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The substitution rate of HIV-1 subtypes: a genomic approach.

ABSTRACT: HIV-1M causes most infections in the AIDS pandemic. Its genetic diversity is defined by nine pure subtypes and more than sixty recombinant forms. We have performed a comparative analysis of the evolutionary rate of five pure subtypes (A1, B, C, D, and G) and two circulating recombinant forms (CRF01_AE and CRF02 AG) using data obtained from nearly complete genome coding sequences. Times to the most recent common ancestor (tMRCA) and substitution rates of these HIV genomes, and their genomic partitions, were estimated by Bayesian coalescent analyses. Genomic substitution rate estimates were compared between the HIV-1 datasets analyzed by means of randomization tests. Significant differences in the rate of evolution were found between subtypes, with subtypes C and A1 and CRF01_AE displaying the highest rates. On the other hand, CRF02_AG and subtype D were the slowest evolving types. Using a different molecular clock model for each genomic partition led to more precise tMRCA estimates than when linking the same clock along the HIV genome. Overall, the earliest tMRCA corresponded to subtype A1 (median?=?1941, 95% HPD?=?1943-55), whereas the most recent tMRCA corresponded to subtype G and CRF01_AE subset 3 (median?=?1971, 95% HPD?=?1967-75 and median?=?1972, 95% HPD?=?1970-75, respectively). These results suggest that both biological and epidemiological differences among HIV-1M subtypes are reflected in their evolutionary dynamics. The estimates obtained for tMRCAs and substitution rates provide information that can be used as prior distributions in future Bayesian coalescent analyses of specific HIV-1 subtypes/CRFs and genes.

SUBMITTER: Patino-Galindo JA

PROVIDER: S-EPMC6007745 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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The substitution rate of HIV-1 subtypes: a genomic approach.

Patiño-Galindo Juan Ángel JÁ González-Candelas Fernando F

Virus evolution 20170701 2

HIV-1M causes most infections in the AIDS pandemic. Its genetic diversity is defined by nine pure subtypes and more than sixty recombinant forms. We have performed a comparative analysis of the evolutionary rate of five pure subtypes (A1, B, C, D, and G) and two circulating recombinant forms (CRF01_AE and CRF02 AG) using data obtained from nearly complete genome coding sequences. Times to the most recent common ancestor (tMRCA) and substitution rates of these HIV genomes, and their genomic parti ...[more]

PMID: 29942652

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Project description:The transmission fitness and pathogenesis of HIV-1 is disproportionately influenced by evolution in the five variable regions (V1-V5) of the surface envelope glycoprotein (gp120). Insertions and deletions (indels) are a significant source of evolutionary change in these regions. However, the rate and composition of indels has not yet been quantified through a large-scale comparative analysis of HIV-1 sequences. Here, we develop and report results from a phylogenetic method to estimate indel rates for the gp120 variable regions across five major subtypes and two circulating recombinant forms (CRFs) of HIV-1 group M. We processed over 26,000 published HIV-1 gp120 sequences, from which we extracted 6,605 sequences for phylogenetic analysis. We reconstructed time-scaled phylogenies by maximum likelihood and fit a binomial-Poisson model to the observed distribution of indels between closely related pairs of sequences in each tree (cherries). By focusing on cherries in each tree, we obtained phylogenetically independent indel reconstructions, and the shorter time scales in cherries reduced the bias due to purifying selection. Rate estimates ranged from 3.0×10-5 to 1.5×10-3 indels/nt/year and varied significantly among variable regions and subtypes. Indel rates were significantly lower in V3 relative to V1, and were also lower in HIV-1 subtype B relative to the 01_AE reference. We also found that V1, V2, and V4 tended to accumulate significantly longer indels. Furthermore, we observed that the nucleotide composition of indels was distinct from the flanking sequence, with higher frequencies of G and lower frequencies of T. Indels affected N-linked glycosylation sites more often in V1 and V2 than expected by chance, consistent with positive selection on glycosylation patterns within these regions. These results represent the first comprehensive measures of indel rates in HIV-1 gp120 across multiple subtypes and CRFs, and identifies novel and unexpected patterns for further research in the molecular evolution of HIV-1.

Project description:Breast cancer is a profoundly heterogeneous disease with respect to biological and clinical behavior. Gene expression profiling has been used to dissect this complexity and stratify tumors into intrinsic gene expression subtypes associated with distinct biology, patient outcome and different genomic alterations. Additionally, breast tumors occurring in individuals with germline BRCA1 or BRCA2 mutations typically fall into distinct subtypes. We applied global DNA copy number and gene expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy number aberrations and genomic subgroups of breast cancer. We identified 31 genomic regions that were highly amplified in >1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions (66 and 67 with DNA copy number gain and loss, respectively) revealed six genomic subtypes, termed: 17q12, basal-complex, luminal-simple, luminal-complex, amplifier and mixed subtype. Four of them had striking similarity to intrinsic gene expression subtypes and showed association to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having better prognosis while the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors from all gene expression subtypes, the former being enriched for 8p12-amplified cases while the mixed subtype included many tumors with predominantly DNA copy number losses and poor prognosis. Genomic profiling of 359 breast tumors using tiling BAC aCGH. A number of cases were hybridized as replicates or replicate as dye-swaps. Gene expression profiling of 359 breast tumors using 55K oligonucleotide microarrays.

Dataset Information

The substitution rate of HIV-1 subtypes: a genomic approach.

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The substitution rate of HIV-1 subtypes: a genomic approach.

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