Human gut microbiome research focuses on populations living in high-income countries and to a lesser extent, non-urban agriculturalist and hunter-gatherer societies. The scarcity of research between ...these extremes limits our understanding of how the gut microbiota relates to health and disease in the majority of the world's population. Here, we evaluate gut microbiome composition in transitioning South African populations using short- and long-read sequencing. We analyze stool from adult females living in rural Bushbuckridge (n = 118) or urban Soweto (n = 51) and find that these microbiomes are taxonomically intermediate between those of individuals living in high-income countries and traditional communities. We demonstrate that reference collections are incomplete for characterizing microbiomes of individuals living outside high-income countries, yielding artificially low beta diversity measurements, and generate complete genomes of undescribed taxa, including Treponema, Lentisphaerae, and Succinatimonas. Our results suggest that the gut microbiome of South Africans does not conform to a simple "western-nonwestern" axis and contains undescribed microbial diversity.
Abstract
Background
Exome sequencing is recommended as a first-line investigation for patients with a developmental delay or intellectual disability. This approach has not been implemented in most ...resource-constraint settings, including Africa, due to the high cost of implementation. Instead, patients have limited access to services and testing options. Here, we evaluate the effectiveness of a limited genetic testing strategy and contrast the findings to a conceivable outcome if exome sequencing were available instead.
Results
A retrospective audit of 934 patient files presenting to a medical genetics clinic in South Africa showed that 83% of patients presented with developmental delay as a clinical feature. Patients could be divided into three groups, representing distinct diagnostic pathways. Patient Group A (18%; mean test cost $131) were confirmed with aneuploidies, following a simple, inexpensive test. Patient Group B (25%; mean test cost $140) presented with clinically recognizable conditions but only 39% received a genetic diagnostic confirmation due to limited testing options. Patient Group C – the largest group (57%; mean test cost $337) – presented with heterogenous conditions and DD, and 92% remained undiagnosed after limited available testing was performed.
Conclusions
Patients with DD are the largest group of patients seen in medical genetics clinics in South Africa. When clinical features are not distinct, limited testing options drastically restricts diagnostic yield. A cost- and time analysis shows most patients would benefit from first-line exome sequencing, reducing their individual diagnostic odysseys.
The rich and diverse genomics of African populations is significantly underrepresented in reference and in disease-associated databases. This renders interpreting the Next Generation Sequencing (NGS) ...data and reaching a diagnostic more difficult in Africa and for the African diaspora. It increases chances for false positives with variants being misclassified as pathogenic due to their novelty or rarity. We can increase African genomic data by (1) making consent for sharing aggregate frequency data an essential component of research toolkit; (2) encouraging investigators with African data to share available data through public resources such as gnomAD, AVGD, ClinVar, DECIPHER and to use MatchMaker Exchange; (3) educating African research participants on the meaning and value of sharing aggregate frequency data; and (4) increasing funding to scale-up the production of African genomic data that will be more representative of the geographical and ethno-linguistic variation on the continent. The RDWG of H3Africa is hereby calling to action because this underrepresentation accentuates the health disparities. Applying the NGS to shorten the diagnostic odyssey or to guide therapeutic options for rare diseases will fully work for Africans only when public repositories include sufficient data from African subjects.
Because African institutions were made the direct recipients ofgrants in the H3Africa programme, Africans have been able to design projects, training and infrastructure according to the needs of ...their own countries. ...H3Africa has increased the profile of African genomics globally. ...H3Africa has enhanced education and awareness about genomics across the continent - principally by requiring that all projects involving participants include some amount of community engagement. Examples include treatment of common, non-infectious conditions (such as diabetes), largely because of a lack of data, and the treatment of rare diseases, largely because of a lack of genomic medicine services. Because African genomes have a longer evolutionary history and harbour more variation than the genomes of people with European ancestry, they offer a richer source of variants linked to traits of interest, such as rare developmental disorders.
Exome sequencing (ES) is a recommended first-tier diagnostic test for many rare monogenic diseases. It allows for the detection of both single-nucleotide variants (SNVs) and copy number variants ...(CNVs) in coding exonic regions of the genome in a single test, and this dual analysis is a valuable approach, especially in limited resource settings. Single-nucleotide variants are well studied; however, the incorporation of copy number variant analysis tools into variant calling pipelines has not been implemented yet as a routine diagnostic test, and chromosomal microarray is still more widely used to detect copy number variants. Research shows that combined single and copy number variant analysis can lead to a diagnostic yield of up to 58%, increasing the yield with as much as 18% from the single-nucleotide variant only pipeline. Importantly, this is achieved with the consideration of computational costs only, without incurring any additional sequencing costs. This mini review provides an overview of copy number variant analysis from exome data and what the current recommendations are for this type of analysis. We also present an overview on rare monogenic disease research standard practices in resource-limited settings. We present evidence that integrating copy number variant detection tools into a standard exome sequencing analysis pipeline improves diagnostic yield and should be considered a significantly beneficial addition, with relatively low-cost implications. Routine implementation in underrepresented populations and limited resource settings will promote generation and sharing of CNV datasets and provide momentum to build core centers for this niche within genomic medicine.
Elevated blood pressure in childhood is a risk factor for adult hypertension which is a global health problem. Excess adiposity in childhood creates a predisposition to develop adult hypertension. ...Our aim was to explore distinct sex-specific adiposity trajectories from childhood to late adolescence and examined their association with blood pressure.
Latent Class Growth Mixture Modeling (LCGMM) on longitudinal data was used to derive sex-specific and distinct body mass index (BMI: kg/m(2)) trajectories. We studied 1824 black children (boys = 877, girls = 947) from the Birth to Twenty (Bt20) cohort from Soweto, South Africa, and obtained BMI measures at ages 5 through 18 years. Participants with at least two age-point BMI measures, were included in the analysis. Analysis of variance (ANOVA), chi-square test, multivariate linear and standard logistic regressions were used to test study characteristics and different associations.
We identified three (3) and four (4) distinct BMI trajectories in boys and girls, respectively. The overall prevalence of elevated blood pressure (BP) was 34.9 % (39.4 % in boys and 30.38 % in girls). Boys and girls in the early onset obesity or overweight BMI trajectories were more likely to have higher BP values in late adolescence. Compared to those in the normal weight BMI trajectory, girls in early onset obesity trajectories had an increased risk of elevated BP with odds ratio (OR) of 2.18 (95 % confidence interval 1.31 to 4.20) and 1.95 (1.01 to 3.77). We also observed the weak association for boys in early onset overweight trajectory, (p-value = 0.18 and odds ratio of 2.39 (0.67 to 8.57)) CONCLUSIONS: Distinct weight trajectories are observed in black South African children from as early as 5 years. Early onset adiposity trajectories are associated with elevated BP in both boys and girls. It is important to consider individual patterns of early-life BMI development, so that intervention strategies can be targeted to at-risk individuals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Exome sequencing is recommended as a first-line investigation for patients with a developmental delay or intellectual disability. This approach has not been implemented in most resource-constraint ...settings, including Africa, due to the high cost of implementation. Instead, patients have limited access to services and testing options. Here, we evaluate the effectiveness of a limited genetic testing strategy and contrast the findings to a conceivable outcome if exome sequencing were available instead.
A retrospective audit of 934 patient files presenting to a medical genetics clinic in South Africa showed that 83% of patients presented with developmental delay as a clinical feature. Patients could be divided into three groups, representing distinct diagnostic pathways. Patient Group A (18%; mean test cost $131) were confirmed with aneuploidies, following a simple, inexpensive test. Patient Group B (25%; mean test cost $140) presented with clinically recognizable conditions but only 39% received a genetic diagnostic confirmation due to limited testing options. Patient Group C - the largest group (57%; mean test cost $337) - presented with heterogenous conditions and DD, and 92% remained undiagnosed after limited available testing was performed.
Patients with DD are the largest group of patients seen in medical genetics clinics in South Africa. When clinical features are not distinct, limited testing options drastically restricts diagnostic yield. A cost- and time analysis shows most patients would benefit from first-line exome sequencing, reducing their individual diagnostic odysseys.
