scholarly journals The effect of habitat choice on evolutionary rescue in subdivided populations

2019 ◽  
Author(s):  
Peter Czuppon ◽  
François Blanquart ◽  
Hildegard Uecker ◽  
Florence Débarre
Keyword(s):  
Environmental Change ◽  
De Novo ◽  
Habitat Choice ◽  
Wild Type ◽  
De Novo Mutations ◽  
Relative Contribution ◽  
Evolutionary Rescue ◽  
Subdivided Populations ◽  
Dynamics Of Population ◽  
Population Survival

AbstractEvolutionary rescue is the process by which a population, in response to an environmental change, successfully avoids extinction through adaptation. In spatially structured environments, dispersal can affect the probability of rescue. Here, we model an environment consisting of patches that degrade one after another, and we investigate the probability of rescue by a mutant adapted to the degraded habitat. We focus on the effects of dispersal and of immigration biases. We find that the probability of evolutionary rescue can undergo up to three phases: (i) starting from low dispersal rates, it increases with dispersal; (ii) at intermediate dispersal rates, it decreases; (iii) finally, at large dispersal rates, the probability of rescue increases again with dispersal, except if mutants are too counter-selected in not-yet-degraded patches. The probability of rescue is generally highest when mutant and wild-type individuals preferentially immigrate into patches that have already undergone environmental change. Additionally, we find that mutants that will eventually rescue the population most likely first appear in non-degraded patches, and that the relative contribution of standing genetic variation vs. de-novo mutations declines with increasing emigration rates. Overall, our results show that habitat choice, when compared to the often studied unbiased immigration scheme, can substantially alter the dynamics of population survival and adaptation to new environments.

scholarly journals Understanding the spread of de novo and transmitted macrolide-resistance in Mycoplasma genitalium

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8913
Author(s):  
Dominique Cadosch ◽  
Victor Garcia ◽  
Jørgen S. Jensen ◽  
Nicola Low ◽  
Christian L. Althaus
Keyword(s):  
Single Dose ◽  
De Novo ◽  
Management Strategies ◽  
Mycoplasma Genitalium ◽  
Macrolide Resistance ◽  
Transmission Model ◽  
De Novo Mutations ◽  
Resistance Mutations ◽  
Relative Contribution ◽  
De Novo Resistance

Background The rapid spread of azithromycin resistance in sexually transmitted Mycoplasma genitalium infections is a growing concern. It is not yet clear to what degree macrolide resistance in M. genitalium results from the emergence of de novo mutations or the transmission of resistant strains. Methods We developed a compartmental transmission model to investigate the contribution of de novo macrolide resistance mutations to the spread of antimicrobial-resistant M. genitalium. We fitted the model to resistance data from France, Denmark and Sweden, estimated the time point of azithromycin introduction and the rates at which infected individuals receive treatment, and projected the future spread of resistance. Results The high probability of de novo resistance in M. genitalium accelerates the early spread of antimicrobial resistance. The relative contribution of de novo resistance subsequently decreases, and the spread of resistant infections in France, Denmark and Sweden is now mainly driven by transmitted resistance. If treatment with single-dose azithromycin continues at current rates, macrolide-resistant M. genitalium infections will reach 25% (95% confidence interval, CI [9–30]%) in France, 84% (95% CI [36–98]%) in Denmark and 62% (95% CI [48–76]%) in Sweden by 2025. Conclusions Blind treatment of urethritis with single-dose azithromycin continues to select for the spread of macrolide resistant M. genitalium. Clinical management strategies for M. genitalium should limit the unnecessary use of macrolides.

scholarly journals De novo mutations in GFAP cause Alexander disease: clinical features, fMRI and functional analysis

2020 ◽  
Author(s):  
Xiaoxuan Song ◽  
Jingwen Jiang ◽  
Wotu Tian ◽  
Feixia Zhan ◽  
Zeyu Zhu ◽  
...  
Keyword(s):  
White Matter ◽  
Posterior Parietal Cortex ◽  
De Novo ◽  
Alexander Disease ◽  
Tail Domain ◽  
Wild Type ◽  
De Novo Mutations ◽  
Functional Studies ◽  
Bulbar Symptoms ◽  
Ubiquitin Proteasome

