HIV-1 full-genome phylogenetics of generalized epidemics in sub-Saharan Africa: impact of missing nucleotide characters in next-generation sequences

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Title: HIV-1 full-genome phylogenetics of generalized epidemics in sub-Saharan Africa: impact of missing nucleotide characters in next-generation sequences
Authors: Ratmann, O
Wymant, C
Colijn, C
Danaviah, S
Essex, M
Frost, S
Gall, A
Von Haeseler, A
Kaleebu, P
Kendall, M
Kozlov, A
Manasa, J
Quang Minh, B
Moyo, S
Novitsky, V
Nsubuga, R
Pillay, S
Quinn, TC
Serwadda, D
Ssemwanga, D
Stamatakis, A
Trininopoulos, J
Wawer, M
Leigh Brown, A
De Oliveira, T
Kellam, P
Pillay, D
Fraser, C
Item Type: Journal Article
Abstract: To characterize HIV-1 transmission dynamics in regions where the burden of HIV-1 is greatest, the “Phylogenetics and Networks for Generalised HIV Epidemics in Africa” consortium (PANGEA-HIV) is sequencing full-genome viral isolates from across sub-Saharan Africa. We report the first 3,985 PANGEA-HIV consensus sequences from four cohort sites (Rakai Community Cohort Study, n = 2,833; MRC/UVRI Uganda, n = 701; Mochudi Prevention Project, n = 359; Africa Health Research Institute Resistance Cohort, n = 92). Next-generation sequencing success rates varied: more than 80% of the viral genome from the gag to the nef genes could be determined for all sequences from South Africa, 75% of sequences from Mochudi, 60% of sequences from MRC/UVRI Uganda, and 22% of sequences from Rakai. Partial sequencing failure was primarily associated with low viral load, increased for amplicons closer to the 3′ end of the genome, was not associated with subtype diversity except HIV-1 subtype D, and remained significantly associated with sampling location after controlling for other factors. We assessed the impact of the missing data patterns in PANGEA-HIV sequences on phylogeny reconstruction in simulations. We found a threshold in terms of taxon sampling below which the patchy distribution of missing characters in next-generation sequences (NGS) has an excess negative impact on the accuracy of HIV-1 phylogeny reconstruction, which is attributable to tree reconstruction artifacts that accumulate when branches in viral trees are long. The large number of PANGEA-HIV sequences provides unprecedented opportunities for evaluating HIV-1 transmission dynamics across sub-Saharan Africa and identifying prevention opportunities. Molecular epidemiological analyses of these data must proceed cautiously because sequence sampling remains below the identified threshold and a considerable negative impact of missing characters on phylogeny reconstruction is expected.
Issue Date: 29-Jun-2017
Date of Acceptance: 25-May-2017
URI: http://hdl.handle.net/10044/1/48724
DOI: https://dx.doi.org/10.1089/AID.2017.0061
ISSN: 1931-8405
Publisher: Mary Ann Liebert
Start Page: 1083
End Page: 1098
Journal / Book Title: Aids Research and Human Retroviruses
Volume: 33
Issue: 11
Copyright Statement: © Oliver Ratmann et al. 2017; Published by Mary Ann Liebert, Inc. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Engineering & Physical Science Research Council (EPSRC)
Medical Research Council (MRC)
Commission of the European Communities
Bill & Melinda Gates Foundation
Funder's Grant Number: EP/K026003/1
MR/K010174/1B
339251
GCAEN 511473
Keywords: Science & Technology
Life Sciences & Biomedicine
Immunology
Infectious Diseases
Virology
human immunodeficiency virus
phylogenomics
phylodynamics
HIV-1 molecular epidemiology
sub-Saharan Africa
PANGEA
MAXIMUM-LIKELIHOOD PHYLOGENIES
FISHING COMMUNITIES
INFECTIOUS-DISEASE
LAKE VICTORIA
UGANDA
TRANSMISSION
RISK
TREE
RECONSTRUCTION
INCONGRUENCE
1103 Clinical Sciences
Virology
Publication Status: Published
Appears in Collections:Mathematics
Statistics
Applied Mathematics and Mathematical Physics
Faculty of Medicine
Faculty of Natural Sciences
Epidemiology, Public Health and Primary Care



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