Bioinformatics pipelines for calling star alleles (haplotypes) in cytochrome P450 (CYP) genes are important for the implementation of precision medicine. Genotyping CYP genes using high throughput ...sequencing data is complicated, e.g., by being highly polymorphic, not to mention the structural variations especially in CYP2D6, CYP2A6, and CYP2B6. Genome graph‐based variant detection approaches have been shown to be reliable for genotyping HLA alleles. However, their application to enhancing star allele calling in CYP genes has not been extensively explored. We present StellarPGx, a Nextflow pipeline for accurately genotyping CYP genes by combining genome graph‐based variant detection, read coverage information from the original reference‐based alignments, and combinatorial diplotype assignments. The implementation of StellarPGx using Nextflow facilitates its portability, reproducibility, and scalability on various user platforms. StellarPGx is currently able to genotype 12 important pharmacogenes belonging to the CYP1, 2, and 3 families. For purposes of validation, we use CYP2D6 as a model gene owing to its high degree of polymorphisms (over 130 star alleles defined to date, including complex structural variants) and clinical importance. We applied StellarPGx and three existing callers to 109 whole genome sequenced samples for which the Genetic Testing Reference Material Coordination Program (GeT‐RM) has recently provided consensus truth CYP2D6 diplotypes. StellarPGx had the highest CYP2D6 diplotype concordance (99%) with GeT‐RM compared with Cyrius (98%), Aldy (82%), and Stargazer (84%). This exemplifies the high accuracy of StellarPGx and highlights its importance for both research and clinical pharmacogenomics applications. The StellarPGx pipeline is open‐source and available from https://github.com/SBIMB/StellarPGx.
Genomic researchers face an ethical dilemma regarding feedback of individual results generated from genomic studies. In the African setting, genomic research is still not widely implemented and, ...coupled with this, the limited African-specific guidelines on how to feedback on individual research findings. A qualitative study was performed to assess participants' expectations and preferences regarding the feedback of secondary findings from genomic research. Participants were parents of children with a developmental disorder, enrolled in the Deciphering Developmental Disorders in Africa (DDD-Africa) research project, and were purposefully selected. Three deliberative focus group discussions were conducted with 14 participants. Each deliberative focus group consisted of two separate audio-recorded interviews and presented different case scenarios for different types of secondary findings that could be theoretically detected during genomic research. We aimed to explore participants' preferences for the extent, nature, timing, and methods for receiving individual study results, specifically pertaining to secondary findings. Thematic content analysis was done, with a deductive approach to coding. Four themes emerged which included participants' perception of readiness to receive secondary findings, queries raised around who has access to research findings and feedback of findings consent, responsibilities of the researcher, and reasons for not wanting/wanting secondary findings. Overall, participants expressed that they want to receive feedback on secondary findings irrespective of disease severity and treatment availability. Lifestyle changes, early prevention or treatment, impact on future generations, and preparedness were strong motivations for wanting feedback on results. Participants felt that when the research involved minors, it was the parents' right to receive results on behalf of their children. This study provides new insights into participants' preferences around feedback on genomic research results and could serve as an important basis for creating guidelines and recommendations for feedback on genomic results in the African context.
•Early life adversity tends to foster higher adult sensory processing sensitivity.•Adversity is reflected in shorter gestational age and high prenatal maternal stress.•Measures of adversity might ...objectively predict later sensitivity levels.•Individual genetic markers are unlikely to predict sensitivity.
Sensory processing sensitivity (SPS) is a personality trait describing individuals who are more receptive to their environmental context. SPS has implications across the lifespan, but few longitudinal predictors of the trait are currently known. We examined potential predictors of adult SPS levels among 858 members of the Birth to Twenty Plus cohort. Available data included birth weight, gestational age, socioeconomic status, prenatal maternal stress (PMS), child behaviour scores, and genotypes for three loci (5-HTTLPR, DRD4, and MAOA). Highly Sensitive Person scale scores at ages 28–29 were regressed on these variables. Early gestational age (p < .01) and PMS (p = .05) were significantly associated with higher SPS. Our results tentatively support the hypothesis that prenatal adversity is associated with heightened sensitivity.
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