Balancing selection is a form of natural selection maintaining diversity at the sites it targets and at linked nucleotide sites. Due to selection favoring heterozygosity, it has the potential to facilitate the accumulation of a "sheltered" load of tightly linked recessive deleterious mutations. However, precisely evaluating the extent of these effects has remained challenging. Taking advantage of plant self-incompatibility as one of the best-understood examples of long-term balancing selection, we provide a highly resolved picture of the genomic extent of balancing selection on the sheltered genetic load. We used targeted genome resequencing to reveal polymorphism of the genomic region flanking the self-incompatibility locus in three sample sets in each of the two closely related plant species Arabidopsis halleri and Arabidopsis lyrata, and used 100 control regions from throughout the genome to factor out differences in demographic histories and/or sample structure. Nucleotide polymorphism increased strongly around the S-locus in all sample sets, but only over a limited genomic region, as it became indistinguishable from the genomic background beyond the first 25-30 kb. Genes in this chromosomal interval exhibited no excess of mutations at 0-fold degenerated sites relative to putatively neutral sites, hence revealing no detectable weakening of the efficacy of purifying selection even for these most tightly linked genes. Overall, our results are consistent with the predictions of a narrow genomic influence of linkage to the S-locus and clarify how natural selection in one genomic region affects the evolution of the adjacent genomic regions.

• Klíčová slova
• Arabidopsis, S-locus, balancing selection, deleterious mutations, linked selection, self-incompatibility, sheltered genetic load,
• MeSH
• Arabidopsis * genetika   MeSH
• genetická zátěž MeSH
• nukleotidy MeSH
• polymorfismus genetický MeSH
• selekce (genetika) MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nukleotidy MeSH

To uncover the selective forces shaping life-history trait evolution across species, we investigate the genomic basis underlying adaptations to seasonal habitat desiccation in African killifishes, identifying the genetic variants associated with positive and relaxed purifying selection in 45 killifish species and 231 wild individuals distributed throughout sub-Saharan Africa. In annual species, genetic drift led to the expansion of nuclear and mitochondrial genomes and caused the accumulation of deleterious genetic variants in key life-history modulating genes such as mtor, insr, ampk, foxo3, and polg. Relaxation of purifying selection is also significantly associated with mitochondrial function and aging in human populations. We find that relaxation of purifying selection prominently shapes genomes and is a prime candidate force molding the evolution of lifespan and the distribution of genetic variants associated with late-onset diseases in different species. VIDEO ABSTRACT.

• Klíčová slova
• aging, distribution of fitness effects, genome evolution, human genetics, killifishes, life history, lifespan, mitochondrial dysfunction, mutation rate, neutral evolution,
• MeSH
• Cyprinodontidae klasifikace   genetika   MeSH
• dlouhověkost * MeSH
• frekvence genu MeSH
• fylogeneze MeSH
• fylogeografie MeSH
• genom mitochondriální MeSH
• mitochondrie genetika   metabolismus   MeSH
• molekulární evoluce MeSH
• mutace MeSH
• replikace DNA MeSH
• selekce (genetika) * MeSH
• stárnutí MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Colorectal cancer incidence rates vary geographically and have changed over time1. Notably, in the past two decades, the incidence of early-onset colorectal cancer, affecting individuals under the age of 50 years, has doubled in many countries2-5. The reasons for this increase are unknown. Here, we investigate whether mutational processes contribute to geographic and age-related differences by examining 981 colorectal cancer genomes from 11 countries. No major differences were found in microsatellite unstable cancers, but variations in mutation burden and signatures were observed in the 802 microsatellite-stable cases. Multiple signatures, most with unknown etiologies, exhibited varying prevalence in Argentina, Brazil, Colombia, Russia, and Thailand, indicating geographically diverse levels of mutagenic exposure. Signatures SBS88 and ID18, caused by the bacteria-produced mutagen colibactin6,7, had higher mutation loads in countries with higher colorectal cancer incidence rates. SBS88 and ID18 were also enriched in early-onset colorectal cancers, being 3.3 times more common in individuals diagnosed before age 40 than in those over 70, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 responsible for about 25% of APC driver indels in colibactin-positive cases. This study reveals geographic and age-related variations in colorectal cancer mutational processes, and suggests that early-life mutagenic exposure to colibactin-producing bacteria may contribute to the rising incidence of early-onset colorectal cancer.

