Restricted range size brings about noteworthy genetic consequences that may affect the viability of a population and eventually its extinction. Particularly, the question if an increase in inbreeding can avert the accumulation of genetic load via purging is hotly debated in the conservation genetic field. Insular populations with limited range sizes represent an ideal setup for relating range size to these genetic factors. Leveraging a set of eight differently sized populations of Galápagos mockingbirds (Mimus), we investigated how island size shaped effective population size (Ne), inbreeding and genetic load. We assembled a genome of M. melanotis and genotyped three individuals per population by whole-genome resequencing. Demographic inference showed that the Ne of most populations remained high after the colonisation of the archipelago 1-2 Mya. Ne decline in M. parvulus happened only 10-20 Kya, whereas the critically endangered M. trifasciatus showed a longer history of reduced Ne. Despite these historical fluctuations, the current island size determines Ne in a linear fashion. In contrast, significant inbreeding coefficients, derived from runs of homozygosity, were identified only in the four smallest populations. The index of additive genetic load suggested purging in M. parvulus, where the smallest populations showed the lowest load. By contrast, M. trifasciatus carried the highest genetic load, possibly due to a recent rapid bottleneck. Overall, our study demonstrates a complex effect of demography on inbreeding and genetic load, providing implications in conservation genetics in general and in a conservation project of M. trifasciatus in particular.

• Klíčová slova
• conservation genetics, demographic inference, genetic diversity, genetic load,
• MeSH
• genetická zátěž * MeSH
• genom * MeSH
• genotyp MeSH
• hustota populace MeSH
• inbreeding * MeSH
• ostrovy MeSH
• Passeriformes * genetika   MeSH
• populační genetika * MeSH
• zachování přírodních zdrojů MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Ekvádor MeSH
• ostrovy MeSH

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

Leishmaniasis is a serious health problem in many countries, and continues expanding to new geographic areas including Europe and USA. This disease, caused by parasites of Leishmania spp. and transmitted by phlebotomine sand flies, causes up to 1.3 million new cases each year and despite efforts toward its functional dissection and treatment it causes 20-50 thousands deaths annually. Dependence of susceptibility to leishmaniasis on sex and host's genes was observed in humans and in mouse models. Several laboratories defined in mice a number of Lmr (Leishmania major response) genetic loci that control functional and pathological components of the response to and outcome of L. major infection. However, the development of its most aggressive form, visceral leishmaniasis, which is lethal if untreated, is not yet understood. Visceral leishmaniasis is caused by infection and inflammation of internal organs. Therefore, we analyzed the genetics of parasite load, spread to internal organs, and ensuing visceral pathology. Using a new PCR-based method of quantification of parasites in tissues we describe a network-like set of interacting genetic loci that control parasite load in different organs. Quantification of Leishmania parasites in lymph nodes, spleen and liver from infected F2 hybrids between BALB/c and recombinant congenic strains CcS-9 and CcS-16 allowed us to map two novel parasite load controlling Leishmania major response loci, Lmr24 and Lmr27. We also detected parasite-controlling role of the previously described loci Lmr4, Lmr11, Lmr13, Lmr14, Lmr15, and Lmr25, and describe 8 genetic interactions between them. Lmr14, Lmr15, Lmr25, and Lmr27 controlled parasite load in liver and lymph nodes. In addition, Leishmania burden in lymph nodes but not liver was influenced by Lmr4 and Lmr24. In spleen, parasite load was controlled by Lmr11 and Lmr13. We detected a strong effect of sex on some of these genes. We also mapped additional genes controlling splenomegaly and hepatomegaly. This resulted in a systematized insight into genetic control of spread and load of Leishmania parasites and visceral pathology in the mammalian organism.

• Klíčová slova
• Leishmania major, PCR-ELISA, QTL, mouse model, parasite load, sex influence, susceptibility to Infection, visceral leishmaniasis,
• MeSH
• interakce hostitele a parazita MeSH
• Leishmania major * MeSH
• leishmanióza viscerální genetika   parazitologie   MeSH
• myši MeSH
• parazitární zátěž * MeSH
• pohlavní dimorfismus MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem 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

