genetics in the field of vaccinomics could lead to a more targeted approach in designing interventions to aid the human immune system in combating mycobacteria. Genome-wide association studies and admixture mapping are approaches that remain to be applied to TB, and it is not clear, as is the case with other complex diseases, how much of the heritability of the TB susceptibility phenotype will be determined by multiple genes of small effect versus rare variants with disproportionately large effects.
Recent genetic studies have established that the KhoeSan populations of southern Africa are distinct from all other African populations and have remained largely isolated during human prehistory ...until ∼2000 years ago. Dozens of different KhoeSan groups exist, belonging to three different language families, but very little is known about their population history. We examine new genome-wide polymorphism data and whole mitochondrial genomes for >100 South Africans from the ≠Khomani San and Nama populations of the Northern Cape, analyzed in conjunction with 19 additional southern African populations. Our analyses reveal fine-scale population structure in and around the Kalahari Desert. Surprisingly, this structure does not always correspond to linguistic or subsistence categories as previously suggested, but rather reflects the role of geographic barriers and the ecology of the greater Kalahari Basin. Regardless of subsistence strategy, the indigenous Khoe-speaking Nama pastoralists and the N|u-speaking ≠Khomani (formerly hunter-gatherers) share ancestry with other Khoe-speaking forager populations that form a rim around the Kalahari Desert. We reconstruct earlier migration patterns and estimate that the southern Kalahari populations were among the last to experience gene flow from Bantu speakers, ∼14 generations ago. We conclude that local adoption of pastoralism, at least by the Nama, appears to have been primarily a cultural process with limited genetic impact from eastern Africa.
Persons living with HIV (PLWH) have an increased risk for tuberculosis (TB). After prolonged and repeated exposure, some PLWH never develop TB and show no evidence of immune sensitization to ...Mycobacterium tuberculosis (Mtb) as defined by persistently negative tuberculin skin tests (TST) and interferon gamma release assays (IGRA). This group has been identified and defined as HIV+ persistently TB, tuberculin and IGRA negative (HITTIN). To investigate potential innate mechanisms unique to individuals with the HITTIN phenotype we compared their neutrophil Mtb infection response to that of PLWH, with no TB history, but who test persistently IGRA positive, and tuberculin positive (HIT). Neutrophil samples from 17 HITTIN (PMN.sub.HITTIN) and 11 HIT (PMN.sub.HIT) were isolated and infected with Mtb H37Rv for 1h and 6h. RNA was extracted and used for RNAseq analysis. Since there was no significant differential transcriptional response at 1h between infected PMN.sub.HITTIN and PMN.sub.HIT, we focused on the 6h timepoint. When compared to uninfected PMN, PMN.sub.HITTIN displayed 3106 significantly upregulated and 3548 significantly downregulated differentially expressed genes (DEGs) (absolute cutoff of a log.sub.2 FC of 0.2, FDR < 0.05) whereas PMN.sub.HIT demonstrated 3816 significantly upregulated and 3794 significantly downregulated DEGs following 6h Mtb infection. Contrasting the log.sub.2 FC 6h infection response to Mtb from PMN.sub.HITTIN against PMN.sub.HIT, 2285 genes showed significant differential response between the two groups. Overall PMN.sub.HITTIN had a lower fold change response to Mtb infection compared to PMN.sub.HIT . According to pathway enrichment, Apoptosis and NETosis were differentially regulated between HITTIN and HIT PMN responses after 6h Mtb infection. To corroborate the blunted NETosis transcriptional response measured among HITTIN, fluorescence microscopy revealed relatively lower neutrophil extracellular trap formation and cell loss in PMN.sub.HITTIN compared to PMN.sub.HIT, showing that PMN.sub.HITTIN have a distinct response to Mtb.
Despite broad agreement that Homo sapiens originated in Africa, considerable uncertainty surrounds specific models of divergence and migration across the continent
. Progress is hampered by a ...shortage of fossil and genomic data, as well as variability in previous estimates of divergence times
. Here we seek to discriminate among such models by considering linkage disequilibrium and diversity-based statistics, optimized for rapid, complex demographic inference
. We infer detailed demographic models for populations across Africa, including eastern and western representatives, and newly sequenced whole genomes from 44 Nama (Khoe-San) individuals from southern Africa. We infer a reticulated African population history in which present-day population structure dates back to Marine Isotope Stage 5. The earliest population divergence among contemporary populations occurred 120,000 to 135,000 years ago and was preceded by links between two or more weakly differentiated ancestral Homo populations connected by gene flow over hundreds of thousands of years. Such weakly structured stem models explain patterns of polymorphism that had previously been attributed to contributions from archaic hominins in Africa
. In contrast to models with archaic introgression, we predict that fossil remains from coexisting ancestral populations should be genetically and morphologically similar, and that only an inferred 1-4% of genetic differentiation among contemporary human populations can be attributed to genetic drift between stem populations. We show that model misspecification explains the variation in previous estimates of divergence times, and argue that studying a range of models is key to making robust inferences about deep history.
