Large Evolutionary Rate Heterogeneity among and within HIV-1 Subtypes and CRFs.
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ABSTRACT:
SUBMITTER: Nasir A
PROVIDER: S-EPMC8473000 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A hallmark of the human immunodeficiency virus 1 (HIV-1) is its rapid rate of evolution within and among its various subtypes. Two complementary hypotheses are suggested to explain the sequence variability among HIV-1 subtypes. The first suggests that the functional constraints at each site remain the same across all subtypes, and the differences among subtypes are a direct reflection of random substitutions, which have occurred during the time elapsed since their divergence. The alternative hypothesis suggests that the functional constraints themselves have evolved, and thus sequence differences among subtypes in some sites reflect shifts in function. To determine the contribution of each of these two alternatives to HIV-1 subtype evolution, we have developed a novel Bayesian method for testing and detecting site-specific rate shifts. The RAte Shift EstimatoR (RASER) method determines whether or not site-specific functional shifts characterize the evolution of a protein and, if so, points to the specific sites and lineages in which these shifts have most likely occurred. Applying RASER to a dataset composed of large samples of HIV-1 sequences from different group M subtypes, we reveal rampant evolutionary shifts throughout the HIV-1 proteome. Most of these rate shifts have occurred during the divergence of the major subtypes, establishing that subtype divergence occurred together with functional diversification. We report further evidence for the emergence of a new sub-subtype, characterized by abundant rate-shifting sites. When focusing on the rate-shifting sites detected, we find that many are associated with known function relating to viral life cycle and drug resistance. Finally, we discuss mechanisms of covariation of rate-shifting sites.
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Project description:Meiotic crossover frequency varies extensively along chromosomes and is typically concentrated in hotspots. As recombination increases genetic diversity, hotspots are predicted to occur at immunity genes, where variation may be beneficial. A major component of plant immunity is recognition of pathogen Avirulence (Avr) effectors by resistance (R) genes that encode NBS-LRR domain proteins. Therefore, we sought to test whether NBS-LRR genes would overlap with meiotic crossover hotspots using experimental genetics in Arabidopsis thaliana. NBS-LRR genes tend to physically cluster in plant genomes; for example, in Arabidopsis most are located in large clusters on the south arms of chromosomes 1 and 5. We experimentally mapped 1,439 crossovers within these clusters and observed NBS-LRR gene associated hotspots, which were also detected as historical hotspots via analysis of linkage disequilibrium. However, we also observed NBS-LRR gene coldspots, which in some cases correlate with structural heterozygosity. To study recombination at the fine-scale we used high-throughput sequencing to analyze ~1,000 crossovers within the RESISTANCE TO ALBUGO CANDIDA1 (RAC1) R gene hotspot. This revealed elevated intragenic crossovers, overlapping nucleosome-occupied exons that encode the TIR, NBS and LRR domains. The highest RAC1 recombination frequency was promoter-proximal and overlapped CTT-repeat DNA sequence motifs, which have previously been associated with plant crossover hotspots. Additionally, we show a significant influence of natural genetic variation on NBS-LRR cluster recombination rates, using crosses between Arabidopsis ecotypes. In conclusion, we show that a subset of NBS-LRR genes are strong hotspots, whereas others are coldspots. This reveals a complex recombination landscape in Arabidopsis NBS-LRR genes, which we propose results from varying coevolutionary pressures exerted by host-pathogen relationships, and is influenced by structural heterozygosity.
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Project description:Negatively selected genes (NSGs) and positively selected genes (PSGs) are the two types of most nuclear protein-coding genes in organisms. However, the evolutionary rates and characteristics of different types of genes have been rarely understood. In the present study, we investigate the rates of synonymous substitution (Ks) and the rates of non-synonymous substitution (Ka) by comparing the orthologous genes of two sequenced Pyrus species, Pyrus bretschneideri and Pyrus communis. Subsequently, we compared the evolutionary rates, gene structures, and expression profiles during different fruit development between PSGs and NSGs. Compared with the NSGs, the PSGs have fewer exons, shorter gene length, lower synonymous substitution rates and have higher evolutionary rates. Remarkably, gene expression patterns between two Pyrus species fruit indicated functional divergence for most of the orthologous genes derived from a common ancestor, and subfunctionalization for some of them. Overall, the present study shows that PSGs differs from NSGs not only under environmental selective pressure (Ka/Ks), but also in their structural, functional, and evolutionary properties. Additionally, our resulting data provides important insights for the evolution and highlights the diversification of orthologous genes in two Pyrus species.
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Project description: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.
| S-EPMC6007745 | biostudies-literature
Project description:In general, proteins do not work alone; they form macromolecular complexes to play fundamental roles in diverse cellular functions. On the basis of their iterative clustering procedure and frequency of occurrence in the macromolecular complexes, the protein subunits have been categorized as core and attachment. Core protein subunits are the main functional elements, whereas attachment proteins act as modifiers or activators in protein complexes. In this article, using the current data set of yeast protein complexes, we found that core proteins are evolving at a faster rate than attachment proteins in spite of their functional importance. Interestingly, our investigation revealed that attachment proteins are present in a higher number of macromolecular complexes than core proteins. We also observed that the protein complex number (defined as the number of protein complexes in which a protein subunit belongs) has a stronger influence on gene/protein essentiality than multifunctionality. Finally, our results suggest that the observed differences in the rates of protein evolution between core and attachment proteins are due to differences in protein complex number and expression level. Moreover, we conclude that proteins which are present in higher numbers of macromolecular complexes enhance their overall expression level by increasing their transcription rate as well as translation rate, and thus the protein complex number imposes a strong selection pressure on the evolution of yeast proteome.
| S-EPMC3730348 | biostudies-literature
Project description:Evolutionary characteristics of HIV-1 have mostly studied focusing its structural genes, Gag, Pol and Env. However, regarding the process of HIV-1's evolution, few studies emphasize on genetic changes in regulatory proteins. Here we investigate the evolutionary dynamics of HIV-1, targeting one of its important regulatory proteins, Tat. We performed a phylogenetic analysis and employed a Bayesian coalescent-based approach using the BEAST package to investigate the evolutionary changes in Tat over time in the process of HIV-1 evolution. HIV-1 sequences of subtypes B and C from different parts of the world were obtained from the Los Alamos database. The mean estimated nucleotide substitution rates for Tat in HIV-1 subtypes B and C were 1.53 x 10(-3) (95% highest probability density- HPD Interval: 1.09 x10-3 to 2.08 x 10(-3)) and 2.14 x 10(-3) (95% HPD Interval: 1.35 x 10(-3) to 2.91 x 10(-3)) per site per year, respectively, which is relatively low compared to structural proteins. The median times of the most recent common ancestors (tMRCA) were estimated to be around 1933 (95% HPD, 1907-1952) and 1956 (95% HPD, 1934-1970) for subtypes B and C, respectively. Our analysis shows that subtype C appeared in the global population two decades after the introduction of subtype B. A Gaussian Markov random field (GMRF) skyride coalescent analysis demonstrates that the early expansion rate of subtype B was quite high, rapidly progressing during the 1960s and 1970s to the early 1990s, after which the rate increased up to the 2010s. In contrast, HIV-1 subtype C exhibited a relatively slow occurrence rate until the late 1980s when there was a sharp increase up to the end of 1990s; thereafter, the rate of occurrence gradually slowed. Our study highlights the importance of examining the internal/regulatory genes of HIV-1 to understand its complete evolutionary dynamics. The study results will therefore contribute to better understanding of HIV-1 evolution.
| S-EPMC4472691 | biostudies-literature
Project description:Transmission lies at the interface of human immunodeficiency virus type 1 (HIV-1) evolution within and among hosts and separates distinct selective pressures that impose differences in both the mode of diversification and the tempo of evolution. In the absence of comprehensive direct comparative analyses of the evolutionary processes at different biological scales, our understanding of how fast within-host HIV-1 evolutionary rates translate to lower rates at the between host level remains incomplete. Here, we address this by analyzing pol and env data from a large HIV-1 subtype C transmission chain for which both the timing and the direction is known for most transmission events. To this purpose, we develop a new transmission model in a Bayesian genealogical inference framework and demonstrate how to constrain the viral evolutionary history to be compatible with the transmission history while simultaneously inferring the within-host evolutionary and population dynamics. We show that accommodating a transmission bottleneck affords the best fit our data, but the sparse within-host HIV-1 sampling prevents accurate quantification of the concomitant loss in genetic diversity. We draw inference under the transmission model to estimate HIV-1 evolutionary rates among epidemiologically-related patients and demonstrate that they lie in between fast intra-host rates and lower rates among epidemiologically unrelated individuals infected with HIV subtype C. Using a new molecular clock approach, we quantify and find support for a lower evolutionary rate along branches that accommodate a transmission event or branches that represent the entire backbone of transmitted lineages in our transmission history. Finally, we recover the rate differences at the different biological scales for both synonymous and non-synonymous substitution rates, which is only compatible with the 'store and retrieve' hypothesis positing that viruses stored early in latently infected cells preferentially transmit or establish new infections upon reactivation.
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Project description:Primary metabolism is essential to plants for growth and development, and secondary metabolism helps plants to interact with the environment. Many plant metabolites are industrially important. These metabolites are produced by plants through complex metabolic pathways. Lack of knowledge about these pathways is hindering the successful breeding practices for these metabolites. For a better knowledge of the metabolism in plants as a whole, evolutionary rate variation of primary and secondary metabolic pathway genes is a prerequisite. In this study, evolutionary rate variation of primary and secondary metabolic pathway genes has been analyzed in the model plant Arabidopsis thaliana. Primary metabolic pathway genes were found to be more conserved than secondary metabolic pathway genes. Several factors such as gene structure, expression level, tissue specificity, multifunctionality, and domain number are the key factors behind this evolutionary rate variation. This study will help to better understand the evolutionary dynamics of plant metabolism.
| S-EPMC4758233 | biostudies-literature
Project description:Site-specific evolutionary rate shifts are defined as protein sites, where the rate of substitution has changed dramatically across the phylogeny. With respect to a given clade, sites may either undergo a rate acceleration or a rate deceleration, reflecting a site that was conserved and became variable, or vice-versa, respectively. Sites displaying such a dramatic evolutionary change may point to a loss or gain of function at the protein site, reflecting adaptation, or they may indicate epistatic interactions among sites. Here, we analyzed full genomes of HIV and SIV-1 and identified 271 rate-shifting sites along the HIV-1/SIV phylogeny. The majority of rate shifts occurred at long branches, often corresponding to cross-species transmission branches. We noted that in most proteins, the number of rate accelerations and decelerations was equal, and we suggest that this reflects epistatic interactions among sites. However, several accessory proteins were enriched for either accelerations or decelerations, and we suggest that this may be a signature of adaptation to new hosts. Interestingly, the non-pandemic HIV-1 group O clade exhibited a substantially higher number of rate-shift events than the pandemic group M clade. We propose that this may be a reflection of the height of the species barrier between gorillas and humans versus chimpanzees and humans. Our results provide a genome-wide view of the constraints operating on proteins of HIV-1 and SIV.
| S-EPMC7696578 | biostudies-literature
Project description:BackgroundMounting evidence has revealed the dynamic variations in the cellular status and phenotype of the smooth muscle cell (SMC) are vital for shaping the atherosclerotic plaque microenvironment and ultimately mapping onto heterogeneous clinical outcomes in coronary artery disease. Currently, the underlying clinical significance of SMC evolutions remains unexplored in atherosclerosis.MethodsThe dissociated cells from diseased segments within the right coronary artery of four cardiac transplant recipients and 1070 bulk samples with atherosclerosis from six bulk cohorts were retrieved. Following the SMC fate trajectory reconstruction, the MOVICS algorithm integrating the nearest template prediction was used to develop a stable and robust molecular classification. Subsequently, multi-dimensional potential biological implications, molecular features, and cell landscape heterogeneity among distinct clusters were decoded.ResultsWe proposed an SMC cell fate decision signature (SCFDS)-based atherosclerosis stratification system and identified three SCFDS subtypes (C1-C3) with distinguishing features: (i) C1 (DNA-damage repair type), elevated base excision repair (BER), DNA replication, as well as oxidative phosphorylation status. (ii) C2 (immune-activated type), stronger immune activation, hyper-inflammatory state, the complex as well as varied lesion microenvironment, advanced stage, the most severe degree of coronary stenosis severity. (iii) C3 (stromal-rich type), abundant fibrous content, stronger ECM metabolism, immune-suppressed microenvironment.ConclusionsThis study uncovered atherosclerosis complex cellular heterogeneity and a differentiated hierarchy of cell populations underlying SMC. The novel high-resolution stratification system could improve clinical outcomes and facilitate individualized management.
| S-EPMC9724432 | biostudies-literature