OBJECTIVE: The aim of this work is to summarize the current knowledge about preimplantation genetic screening and diagnostics. DESIGN: A review article. SETTING: Department of Gynecology and Obstetrics, District Hospital Šternberk, IVF Clinic, Olomouc. RESULTS: Preimplantation genetic testing is a complex of genetic and molecular cytogenetic examinations, which can help to detect abnormalities in embryos before transfer into the uterus of the mother. These specialized examinations are based on the latest findings in genetics and assisted reproduction. The preimplantation genetic testing is necessarily associated with a method of in vitro fertilization. It is performed on isolated blastomeres on the third day of embryo cultivation. Nowadays, it is preferred trophectoderm examination of cells from the five-day blastocysts. Generally speaking, after preimplantation genetic testing, we can select only embryos without genetic load to transfer into uterus. CONCLUSION: Preimplantation genetic testing is an important part of treatment of infertility. Complex diagnostics and treatment of infertile couples are increasingly influenced by the development and use of advanced genomic technologies. Further development and application of these modern methods require close cooperation between the field of assisted reproduction and clinical genetics.

• Klíčová slova
• FISH, PGD, PGS, aCGH, fluorescence in situ hybridization, karyomapping NGS., preimplantation genetic diagnosis, preimplantation genetic screening,
• MeSH
• genetické testování * MeSH
• lidé MeSH
• preimplantační diagnóza * MeSH
• těhotenství MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Epigenetic changes are generally based on the switching of alternative functional or structural states and result in the adaptation of cellular expression patterns during proliferation, differentiation or plastic changes in the adult organism, whereas some epigenetic information can be passed on other generations while other is not. Hence, the principal question is: why is some information reset or resolved during the meiosis process and other is passed from one generation to another, or, in other words: what "adaptation trigger" level initiates transgenerationally transmitted epigenome change? Hereto, we propose a theory which states that stress, or, more specifically, the energy cost of an individual's adaptation to stress, represents a viable candidate for the transgenerational transmission trigger of a given acquired trait. It has been reported recently that the higher lifetime entropy generation of a unit's body mass, the higher the entropy stress level (which is a measure of energy released by a unit's organ mass) and the irreversibility within the organ, resulting in faster organ degradation and consequent health problems for the entire biological system. We therefore suggest a new term: "stress entropic load" will reflect the actual energetic cost of an individual's adaptation and may be used to estimate the probability of inducing transgenerational response once characterized or measured.

• MeSH
• entropie MeSH
• epigeneze genetická * MeSH
• fyziologický stres * MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Apolipoprotein A-V plays an important role in the determination of plasma triglyceride (TG) concentration. We aimed to determine whether polymorphisms -1131T>C (rs662799) and 56C>G (rs3135506) of the APOA5 gene have an impact on the course of postprandial lipemia induced by a fat load and a fat load with added glucose. Thirty healthy male volunteers, seven heterozygous for the -1131C variant and three for the 56G variant (HT) carriers, and 20 wild-type (WT) carriers underwent two 8-hour tests of postprandial lipemia - one after an experimental breakfast consisting of 75 g of fat and second after a breakfast consisting of 75 g of fat and 25 g of glucose. HT carriers had a higher postprandial response after fat load than WT carriers (AUC TG: 14.01+/-4.27 vs. 9.84+/-3.32 mmol*h/l, respectively, p=0.016). Glucose added to the test meal suppressed such a difference. Heterozygous carriers of the variants of APOA5 (-1131C and 56G) display more pronounced postprandial lipemia after pure fat load than WT carriers. This statistically significant difference disappears when glucose is added to a fat load, suggesting that meal composition modulates the effect of these polymorphisms on the magnitude of postprandial lipemia.

• MeSH
• apolipoprotein A-V genetika   MeSH
• dietní cukry aplikace a dávkování   MeSH
• dietní tuky aplikace a dávkování   MeSH
• dospělí MeSH
• genetická variace genetika   MeSH
• glukosa aplikace a dávkování   MeSH
• heterozygot MeSH
• lidé MeSH
• postprandiální období fyziologie   MeSH
• triglyceridy krev   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• APOA5 protein, human MeSH Prohlížeč
• apolipoprotein A-V MeSH
• dietní cukry MeSH
• dietní tuky MeSH
• glukosa MeSH
• triglyceridy MeSH

