Evolution, Medicine, and Public Health最新文献

{"title":"Evolution of higher mesenchymal CD44 expression in the human lineage: A gene linked to cancer malignancy.","authors":"Xinghong Ma,&nbsp;Anasuya Dighe,&nbsp;Jamie Maziarz,&nbsp;Edwin Neumann,&nbsp;Eric Erkenbrack,&nbsp;Yuan-Yuan Hei,&nbsp;Yansheng Liu,&nbsp;Yasir Suhail,&nbsp;Irene Pak,&nbsp;Andre Levchenko,&nbsp;Günter P Wagner","doi":"10.1093/emph/eoac036","DOIUrl":"https://doi.org/10.1093/emph/eoac036","url":null,"abstract":"<p><p>CD44 is an extracellular matrix receptor implicated in cancer progression. CD44 increases the invasibility of skin (SF) and endometrial stromal fibroblasts (ESF) by cancer and trophoblast cells. We reasoned that the evolution of CD44 expression can affect both, the fetal-maternal interaction through CD44 in ESF as well as vulnerability to malignant cancer through expression in SF. We studied the evolution of <i>CD44</i> expression in mammalian SF and ESF and demonstrate that in the human lineage evolved higher <i>CD44</i> expression. Isoform expression in cattle and human is very similar suggesting that differences in invasibility are not due to the nature of expressed isoforms. We then asked whether the concerted gene expression increase in both cell types is due to shared regulatory mechanisms or due to cell type-specific factors. Reporter gene experiments with cells and <i>cis</i>-regulatory elements from human and cattle show that the difference of <i>CD44</i> expression is due to <i>cis</i> effects as well as cell type-specific <i>trans</i> effects. These results suggest that the concerted expression increase is likely due to selection acting on both cell types because the evolutionary change in cell type-specific factors requires selection on cell type-specific functions. This scenario implies that the malignancy enhancing effects of elevated CD44 expression in humans likely evolved as a side-effect of positive selection on a yet unidentified other function of CD44. A possible candidate is the anti-fibrotic effect of CD44 but there are no reliable data showing that humans and primates are less fibrotic than other mammals.</p>","PeriodicalId":12156,"journal":{"name":"Evolution, Medicine, and Public Health","volume":" ","pages":"447-462"},"PeriodicalIF":3.7,"publicationDate":"2022-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9487634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33477224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early life adversity, reproductive history and breast cancer risk.","authors":"Amy M Boddy, Shawn Rupp, Zhe Yu, Heidi Hanson, Athena Aktipis, Ken Smith","doi":"10.1093/emph/eoac034","DOIUrl":"10.1093/emph/eoac034","url":null,"abstract":"<p><strong>Background and objectives: </strong>Individuals who experience early life adversity are at an increased risk for chronic disease later in life. Less is known about how early life factors are associated with cancer susceptibility. Here, we use a life history framework to test whether early life adversity increases the risk of breast cancer. We predict that early life adversity can shift investment in somatic maintenance and accelerate the timing of reproduction, which may mediate or interact with the risk of breast cancer.</p><p><strong>Methodology: </strong>We use population-wide data from the Utah Population Database (UPDB) and Utah Cancer Registry, leading to 24 957 cases of women diagnosed with breast cancer spanning 20 years (1990-2010) and 124 785 age-matched controls. We generated a cumulative early life adversity summation score to evaluate the interaction (moderation) and mediation between early life adversity, reproductive history and their association with breast cancer risk.</p><p><strong>Results: </strong>Our analyses led to three key findings: (i) more early life adversity, when considered as a main effect, accelerates the time to first birth and death, (ii) early age at first birth and high parity decreases the risk of breast cancer and (iii) we find no association between early adversity and breast cancer risk either as a main effect or in its interaction with reproductive history.</p><p><strong>Conclusion and implications: </strong>Early adversity elevates the risk of overall mortality through mechanisms other than breast cancer risk. This suggests early life factors can generate different effects on health. Future work should incorporate more complex view of life history patterns, including multiple life stages, when making predictions about cancer susceptibility.</p>","PeriodicalId":12156,"journal":{"name":"Evolution, Medicine, and Public Health","volume":"10 1","pages":"429-438"},"PeriodicalIF":3.7,"publicationDate":"2022-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9464099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9953211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Socioeconomic impacts on Andean adolescents' growth: Variation between households, between communities and over time.","authors":"Mecca E Burris,&nbsp;Esperanza Caceres,&nbsp;Emily M Chester,&nbsp;Kathryn A Hicks,&nbsp;Thomas W McDade,&nbsp;Lynn Sikkink,&nbsp;Hilde Spielvogel,&nbsp;Jonathan Thornburg,&nbsp;Virginia J Vitzthum","doi":"10.1093/emph/eoac033","DOIUrl":"https://doi.org/10.1093/emph/eoac033","url":null,"abstract":"<p><strong>Background/objectives: </strong>We evaluated potential socioeconomic contributors to variation in Andean adolescents' growth between households within a peri-urban community undergoing rapid demographic and economic change, between different community types (rural, peri-urban, urban) and over time. Because growth monitoring is widely used for assessing community needs and progress, we compared the prevalences of stunting, underweight, and overweight estimated by three different growth references.</p><p><strong>Methods: </strong>Anthropometrics of 101 El Alto, Bolivia, adolescents (Alteños), 11.0-14.9 years old in 2003, were compared between households (economic status assessed by parental occupations); to one urban and two rural samples collected in 1983/1998/1977, respectively; and to the WHO growth reference, a representative sample of Bolivian children (MESA), and a region-wide sample of high-altitude Peruvian children (Puno).</p><p><strong>Results: </strong>Female Alteños' growth was positively associated with household and maternal income indices. Alteños' height averaged ∼0.8SD/∼0.6SD/∼2SDs greater than adolescents' height in urban and rural communities measured in 1983/1998/1977, respectively. Overweight prevalence was comparable to the WHO, and lower than MESA and Puno, references. Stunting was 8.5/2.5/0.5 times WHO/MESA/Puno samples, respectively.</p><p><strong>Conclusions/implications: </strong>Both peri-urban conditions and temporal trends contributed to gains in Alteños' growth. Rural out-migration can alleviate migrants' poverty, partly because of more diverse economic options in urbanized communities, especially for women. Nonetheless, Alteños averaged below WHO and MESA height and weight medians. Evolved biological adaptations to environmental challenges, and the consequent variability in growth trajectories, favor using multiple growth references. Growth monitoring should be informed by community- and household-level studies to detect and understand local factors causing or alleviating health disparities.</p>","PeriodicalId":12156,"journal":{"name":"Evolution, Medicine, and Public Health","volume":" ","pages":"409-428"},"PeriodicalIF":3.7,"publicationDate":"2022-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33460122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selfish evolution of placental hormones.","authors":"Grace Keegan,&nbsp;Manus M Patten","doi":"10.1093/emph/eoac031","DOIUrl":"https://doi.org/10.1093/emph/eoac031","url":null,"abstract":"<p><p>We hypothesize that some placental hormones-specifically those that arise by tandem duplication of genes for maternal hormones-may behave as gestational drivers, selfish genetic elements that encourage the spontaneous abortion of offspring that fail to inherit them. Such drivers are quite simple to evolve, requiring just three things: a decrease in expression or activity of some essential maternal hormone during pregnancy; a compensatory increase in expression or activity of the homologous hormone by the placenta; and genetic linkage between the two effects. Gestational drive may therefore be a common selection pressure experienced by any of the various hormones of mammalian pregnancy that have arisen by tandem gene duplication. We examine the evolution of chorionic gonadotropin in the human lineage in light of this hypothesis. Finally, we postulate that some of the difficulties of human pregnancy may be a consequence of the action of selfish genes.</p>","PeriodicalId":12156,"journal":{"name":"Evolution, Medicine, and Public Health","volume":" ","pages":"391-397"},"PeriodicalIF":3.7,"publicationDate":"2022-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9426663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40341508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heritage-specific oral microbiota in Indigenous Australian dental calculus.","authors":"Matilda Handsley-Davis,&nbsp;Kostas Kapellas,&nbsp;Lisa M Jamieson,&nbsp;Joanne Hedges,&nbsp;Emily Skelly,&nbsp;John Kaidonis,&nbsp;Poppy Anastassiadis,&nbsp;Laura S Weyrich","doi":"10.1093/emph/eoac024","DOIUrl":"https://doi.org/10.1093/emph/eoac024","url":null,"abstract":"<p><strong>Background and objectives: </strong>Aboriginal Australians and Torres Strait Islanders (hereafter respectfully referred to as Indigenous Australians) experience a high burden of chronic non-communicable diseases (NCDs). Increased NCD risk is linked to oral diseases mediated by the oral microbiota, a microbial community influenced by both vertical transmission and lifestyle factors. As an initial step towards understanding the oral microbiota as a factor in Indigenous health, we present the first investigation of oral microbiota in Indigenous Australian adults.</p><p><strong>Methodology: </strong>Dental calculus samples from Indigenous Australians with periodontal disease (PD; <i>n</i> = 13) and non-Indigenous individuals both with (<i>n</i> = 19) and without PD (<i>n</i> = 20) were characterized using 16S ribosomal RNA gene amplicon sequencing. Alpha and beta diversity, differentially abundant microbial taxa and taxa unique to different participant groups were analysed using QIIME2.</p><p><strong>Results: </strong>Samples from Indigenous Australians were more phylogenetically diverse (Kruskal-Wallis <i>H</i> = 19.86, <i>P</i> = 8.3 × 10^-6), differed significantly in composition from non-Indigenous samples (PERMANOVA pseudo-<i>F</i> = 10.42, <i>P</i> = 0.001) and contained a relatively high proportion of unique taxa not previously reported in the human oral microbiota (e.g. Endomicrobia). These patterns were robust to stratification by PD status. Oral microbiota diversity and composition also differed between Indigenous individuals living in different geographic regions.</p><p><strong>Conclusions and implications: </strong>Indigenous Australians may harbour unique oral microbiota shaped by their long relationships with Country (ancestral homelands). Our findings have implications for understanding the origins of oral and systemic NCDs and for the inclusion of Indigenous peoples in microbiota research, highlighting the microbiota as a novel field of enquiry to improve Indigenous health.</p>","PeriodicalId":12156,"journal":{"name":"Evolution, Medicine, and Public Health","volume":" ","pages":"352-362"},"PeriodicalIF":3.7,"publicationDate":"2022-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9400808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33442130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Girls start life on an uneven playing field: Evidence from lowland rural Nepal.","authors":"Akanksha A Marphatia,&nbsp;Naomi S Saville,&nbsp;Dharma S Manandhar,&nbsp;Mario Cortina-Borja,&nbsp;Alice M Reid,&nbsp;Jonathan C K Wells","doi":"10.1093/emph/eoac029","DOIUrl":"https://doi.org/10.1093/emph/eoac029","url":null,"abstract":"<p><strong>Background and objectives: </strong>Evolutionary research on the sex ratio at birth (SRB) has focused on explaining variability within and between populations, and whether parental fitness is maximized by producing daughters or sons. We tested predictors of SRB in a low-income setting, to understand whether girls differ from boys in their likelihood of being born into families with the capacity to invest in them, which has implications for their future health and fitness.</p><p><strong>Methodology: </strong>We used data from a cluster randomized control trial from lowland rural Nepal (16 115 mother-child dyads). We applied principal component analysis to extract two composite indices reflecting maternal socio-economic and reproductive (parity, age) capital. We fitted mixed-effects logistic regression models to estimate odds ratios of having a girl in association with these individual factors and indices.</p><p><strong>Results: </strong>The SRB was 112. Compared to the global reference SRB (105), there were seven missing girls per 100 boys. Uneducated, early-marrying, poorer and shorter mothers were more likely to give birth to girls. Analysing composite maternal indices, lower socio-economic and reproductive capital were independently associated with a greater likelihood of having a girl.</p><p><strong>Conclusions and implications: </strong>In this population, girls start life facing composite disadvantages, being more likely than boys to be born to mothers with lower socio-economic status and reproductive capital. Both physiological and behavioural mechanisms may contribute to these epidemiological associations. Differential early exposure by sex to maternal factors may underpin intergenerational cycles of gender inequality, mediated by developmental trajectory, education and socio-economic status.