Cargando…

Genome-Wide Association Study of HIV Whole Genome Sequences Validated using Drug Resistance

BACKGROUND: Genome-wide association studies (GWAS) have considerably advanced our understanding of human traits and diseases. With the increasing availability of whole genome sequences (WGS) for pathogens, it is important to establish whether GWAS of viral genomes could reveal important biological i...

Descripción completa

Detalles Bibliográficos
Autores principales: Power, Robert A., Davaniah, Siva, Derache, Anne, Wilkinson, Eduan, Tanser, Frank, Gupta, Ravindra K., Pillay, Deenan, de Oliveira, Tulio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038937/
https://www.ncbi.nlm.nih.gov/pubmed/27677172
http://dx.doi.org/10.1371/journal.pone.0163746
_version_ 1782455975474626560
author Power, Robert A.
Davaniah, Siva
Derache, Anne
Wilkinson, Eduan
Tanser, Frank
Gupta, Ravindra K.
Pillay, Deenan
de Oliveira, Tulio
author_facet Power, Robert A.
Davaniah, Siva
Derache, Anne
Wilkinson, Eduan
Tanser, Frank
Gupta, Ravindra K.
Pillay, Deenan
de Oliveira, Tulio
author_sort Power, Robert A.
collection PubMed
description BACKGROUND: Genome-wide association studies (GWAS) have considerably advanced our understanding of human traits and diseases. With the increasing availability of whole genome sequences (WGS) for pathogens, it is important to establish whether GWAS of viral genomes could reveal important biological insights. Here we perform the first proof of concept viral GWAS examining drug resistance (DR), a phenotype with well understood genetics. METHOD: We performed a GWAS of DR in a sample of 343 HIV subtype C patients failing 1(st) line antiretroviral treatment in rural KwaZulu-Natal, South Africa. The majority and minority variants within each sequence were called using PILON, and GWAS was performed within PLINK. HIV WGS from patients failing on different antiretroviral treatments were compared to sequences derived from individuals naïve to the respective treatment. RESULTS: GWAS methodology was validated by identifying five associations on a genetic level that led to amino acid changes known to cause DR. Further, we highlighted the ability of GWAS to identify epistatic effects, identifying two replicable variants within amino acid 68 of the reverse transcriptase protein previously described as potential fitness compensatory mutations. A possible additional DR variant within amino acid 91 of the matrix region of the Gag protein was associated with tenofovir failure, highlighting GWAS’s ability to identify variants outside classical candidate genes. Our results also suggest a polygenic component to DR. CONCLUSIONS: These results validate the applicability of GWAS to HIV WGS data even in relative small samples, and emphasise how high throughput sequencing can provide novel and clinically relevant insights. Further they suggested that for viruses like HIV, population structure was only minor concern compared to that seen in bacteria or parasite GWAS. Given the small genome length and reduced burden for multiple testing, this makes HIV an ideal candidate for GWAS.
format Online
Article
Text
id pubmed-5038937
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-50389372016-10-27 Genome-Wide Association Study of HIV Whole Genome Sequences Validated using Drug Resistance Power, Robert A. Davaniah, Siva Derache, Anne Wilkinson, Eduan Tanser, Frank Gupta, Ravindra K. Pillay, Deenan de Oliveira, Tulio PLoS One Research Article BACKGROUND: Genome-wide association studies (GWAS) have considerably advanced our understanding of human traits and diseases. With the increasing availability of whole genome sequences (WGS) for pathogens, it is important to establish whether GWAS of viral genomes could reveal important biological insights. Here we perform the first proof of concept viral GWAS examining drug resistance (DR), a phenotype with well understood genetics. METHOD: We performed a GWAS of DR in a sample of 343 HIV subtype C patients failing 1(st) line antiretroviral treatment in rural KwaZulu-Natal, South Africa. The majority and minority variants within each sequence were called using PILON, and GWAS was performed within PLINK. HIV WGS from patients failing on different antiretroviral treatments were compared to sequences derived from individuals naïve to the respective treatment. RESULTS: GWAS methodology was validated by identifying five associations on a genetic level that led to amino acid changes known to cause DR. Further, we highlighted the ability of GWAS to identify epistatic effects, identifying two replicable variants within amino acid 68 of the reverse transcriptase protein previously described as potential fitness compensatory mutations. A possible additional DR variant within amino acid 91 of the matrix region of the Gag protein was associated with tenofovir failure, highlighting GWAS’s ability to identify variants outside classical candidate genes. Our results also suggest a polygenic component to DR. CONCLUSIONS: These results validate the applicability of GWAS to HIV WGS data even in relative small samples, and emphasise how high throughput sequencing can provide novel and clinically relevant insights. Further they suggested that for viruses like HIV, population structure was only minor concern compared to that seen in bacteria or parasite GWAS. Given the small genome length and reduced burden for multiple testing, this makes HIV an ideal candidate for GWAS. Public Library of Science 2016-09-27 /pmc/articles/PMC5038937/ /pubmed/27677172 http://dx.doi.org/10.1371/journal.pone.0163746 Text en © 2016 Power et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Power, Robert A.
Davaniah, Siva
Derache, Anne
Wilkinson, Eduan
Tanser, Frank
Gupta, Ravindra K.
Pillay, Deenan
de Oliveira, Tulio
Genome-Wide Association Study of HIV Whole Genome Sequences Validated using Drug Resistance
title Genome-Wide Association Study of HIV Whole Genome Sequences Validated using Drug Resistance
title_full Genome-Wide Association Study of HIV Whole Genome Sequences Validated using Drug Resistance
title_fullStr Genome-Wide Association Study of HIV Whole Genome Sequences Validated using Drug Resistance
title_full_unstemmed Genome-Wide Association Study of HIV Whole Genome Sequences Validated using Drug Resistance
title_short Genome-Wide Association Study of HIV Whole Genome Sequences Validated using Drug Resistance
title_sort genome-wide association study of hiv whole genome sequences validated using drug resistance
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038937/
https://www.ncbi.nlm.nih.gov/pubmed/27677172
http://dx.doi.org/10.1371/journal.pone.0163746
work_keys_str_mv AT powerroberta genomewideassociationstudyofhivwholegenomesequencesvalidatedusingdrugresistance
AT davaniahsiva genomewideassociationstudyofhivwholegenomesequencesvalidatedusingdrugresistance
AT deracheanne genomewideassociationstudyofhivwholegenomesequencesvalidatedusingdrugresistance
AT wilkinsoneduan genomewideassociationstudyofhivwholegenomesequencesvalidatedusingdrugresistance
AT tanserfrank genomewideassociationstudyofhivwholegenomesequencesvalidatedusingdrugresistance
AT guptaravindrak genomewideassociationstudyofhivwholegenomesequencesvalidatedusingdrugresistance
AT pillaydeenan genomewideassociationstudyofhivwholegenomesequencesvalidatedusingdrugresistance
AT deoliveiratulio genomewideassociationstudyofhivwholegenomesequencesvalidatedusingdrugresistance