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bioRxiv2019

Genetic and environmental perturbations drive modular transcriptome responses

Understanding the plasticity, robustness, and modularity of transcriptome expression to genetic and environmental conditions is crucial to deciphering how organisms adapt in nature. To test how genome architecture influences transcriptome profiles, we quantified expression responses for distinct temperature-adapted genotypes of the nematode Caenorhabditis briggsae when exposed to chronic temperature stresses throughout development. We found that 56% of the 8795 differentially-expressed genes show genotype-specific changes in expression in response to temperature (genotype-by-environment interactions, GxE). Most genotype-specific responses occur under heat stress, indicating that cold versus heat stress responses involve distinct genomic architectures. The 22 co-expression modules that we identified differ in their enrichment of genes with genetic versus environmental versus interaction effects, as well as their genomic spatial distributions, functional attributes, and rates of molecular evolution at the sequence level. Genes in modules enriched for simple effects of either genotype or temperature alone tend to evolve especially rapidly, consistent with disproportionate influence of adaptation or weaker constraint on these subsets of loci. Chromosome scale heterogeneity in nucleotide polymorphism, however, rather than the scale of individual genes, predominate as the source of genetic differences among expression profiles, and natural selection regimes are largely decoupled between coding sequences and non-coding flanking sequences that contain cis-regulatory elements. These results illustrate how the form of transcriptome modularity and genome structure contribute to predictable profiles of evolutionary change.

genomics↗

bioRxiv2019

Genetic Risk for Rheumatoid Arthritis is Associated with Increased Striatal Volume in Healthy Young Adults

Rheumatoid arthritis (RA), an autoimmune disease, has recently been associated with increased striatal volume and decreased intracranial volume (ICV) in longstanding patients. As inflammation has been shown to precede the clinical diagnosis of RA and it is a known moderator of neuro- and gliogenesis, we were interested in testing whether these brain morphological changes appear before the clinical onset of disease in healthy young adult volunteers, as a function of relative genetic risk for RA. Genetic and structural MRI data were available for 516 healthy non-Hispanic Caucasian university students (275 women, mean age 19.78{+/-}1.24 years). Polygenic risk scores were computed for each individual based on a genome-wide association study of RA, so that higher scores indicated higher risk. Striatal volume (sum of caudate, putamen, and nucleus accumbens volumes) and ICV were derived for each individual from high-resolution T1-weighted images. After controlling for sex, age, genetic components of ethnicity, socioeconomic status, and depressive symptoms, we found that higher RA polygenic risk scores were associated with increased striatal volume, but not decreased ICV. Our findings suggest that increased striatal volume may be linked to processes that precede disease onset, such as inflammation, while decreased ICV may relate to disease progression.

neuroscience↗

bioRxiv2019

Benefits of improved air quality on aging lungs. Impacts of genetics and obesity

IntroductionThe beneficial effect of improving air quality on lung function in the elderly remains unclear. We examined associations between decline in air pollutants and lung function and effect modifications by genetics and BMI in elderly German women.\n\nMethodsData were analysed from the prospective SALIA cohort study (N=601). Spirometry was conducted at baseline (1985-1994; 55 years), in 2007-2010 and in 2012-2013. Air pollution concentrations at home addresses were determined for each time point using land-use regression models. GLI z-scores were calculated. Weighted genetic risk scores (GRS) were determined from lung function-related risk alleles and used to investigate interactions with improved air quality. Adjusted linear mixed models were fitted.\n\nResultsAir pollution levels decreased substantially during the study period. Reduction of air pollution was associated with an increase of z-scores for FEV1 and FEV1/FVC. For a decrease of 10 g/m3 in NO2, the z-score for FEV1 increased by 0.14 (95%CI: 0.01; 0.26). However, with an increasing number of lung function-related risk alleles, the benefit from improved air quality decreased (GRSxNO2-interaction:p=0.029). Interactions with BMI were not significant.\n\nConclusionsReduction of air pollution is associated with a relative improvement of lung function in elderly women, but also depends on their genetic make-up.

epidemiology↗

bioRxiv2019

Distinct genetic signatures of cortical and subcortical regions associated with human memory