• Publikační typ
• časopisecké články MeSH

Colorectal cancer incidence rates vary geographically and have changed over time. Notably, in the past two decades, the incidence of early-onset colorectal cancer, affecting individuals under the age of 50 years, has doubled in many countries. The reasons for this increase are unknown. Here, we investigate whether mutational processes contribute to geographic and age-related differences by examining 981 colorectal cancer genomes from 11 countries. No major differences were found in microsatellite unstable cancers, but variations in mutation burden and signatures were observed in the 802 microsatellite-stable cases. Multiple signatures, most with unknown etiologies, exhibited varying prevalence in Argentina, Brazil, Colombia, Russia, and Thailand, indicating geographically diverse levels of mutagenic exposure. Signatures SBS88 and ID18, caused by the bacteria-produced mutagen colibactin, had higher mutation loads in countries with higher colorectal cancer incidence rates. SBS88 and ID18 were also enriched in early-onset colorectal cancers, being 3.3 times more common in individuals diagnosed before age 40 than in those over 70, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 responsible for about 25% of APC driver indels in colibactin-positive cases. This study reveals geographic and age-related variations in colorectal cancer mutational processes, and suggests that early-life mutagenic exposure to colibactin-producing bacteria may contribute to the rising incidence of early-onset colorectal cancer.

• Publikační typ
• časopisecké články MeSH
• preprinty MeSH

Inheritance and expression of mitochondrial DNA (mtDNA) mutations are crucial for the pathogenesis of Leber hereditary optic neuropathy (LHON). We have investigated the segregation and functional consequences of G3460A mtDNA mutation in 27 members of a three-generation family with LHON syndrome. Specific activity of respiratory chain complex I in platelets was reduced in average to 56%, but no direct correlation between the mutation load and its biochemical expression was found. Heteroplasmy in blood, platelets and hair follicles varied from 7% to 100%. Segregation pattern exhibited tissue specificity and influence of different nuclear backgrounds in four branches of the pedigree. Longitudinal analysis revealed a significant (p=0.02) decrease in blood mutation load. Although enzyme assay showed reduction of complex I activity, our results give additional support to the hypothesis that expression of LHON mutation depends on complex nuclear-mitochondrial interaction.

• MeSH
• alanin genetika   MeSH
• analýza rozptylu MeSH
• bodová mutace * MeSH
• glycin genetika   MeSH
• Leberova atrofie zrakového nervu krev   genetika   MeSH
• lidé MeSH
• longitudinální studie MeSH
• mitochondriální DNA krev   genetika   MeSH
• mutační analýza DNA metody   MeSH
• NAD krev   MeSH
• oxidoreduktasy krev   MeSH
• rodokmen MeSH
• rotenon MeSH
• zdraví rodiny * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• alanin MeSH
• glycin MeSH
• mitochondriální DNA MeSH
• NAD MeSH
• oxidoreduktasy MeSH
• rotenon MeSH

Despite its inherent costs, sexual reproduction is ubiquitous in nature, and the mechanisms to protect it from a competitive displacement by asexuality remain unclear. Popular mutation-based explanations, like the Muller's ratchet and the Kondrashov's hatchet, assume that purifying selection may not halt the accumulation of deleterious mutations in the nonrecombining genomes, ultimately leading to their degeneration. However, empirical evidence is scarce and it remains particularly unclear whether mutational degradation proceeds fast enough to ensure the decay of clonal organisms and to prevent them from outcompeting their sexual counterparts. To test this hypothesis, we jointly analysed the exome sequences and the fitness-related phenotypic traits of the sexually reproducing fish species and their clonal hybrids, whose evolutionary ages ranged from F1 generations to 300 ky. As expected, mutations tended to accumulate in the clonal genomes in a time-dependent manner. However, contrary to the predictions, we found no trend towards increased nonsynonymity of mutations acquired by clones, nor higher radicality of their amino acid substitutions. Moreover, there was no evidence for fitness degeneration in the old clones compared with that in the younger ones. In summary, although an efficacy of purifying selection may still be reduced in the asexual genomes, our data indicate that its efficiency is not drastically decreased. Even the oldest investigated clone was found to be too young to suffer fitness consequences from a mutation accumulation. This suggests that mechanisms other than mutation accumulation may be needed to explain the competitive advantage of sex in the short term.