Abstract Background: Alexander disease (AxD) is a progressive and fatal neurological disorder characterized by white matter degeneration and Rosenthal fibers inclusions, which was caused by GFAP mutations. Since the first description of AxD, more than 550 cases have been reported. We identified two patients with de novo mutations in GFAP gene causing bulbospinal AxD, and further investigated the pathogenicity of identified variants. Results: Two de novo mutations in GFAP gene were identified (c.214G>A, p.E72K and c.1235C>T, p.T412I) by whole exome sequencing, of which c.1235C>T was the first reported. Clinical assessment revealed that both probands similarly presented bulbar symptoms, pyramidal signs and white matter atrophy in periventricular regions. We conducted a novel data-driven method to analyze fMRI characteristics. Increased brain functional connectivity in occipital and posterior parietal cortex was first discovered in AxD. Grey matter atrophy was also observed in one patient. Functional studies showed that the solubility of p.T412I GFAP was lower than wild type, while p.E72K and p.T412I were at a similar level to wild type, suggesting that mutations located in the tail domain could decrease the solubility of GFAP. Abnormal inclusions of mutant GFAP were colocalized with ubiquitin, 20S proteasome, protein 1 light chain 3-II (LC3-II) and lysosome. Western blotting indicated the ubiquitin-proteasome pathway was blocked while autophagy was activated as a mechanism for degrading aggregates. Conclusions: GFAP mutations identified in our study were associated with AxD and accompanied by protein functional alterations. Our findings further expand the clinical and genetic spectrum of AxD.

scholarly journals Evolutionary rescue in randomly mating, selfing, and clonal populations

2016 ◽  
Author(s):  
Hildegard Uecker
Keyword(s):  
Environmental Change ◽  
Random Mating ◽  
Diploid Species ◽  
Evolutionary Rescue ◽  
Before And After ◽  
Establishment Probability ◽  
Population Survival ◽  
Set Up ◽  
Mutant Homozygote ◽  
Allele Model

AbstractSevere environmental change can drive a population extinct unless the population adapts in time to the new conditions (“evolutionary rescue”). How does bi-parental sexual reproduction influence the chances of population persistence compared to clonal reproduction or selfing? In this paper, we set up a one-locus two-allele model for adaptation in diploid species, where rescue is contingent on the establishment of the mutant homozygote. Reproduction can occur by random mating, selfing, or clonally. Random mating generates and destroys the rescue mutant; selfing is efficient at generating it but at the same time depletes the heterozygote, which can lead to a low mutant frequency in the standing genetic variation and also affects the establishment probability of the mutation. Due to these antagonistic effects, we find a non-trivial dependence of population survival on the rate of sex/selfing, which is strongly affected by the dominance coefficient of the mutation before and after the environmental change. Importantly, since mating with the wildtype breaks the mutant homozygote up, a slow decay of the wildtype population size can impede rescue in randomly mating populations.

scholarly journals The effect of habitat choice on evolutionary rescue in subdivided populations

2021 ◽  
Author(s):  
Peter Czuppon ◽  
François Blanquart ◽  
Hildegard Uecker ◽  
Florence Débarre
Keyword(s):  
Habitat Choice ◽  
Evolutionary Rescue ◽  
Subdivided Populations

FLT3/Internal Tandem Duplication in Paired Presentation and Relapse Pediatric AML Samples.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 94-94
Author(s):  
Jacqueline Cloos ◽  
Christian M. Zwaan ◽  
Sophie L. Corthals ◽  
Bianca F. Goemans ◽  
Quinten Waisfisz ◽  
...  
Keyword(s):  
Median Time ◽  
De Novo ◽  
Pcr Amplification ◽  
Patient Characteristics ◽  
Initial Diagnosis ◽  
Time Interval ◽  
Wild Type ◽  
De Novo Mutations ◽  
First Relapse ◽  
Pediatric Aml