Despite the discovery of gene variants linked to memory performance, understanding the genetic basis of human memory remains a challenge. Here, we devised a framework combining human transcriptome data and a functional neuroimaging map to uncover the genetic signatures of memory in functionally-defined cortical and subcortical memory regions. Results were validated with animal literature and our framework proved to be highly effective and specific to the targeted cognitive function versus a control function. Genes preferentially expressed in cortical memory regions are linked to associative learning and ribosome biogenesis. Genes expressed in subcortical memory regions are associated with synaptic signaling and epigenetic processes. Cortical and subcortical regions share a number of memory-related biological processes and genes, e.g. translational initiation and GRIN1. Thus, cortical and subcortical memory regions exhibit distinct genetic signatures that potentially reflect functional differences in health and disease, and propose gene candidates for the targeted treatment of memory disorders.

neuroscience↗

bioRxiv2019

Isogenic human iPSC pairs reveal a neuronal subtype-specific and genetic background-independent mechanism of SCN1A epilepsy

Over 1250 mutations in SCN1A, the Nav1.1 voltage-gated sodium channel gene, are associated with seizure disorders including GEFS+. To evaluate how a specific mutation, independent of genetic background, causes seizure activity we generated two pairs of isogenic human iPSC lines by CRISPR/Cas9 gene editing. One pair is a control line from an unaffected sibling, and the mutated control carrying the GEFS+ K1270T SCN1A mutation. The second pair is a GEFS+ patient line with the K1270T mutation, and the corrected patient line. By comparing the electrophysiological properties in inhibitory and excitatory iPSC-derived neurons from these pairs, we found the K1270T mutation causes cell type-specific alterations in sodium current density and evoked firing, resulting in hyperactive neural networks. We also identified differences associated with genetic background and interaction between the mutation and genetic background. Comparisons within and between dual pairs of isogenic iPSC-derived neuronal cultures provide a novel platform for evaluating cellular mechanisms underlying a disease phenotype and for developing patient-specific anti-seizure therapies.

neuroscience↗

bioRxiv2019

The visual system of the genetically tractable crustacean Parhyale hawaiensis: diversification of eyes and visual circuits associated with low-resolution vision

BackgroundArthropod eyes have diversified during evolution to serve multiple needs, such as finding mates, hunting prey, and navigating in complex surroundings under varying light conditions. This diversity is reflected in the optical apparatus, photoreceptors and neural circuits that underpin vision. While this diversity has been extensively documented, our ability to genetically manipulate the visual system to investigate its function is largely limited to a single species, the fruitfly Drosophila melanogaster. Here, we describe the visual system of Parhyale hawaiensis, an amphipod crustacean for which we have established tailored genetic tools. ResultsAdult Parhyale have apposition-type compound eyes made up of [~]50 ommatidia. Each ommatidium contains four photoreceptor cells with large rhabdomeres (R1-4), expected to be sensitive to the polarisation of light, and one photoreceptor cell with a smaller rhabdomere (R5). The two types of photoreceptors express different opsins, belonging to families with distinct wavelength sensitivities. Using the cis.-regulatory regions of opsin genes, we established transgenic reporters expressed in each photoreceptor cell type. Based on these reporters, we show that R1-4 and R5 photoreceptors extend axons to the first optic lobe neuropil, revealing striking differences compared with the photoreceptor projections found in related crustaceans and insects. Investigating visual function, we show that Parhyale has a positive phototactic response and is capable of adapting its eyes to different levels of light intensity. ConclusionsWe propose that the visual system of Parhyale serves low-resolution visual tasks, such as orientation and navigation, based on broad gradients of light intensity and polarisation. Optic lobe structure and photoreceptor projections point to significant divergence from the conserved visual circuits found in other malacostracan crustaceans and insects, which could be associated with a shift to low-resolution vision. Our study provides the foundation for research in the visual system of this genetically tractable species.

zoology↗

bioRxiv2019

Genetic instability as a driver for immune surveillance

Genetic instability is known to relate with carcinogenesis by providing tumors with a mechanism for fast adaptation. However, mounting evidence also indicates causal relation between genetic instability and improved cancer prognosis resulting from efficient immune response. Highly unstable tumors seem to accumulate mutational burdens that result in dynamical landscapes of neoantigen production, eventually inducing acute immune recognition. How are tumor instability and enhanced immune response related? An important step towards future developments involving combined therapies would benefit from unraveling this connection. In this paper we present a minimal mathematical model to describe the ecological interactions that couple tumor adaptation and immune recognition while making use of available clinical estimates of relevant parameters. The possible evolutionary trade-offs associated to both cancer replication and T cell response are analysed, indicating that cancer-clearance states become attainable when both mutational load and immune migration are enhanced. Furthermore, the model predicts the presence of well-defined transitions towards tumor control and eradication after increases in genetic instability consistent with available data of tumor control after Mismatch Repair knockout.

systems biology↗

bioRxiv2019

Mobile genetic element insertions drive antibiotic resistance across pathogens

Mobile genetic elements contribute to bacterial adaptation and evolution; however, detecting these elements in a high-throughput and unbiased manner remains challenging. Here, we demonstrate a de novo approach to identify mobile elements from short-read sequencing data. The method identifies the precise site of mobile element insertion and infers the identity of the inserted sequence. This is an improvement over previous methods that either rely on curated databases of known mobile elements or rely on split-read alignments that assume the inserted element exists within the reference genome. We apply our approach to 12,419 sequenced isolates of nine prevalent bacterial pathogens, and we identify hundreds of known and novel mobile genetic elements, including many candidate insertion sequences. We find that the mobile element repertoire and insertion rate vary considerably across species, and that many of the identified mobile elements are biased toward certain target sequences, several of them being highly specific. Mobile element insertion hotspots often cluster near genes involved in mechanisms of antibiotic resistance, and such insertions are associated with antibiotic resistance in laboratory experiments and clinical isolates. Finally, we demonstrate that mutagenesis caused by these mobile elements contributes to antibiotic resistance in a genome-wide association study of mobile element insertions in pathogenic Escherichia coli. In summary, by applying a de novo approach to precisely identify mobile genetic elements and their insertion sites, we thoroughly characterize the mobile element repertoire and insertion spectrum of nine pathogenic bacterial species and find that mobile element insertions play a significant role in the evolution of clinically relevant phenotypes, such as antibiotic resistance.

microbiology↗

bioRxiv2019

Individuals' expected genetic contributions to future generations, reproductive value, and short-term metrics of fitness in free-living song sparrows (Melospiza melodia)

Appropriately defining and enumerating fitness is fundamental to explaining and predicting evolutionary dynamics. Yet theoretical concepts of fitness are often hard to translate into quantities that can be quantified in wild populations experiencing complex environmental, demographic, genetic and selective variation. While the fittest entities might be widely understood to be those that ultimately leave most descendants at some future time, such long-term legacies are hard to measure, impeding evaluation of how well more tractable short-term metrics of individual fitness directly predict longer-term outcomes. One opportunity for conceptual and empirical convergence stems from the principle of individual reproductive value (Vi), defined as the number of copies of each of an individuals alleles that is expected to be present in future generations given the individuals realised pedigree of descendants. Since Vi tightly predicts an individuals longer-term genetic contribution, quantifying Vi provides a tractable route to quantifying what, to date, has been an abstract fitness concept. We used complete pedigree data from free-living song sparrows (Melospiza melodia) to demonstrate that individuals expected genetic contributions stabilise within an observed 20-year time period, allowing individual Vi to be evaluated. Considerable among-individual variation in Vi was evident in both sexes. However, standard short-term metrics of individual fitness, comprising lifespan, lifetime reproductive success and projected growth rate, typically explained less than half the variation. Given these results, we discuss what evolutionary inferences can and cannot be directly drawn from short-term versus longer-term fitness metrics observed on individuals, and highlight that analyses of pedigree structure may provide useful complementary insights into evolutionary processes and outcomes.

evolutionary biology↗

bioRxiv2019

Evaluating potential drug targets through human loss-of-function genetic variation

Human genetics has informed the clinical development of new drugs, and is beginning to influence the selection of new drug targets. Large-scale DNA sequencing studies have created a catalogue of naturally occurring genetic variants predicted to cause loss of function in human genes, which in principle should provide powerful in vivo models of human genetic "knockouts" to complement model organism knockout studies and inform drug development. Here, we consider the use of predicted loss-of-function (pLoF) variation catalogued in the Genome Aggregation Database (gnomAD) for the evaluation of genes as potential drug targets. Many drug targets, including the targets of highly successful inhibitors such as aspirin and statins, are under natural selection at least as extreme as known haploinsufficient genes, with pLoF variants almost completely depleted from the population. Thus, metrics of gene essentiality should not be used to eliminate genes from consideration as potential targets. The identification of individual humans harboring "knockouts" (biallelic gene inactivation), followed by individual recall and deep phenotyping, is highly valuable to study gene function. In most genes, pLoF alleles are sufficiently rare that ascertainment will be largely limited to heterozygous individuals in outbred populations. Sampling of diverse bottlenecked populations and consanguineous individuals will aid in identification of total "knockouts". Careful filtering and curation of pLoF variants in a gene of interest is necessary in order to identify true LoF individuals for follow-up, and the positional distribution or frequency of true LoF variants may reveal important disease biology. Our analysis suggests that the value of pLoF variant data for drug discovery lies in deep curation informed by the nature of the drug and its indication, as well as the biology of the gene, followed by recall-by-genotype studies in targeted populations.

