  Citation: Akoniyon, O.P.; Adewumi, T.S.; Maharaj, L.; Oyegoke, O.O.; Roux, A.; Adeleke, M.A.; Maharaj, R.; Okpeku, M. Whole Genome Sequencing Contributions and Challenges in Disease Reduction Focused on Malaria. Biology 2022, 11, 587. https://doi.org/10.3390/ biology11040587 Received: 13 March 2022 Accepted: 1 April 2022 Published: 13 April 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). biology Review Whole Genome Sequencing Contributions and Challenges in Disease Reduction Focused on Malaria Olusegun Philip Akoniyon 1 , Taiye Samson Adewumi 1 , Leah Maharaj 1 , Olukunle Olugbenle Oyegoke 1 , Alexandra Roux 1 , Matthew A. Adeleke 1 , Rajendra Maharaj 2 and Moses Okpeku 1, * 1 Discipline of Genetics, School of Life Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4041, South Africa; akohseg@gmail.com (O.P.A.); ttai_adewumi@yahoo.com (T.S.A.); leahmaharaj@gmail.com (L.M.); brokunle2002@gmail.com (O.O.O.); alextroux@gmail.com (A.R.); adelekem@ukzn.ac.za (M.A.A.) 2 Office of Malaria Research, South African Medical Research Council, Cape Town 7505, South Africa; rmaharaj@mrc.ac.za * Correspondence: okpekum@ukzn.ac.za Simple Summary: Malaria is one of the most severe life-threatening human vector-borne diseases worldwide today, leading to high mortality. Children under the age of five and pregnant women in many developing countries are the most vulnerable groups. However, significant reduction has been achieved globally. This is owed to the advancement in technology. Whole genome sequencing (WGS) is such a high throughput technology, which provides unprecedented relevant information concerning malaria parasite genomes used to study malaria pathology. Here, we present the roles of WGS in malaria elimination. This review also found insufficient availability of WGS within sub- Saharan Africa which bears the highest malaria burden and proposed that if malaria elimination is to be achieved in this region, laboratories should be strategically equipped with WGS machines, where clinical isolates could be received and processed affordably within the region. Abstract: Malaria elimination remains an important goal that requires the adoption of sophisticated science and management strategies in the era of the COVID-19 pandemic. The advent of next generation sequencing (NGS) is making whole genome sequencing (WGS) a standard today in the field of life sciences, as PCR genotyping and targeted sequencing provide insufficient information compared to the whole genome. Thus, adapting WGS approaches to malaria parasites is pertinent to studying the epidemiology of the disease, as different regions are at different phases in their malaria elimination agenda. Therefore, this review highlights the applications of WGS in disease management, challenges of WGS in controlling malaria parasites, and in furtherance, provides the roles of WGS in pursuit of malaria reduction and elimination. WGS has invaluable impacts in malaria research and has helped countries to reach elimination phase rapidly by providing required information needed to thwart transmission, pathology, and drug resistance. However, to eliminate malaria in sub-Saharan Africa (SSA), with high malaria transmission, we recommend that WGS machines should be readily available and affordable in the region. Keywords: whole genome sequencing; next generation sequencing; malaria; elimination; drug resistance 1. Introduction Malaria is an infectious, vector-borne and parasitic disease caused by Plasmodium species and transmitted through infected female Anopheles mosquitoes [1]. It has been a major global health problem to humans through history and is a leading cause of disease and death across many tropical and subtropical countries [2]. It is one of the deadliest infectious diseases, constituting clinical problems and hampering national socioeconomic development, particularly in low income countries [3]. The infection and proliferation Biology 2022, 11, 587. https://doi.org/10.3390/biology11040587 https://www.mdpi.com/journal/biology