Abstract We have previously reported that FLT3 internal tandem duplications (FLT3/ITD) were detectable in 11.5% of 234 pediatric AML samples at initial diagnoses, and conferred a poor prognosis (Zwaan et al, Blood 2003). However, no data were available on relapsed pediatric AML and on paired initial-relapse samples. Currently we have studied genomic DNA of 99 relapsed and 42 paired initial-relapse pediatric AML samples for FLT3/ITD. Samples were obtained from the AML-BFM-SG, the Dutch Childhood Oncology Group, and by centers participating in the International BFM Relapsed AML 2001/01 study. Of the 99 relapsed patients the median age was 10.2 years and 71% were boys. Median time from diagnosis to first relapse was 14 months. Patient characteristics of the 42 pairs were at diagnosis: median age 7.7 years, sex 80% boys; at relapse: median age 14.3 years. Median time from diagnosis to first relapse was 14 months. ITDs were detected by PCR amplification including a fluorescent labeled primer. Fragments were separated by capillary electrophoresis on an ABI 3100 and analyzed using Genescan software. Of the 99 relapsed samples, 20 were ITD positive (20.2%), with ITDs varying in length from 18–129 bp. ITDs occurred in 15% of children <10 years of age, and in 21% ≥ 10 years (p=0.5). ITD pos. patients were boys in 84% vs. 68% in wild type (wt) patients (p=0.16). WBC, blast percentage and FAB-types were not different between ITD and wt patients. The time-interval between diagnosis and relapse was significantly shorter in ITD pos. patients (10 months) than in wt ones (15 months, p=0.003). Flt3/ITD in paired initial vs relapse samples of pediatric AML Relapse ITD pos Relapse wild type Total Initial ITD pos 6 (14%) 4 (10%) 10 (24%) Initial wild type 4 (10%) 28 (66%) 32 (76%) Total 10 (24%) 32 (76%) 42 (100%) Two of the 42 paired samples had 2 different length mutations at initial diagnosis and only 1 at relapse. Four acquired an ITD at relapse (one at 2nd relapse), which varied from 21–129 bp. FAB-types were: 1xM1, 2xM2, 1x M6. Median time to first relapse was only 6 months. Four patients (FAB-types were 2xM1 and 2xM2) lost the ITD, which at diagnosis varied from 30–72 bp and interestingly the median time to relapse was relatively long (median of 30 months). All ITDs were confirmed by sequencing and they were all located in exon 14. We conclude that: a) detectable FLT3/ITD is more frequent in the relapsed patients (±20%) compared to our previous study with patients at initial diagnosis (11.5%); b) patients with initially detectable FLT3/ITD relapse earlier than wt patients; c) there were no significant differences in clinical and cell-biological characteristics between wt and ITD patients at relapse d) gain and loss of ITDs at relapse does occur e) patients who gain an ITD seem to relapse early, patients who lose an ITD relapse relatively late. The changes in ITD status may reflect true de novo mutations or a selection of specific clones. In the latter case a small ITD positive subclone was not detected. We will further elucidate this with specific PCRs we are currently developing. These results have relevance for Flt3-targeted therapy and minimal disease monitoring.

scholarly journals Androgen Insensitivity Syndrome: Somatic Mosaicism of the Androgen Receptor in Seven Families and Consequences for Sex Assignment and Genetic Counseling

2005 ◽  
Vol 90 (1) ◽  
pp. 106-111 ◽  
Author(s):  
Birgit Köhler ◽  
Serge Lumbroso ◽  
Juliane Leger ◽  
Francoise Audran ◽  
Enric Sarret Grau ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Androgen Receptor ◽  
De Novo ◽  
Somatic Mosaicism ◽  
Androgen Insensitivity Syndrome ◽  
De Novo Mutation ◽  
Wild Type ◽  
De Novo Mutations ◽  
Androgen Insensitivity ◽  
Sex Assignment