genomics↗

bioRxiv2019

Using genetic instruments to estimate interactions in Mendelian Randomization studies

BACKGROUNDThe interactive effect of two exposures on an outcome can be confounded. We demonstrate the use of Mendelian Randomization (MR) to estimate unconfounded additive interactions. METHODSUsing simulation, we test an extension to multivariable MR using two-stage least squares to estimate the additive interaction between two continuous exposures on a continuous outcome, including scenarios where one exposure has a causal effect on the other (mediation). The interaction parameters were set to be one third of the main effects parameters to impose a limit on the variance explained by interaction terms. We compare the performance of the two-stage least squares estimator to a Factorial MR design, in which genetic risk scores for each exposure are dichotomised to create four groups, akin to a factorial randomized controlled trial. As an illustrative example, we apply factorial MR and the 2SLS estimator to the interactive effect of education and BMI on systolic blood pressure in UK Biobank. RESULTSOur simulations demonstrate that factorial MR has very low statistical power; 5-7% at N=50,000 and 8-23% at N=500,000 across the range of parameters tested. The two-stage least squares estimator had higher power to detect interactions than factorial MR and a lower type I error. For N=500,000, the two-stage least squares estimator had a power ranging from 29.7-92.9% and a type I error ranging from 4-6%. 95% Monte Carlo confidence intervals suggested that the estimator was unbiased to a reasonable degree of accuracy at this sample size. In comparison, the power at N=50,000 was 7-55%. CONCLUSIONSA two-stage least squares estimator using genetic risk scores for each exposure is a more powerful alternative for detecting an unconfounded additive interaction of two exposures on an outcome than existing approaches that rely on dichotomising genetic risk scores, but it requires a large sample size and instruments of adequate strength.

epidemiology↗

bioRxiv2019

The essential role played by B cells in supporting protective immunity against Trichuris muris infection is dependent on host genetic background and is independent of antibody

This study investigates the role of B cells in immunity to Trichuris muris (T. muris) infection in two genetically distinct strains of mouse, using anti-CD20 monoclonal antibody (mAb) (Genentech-clone 5D2) to deplete B cells. Data is presented for the mouse strains: C57BL/6 and BALB/c, which mount mixed Th1/Th2, and highly polarised Th2 immune responses to T. muris, respectively. C57BL/6 mice receiving anti-CD20 treatment prior to and during, or anti-CD20 treatment that commenced two weeks post infection (p.i.), were susceptible to T. muris. Parasite-specific IgG1 antibodies were absent and Th2 type cytokines produced by mesenteric lymph nodes cells from mice receiving -CD20 mAb treatment were significantly lower than produced by cells from isotype control treated mice. T follicular helper cells were also significantly reduced. Importantly, and in complete contrast, BALB/c mice were still able to expel T.muris in the absence of B cells, revealing that the essential role played by B cells in protective immunity was dependent on genetic background. To explore whether the important role played by the B cell in the protective immune response of C57BL/6 mice was in enabling strong Th2 responses in the presence of IFN-{gamma}, IFN-{gamma} was blocked using anti-IFN-{gamma} mAb post B cell depletion. Depleting IFN-{gamma}, in the absence of B cells restored worm expulsion in the absence of parasite-specific IgG1/IgG2c and partially rescued the T. muris specific IL-13 response. Thus, our data suggest an important, antibody independent role for B cells in supporting Th2 type immune responses in mixed IFN-{gamma}-rich Th1/Th2 immune response settings. Author summaryHow B cells contribute to protective immunity against parasitic nematodes remains unclear, with their importance as accessory cells under-explored. This study reveals that, on some genetic backgrounds, B cells are important for the expulsion of T. muris by acting as accessory cells, supporting Th2 immune responses.

immunology↗

bioRxiv2019

The value of non-motor features and genetic variants of Parkinson's disease for clustering Lewy body diseases

