High-depth African genomes inform human migration and health.

The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity among African individuals has been surveyed1. Here we performed whole-genome sequencing analyses of 426 individuals-comprising 50 ethnolinguistic groups, including previously unsampled populations-to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon-but in other genes, variants denoted as 'likely pathogenic' in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health.

SysBiolPGWAS: simplifying post-GWAS analysis through the use of computational technologies and integration of diverse omics datasets.

MOTIVATION: Post-genome-wide association studies (pGWAS) analysis is designed to decipher the functional consequences of significant single-nucleotide polymorphisms (SNPs) in the era of GWAS. This can be translated into research insights and clinical benefits such as the effectiveness of strategies for disease screening, treatment and prevention. However, the setup of pGWAS (pGWAS) tools can be quite complicated, and it mostly requires big data. The challenge however is, scientists are required to have sufficient experience with several of these technically complex and complicated tools in order to complete the pGWAS analysis. RESULTS: We present SysBiolPGWAS, a pGWAS web application that provides a comprehensive functionality for biologists and non-bioinformaticians to conduct several pGWAS analyses to overcome the above challenges. It provides unique functionalities for analysis involving multi-omics datasets and visualization using various bioinformatics tools. SysBiolPGWAS provides access to individual pGWAS tools and a novel custom pGWAS pipeline that integrates several individual pGWAS tools and data. The SysBiolPGWAS app was developed to be a one-stop shop for pGWAS analysis. It targets researchers in the area of the human genome and performs its analysis mainly in the autosomal chromosomes. AVAILABILITY AND IMPLEMENTATION: SysBiolPGWAS web app was developed using JavaScript/TypeScript web frameworks and is available at: https://spgwas.waslitbre.org/. All codes are available in this GitHub repository https://github.com/covenant-university-bioinformatics.

The clinical utility of polygenic risk scores in genomic medicine practices: a systematic review.

Genomic medicine aims to improve health using the individual genomic data of people to inform care. While clinical utility of genomic medicine in many monogenic, Mendelian disorders is amply demonstrated, clinical utility is less evident in polygenic traits, e.g., coronary artery disease or breast cancer. Polygenic risk scores (PRS) are subsets of individual genotypes designed to capture heritability of common traits, and hence to allow the stratification of risk of the trait in a population. We systematically reviewed the PubMed database for unequivocal evidence of clinical utility of polygenic risk scores, using stringent inclusion and exclusion criteria. While we identified studies demonstrating clinical validity in conditions where medical intervention based on a PRS is likely to benefit patient outcome, we did not identify a single study demonstrating unequivocally such a benefit, i.e. clinical utility. We conclude that while the routine use of PRSs hold great promise, translational research is still needed before they should enter mainstream clinical practice.

Detecting genetic modifiers of spondyloepimetaphyseal dysplasia with joint laxity in the Caucasian Afrikaner community.

Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL) is an autosomal-recessive skeletal dysplasia. A relatively large number of patients with SEMDJL have been identified in the Caucasian Afrikaans-speaking community in South Africa. We used a combination of Genome-Wide Human Single Nucleotide Polymorphism (SNP) Array 6.0 data and whole exomic data to potentially dissect genetic modifiers associated with SEMDJL in Caucasian Afrikaans-speaking patients. Leveraging the family-based association signal in prioritizing candidate mutations, we identified two potential modifier genes, COL1A2 and MATN1, and replicating previously identified mutation in KIF22. Importantly, our findings of genetic modifier genes and previously identified mutations are layered on the same sub-network implicated in syndromes characterized by skeletal abnormalities and intellectual disability, bone and connective tissue fragility. This study has potentially provided crucial insights in identifying the indirect modifying mutation(s) linked to the true causal mutation associated with SEMDJL. It is a critical lesson that one may use constructively especially when the pace of exomic sequencing of rare disorders continues apace.

Ten simple rules for providing effective bioinformatics research support.

Life scientists are increasingly turning to high-throughput sequencing technologies in their research programs, owing to the enormous potential of these methods. In a parallel manner, the number of core facilities that provide bioinformatics support are also increasing. Notably, the generation of complex large datasets has necessitated the development of bioinformatics support core facilities that aid laboratory scientists with cost-effective and efficient data management, analysis, and interpretation. In this article, we address the challenges-related to communication, good laboratory practice, and data handling-that may be encountered in core support facilities when providing bioinformatics support, drawing on our own experiences working as support bioinformaticians on multidisciplinary research projects. Most importantly, the article proposes a list of guidelines that outline how these challenges can be preemptively avoided and effectively managed to increase the value of outputs to the end user, covering the entire research project lifecycle, including experimental design, data analysis, and management (i.e., sharing and storage). In addition, we highlight the importance of clear and transparent communication, comprehensive preparation, appropriate handling of samples and data using monitoring systems, and the employment of appropriate tools and standard operating procedures to provide effective bioinformatics support.