</p>","PeriodicalId":12156,"journal":{"name":"Evolution, Medicine, and Public Health","volume":" ","pages":"339-351"},"PeriodicalIF":3.7,"publicationDate":"2022-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9384836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40628666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phylogenetic prioritization of HIV-1 transmission clusters with viral lineage-level diversification rates.","authors":"Rachel L Miller,&nbsp;Angela McLaughlin,&nbsp;Richard H Liang,&nbsp;John Harding,&nbsp;Jason Wong,&nbsp;Anh Q Le,&nbsp;Chanson J Brumme,&nbsp;Julio S G Montaner,&nbsp;Jeffrey B Joy","doi":"10.1093/emph/eoac026","DOIUrl":"https://doi.org/10.1093/emph/eoac026","url":null,"abstract":"<p><strong>Background and objectives: </strong>Public health officials faced with a large number of transmission clusters require a rapid, scalable and unbiased way to prioritize distribution of limited resources to maximize benefits. We hypothesize that transmission cluster prioritization based on phylogenetically derived lineage-level diversification rates will perform as well as or better than commonly used growth-based prioritization measures, without need for historical data or subjective interpretation.</p><p><strong>Methodology: </strong>9822 HIV pol sequences collected during routine drug resistance genotyping were used alongside simulated sequence data to infer sets of phylogenetic transmission clusters via patristic distance threshold. Prioritized clusters inferred from empirical data were compared to those prioritized by the current public health protocols. Prioritization of simulated clusters was evaluated based on correlation of a given prioritization measure with future cluster growth, as well as the number of direct downstream transmissions from cluster members.</p><p><strong>Results: </strong>Empirical data suggest diversification rate-based measures perform comparably to growth-based measures in recreating public heath prioritization choices. However, unbiased simulated data reveals phylogenetic diversification rate-based measures perform better in predicting future cluster growth relative to growth-based measures, particularly long-term growth. Diversification rate-based measures also display advantages over growth-based measures in highlighting groups with greater future transmission events compared to random groups of the same size. Furthermore, diversification rate measures were notably more robust to effects of decreased sampling proportion.</p><p><strong>Conclusions and implications: </strong>Our findings indicate diversification rate-based measures frequently outperform growth-based measures in predicting future cluster growth and offer several additional advantages beneficial to optimizing the public health prioritization process.</p>","PeriodicalId":12156,"journal":{"name":"Evolution, Medicine, and Public Health","volume":" ","pages":"305-315"},"PeriodicalIF":3.7,"publicationDate":"2022-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40554594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implications of leg length for metabolic health and fitness.","authors":"Meghan K Shirley, Owen J Arthurs, Kiran K Seunarine, Tim J Cole, Simon Eaton, Jane E Williams, Chris A Clark, Jonathan C K Wells","doi":"10.1093/emph/eoac023","DOIUrl":"10.1093/emph/eoac023","url":null,"abstract":"<p><strong>Background and objectives: </strong>Several studies have linked longer legs with favorable adult metabolic health outcomes and greater offspring birth weight. A recent Mendelian randomization study suggested a causal link between height and cardiometabolic risk; however, the underlying reasons remain poorly understood.</p><p><strong>Methodology: </strong>Using a cross-sectional design, we tested in a convenience sample of 70 healthy young women whether birth weight and tibia length as markers of early-life conditions associated more strongly with metabolically beneficial traits like organ size and skeletal muscle mass (SMM) than a statistically derived height-residual variable indexing later, more canalized growth.</p><p><strong>Results: </strong>Consistent with the 'developmental origins of health and disease' hypothesis, we found relatively strong associations of tibia length-but not birth weight-with adult organ size, brain size, SMM and resting energy expenditure measured by magnetic resonance imaging (MRI), dual-energy X-ray absorptiometry and indirect calorimetry, respectively.</p><p><strong>Conclusions and implications: </strong>Building on prior work, these results suggest that leg length is a sensitive marker of traits directly impacting metabolic and reproductive health. Alongside findings in the same sample relating tibia length and height-residual to MRI-measured pelvic dimensions, we suggest there may exist a degree of coordination in the development of long bone, lean mass and pelvic traits, possibly centered on early, pre-pubertal growth periods. Such phenotypic coordination has important implications for fitness, serving to benefit both adult health and the health of offspring in subsequent generations.</p>","PeriodicalId":12156,"journal":{"name":"Evolution, Medicine, and Public Health","volume":"10 1","pages":"316-324"},"PeriodicalIF":3.3,"publicationDate":"2022-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9326181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10701439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple sclerosis and the microbiota: Progress in understanding the contribution of the gut microbiome to disease.","authors":"Hendrik J Engelenburg,&nbsp;Paul J Lucassen,&nbsp;Joshua T Sarafian,&nbsp;William Parker,&nbsp;Jon D Laman","doi":"10.1093/emph/eoac009","DOIUrl":"https://doi.org/10.1093/emph/eoac009","url":null,"abstract":"<p><p>Multiple sclerosis (MS), a neurological autoimmune disorder, has recently been linked to neuro-inflammatory influences from the gut. In this review, we address the idea that evolutionary mismatches could affect the pathogenesis of MS via the gut microbiota. The evolution of symbiosis as well as the recent introduction of evolutionary mismatches is considered, and evidence regarding the impact of diet on the MS-associated microbiota is evaluated. Distinctive microbial community compositions associated with the gut microbiota of MS patients are difficult to identify, and substantial study-to-study variation and even larger variations between individual profiles of MS patients are observed. Furthermore, although some dietary changes impact the progression of MS, MS-associated features of microbiota were found to be not necessarily associated with diet per se. In addition, immune function in MS patients potentially drives changes in microbial composition directly, in at least some individuals. Finally, assessment of evolutionary histories of animals with their gut symbionts suggests that the impact of evolutionary mismatch on the microbiota is less concerning than mismatches affecting helminths and protists. These observations suggest that the benefits of an anti-inflammatory diet for patients with MS may not be mediated by the microbiota per se. Furthermore, any alteration of the microbiota found in association with MS may be an effect rather than a cause. This conclusion is consistent with other studies indicating that a loss of complex eukaryotic symbionts, including helminths and protists, is a pivotal evolutionary mismatch that potentiates the increased prevalence of autoimmunity within a population.</p>","PeriodicalId":12156,"journal":{"name":"Evolution, Medicine, and Public Health","volume":" ","pages":"277-294"},"PeriodicalIF":3.7,"publicationDate":"2022-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9211007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40391337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolved resistance to a novel cationic peptide antibiotic requires high mutation supply.","authors":"Alfonso Santos-Lopez, Melissa J Fritz, Jeffrey B Lombardo, Ansen H P Burr, Victoria A Heinrich, Christopher W Marshall, Vaughn S Cooper","doi":"10.1093/emph/eoac022","DOIUrl":"10.1093/emph/eoac022","url":null,"abstract":"<p><strong>Background and objectives: </strong>A key strategy for resolving the antibiotic resistance crisis is the development of new drugs with antimicrobial properties. The engineered cationic antimicrobial peptide WLBU2 (also known as PLG0206) is a promising broad-spectrum antimicrobial compound that has completed Phase I clinical studies. It has activity against Gram-negative and Gram-positive bacteria including infections associated with biofilm. No definitive mechanisms of resistance to WLBU2 have been identified.</p><p><strong>Methodology: </strong>Here, we used experimental evolution under different levels of mutation supply and whole genome sequencing (WGS) to detect the genetic pathways and probable mechanisms of resistance to this peptide. We propagated populations of wild-type and hypermutator <i>Pseudomonas aeruginosa</i> in the presence of WLBU2 and performed WGS of evolved populations and clones.</p><p><strong>Results: </strong>Populations that survived WLBU2 treatment acquired a minimum of two mutations, making the acquisition of resistance more difficult than for most antibiotics, which can be tolerated by mutation of a single target. Major targets of resistance to WLBU2 included the <i>orfN</i> and <i>pmrB</i> genes, previously described to confer resistance to other cationic peptides. More surprisingly, mutations that increase aggregation such as the <i>wsp</i> pathway were also selected despite the ability of WLBU2 to kill cells growing in a biofilm.</p><p><strong>Conclusions and implications: </strong>The results show how experimental evolution and WGS can identify genetic targets and actions of new antimicrobial compounds and predict pathways to resistance of new antibiotics in clinical practice.</p>","PeriodicalId":12156,"journal":{"name":"Evolution, Medicine, and Public Health","volume":"10 1","pages":"266-276"},"PeriodicalIF":3.3,"publicationDate":"2022-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9198447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71520954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}