IntroductionThe use of non-motor Parkinsons disease (PD) features and genetic PD variants for clustering analyses may refine the phenotypic classification of idiopathic Lewy body (LB) diseases. MethodsOne-hundred participants [n=7 E46K-SNCA (n=5 symptomatic and n=2 asymptomatic), n=4 PARK2, n=3 LRRK2, n=8 dementia with Lewy bodies (DLB), n=48 idiopathic PD (iPD), n=30 healthy controls (HC)] underwent a comprehensive evaluation of non-motor and motor PD features. Non-motor features were used to perform a hierarchical clustering analysis with patients and HC using a Scikit-learn toolkit. ResultsClustering analysis suggested three clusters of subjects including Cluster 1 or "Normal-to-mild": young iPD (< 60 years) classified together with most HC and the variable LB burden genetic PD variants (PARK2 and LRRK2) characterized by having normal-to-mild cognitive disabilities and mild-to-moderate motor disability with few axial symptoms; Cluster 2 or "Mild-to-moderate": old iPD patients (>60 years) classified together with the lowest symptomatic E46K-SNCA, PARK2 carriers and HCs, characterizing by having mild-to-moderate cognitive and motor disabilities with few axial symptoms; and Cluster 3 or "Severe": old iPD (>60 years) classified together with all DLB and the most symptomatic E46K-SNCA carriers, characterized by having severe pattern-specific cognitive disabilities (visual attention, perception, processing speed, memory and executive functions) and severe motor PD manifestations with marked axial symptoms. ConclusionsOur study supports the potential value of incorporating genetic PD variants in data-driven iPD classification algorithms and the usefulness of non-motor PD features, especially visual cognition abnormalities, to facilitate the identification of aggressive LB diseases.

neuroscience↗

bioRxiv2019

Genetic variation influences pluripotent ground state stability in mouse embryonic stem cells through a hierarchy of molecular phenotypes

Mouse embryonic stem cells (mESCs) cultured under controlled conditions occupy a stable ground state where pluripotency-associated transcriptional and epigenetic circuitry are highly active. However, mESCs from some genetic backgrounds exhibit metastability, where ground state pluripotency is lost in the absence of ERK1/2 and GSK3 inhibition. We dissected the genetic basis of metastability by profiling gene expression and chromatin accessibility in 185 genetically heterogeneous mESCs. We mapped thousands of loci affecting chromatin accessibility and/or transcript abundance, including eleven instances where distant QTL co-localized in clusters. For one cluster we identified Lifr transcript abundance as the causal intermediate regulating 122 distant genes enriched for roles in maintenance of pluripotency. Joint mediation analysis implicated a single enhancer variant ~10kb upstream of Lifr that alters chromatin accessibility and precipitates a cascade of molecular events affecting maintenance of pluripotency. We validated this hypothesis using reciprocal allele swaps, revealing mechanistic details underlying variability in ground state metastability in mESCs.

genomics↗

bioRxiv2019

Genetic variation in the odorant receptor gene OR4 and bit habits in natural populations of Aedes aegypti from Antioquia department, Colombia.

It has been determined factors that make humans more attractive to mosquitoes and which strategies they use to detect a potential host. Preferential differences for human/non-human hosts are related to variations in odorant receptors (OR) genes in the Aedes aegypti mosquitoes. This study use sequencing to establish the genetic variation in the odor receptor OR4 in 900 mosquitoes from different regions of Antioquia. A behavioral test using an olfactometer was also made to stablish the relationship of these variation with the attraction on different human hosts. The analysis in the attraction and OR4 variants did not show significant differences in the arrival rate among different human hosts. No significant differences in the description of OR4 variants between populations and between hosts, show that this gene is homogeneously distributed. The analysis showed a high genetic population diversity, measured as polymorphism and heterozygosity. This may be due to a few high frequency haplotypes in all the populations examined, suggesting a model of high gene flow between populations and/or selection in favor of these variants in all populations. Other low-frequency variants, many of which are population-specific, reflect the effect of genetic drift probably due to stochastic changes in the size of natural mosquito populations.

molecular biology↗

bioRxiv2019

Characterisation of the genetic architecture underlying eye size variation within Drosophila melanogaster and Drosophila simulans

The compound eyes of insects exhibit striking variation in size, reflecting adaptation to different lifestyles and habitats. However, the genetic and developmental bases of variation in insect eye size is poorly understood, which limits our understanding of how these important morphological differences evolve. To address this, we further explored natural variation in eye size within and between four species of the Drosophila melanogaster species subgroup. We found extensive variation in eye size among these species, and flies with larger eyes generally had a shorter inter-ocular distance and vice versa. We then carried out quantitative trait loci (QTL) mapping of intra-specific variation in eye size and inter-ocular distance in both D. melanogaster and D. simulans. This revealed that different genomic regions underlie variation in eye size and inter-ocular distance in both species, which we corroborated by introgression mapping in D. simulans. This suggests that although there is a trade-off between eye size and inter-ocular distance, variation in these two traits is likely to be caused by different genes and so can be genetically decoupled. Finally, although we detected QTL for intra-specific variation in eye size at similar positions in D. melanogaster and D. simulans, we observed differences in eye fate commitment between strains of these two species. This indicates that different developmental mechanisms and therefore, most likely, different genes contribute to eye size variation in these species. Taken together with the results of previous studies, our findings suggest that the gene regulatory network that specifies eye size has evolved at multiple genetic nodes to give rise to natural variation in this trait within and among species.