Human genetic studies have long been vastly Eurocentric, raising a key question about the generalizability of these study findings to other populations. Because humans originated in Africa, these ...populations retain more genetic diversity, and yet individuals of African descent have been tremendously underrepresented in genetic studies. The diversity in Africa affords ample opportunities to improve fine-mapping resolution for associated loci, discover novel genetic associations with phenotypes, build more generalizable genetic risk prediction models, and better understand the genetic architecture of complex traits and diseases subject to varying environmental pressures. Thus, it is both ethically and scientifically imperative that geneticists globally surmount challenges that have limited progress in African genetic studies to date. Additionally, African investigators need to be meaningfully included, as greater inclusivity and enhanced research capacity afford enormous opportunities to accelerate genomic discoveries that translate more effectively to all populations. We review the advantages, challenges, and examples of genetic architecture studies of complex traits and diseases in Africa. For example, with greater genetic diversity comes greater ancestral heterogeneity; this higher level of understudied diversity can yield novel genetic findings, but some methods that assume homogeneous population structure and work well in European populations may work less well in the presence of greater heterogeneity in African populations. Consequently, we advocate for methodological development that will accelerate studies important for all populations, especially those currently underrepresented in genetics.
Abstract
For centuries, the Mycobacterium tuberculosis complex (MTBC) has infected numerous populations, both human and non-human, causing symptomatic tuberculosis (TB) in some hosts. Research ...investigating the MTBC and how it has evolved with its host over time is sparse and has not resulted in many significant findings. There are even fewer studies investigating adaptation of the human host susceptibility to TB and these have largely focused on genome-wide association and candidate gene association studies. However, results emanating from these association studies are rarely replicated and appear to be population specific. It is, therefore, necessary to relook at the approach taken to investigate the relationship between the MTBC and the human host. Understanding that the evolution of the pathogen is coupled to the evolution of the host might be the missing link needed to effectively investigate their relationship. We hypothesize that this knowledge will bolster future efforts in combating the disease.
Certain individuals are able to resist
infection despite persistent and intense exposure. These persons do not exhibit adaptive immune priming as measured by tuberculin skin test (TST) and ...interferon-γ (IFN-γ) release assay (IGRA) responses, nor do they develop active tuberculosis (TB). Genetic investigation of individuals who are able to resist
infection shows there are likely a combination of genetic variants that contribute to the phenotype. The contribution of the innate immune system and the exact cells involved in this phenotype remain incompletely elucidated. Neutrophils are prominent candidates for possible involvement as primers for microbial clearance. Significant variability is observed in neutrophil gene expression and DNA methylation. Furthermore, inter-individual variability is seen between the mycobactericidal capacities of donor neutrophils. Clearance of
infection is favored by the mycobactericidal activity of neutrophils, apoptosis, effective clearance of cells by macrophages, and resolution of inflammation. In this review we will discuss the different mechanisms neutrophils utilize to clear
infection. We discuss the duality between neutrophils' ability to clear infection and how increasing numbers of neutrophils contribute to active TB severity and mortality. Further investigation into the potential role of neutrophils in innate immune-mediated
infection resistance is warranted since it may reveal clinically important activities for prevention as well as vaccine and treatment development.
The worldwide burden of tuberculosis (TB) remains an enormous problem, and is particularly severe in the admixed South African Coloured (SAC) population residing in the Western Cape. Despite evidence ...from twin studies suggesting a strong genetic component to TB resistance, only a few loci have been identified to date. In this work, we conduct a genome-wide association study (GWAS), meta-analysis and trans-ethnic fine mapping to attempt the replication of previously identified TB susceptibility loci. Our GWAS results confirm the WT1 chr11 susceptibility locus (rs2057178: odds ratio = 0.62, P = 2.71e(-06)) previously identified by Thye et al., but fail to replicate previously identified polymorphisms in the TLR8 gene and locus 18q11.2. Our study demonstrates that the genetic contribution to TB risk varies between continental populations, and illustrates the value of including admixed populations in studies of TB risk and other complex phenotypes. Our evaluation of local ancestry based on the real and simulated data demonstrates that case-only admixture mapping is currently impractical in multi-way admixed populations, such as the SAC, due to spurious deviations in average local ancestry generated by current local ancestry inference methods. This study provides insights into identifying disease genes and ancestry-specific disease risk in multi-way admixed populations.
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