Abstract Androgen insensitivity syndrome (AIS) is caused by numerous mutations of the androgen receptor (AR) gene. The phenotype may range from partial AIS (PAIS) with ambiguous genitalia to complete AIS (CAIS) with female genitalia. In 70% of the cases, AR mutations are transmitted in an X-linked recessive manner through the carrier mothers, but in 30%, the mutations arise de novo. When de novo mutations occur after the zygotic stage, they result in somatic mosaicisms, which are an important consideration for both virilization in later life—because both mutant and wild-type receptors are expressed—and genetic counseling. We report here six patients with AIS due to somatic mutations of the AR and one mother with somatic mosaicism who transmitted the mutation twice. Of the four patients with PAIS, three presented spontaneous or induced virilization at birth or puberty. These cases underline the crucial role of the remnant wild-type AR for virilization because the same mutations, when they are inherited, lead to CAIS. We also report two novel mutations of the AR, with somatic mosaicism, detected in patients with CAIS. Thus, the remnant wild-type receptor does not always lead to virilization. In one of these patients, a high ratio of wild-type to mutant AR expression was found in the gonads and genital skin fibroblasts. Although no prenatal virilization occurred, the possibility of virilization at puberty could not be excluded, and early gonadectomy was performed. A seventh patient had a CAIS with a novel germline AR mutation. The mutation was inherited from the mother, in whom mosaicism was detected in blood and who transmitted the mutation to a second, XX, offspring. The detection of somatic AR mutations is particularly important for the clinical management and genetic counseling of patients with AIS. Before definite sex assignment, a testosterone treatment trial should be performed in all patients with PAIS, but it becomes crucial when an AR mosaicism has been detected. In patients with CAIS or severe PAIS raised as female, there is no consensus about when (early childhood or puberty) gonadectomy should be performed. When somatic AR mutations are detected, however, gonadectomy should be performed earlier because of the risk of virilization during puberty. When a germline de novo mutation is identified in the index case, the risk of transmission to a second child due to a possible germ cell mosaicism in the mother cannot be excluded. However, given the high number of AR de novo mutations and the rarity of such reports, this risk appears to be very low.

Arabidopsis 4-COUMAROYL-COA LIGASE 8 contributes to the biosynthesis of the benzenoid ring of coenzyme Q in peroxisomes

2019 ◽  
Vol 476 (22) ◽  
pp. 3521-3532
Author(s):  
Eric Soubeyrand ◽  
Megan Kelly ◽  
Shea A. Keene ◽  
Ann C. Bernert ◽  
Scott Latimer ◽  
...  
Keyword(s):  
Oxidative Metabolism ◽  
Time Course ◽  
Reverse Genetics ◽  
De Novo ◽  
Coenzyme Q ◽  
Control Level ◽  
Wild Type ◽  
Fluorescent Reporters ◽  
Coa Ligase ◽  
Peroxisomal Targeting

Plants have evolved the ability to derive the benzenoid moiety of the respiratory cofactor and antioxidant, ubiquinone (coenzyme Q), either from the β-oxidative metabolism of p-coumarate or from the peroxidative cleavage of kaempferol. Here, isotopic feeding assays, gene co-expression analysis and reverse genetics identified Arabidopsis 4-COUMARATE-COA LIGASE 8 (4-CL8; At5g38120) as a contributor to the β-oxidation of p-coumarate for ubiquinone biosynthesis. The enzyme is part of the same clade (V) of acyl-activating enzymes than At4g19010, a p-coumarate CoA ligase known to play a central role in the conversion of p-coumarate into 4-hydroxybenzoate. A 4-cl8 T-DNA knockout displayed a 20% decrease in ubiquinone content compared with wild-type plants, while 4-CL8 overexpression boosted ubiquinone content up to 150% of the control level. Similarly, the isotopic enrichment of ubiquinone's ring was decreased by 28% in the 4-cl8 knockout as compared with wild-type controls when Phe-[Ring-13C6] was fed to the plants. This metabolic blockage could be bypassed via the exogenous supply of 4-hydroxybenzoate, the product of p-coumarate β-oxidation. Arabidopsis 4-CL8 displays a canonical peroxisomal targeting sequence type 1, and confocal microscopy experiments using fused fluorescent reporters demonstrated that this enzyme is imported into peroxisomes. Time course feeding assays using Phe-[Ring-13C6] in a series of Arabidopsis single and double knockouts blocked in the β-oxidative metabolism of p-coumarate (4-cl8; at4g19010; at4g19010 × 4-cl8), flavonol biosynthesis (flavanone-3-hydroxylase), or both (at4g19010 × flavanone-3-hydroxylase) indicated that continuous high light treatments (500 µE m−2 s−1; 24 h) markedly stimulated the de novo biosynthesis of ubiquinone independently of kaempferol catabolism.

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