BACKGROUND: PNPLA3 rs738409 minor allele c.444G represents a risk factor for liver steatosis and fibrosis progression also in chronic hepatitis C (HCV). We investigated its impact on the timing of liver transplantation (LT) in patients with genotype 1b HCV cirrhosis. METHODS: We genotyped and evaluated 172 LT candidates with liver cirrhosis owing to chronic HCV infection, genotype 1b. One hundred patients needed LT for chronic liver failure (CLF) and 72 for a small hepatocellular carcinoma (HCC) in the cirrhotic liver without CLF. Population controls (n = 647) were selected from the Czech cross-sectional study MONICA. RESULTS: The CLF patients were younger (53.5 ± 7.2 vs. 59.6 ± 6.6, P < 0.001) with more advanced liver disease than HCC patients (Child-Pugh's score 9.1 ± 1.8 vs. 7.1 ± 1.9, P < 0.001, MELD 14.1 ± 3.9 vs. 11.1 ± 3.7, P < 0.001). PNPLA3 G allele increased the risk of LT for CLF in both allelic and recessive models (CG + GG vs. CC: OR, 1.90; 95% CI, 1.017-3.472, P = 0.045 and GG vs. CC + CG: OR, 2.94; 95% CI, 1.032-7.513, P = 0.042). Multivariate analysis identified younger age (P < 0.001) and the G allele (P < 0.05) as risk factors for CLF. The genotype frequencies between the CLF group and MONICA study significantly differed in both, allelic and recessive model (P = 0.004, OR 1.87, 95% CI 1.222-2.875; P < 0.001, OR 3.33, 95% CI 1.824-6.084, respectively). The OR values almost doubled in the recessive model compared with the allelic model suggesting the additive effect of allele G. In contrast, genotype frequencies in the HCC group were similar to the MONICA study in both models. Pretransplant viral load was significantly lower in GG than in CC + CG genotypes (median, IQR; 162,500 (61,550-319,000) IU/ml vs. 570,000 (172,000-1,595,000) IU/ml, P < 0.0009). CONCLUSIONS: Our results suggest that PNPLA3 rs738409 G allele carriage may be associated with a faster progression of HCV cirrhosis to chronic liver failure.

• MeSH
• alely MeSH
• chronická hepatitida C genetika   virologie   MeSH
• genetická predispozice k nemoci genetika   MeSH
• genotyp MeSH
• hepatocelulární karcinom genetika   virologie   MeSH
• jaterní cirhóza genetika   virologie   MeSH
• játra virologie   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipasa genetika   MeSH
• membránové proteiny genetika   MeSH
• nádory jater genetika   virologie   MeSH
• průřezové studie MeSH
• retrospektivní studie MeSH
• selhání jater genetika   virologie   MeSH
• studie případů a kontrol MeSH
• transplantace jater metody   MeSH
• virová nálož metody   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adiponutrin, human MeSH Prohlížeč
• lipasa MeSH
• membránové proteiny MeSH

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066-11G>A (IVS10-11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066-11G>A];[1066-11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.

• Klíčová slova
• BH4, PAH deficiency, PKU, hyperphenylalaninemia, phenylalanine, tetrahydrobiopterin,
• MeSH
• alely MeSH
• biopteriny analogy a deriváty   genetika   MeSH
• fenotyp MeSH
• fenylalanin krev   MeSH
• fenylalaninhydroxylasa genetika   MeSH
• fenylketonurie krev   epidemiologie   genetika   MeSH
• frekvence genu genetika   MeSH
• genetická predispozice k nemoci genetika   MeSH
• genetické asociační studie metody   MeSH
• genotyp MeSH
• homozygot MeSH
• lidé MeSH
• mutace genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• biopteriny MeSH
• fenylalanin MeSH
• fenylalaninhydroxylasa MeSH
• sapropterin MeSH Prohlížeč

BACKGROUND: Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking behaviors and DNA repair genes, but further work is required to identify susceptibility variants. METHODS: To identify LC susceptibility loci, a family history-based genome-wide association by proxy (GWAx) of LC (48 843 European proxy LC patients, 195 387 controls) was combined with a previous LC GWAS (29 266 patients, 56 450 controls) by meta-analysis. Colocalization was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic risk scores (PRS) were tested within an independent validation cohort (1 666 LC patients vs 6 664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumor resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided. RESULTS: The GWAx-GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1), and smoking propensity genes (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as subgenome-wide significant variants related to expression quantitative trait loci and/or smoking propensity, assisted in LC genetic risk prediction (odds ratio = 1.37, 95% confidence interval = 1.29 to 1.45; P < .001). Patients with higher genetic PRS loads of smoking-related variants tended to have higher mutation burdens in their lung tumors. CONCLUSIONS: This study has expanded the number of LC susceptibility loci and provided insights into the molecular mechanisms by which these susceptibility variants contribute to LC development.

• MeSH
• celogenomová asociační studie * MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• mutace MeSH
• nádory plic * epidemiologie   genetika   patologie   MeSH
• zárodečné buňky patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH