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Results for “genetics”

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bioRxiv2021

Analysis of the Genetic Structure and Diversity of Upland Cotton Groups in Different Planting Areas Based on SNP Markers

Genetic diversity, kinship and population genetic structure analyses of Gossypium hirsutum germplasm can provide a better understanding of the origin and evolution of G. hirsutum biodiversity. In this study, 1313331 SNP molecular markers were used to construct a phylogenetic tree of each sample using MEGAX, to perform population structure analysis by ADMIXTURE software and principal component analysis (PCA) by EIGENSOFT software, and to estimate relatedness using SPAGeDi. ADMIXTURE software divided the experimental cotton population into 16 subgroups, and the Gossypium hirsutum samples could be roughly clustered according to source place, but there were some overlapping characteristics among samples. The experimental cotton population was divided into six groups according to source to calculate the genetic diversity index (H), and the obtained value (0.306) was close to that for germplasm collected by others in China. Cluster 4 had a relatively high genetic diversity level (0.390). The degrees of genetic differentiation within the experimental cotton population groups were low (the population differentiation indexes ranged from 0.02368 to 0.10664). The genetic distance among cotton accessions varied from 0.000332651 to 0.562664014, with an average of 0.25240429. The results of this study may provide a basis for mining elite alleles and using them for subsequent association analysis.

genomics↗

bioRxiv2021

Parallel genetic changes underlie integrated craniofacial traits in an adaptive radiation of trophic specialist pupfishes

Many factors such as divergence time, shared standing genetic variation, frequency of introgression, and mutation rates can influence the likelihood of whether populations adapt to similar environments via parallel or non-parallel genetic changes. However, the frequency of parallel vs non-parallel genetic changes resulting in parallel phenotypic evolution is still unknown. In this study, we used a QTL mapping approach to investigate the genetic basis of highly divergent craniofacial traits between scale- and snail-eating trophic specialist species across similar hypersaline lake environments in an adaptive radiation of pupfishes endemic to San Salvador Island, Bahamas. We raised F2 intercrosses of scale- and snail-eaters from two different lake populations of sympatric specialists, estimated linkage maps, scanned for significant QTL for 30 skeletal and craniofacial traits, and compared the location of QTL between lakes to quantify parallel and non-parallel genetic changes. We found strong support for parallel genetic changes in both lakes for five traits in which we detected a significant QTL in at least one lake. However, many of these shared QTL affected different, but highly correlated craniofacial traits in each lake, suggesting that pleiotropy and trait integration should not be neglected when estimating rates of parallel evolution. We further observed a 23-52% increase in adaptive introgression within shared QTL, suggesting that introgression may be important for parallel evolution. Overall, our results suggest that the same genomic regions contribute to parallel integrated craniofacial phenotypes across lakes. We also highlight the need for more expansive searches for shared QTL when testing for parallel evolution.

evolutionary biology↗

bioRxiv2021

The first crested duck genome reveals clues to genetic compensation and crest cushion formation

The Chinese crested (CC) duck is a unique indigenous waterfowl breed with a phenotypic crest trait that affects its high survival rate. Therefore, the CC duck is an ideal model to investigate the genetic compensation response to maintain genetic stability. In the present study, we first generated a chromosome-level genome of CC ducks. Comparative genomics revealed genes related to tissue repair, immune function, and tumors were under strong positive selection, which suggested that these adaptive changes might enhance cancer resistance and immune response to maintain the genetic stability of CC ducks. We sub-assembled a Chinese spot-billed duck genome and detected genome-assembled structure variants among three ducks. Functional analysis revealed that a large number of structural variants were related to the immune system, which strongly suggests the occurrence of genetic compensation in the anti-tumor and immune systems to further support the survival of CC ducks. Moreover, we confirmed that the CC duck originated from the mallard ducks. Finally, we revealed the physiological and genetic basis of crest traits and identified a causative mutation in TAS2R40 that leads to crest formation. Overall, the findings of this study provide new insights into the role of genetic compensation in adaptive evolution.

genomics↗

bioRxiv2021

Genetic and genomic architecture in eight strains of the laboratory opossum Monodelphis domestica

The gray short-tailed opossum is an established laboratory-bred marsupial model for biomedical research. It serves as a critical species for comparative genomics research, providing the pivotal phylogenetic outgroup for studies of derived vs. ancestral states of genomic/epigenomic characteristics for all eutherian mammal lineages. To characterize the current genetic profile of this laboratory marsupial, we examined 79 individuals from eight established laboratory strains. Double digest restriction-site associated DNA sequencing (ddRAD-seq) and whole-genome resequencing experiments were performed to investigate the genetic architecture in these strains. A total of 66,640 high-quality single nucleotide polymorphisms (SNPs) were identified. We analyzed SNP density, average heterozygosity, nucleotide diversity, and population differentiation parameter Fst within and between the eight strains. Principal component and population structure analysis clearly resolve the strains at the level of their ancestral founder populations, and the genetic architecture of these strains correctly reflects their breeding history. We confirmed the successful establishment of the first inbred laboratory opossum strain LSD (inbreeding coefficient F > 0.99) and a nearly inbred strain FD2M1 (0.98 < F < 0.99), each derived from a different ancestral background. These strains are suitable for various experimental protocols requiring controlled genetic backgrounds and for intercrosses and backcrosses that can generate offspring with informative SNPs for studying a variety of genetic and epigenetic processes. Together with recent advances in reproductive manipulation and CRISPR/Cas9 techniques for M. domestica, the existence of distinctive inbred strains will enable genome editing on different genetic backgrounds, greatly expanding the utility of this marsupial model for biomedical research.

genomics↗

bioRxiv2021

Complex genetic patterns and distribution limits mediated by native congeners of the worldwide invasive red-eared slider turtle

Non-native (invasive) species offer a unique opportunity to study the geographic distribution and range limits of species, wherein the evolutionary change driven by interspecific interactions between native and non-native closely related species is a key component. The red-eared slider turtle, Trachemys scripta elegans (TSE), has been introduced and successfully established worldwide. It can coexist with its native congeners T. cataspila, T. venusta and T. taylori in Mexico. We performed comprehensive fieldwork, executed a battery of genetic analyses and applied a novel species distribution modeling approach to evaluate their historical lineage relationships and contemporary population genetic patterns. Our findings support the historical common ancestry between native TSE and non-native (TSEalien), while also highlighting the genetic differentiation of the exotic lineage. Genetic patterns are associated with their range size/endemism gradient, the microendemic T. taylori showed significant reduced genetic diversity and high differentiation, whereas TSEalien showed the highest diversity and signals of population size expansion. Counter to our expectations, lower naturally occurring distribution overlap and little admixture patterns were found between and its congeners, exhibiting reduced gene flow and clear genetic separation across neighboring species despite having zones of contact. We demonstrate that these native Trachemys species have distinct climatic niche suitability, likely preventing establishment of and displacement by the non-native TSE. Additionally, we found major niche overlap between TSEalien and native species worldwide, supporting our prediction that sites with closer ecological optima to the invasive species have higher establishment risk than those that are closer to the niche-center of the native species.

evolutionary biology↗

bioRxiv2021

Combining genotypes and T cell receptor distributions to infer genetic loci determining V(D)J recombination probabilities

Every T cell receptor (TCR) repertoire is shaped by a complex probabilistic tangle of genetically determined biases and immune exposures. T cells combine a random V(D)J recombination process with a selection process to generate highly diverse and functional TCRs. The extent to which an individuals genetic background is associated with their resulting TCR repertoire diversity has yet to be fully explored. Using a previously published repertoire sequencing dataset paired with high-resolution genome-wide genotyping from a large human cohort, we infer specific genetic loci associated with V(D)J recombination probabilities using genome-wide association inference. We show that V(D)J gene usage profiles are associated with variation in the TCRB locus and, specifically for the functional TCR repertoire, variation in the major histocompatibility complex locus. Further, we identify specific variations in the genes encoding the Artemis protein and the TdT protein to be associated with biasing junctional nucleotide deletion and N-insertion, respectively. These results refine our understanding of genetically-determined TCR repertoire biases by confirming and extending previous studies on the genetic determinants of V(D)J gene usage and providing the first examples of trans genetic variants which are associated with modifying junctional diversity. Together, these insights lay the groundwork for further explorations into how immune responses vary between individuals.

immunology↗

bioRxiv2021

Insights into opium poppy (Papaver spp.) genetic diversity from genotyping-by-sequencing analysis

Opium poppy (Papaver somniferum) is one of the worlds oldest medicinal plants and a versatile model system to study secondary metabolism. However, our knowledge of its genetic diversity is limited, restricting utilization of the available germplasm for research and crop improvement. We used genotyping-by-sequencing to investigate the extent of genetic diversity and population structure in a collection of poppy germplasm consisting of 91 accessions originating in 30 countries of Europe, North Africa, America, and Asia. We identified five genetically distinct subpopulations using discriminate analysis of principal components and STRUCTURE analysis. Most accessions obtained from the same country were grouped together within subpopulations, likely a consequence of the restriction on movement of poppy germplasm. Alkaloid profiles of accessions were highly diverse, with morphine being dominant. Phylogenetic analysis identified genetic groups that were largely consistent with the subpopulations detected and that could be differentiated broadly based on traits such as number of branches and seed weight. These accessions and the associated genotypic data are valuable resources for further genetic diversity analysis, which could include definition of poppy core sets to facilitate genebank management and use of the diversity for genetic improvement of this valuable crop.

plant biology↗

bioRxiv2021

The Evolution of Larger Size in High Altitude Drosophila melanogaster has a Polymorphic Genetic Architecture

Important uncertainties persist regarding the genetic architecture of adaptive trait evolution in natural populations, including the number of genetic variants involved, whether they are drawn from standing genetic variation, and whether directional selection drives them to complete fixation. Here, we take advantage of a unique natural population of Drosophila melanogaster from the Ethiopian highlands, which has evolved larger body size than any other known population of this species. We apply a bulk segregant quantitative trait locus (QTL) mapping approach to four unique crosses between highland Ethiopian and lowland Zambian populations for both thorax length and wing length. Results indicated a persistently variable genetic basis for these evolved traits (with largely distinct sets of QTLs for each cross), and at least a moderately polygenic architecture with relatively strong effects present. We complemented these mapping experiments with population genetic analyses of QTL regions and gene ontology enrichment analysis, generating strong hypotheses for specific genes and functional processes that may have contributed to these adaptive trait changes. Finally, we find that the genetic architectures our QTL mapping results for size traits mirror those from similar experiments on other recently-evolved traits in this species. Collectively, these studies suggest a recurring pattern of polygenic adaptation in this species, in which causative variants do not approach fixation and moderately strong effect loci are present.

evolutionary biology↗

bioRxiv2021

Missing genetic links between general factors of brain resting-state functional magnetic resonance imaging, cognition and psychopathology

General factors capturing the shared genetics in psychiatric (genomic p-factor) and cognitive traits (genomic g-factor), and more recently in resting-state functional magnetic resonance imaging-derived brain networks, have contributed to our increased understanding of the etiologies in their respective domains. Yet it remains unclear whether general factors can capture the three-way genetic overlap of psychopathology, cognition and brain function. Here we tested for the presence of this genetic overlap via genetic correlation analyses using summary statistics of genome-wide association studies of the p-factor (N = 162,151 cases and 276,846 controls), the g-factor (N = 269,867), and the two genomic factors estimated from the amplitude in resting-state functional magnetic resonance imaging-derived brain networks (N = 31,688). Unlike hypothesized, only the genetic correlation between the p-factor and the g-factor was significant. We conclude that specific functional brain network constructs may have more potential than their derived general dimensions to capture relevant genetic variation for cognition and psychopathology.

neuroscience↗

bioRxiv2021

Archetypal Analysis for Population Genetics

The estimation of genetic clusters using genomic data has application from genome-wide association studies (GWAS) to demographic history to polygenic risk scores (PRS) and is expected to play an important role in the analyses of increasingly diverse, large-scale cohorts. However, existing methods are computationally-intensive, prohibitively so in the case of nationwide biobanks. Here we explore Archetypal Analysis as an efficient, unsupervised approach for identifying genetic clusters and for associating individuals with them. Such unsupervised approaches help avoid conflating socially constructed ethnic labels with genetic clusters by eliminating the need for exogenous training labels. We show that Archetypal Analysis yields similar cluster structure to existing unsupervised methods such as ADMIXTURE and provides interpretative advantages. More importantly, we show that since Archetypal Analysis can be used with lower-dimensional representations of genetic data, significant reductions in computational time and memory requirements are possible. When Archetypal Analysis is run in this fashion, it takes several orders of magnitude less compute time than the current standard, ADMIXTURE. Finally, we demonstrate uses ranging across datasets from humans to canids. Author summaryThis work introduces a method that combines the singular value decomposition (SVD) with Archetypal Analysis to perform fast and accurate genetic clustering by first reducing the dimensionality of the space of genomic sequences. Each sequence is described as a convex combination (admixture) of archetypes (cluster representatives) in the reduced dimensional space. We compare this interpretable approach to the widely used genetic clustering algorithm, ADMIXTURE, and show that, without significant degradation in performance, Archetypal Analysis outperforms, offering shorter run times and representational advantages. We include theoretical, qualitative, and quantitative comparisons between both methods.

bioinformatics↗

bioRxiv2021

Transcription factor competition facilitates self-sustained oscillations in single gene genetic circuits

Genetic feedback loops can be used by cells to regulate internal processes or to keep track of time. It is often thought that, for a genetic circuit to display self-sustained oscillations, a degree of cooperativity is needed in the binding and unbinding of actor species. This cooperativity is usually modeled using a Hill function, regardless of the actual promoter architecture. Furthermore, genetic circuits do not operate in isolation and often transcription factors are shared between different promoters. In this work we show how mathematical modelling of genetic feedback loops can be facilitated with a mechanistic fold-change function that takes into account the titration effect caused by competing binding sites for transcription factors. The model shows how the titration effect facilitates self-sustained oscillations in a minimal genetic feedback loop: a gene that produces its own repressor directly without cooperative transcription factor binding. The use of delay-differential equations leads to a stability contour that predicts whether a genetic feedback loop will show self-sustained oscillations, even when taking the bursty nature of transcription into account.

systems biology↗

bioRxiv2021

A novel framework for analysis of the shared genetic background of correlated traits

We propose a novel effective framework for analysis of the shared genetic background for a set of genetically correlated traits using SNP-level GWAS summary statistics. This framework called SHAHER is based on the construction of a linear combination of traits by maximizing the proportion of its genetic variance explained by the shared genetic factors. SHAHER requires only full GWAS summary statistics and matrices of genetic and phenotypic correlations between traits as inputs. Our framework allows both shared and unshared genetic factors to be to effectively analyzed. We tested our framework using simulation studies, compared it with previous developments, and assessed its performance using three real datasets: anthropometric traits, psychiatric conditions and lipid concentrations. SHAHER is versatile and applicable to summary statistics from GWASs with arbitrary sample sizes and sample overlaps, allows incorporation of different GWAS models (Cox, linear and logistic) and is computationally fast.

bioinformatics↗

bioRxiv2022

Genetic background and mistranslation frequency determine the impact of mistranslating tRNASerUGG

Transfer RNA variants increase the frequency of mistranslation, the mis-incorporation of an amino acid not specified by the "standard" genetic code, to frequencies approaching 10% in yeast and bacteria. Cells cope with these variants by having multiple copies of each tRNA isodecoder and through pathways that deal with proteotoxic stress. In this study, we define the genetic interactions of the gene encoding tRNASerUGG,G26A, which mistranslates serine at proline codons. Using a collection of yeast temperature sensitive alleles, we identify negative synthetic genetic interactions between the mistranslating tRNA and 109 alleles representing 91 genes, with nearly half of the genes having roles in RNA processing or protein folding and turnover. By regulating tRNA expression, we then compare the strength of the negative genetic interaction for a subset of identified alleles under differing amounts of mistranslation. The frequency of mistranslation correlated with impact on cell growth for all strains analyzed; however, there were notable differences in the extent of the synthetic interaction at different frequencies of mistranslation depending on the genetic background. For many of the strains the extent of the negative interaction with tRNASerUGG,G26A was proportional to the frequency of mistranslation or only observed at intermediate or high frequencies. For others the synthetic interaction was approximately equivalent at all frequencies of mistranslation. As humans contain similar mistranslating tRNAs these results are important when analyzing the impact of tRNA variants on disease, where both the individuals genetic background and the expression of the mistranslating tRNA variant need to be considered.

molecular biology↗

bioRxiv2022

A macroecological perspective on genetic diversity in the human gut microbiome

While the human gut microbiome has been intensely studied, we have yet to obtain a sufficient understanding of the genetic diversity that it harbors. Research efforts have demonstrated that a considerable fraction of within-host genetic variation in the human gut is driven by the ecological dynamics of co-occurring strains belonging to the same species, suggesting that an ecological lens may provide insight into empirical patterns of genetic diversity. Indeed, an ecological model of self-limiting growth and environmental noise known as the Stochastic Logistic Model (SLM) was recently shown to successfully predict the temporal dynamics of strains within a single human host. However, its ability to predict patterns of genetic diversity across human hosts has yet to be tested. In this manuscript I determine whether the predictions of the SLM explain patterns of genetic diversity across unrelated human hosts for 22 common microbial species. Specifically, the stationary distribution of the SLM explains the distribution of allele frequencies across hosts and predicts the fraction of hosts harboring a given allele (i.e., prevalence) for a considerable fraction of sites. The accuracy of the SLM was correlated with independent estimates of strain structure, suggesting that patterns of genetic diversity in the gut microbiome follow statistically similar forms across human hosts due to the existence of strain-level ecology.

ecology↗

bioRxiv2022

Plasmodium falciparum genetic diversity in coincident human and mosquito hosts

Population genetic diversity of P. falciparum antigenic loci is high despite large bottlenecks in population size during the parasite life cycle. The extent of this diversity in human blood-stage infections, following expansion from a small number of liver-stage schizonts, has been well described. However, little is known about parasite genetic diversity in the vector, where a similar bottleneck and expansion occurs following parasite mating and where parasite genotypes from several different human infections may accumulate. We assessed parasite genetic diversity within human and mosquito P. falciparum infections collected from the same households during a 14-month longitudinal cohort study using amplicon deep sequencing of two antigenic gene fragments (ama1 and csp). To a prior set of infected humans (n=1175/2813; 86.2% sequencing success) and mosquito abdomens (n=199/1448; 95.5% sequencing success), we added sequences from infected mosquito heads (n=134/1448; 98.5% sequencing success). Across all sample types we observed 456 ama1 and 289 csp unique haplotypes. While both hosts contained many rare haplotypes, population genetic metrics indicated that the overall and sample-level parasite populations were more diverse in mosquitoes than in humans, and infections were more likely to harbor a dominant haplotype in humans than in mosquitoes (based on relative read abundance). Finally, within a given mosquito there was little overlap in genetic composition of abdomen and head infections, suggesting that infections may be cleared from the abdomen during a mosquitos lifespan. Taken together, our observations provide evidence for the role of the mosquito vector in maintaining sequence diversity of malaria parasite populations. Significance statementConcurrent infections with multiple strains of Plasmodium falciparum, the leading causative agent of death due to malaria, are common in highly endemic regions. During transitions within and between the parasites mosquito and human hosts, population bottlenecks occur, and distinct parasite strains may have differential fitness in the various environments encountered. These bottlenecks and fitness differences may lead to differences in strain prevalence and diversity between hosts. We investigated differences in genetic diversity between P. falciparum parasites in human and mosquito hosts and found that, compared to human parasite populations and infections, mosquito populations and infections were more diverse. This suggests that the mosquito vector may play a role in in maintaining sequence diversity in malaria parasite populations.

microbiology↗

bioRxiv2022

Draft genome of six Cuban Anolis lizards and insights into genetic changes during the diversification

The detection of various type of genomic variants and their accumulation processes during species diversification and adaptive radiation is important for understanding the molecular and genetic basis of evolution. Anolis lizards in the West Indies are good models for studying the mechanism of the evolution because of the repeated evolution of their morphology and the ecology. In this study, we performed de novo genome assembly of six Cuban Anolis lizards with different ecomorphs and thermal habitats (Anolis isolepis, Anolis allisoni, Anolis porcatus, Anolis allogus, Anolis homolechis, and Anolis sagrei). As a result, we obtained six novel draft genomes with relatively long and high gene completeness, with scaffold N50 ranging from 5.56-39.79 Mb, and vertebrate Benchmarking Universal Single-Copy Orthologs completeness ranging from 77.5% to 86.9%. Subsequently, we performed comparative analysis of genomic contents including those of mainland Anolis lizards to estimate genetic variations that had emerged and accumulated during the diversification of Anolis lizards. Comparing the repeat element compositions and repeat landscapes revealed differences in the accumulation process between Cuban trunk-crown and trunk-ground species, LTR accumulation observed only in A. carolinensis, and separate expansions of several families of LINE in each of Cuban trunk-ground species. The analysis of duplicated genes suggested that the proportional difference of duplicated gene number among Cuban Anolis lizards may be associated to the difference of their habitat range. Furthermore, Pairwise Sequentially Markovian Coalescent analysis proposed that the effective population sizes of each species might have been affected by Cubas geohistory. Hence, these six novel draft genome assemblies and detected genetic variations can be a springboard for the further genetic elucidation of the Anolis lizards diversification. SignificanceAnolis lizard in the West Indies is excellent model for studying the mechanisms of speciation and adaptive evolution. Still, due to a lack of genome assemblies, genetic variations and accumulation process of them involved in the diversification remain largely unexplored. In this study, we reported the novel genome assemblies of six Cuban Anolis lizards and analyzed evolution of genome contents. From comparative genomic analysis and inferences of genetic variation accumulation process, we detected species- and lineage-specific transposon accumulation processes and gene copy number evolution, considered to be associated with the adaptation to their habitats. Additionally, we estimated past effective population sizes and the results suggested its relationship to Cubas geohistory.

genomics↗

bioRxiv2022

Investigating And Modeling the Factors that Effects the Performance of Genetic Circuits

Over the past two decades, synthetic biology has yielded ever more complex genetic circuits able to perform sophisticated functions in response to specific signals. Yet, genetic circuits are not immediately transferable to an outside-the-lab setting where their performance is highly compromised. We propose introducing a scale step to the design-build-test workflow to include factors that might contribute to unexpected genetic circuit performance. As a proof-of-concept, we designed and tested a genetic circuit under different temperatures, mediums, inducer concentrations, and bacterial growth phases. We determined that the circuits performance is dramatically altered when these factors differ from the optimal lab conditions. Based on these results, a scaling effort, coupled with a learning process, proceeded to generate model predictions for the genetic circuits performance under untested conditions, which is currently lacking in synthetic biology application design. As the synthetic biology discipline transitions from proof-of-concept genetic programs to appropriate and safe application implementations, more emphasis on a scale step is needed to ensure correct and robust performances.

synthetic biology↗

bioRxiv2022

HIV proviral genetic diversity, compartmentalization and inferred dynamics in lung and blood during long-term suppressive antiretroviral therapy

The lung is an understudied site of HIV persistence. We isolated 882 subgenomic proviral sequences by single-genome approaches from blood and lung from nine individuals on long-term suppressive antiretroviral therapy (ART), and characterized genetic diversity and compartmentalization using formal tests. Consistent with clonal expansion as a driver of HIV persistence, identical sequences comprised between 9% to 86% of within-host datasets, though their location (blood vs. lung) followed no consistent pattern. The majority (77%) of participants harbored at least one sequence shared across blood and lung, supporting the migration of clonally-expanded cells between sites. No participant exhibited genetic compartmentalization so obvious that it was visually apparent in a phylogeny. When formal tests were applied however, two (22%) participants showed modest yet significant support for compartmentalization when analysis was restricted to distinct proviruses per site. This increased to four participants (44%) when considering all within-host sequences. Thus, while a minority of individuals harbor somewhat distinctive proviral populations in blood and lung, these can simply be due to unequal distributions of clonally-expanded sequences. Importantly, the extent of lung proviral diversity on ART strongly reflected that in blood (Spearman {rho} = 0.98, p < 0.0001), confirming blood as a strong indicator of total body proviral diversity. Analysis of on-ART proviral diversity in context of pre-therapy viral diversity in two participants revealed marked differences in proviral longevity and dynamics. Whereas one participants proviral pool was rich in ancestral sequences that recapitulated more of HIVs within-host evolutionary history, the others largely comprised more contemporary sequences, including ones that re-seeded the reservoir during a three-year treatment interruption. Results highlight the genetic complexity of proviruses persisting in lung and blood during ART, and the uniqueness of each individuals proviral composition. Individualized HIV remission and cure strategies may be needed to overcome these challenges. Author SummaryHIV persists in the body despite long-term suppressive antiretroviral therapy. Much of our knowledge about the HIV reservoir comes from studying proviruses in blood, but a fundamental question is whether these are distinct from those in tissues. The lung could theoretically engender genetically distinctive HIV populations, but this remains understudied. Our analysis of nearly 900 proviral sequences from blood and lung of nine individuals with HIV receiving long-term therapy revealed substantial within-host heterogeneity, yet some common patterns. Identical sequences (consistent with clonal expansion of infected cells) were observed in everyone, though at different (9-86%) frequencies. Recovery of shared sequences across blood and lung was common (77% of participants). Fewer than half of participants exhibited blood-lung genetic compartmentalization, and only modestly so. Moreover, when present, compartmentalization was often attributable to differential distribution of identical sequences, not the presence of genetically distinctive populations, across sites. Results also revealed marked inter-individual differences in proviral dynamics, as evidenced by the proportion of persisting proviruses that represented ancestral versus more recently-circulating viral sequences. Critically, the extent of within-host proviral diversity in blood correlated strongly with that in lung, indicating that despite inter-individual heterogeneity, blood is a strong indicator of proviral diversity elsewhere in the body.

molecular biology↗