• Klíčová slova
• Muller’s ratchet, asexuality, clonal decay, exome capture, fitness, mutation load,
• MeSH
• biologická evoluce * MeSH
• emoce MeSH
• genom MeSH
• modely genetické MeSH
• mutace MeSH
• nepohlavní rozmnožování genetika   MeSH
• rozmnožování * genetika   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Peptide-based anticancer vaccination aims at stimulating an immune response against one or multiple tumor-associated antigens (TAAs) following immunization with purified, recombinant or synthetically engineered epitopes. Despite high expectations, the peptide-based vaccines that have been explored in the clinic so far had limited therapeutic activity, largely due to cancer cell-intrinsic alterations that minimize antigenicity and/or changes in the tumor microenvironment that foster immunosuppression. Several strategies have been developed to overcome such limitations, including the use of immunostimulatory adjuvants, the co-treatment with cytotoxic anticancer therapies that enable the coordinated release of damage-associated molecular patterns, and the concomitant blockade of immune checkpoints. Personalized peptide-based vaccines are also being explored for therapeutic activity in the clinic. Here, we review recent preclinical and clinical progress in the use of peptide-based vaccines as anticancer therapeutics.Abbreviations: CMP: carbohydrate-mimetic peptide; CMV: cytomegalovirus; DC: dendritic cell; FDA: Food and Drug Administration; HPV: human papillomavirus; MDS: myelodysplastic syndrome; MHP: melanoma helper vaccine; NSCLC: non-small cell lung carcinoma; ODD: orphan drug designation; PPV: personalized peptide vaccination; SLP: synthetic long peptide; TAA: tumor-associated antigen; TNA: tumor neoantigen.

• Klíčová slova
• CAR T cells, MAGEA3, NY-ESO-1, immune checkpoint blockers, mutational load, synthetic long peptides, tumor neoantigens,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

The presented case displays a clinical study of a cancer phenotype with a poor clinical outcome. Prediction of cancer development and effects of treatment at the beginning of the clinical stage is difficult as the knowledge of cancer process and all necessary parameters of the host body are limited. Cancer is mainly studied on the basis of biochemical-genetic processes and their morphological manifestation. However, the malignant process is assumed to be of essential biophysical nature and develops after mitochondrial dysfunction, which is a direct result of oncogene mutation. Cancers based on the normal and the reverse Warburg effect should be distinguished. The cancer tumors with the reverse Warburg effect display aggressiveness associated with a high rate of recurrence and metastatic implantation. Besides the nature of the two basic types of breast cancer tumors the outcome depends not only on their type, size, and site but also on reactions and interaction with the surrounding tissue and the body aptitude for metastatic activity connected with individual blood or lymphatic vessels for metastatic transport. It is necessary to assess all favourable and adverse factors for cancer development. General reliable method of their specification for all cancers is not available. Nevertheless, the main factor seems to be aggressiveness of cancer cells as follows from interpretation. To reveal the aggressive reverse Warburg effect tumors, metabolic biomarkers of the fibroblast stress should be examined.

• MeSH
• duktální karcinom prsu patologie   terapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu patologie   terapie   MeSH
• prognóza MeSH
• tumor burden * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

During the last few decades, the treatment of HIV-infected patients by highly active antiretroviral therapy, including protease inhibitors (PIs), has become standard. Here, we present results of analysis of a patient-derived, multiresistant HIV-1 CRF02_AG recombinant strain with a highly mutated protease (PR) coding sequence, where up to 19 coding mutations have accumulated in the PR. The results of biochemical analysis in vitro showed that the patient-derived PR is highly resistant to most of the currently used PIs and that it also exhibits very poor catalytic activity. Determination of the crystal structure revealed prominent changes in the flap elbow region and S1/S1' active site subsites. While viral loads in the patient were found to be high, the insertion of the patient-derived PR into a HIV-1 subtype B backbone resulted in reduction of infectivity by 3 orders of magnitude. Fitness compensation was not achieved by elevated polymerase (Pol) expression, but the introduction of patient-derived gag and pol sequences in a CRF02_AG backbone rescued viral infectivity to near wild-type (wt) levels. The mutations that accumulated in the vicinity of the processing sites spanning the p2/NC, NC/p1, and p6pol/PR proteins lead to much more efficient hydrolysis of corresponding peptides by patient-derived PR in comparison to the wt enzyme. This indicates a very efficient coevolution of enzyme and substrate maintaining high viral loads in vivo under constant drug pressure.

• MeSH
• buněčné linie MeSH
• genové produkty gag - virus lidské imunodeficience genetika   MeSH
• genové produkty pol - virus lidské imunodeficience genetika   MeSH
• geny gag MeSH
• geny pol MeSH
• HEK293 buňky MeSH
• HIV infekce farmakoterapie   virologie   MeSH
• HIV-1 genetika   izolace a purifikace   fyziologie   MeSH
• HIV-proteasa chemie   genetika   metabolismus   MeSH
• inhibitory HIV-proteasy terapeutické užití   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• mutace MeSH
• peptidové fragmenty genetika   MeSH
• virová léková rezistence genetika   MeSH
• virová nálož MeSH
• vysoce aktivní antiretrovirová terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• gag protein p1, Human immunodeficiency virus MeSH Prohlížeč
• genové produkty gag - virus lidské imunodeficience MeSH
• genové produkty pol - virus lidské imunodeficience MeSH
• HIV-proteasa MeSH
• inhibitory HIV-proteasy MeSH
• p2 gag peptide, Human immunodeficiency virus 1 MeSH Prohlížeč
• peptidové fragmenty MeSH

BACKGROUND: The most frequent manifestations of heteroplasmic mitochondrial DNA (mtDNA) mutation 8993 T > G are Leigh syndrome or NARP syndrome (Neurogenic Muscle Weakness, Ataxia, and Retinitis Pigmentosa). The authors describe heterogeneity of clinical symptoms and results of biochemical and molecular analyses in seven severely clinically affected children from two unrelated families with heteroplasmic mtDNA mutation 8993 T > G. METHODS AND RESULTS: Seven clinically affected children from two unrelated families were born in term after an uneventful pregnancy. The failure to thrive, psychomotor retardation, hypotonic or spastic quadruparesis, hypertrophic cardiomyopathy, hepatopathy and hyperlactacidaemia developed after birth. Five children died in the first year of life during acute respiratory infection, one girl died at the age of 3 months with sudden death syndrome, only one boy with spastic quadruparesis and severe psychomotor retardation survived to the age of 8 years. Molecular analyses in all investigated children and their clinically non-affected mothers revealed the presence of heteroplasmic mtDNA mutation 8993 T > G. Mutated copies of mtDNA molecules in maternal tissues were in the range of 15-22%. The mutation load in all analysed children's tissues was higher than 90%. CONCLUSIONS: A broad spectrum of clinical symptoms may be observed in families with heteroplasmic mtDNA mutations 8993 T > G. Affected children with a mutation load higher than 90% usually do not survive after infancy. In both investigated families, a profound increase in the levels of heteroplasmy of mtDNA mutation 8993 T > G was observed in two subsequent generations.

• MeSH
• ataxie genetika   MeSH
• bodová mutace * MeSH
• dítě MeSH
• kojenec MeSH
• Leighova nemoc genetika   MeSH
• lidé MeSH
• mitochondriální DNA genetika   MeSH
• retinopathia pigmentosa genetika   MeSH
• svalová slabost genetika   MeSH
• syndrom MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• mitochondriální DNA MeSH