evolutionary biology↗

bioRxiv2019

Genetic and genomic analysis of early abortions in Israeli dairy cattle

Female infertility accounts for at least 50% of all human infertility cases. One of the causes contributing for female infertility is embryo loss after fertilization. Previous findings suggested that more than half of fertilizations results in embryo loss before pregnancy is detected. Dairy cattle may be a useful model for study of the genetic architecture of this trait. In advanced commercial populations, all breeding is by artificial insemination, and extensive records of the cows estrus, insemination and pregnancies are available. We proposed re-insemination between 49 and 100 days after the first insemination as an indicator trait for early abortion in dairy cattle, based on the mean estrus interval of 21 days. Israeli Holstein cows scored as early abortion were compare to cows recorded as pregnant from the first insemination. This trait was compare to conception rate from first insemination. Animal model variance components were estimated by REML, including parents and grandparents of cows with records. First parity heritability for conception rate was 3%. In the multi-trait analysis of parities 1-3 for abortion rate heritabilities ranged from 8.9% for first parity to 10.4% for second parity. The variance component for the service sire effect for abortion rate were less than half the variance component for conception rate. Thus genetic control of the two traits is clearly different. Genome wide association study were performed based on the genetic evaluations of [~]1200 sires with reliabilities >50%. The markers with the lowest probabilities for early abortion were also included among the markers with the lowest probabilities for conception rate, but not vice versa. The marker explaining the most variance for abortion rate is located within the ABCA9 gene, which is found within an ABC genes cluster. The ATP-binding cassette family is the major class of primary active transporters in the placenta. Author summaryApproximately 70% of human conceptions fail to achieve viability. Almost 50% of all pregnancies end in miscarriage before the clinical recognition of a missed period. Cattle are a useful model for human female reproductive processes, because of the similarities in the reproductive cycles, and the extensive documentation in commercial cattle populations, including estrus and insemination records. In addition to the expected benefits from cow fertility research for human biomedical applications, fertility is an economically important trait in dairy cattle with very low heritability. The mean estrous interval for cattle is 21 days. We therefore proposed re-insemination between 49 and 100 days after the first insemination as an indicator trait for early abortion. Israeli Holstein cows scored as having early abortion based on first insemination after parturition were compare to cows recorded as pregnant from the first insemination. Heritability for early abortion rate was three-fold the heritability for conception rate. In a genome wide association study based on 1200 dairy bulls genotyped for 41,000 markers, six markers were found with nominal probabilities of < 10-12 to reject the null hypothesis of no effect on early abortion rate. Early abortion rate may be a useful indicator trait for improvement of fertility in dairy cattle.

genomics↗

bioRxiv2019

Bacterial transformation buffers environmental fluctuations through the reversible integration of mobile genetic elements

Horizontal gene transfer (HGT) is known to promote the spread of genes in bacterial communities, which is of primary importance to human health when these genes provide resistance to antibiotics. Among the main HGT mechanisms, natural transformation stands out as being widespread and encoded by the bacterial core genome. From an evolutionary perspective, transformation is often viewed as a mean to generate genetic diversity and mixing within bacterial populations. However, another recent paradigm proposes that its main evolutionary function would be to cure bacterial genomes from their parasitic mobile genetic elements (MGEs). Here, we propose to combine these two seemingly opposing points of view because MGEs, although costly for bacterial cells, can carry functions that are point-in-time beneficial to bacteria under stressful conditions (e.g. antibiotic resistance genes under antibiotic exposure). Using computational modeling, we show that, in stochastic environments (unpredictable stress exposure), an intermediate transformation rate maximizes bacterial fitness by allowing the reversible integration of MGEs carrying resistance genes but costly for the replication of host cells. By ensuring such reversible genetic diversification (acquisition then removal of MGEs), transformation would be a key mechanism for stabilizing the bacterial genome in the long term, which would explain its striking conservation.

microbiology↗