Data Management Plans in the genomics research revolution of Africa: Challenges and recommendations.

Drafting and writing a data management plan (DMP) is increasingly seen as a key part of the academic research process. A DMP is a document that describes how a researcher will collect, document, describe, share, and preserve the data that will be generated as part of a research project. The DMP illustrates the importance of utilizing best practices through all stages of working with data while ensuring accessibility, quality, and longevity of the data. The benefits of writing a DMP include compliance with funder and institutional mandates; making research more transparent (for reproduction and validation purposes); and FAIR (findable, accessible, interoperable, reusable); protecting data subjects and compliance with the General Data Protection Regulation (GDPR) and/or local data protection policies. In this review, we highlight the importance of a DMP in modern biomedical research, explaining both the rationale and current best practices associated with DMPs. In addition, we outline various funders' requirements concerning DMPs and discuss open-source tools that facilitate the development and implementation of a DMP. Finally, we discuss DMPs in the context of African research, and the considerations that need to be made in this regard.

The H3ABioNet helpdesk: an online bioinformatics resource, enhancing Africa's capacity for genomics research.

BACKGROUND: Currently, formal mechanisms for bioinformatics support are limited. The H3Africa Bioinformatics Network has implemented a public and freely available Helpdesk (HD), which provides generic bioinformatics support to researchers through an online ticketing platform. The following article reports on the H3ABioNet HD (H3A-HD)'s development, outlining its design, management, usage and evaluation framework, as well as the lessons learned through implementation. RESULTS: The H3A-HD evaluated using automatically generated usage logs, user feedback and qualitative ticket evaluation. Evaluation revealed that communication methods, ticketing strategies and the technical platforms used are some of the primary factors which may influence the effectivity of HD. CONCLUSION: To continuously improve the H3A-HD services, the resource should be regularly monitored and evaluated. The H3A-HD design, implementation and evaluation framework could be easily adapted for use by interested stakeholders within the Bioinformatics community and beyond.

H3ABioNet, a sustainable pan-African bioinformatics network for human heredity and health in Africa.

The application of genomics technologies to medicine and biomedical research is increasing in popularity, made possible by new high-throughput genotyping and sequencing technologies and improved data analysis capabilities. Some of the greatest genetic diversity among humans, animals, plants, and microbiota occurs in Africa, yet genomic research outputs from the continent are limited. The Human Heredity and Health in Africa (H3Africa) initiative was established to drive the development of genomic research for human health in Africa, and through recognition of the critical role of bioinformatics in this process, spurred the establishment of H3ABioNet, a pan-African bioinformatics network for H3Africa. The limitations in bioinformatics capacity on the continent have been a major contributory factor to the lack of notable outputs in high-throughput biology research. Although pockets of high-quality bioinformatics teams have existed previously, the majority of research institutions lack experienced faculty who can train and supervise bioinformatics students. H3ABioNet aims to address this dire need, specifically in the area of human genetics and genomics, but knock-on effects are ensuring this extends to other areas of bioinformatics. Here, we describe the emergence of genomics research and the development of bioinformatics in Africa through H3ABioNet.

Assessing computational genomics skills: Our experience in the H3ABioNet African bioinformatics network.

The H3ABioNet pan-African bioinformatics network, which is funded to support the Human Heredity and Health in Africa (H3Africa) program, has developed node-assessment exercises to gauge the ability of its participating research and service groups to analyze typical genome-wide datasets being generated by H3Africa research groups. We describe a framework for the assessment of computational genomics analysis skills, which includes standard operating procedures, training and test datasets, and a process for administering the exercise. We present the experiences of 3 research groups that have taken the exercise and the impact on their ability to manage complex projects. Finally, we discuss the reasons why many H3ABioNet nodes have declined so far to participate and potential strategies to encourage them to do so.

Bioinformatics education--perspectives and challenges out of Africa.

The discipline of bioinformatics has developed rapidly since the complete sequencing of the first genomes in the 1990s. The development of many high-throughput techniques during the last decades has ensured that bioinformatics has grown into a discipline that overlaps with, and is required for, the modern practice of virtually every field in the life sciences. This has placed a scientific premium on the availability of skilled bioinformaticians, a qualification that is extremely scarce on the African continent. The reasons for this are numerous, although the absence of a skilled bioinformatician at academic institutions to initiate a training process and build sustained capacity seems to be a common African shortcoming. This dearth of bioinformatics expertise has had a knock-on effect on the establishment of many modern high-throughput projects at African institutes, including the comprehensive and systematic analysis of genomes from African populations, which are among the most genetically diverse anywhere on the planet. Recent funding initiatives from the National Institutes of Health and the Wellcome Trust are aimed at ameliorating this shortcoming. In this paper, we discuss the problems that have limited the establishment of the bioinformatics field in Africa, as well as propose specific actions that will help with the education and training of bioinformaticians on the continent. This is an absolute requirement in anticipation of a boom in high-throughput approaches to human health issues unique to data from African populations.

The Development of Computational Biology in South Africa: Successes Achieved and Lessons Learnt.

Bioinformatics is now a critical skill in many research and commercial environments as biological data are increasing in both size and complexity. South African researchers recognized this need in the mid-1990s and responded by working with the government as well as international bodies to develop initiatives to build bioinformatics capacity in the country. Significant injections of support from these bodies provided a springboard for the establishment of computational biology units at multiple universities throughout the country, which took on teaching, basic research and support roles. Several challenges were encountered, for example with unreliability of funding, lack of skills, and lack of infrastructure. However, the bioinformatics community worked together to overcome these, and South Africa is now arguably the leading country in bioinformatics on the African continent. Here we discuss how the discipline developed in the country, highlighting the challenges, successes, and lessons learnt.

"Broadband" Bioinformatics Skills Transfer with the Knowledge Transfer Programme (KTP): Educational Model for Upliftment and Sustainable Development.

A shortage of practical skills and relevant expertise is possibly the primary obstacle to social upliftment and sustainable development in Africa. The "omics" fields, especially genomics, are increasingly dependent on the effective interpretation of large and complex sets of data. Despite abundant natural resources and population sizes comparable with many first-world countries from which talent could be drawn, countries in Africa still lag far behind the rest of the world in terms of specialized skills development. Moreover, there are serious concerns about disparities between countries within the continent. The multidisciplinary nature of the bioinformatics field, coupled with rare and depleting expertise, is a critical problem for the advancement of bioinformatics in Africa. We propose a formalized matchmaking system, which is aimed at reversing this trend, by introducing the Knowledge Transfer Programme (KTP). Instead of individual researchers travelling to other labs to learn, researchers with desirable skills are invited to join African research groups for six weeks to six months. Visiting researchers or trainers will pass on their expertise to multiple people simultaneously in their local environments, thus increasing the efficiency of knowledge transference. In return, visiting researchers have the opportunity to develop professional contacts, gain industry work experience, work with novel datasets, and strengthen and support their ongoing research. The KTP develops a network with a centralized hub through which groups and individuals are put into contact with one another and exchanges are facilitated by connecting both parties with potential funding sources. This is part of the PLOS Computational Biology Education collection.

Developing Clinical Phenotype Data Collection Standards for Research in Africa.

Modern biomedical research is characterised by its high-throughput and interdisciplinary nature. Multiproject and consortium-based collaborations requiring meaningful analysis of multiple heterogeneous phenotypic datasets have become the norm; however, such analysis remains a challenge in many regions across the world. An increasing number of data harmonisation efforts are being undertaken by multistudy collaborations through either prospective standardised phenotype data collection or retrospective phenotype harmonisation. In this regard, the Phenotype Harmonisation Working Group (PHWG) of the Human Heredity and Health in Africa (H3Africa) consortium aimed to facilitate phenotype standardisation by both promoting the use of existing data collection standards (hosted by PhenX), adapting existing data collection standards for appropriate use in low- and middle-income regions such as Africa, and developing novel data collection standards where relevant gaps were identified. Ultimately, the PHWG produced 11 data collection kits, consisting of 82 protocols, 38 of which were existing protocols, 17 were adapted, and 27 were novel protocols. The data collection kits will facilitate phenotype standardisation and harmonisation not only in Africa but also across the larger research community. In addition, the PHWG aims to feed back adapted and novel protocols to existing reference platforms such as PhenX.

Equity, diversity, and inclusion at the Global Alliance for Genomics and Health.

A lack of diversity in genomics for health continues to hinder equitable leadership and access to precision medicine approaches for underrepresented populations. To avoid perpetuating biases within the genomics workforce and genomic data collection practices, equity, diversity, and inclusion (EDI) must be addressed. This paper documents the journey taken by the Global Alliance for Genomics and Health (a genomics-based standard-setting and policy-framing organization) to create a more equitable, diverse, and inclusive environment for its standards and members. Initial steps include the creation of two groups: the Equity, Diversity, and Inclusion Advisory Group and the Regulatory and Ethics Diversity Group. Following a framework that we call "Reflected in our Teams, Reflected in our Standards," both groups address EDI at different stages in their policy development process.

Polygenic Risk Score in African populations: progress and challenges.

Polygenic Risk Score (PRS) analysis is a method that predicts the genetic risk of an individual towards targeted traits. Even when there are no significant markers, it gives evidence of a genetic effect beyond the results of Genome-Wide Association Studies (GWAS). Moreover, it selects  single nucleotide polymorphisms (SNPs) that  contribute to the disease with low effect size  making it more precise at individual level risk prediction. PRS  analysis addresses the shortfall of GWAS by taking into account the SNPs/alleles with  low effect size but play an indispensable role to the observed phenotypic/trait variance.  PRS analysis has  applications that investigate the genetic basis of several traits, which includes rare diseases. However, the accuracy of PRS analysis depends on the genomic data of the underlying population. For instance, several studies  show   that obtaining higher prediction power of PRS analysis is challenging for non-Europeans. In this manuscript, we review the conventional PRS methods and their application to sub-Saharan African communities. We conclude that  lack of sufficient GWAS data and tools is  the limiting factor of applying PRS analysis to sub-Saharan populations.   We recommend developing Africa-specific PRS methods and tools for estimating and analyzing  African population data   for clinical  evaluation of PRSs of interest and predicting  rare diseases.

Increasing African genomic data generation and sharing to resolve rare and undiagnosed diseases in Africa: a call-to-action by the H3Africa rare diseases working group.

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.

A View on Genomic Medicine Activities in Africa: Implications for Policy.

Genomics policy development involves assessing a wide range of issues extending from specimen collection and data sharing to whether and how to utilize advanced technologies in clinical practice and public health initiatives. A survey was conducted among African scientists and stakeholders with an interest in genomic medicine, seeking to evaluate: 1) Their knowledge and understanding of the field. 2) The institutional environment and infrastructure available to them. 3) The state and awareness of the field in their country. 4) Their perception of potential barriers to implementation of precision medicine. We discuss how the information gathered in the survey could instruct the policies of African institutions seeking to implement precision, and more specifically, genomic medicine approaches in their health care systems in the following areas: 1) Prioritization of infrastructures. 2) Need for translational research. 3) Information dissemination to potential users. 4) Training programs for specialized personnel. 5) Engaging political stakeholders and the public. A checklist with key requirements to assess readiness for implementation of genomic medicine programs is provided to guide the process from scientific discovery to clinical application.

African Genomic Medicine Portal: A Web Portal for Biomedical Applications.

Genomics data are currently being produced at unprecedented rates, resulting in increased knowledge discovery and submission to public data repositories. Despite these advances, genomic information on African-ancestry populations remains significantly low compared with European- and Asian-ancestry populations. This information is typically segmented across several different biomedical data repositories, which often lack sufficient fine-grained structure and annotation to account for the diversity of African populations, leading to many challenges related to the retrieval, representation and findability of such information. To overcome these challenges, we developed the African Genomic Medicine Portal (AGMP), a database that contains metadata on genomic medicine studies conducted on African-ancestry populations. The metadata is curated from two public databases related to genomic medicine, PharmGKB and DisGeNET. The metadata retrieved from these source databases were limited to genomic variants that were associated with disease aetiology or treatment in the context of African-ancestry populations. Over 2000 variants relevant to populations of African ancestry were retrieved. Subsequently, domain experts curated and annotated additional information associated with the studies that reported the variants, including geographical origin, ethnolinguistic group, level of association significance and other relevant study information, such as study design and sample size, where available. The AGMP functions as a dedicated resource through which to access African-specific information on genomics as applied to health research, through querying variants, genes, diseases and drugs. The portal and its corresponding technical documentation, implementation code and content are publicly available.