Genome-Wide Association Study of HIV Whole Genome Sequences Validated using Drug Resistance.
Genome-Wide Association Study of HIV Whole Genome Sequences Validated using Drug Resistance.
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DOI：
10.1371/journal.pone.0163746
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
de Oliveira T
中科院分区：
文献类型：
--
作者：
Power RA;Davaniah S;Derache A;Wilkinson E;Tanser F;Gupta RK;Pillay D;de Oliveira T
全基因组关联研究（GWAS）极大地增进了我们对人类特征和疾病的理解。随着病原体全基因组序列 (WGS) 的可用性不断增加，确定病毒基因组的 GWAS 是否能够揭示重要的生物学见解非常重要。在这里，我们进行了第一个病毒 GWAS 概念验证，检查耐药性 (DR)，这是一种具有众所周知的遗传学的表型。我们对南非夸祖鲁-纳塔尔省农村地区 343 名未接受一线抗逆转录病毒治疗的 HIV C 亚型患者样本进行了 DR GWAS。使用 PILON 调用每个序列中的大多数和少数变异，并在 PLINK 中执行 GWAS。将接受不同抗逆转录病毒治疗失败的患者的 HIV WGS 与从未接受过相应治疗的个体的序列进行比较。 GWAS 方法通过确定基因水平上的五种关联进行了验证，这些关联导致已知会导致 DR 的氨基酸变化。此外，我们强调了 GWAS 识别上位效应的能力，识别逆转录酶蛋白第 68 号氨基酸内的两个可复制变体，之前被描述为潜在的适应性补偿突变。 Gag 蛋白基质区域第 91 号氨基酸内可能存在的额外 DR 变体与替诺福韦失败相关，这凸显了 GWAS 识别经典候选基因之外的变体的能力。我们的结果还表明 DR 存在多基因成分。这些结果验证了 GWAS 对 HIV WGS 数据的适用性，即使在相对较小的样本中也是如此，并强调了高通量测序如何能够提供新颖且与临床相关的见解。此外，他们还指出，对于艾滋病毒等病毒来说，与细菌或寄生虫 GWAS 中观察到的群体结构相比，群体结构只是次要问题。鉴于基因组长度较小且多重检测的负担减轻，这使得 HIV 成为 GWAS 的理想候选者。
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. We performed a GWAS of DR in a sample of 343 HIV subtype C patients failing 1st 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. 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. 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.
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影响因子：
4.5
作者：
Chewapreecha C;Marttinen P;Croucher NJ;Salter SJ;Harris SR;Mather AE;Hanage WP;Goldblatt D;Nosten FH;Turner C;Turner P;Bentley SD;Parkhill J
通讯作者：
Parkhill J
DOI：
10.1126/science.1228160
发表时间：
2013-02-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Tanser F;Bärnighausen T;Grapsa E;Zaidi J;Newell ML
通讯作者：
Newell ML
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
3.7
作者：
Manasa, Justen;Lessells, Richard J.;de Oliveira, Tulio
通讯作者：
de Oliveira, Tulio
影响因子：
3.3
作者：
Alam MT;Petit RA 3rd;Crispell EK;Thornton TA;Conneely KN;Jiang Y;Satola SW;Read TD
通讯作者：
Read TD