Despite the high burden of HIV-1 in Botswana, the population of Botswana is significantly underrepresentation in host genetics studies of HIV-1. Furthermore, the bulk of previous genomics studies evaluated common human genetic variations, however, there is increasing evidence of the influence of rare variants in the outcome of diseases which may be uncovered by comprehensive complete and deep genome sequencing. This research aimed to evaluate the role of rare-variants in susceptibility to HIV-1 and progression through whole genome sequencing. Whole genome sequences (WGS) of 265 HIV-1 positive and 125 were HIV-1 negative unrelated individuals from Botswana were mapped to the human reference genome GRCh38. Population joint variant calling was performed using Genome Analysis Tool Kit (GATK) and BCFTools. Cumulative effects of rare variant sets on susceptibility to HIV-1 and progression (CD4+ T-cell decline) were determined with optimized Sequence Kernel Association Test (SKAT-O). In silico functional analysis of the prioritized variants was performed through gene-set enrichment using databases in GeneMANIA and Enrichr. Novel rare-variants within the ANKRD39 (8.48 x 10-8), LOC105378523 (7.45 x 10-7) and GTF3C3 (1.36 x 10-6) genes were significantly associated with HIV-1 progression. Functional analysis revealed that these genes are involved in viral translation and transcription. These findings highlight the significance of whole genome sequencing in pinpointing rare-variants of clinical relevance. The research contributes towards a deeper understanding of the host genetics HIV-1 and offers promise of population specific interventions against HIV-1.

中文翻译：

---

南部非洲人群中HIV-1进程的全基因组稀有变异研究

尽管博茨瓦纳的HIV-1负担很高，但在HIV-1的宿主遗传学研究中，博茨瓦纳的人口代表性明显不足。此外，以前的大部分基因组学研究都评估了人类常见的遗传变异，然而，越来越多的证据表明，罕见的变异对疾病结果的影响可能由全面的完整基因组测序和深层基因测序发现。这项研究旨在通过全基因组测序评估稀有变异体在HIV-1易感性和进展中的作用。将来自博茨瓦纳的265个HIV-1阳性和125个HIV-1阴性无关个体的全基因组序列（WGS）定位到人类参考基因组GRCh38。使用基因组分析工具套件（GATK）和BCFTools进行了群体关节变异的调用。通过优化的序列内核关联测试（SKAT-O）确定了罕见变体集对HIV-1易感性和进展（CD4 + T细胞下降）的累积影响。使用GeneMANIA和Enrichr中的数据库通过基因集富集对优先变体进行计算机功能分析。ANKRD39（8.48 x 10-8），LOC105378523（7.45 x 10-7）和GTF3C3（1.36 x 10-6）基因中的新型稀有变异与HIV-1进程显着相关。功能分析表明，这些基因参与了病毒的翻译和转录。这些发现突出了全基因组测序在查明临床相关稀有变异中的重要性。