Whole genome sequencing reveals population diversity and variation in HIV-1 specific host genes

Prisca K Thami; Wonderful T Choga; Collet Dandara; Stephen J O'Brien; Myron Essex; Simani Gaseitsiwe; Emile R Chimusa

doi:10.3389/fgene.2023.1290624

Whole genome sequencing reveals population diversity and variation in HIV-1 specific host genes

Front Genet. 2023 Dec 20:14:1290624. doi: 10.3389/fgene.2023.1290624. eCollection 2023.

Authors

Prisca K Thami¹, Wonderful T Choga^{1

2}, Collet Dandara^{1

3

4}, Stephen J O'Brien^{5

6}, Myron Essex⁷, Simani Gaseitsiwe^{2

7}, Emile R Chimusa^{3

8}

Affiliations

¹ Division of Human Genetics, Department of Pathology, University of Cape Town, Cape Town, South Africa.
² Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.
³ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
⁴ UCT/SAMRC Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South African Medical Research Council, Cape Town, South Africa.
⁵ Laboratory of Genomics Diversity, Center for Computer Technologies, ITMO University, St. Petersburg, Russia.
⁶ Guy Harvey Oceanographic Center Halmos College of Arts and Sciences, Nova Southeastern University, Fort Lauderdale, FL, United States.
⁷ Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health AIDS Initiative, Harvard T. H. Chan School of Public Health, Boston, MA, United States.
⁸ Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle, United Kingdom.

Abstract

HIV infection continues to be a major global public health issue. The population heterogeneity in susceptibility or resistance to HIV-1 and progression upon infection is attributable to, among other factors, host genetic variation. Therefore, identifying population-specific variation and genetic modifiers of HIV infectivity can catapult the invention of effective strategies against HIV-1 in African populations. Here, we investigated whole genome sequences of 390 unrelated HIV-positive and -negative individuals from Botswana. We report 27.7 million single nucleotide variations (SNVs) in the complete genomes of Botswana nationals, of which 2.8 million were missing in public databases. Our population structure analysis revealed a largely homogenous structure in the Botswana population. Admixture analysis showed elevated components shared between the Botswana population and the Niger-Congo (65.9%), Khoe-San (32.9%), and Europeans (1.1%) ancestries in the population of Botswana. Statistical significance of the mutational burden of deleterious and loss-of-function variants per gene against a null model was estimated. The most deleterious variants were enriched in five genes: ACTRT2 (the Actin Related Protein T2), HOXD12 (homeobox D12), ABCB5 (ATP binding cassette subfamily B member 5), ATP8B4 (ATPase phospholipid transporting 8B4) and ABCC12 (ATP Binding Cassette Subfamily C Member 12). These genes are enriched in the glycolysis and gluconeogenesis (p < 2.84e-6) pathways and therefore, may contribute to the emerging field of immunometabolism in which therapy against HIV-1 infection is being evaluated. Published transcriptomic evidence supports the role of the glycolysis/gluconeogenesis pathways in the regulation of susceptibility to HIV, and that cumulative effects of genetic modifiers in glycolysis/gluconeogenesis pathways may potentially have effects on the expression and clinical variability of HIV-1. Identified genes and pathways provide novel avenues for other interventions, with the potential for informing the design of new therapeutics.

Keywords: Africa; Botswana; functional prediction; genome variation; genomics; human immunodeficiency virus (HIV-1); population genetics.

Grants and funding

WT_/Wellcome Trust/United Kingdom