Rhesus factor polymorphism has been an evolutionary enigma since its discovery in 1939. Carriers of the rarer allele should be eliminated by selection against Rhesus positive children born to Rhesus negative mothers. Here I used an ecologic regression study to test the hypothesis that Rhesus factor polymorphism is stabilized by heterozygote advantage. The study was performed in 65 countries for which the frequencies of RhD phenotypes and specific disease burden data were available. I performed multiple multivariate covariance analysis with five potential confounding variables: GDP, latitude (distance from the equator), humidity, medical care expenditure per capita and frequencies of smokers. The results showed that the burden associated with many diseases correlated with the frequencies of particular Rhesus genotypes in a country and that the direction of the relation was nearly always the opposite for the frequency of Rhesus negative homozygotes and that of Rhesus positive heterozygotes. On the population level, a Rhesus-negativity-associated burden could be compensated for by the heterozygote advantage, but for Rhesus negative subjects this burden represents a serious problem.

• MeSH
• dítě MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• genotyp MeSH
• heterozygot MeSH
• homozygot MeSH
• krevní skupiny - systém Rh-Hr genetika   MeSH
• lidé MeSH
• míra přežití MeSH
• polymorfismus genetický * MeSH
• regresní analýza MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.

• MeSH
• detekce genetických nosičů MeSH
• dospělí MeSH
• efekt zakladatele * MeSH
• haplotypy MeSH
• jaderné proteiny genetika   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace * MeSH
• oprava DNA MeSH
• poškození DNA MeSH
• proteiny buněčného cyklu genetika   MeSH
• rozmnožování genetika   MeSH
• syndrom Nijmegen breakage etnologie   genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Slovenská republika MeSH

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086-96. ©2018 AACR.

• MeSH
• celogenomová asociační studie metody   MeSH
• genetická heterogenita MeSH
• heterozygot MeSH
• lidé MeSH
• MHC antigeny I. třídy genetika   MeSH
• MHC antigeny II. třídy genetika   MeSH
• nehodgkinský lymfom genetika   MeSH
• prospektivní studie MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH

Syndromy chromosomální instability (SCI) jsou autosomálně recesivně dědičné poruchy reparace změn DNA, a proto vysoce citlivé k mutagenním vlivům, zejména ionizaci a chemikáliím.(1, 2) Enzymatická porucha na úrovni DNA se manifestuje multisystémovým postižením. Individuální incidence jednotlivých afekcí jsou nízké – Louis-Barové syndrom ataxia telangiectasia 1 : 30 000–40 000, Nijmegen breakage syndrom 1 : 70 000, Fanconiho anémie 1 : 250 000 s výjimkou malarických oblastí Afriky, kde v důsledku selekční výhody heterozygotů (tj. přenašečů) je incidence 1 : 22 000, deficience ligázy I 1 : 1 milión, deficience ligázy IV 1 : 1 milión, Bloomův syndrom 1 : 2 milióny s výjimkou až desetkrát vyšší incidence v Ashkenazi-židovské a japonské populaci z neznámých příčin, xeroderma pigmentosum 1 : 3 milióny, Wernerův syndrom 1 : 5 miliónů. Společnými klinickými příznaky SCI jsou prenatální a postnatální růstová retardace, humorální i celulární imunodeficience, opakované infekty, zvláště respirační, poruchy pohlavního zrání a fertility, známky předčasného stárnutí a vysoké riziko lymforetikulárních malignit v dětství a solidních nádorů bez predilekce v dospělosti. Společným laboratorním příznakem je genomová instabilita, zvýšená spontánní lomivost chromatid, chromosomů, hypersenzitivita k mutagenním vlivům manifestovaná zvýšením chromosomální instability po expozici buněk. Význam syndromů chromosomální instability představuje nutnost respektovat hypersenzitivitu k mutagenům, a tedy ochranu homozygotů i heterozygotů před stykem s mutageny. Omezí se a oddálí manifestace malignity. Zohlednění hypersenzitivity je nezbytné při volbě léčby malignity. Incidence homozygotů SCI je nízká, avšak heterozygoti SCI představují téměř 3 % populace s vysokým rizikem manifestace malignit od středního věku, které je účinně ovlivnitelné respektováním ochranného režimu (omezením styku s mutageny, dostatečným přívodem antioxidantů, nejlépe v potravě, a kontrolou účinnosti ochranného režimu sledováním míry hladiny chromosomální instability). V naší republice je dosud dostupná molekulárněgenetická přímá diagnostika mutací ATM genu a NBN genu pro Louis-Barové a Nijmegen breakage syndrom. Pro DNA diagnostiku ostatních vzácně se vyskytujících SCI je zatím nutné se obracet na zahraniční referenční centra. Včasná diagnostika SCI je nezbytná pro efektivitu ochranného režimu k prevenci maligních procesů u homozygotů i heterozygotů. Práce uvádí přehled fenotypů jednotlivých SCI s důrazem na signální příznaky, které by měly vést k diagnóze SCI.

Syndromes of chromosomal instability (SCI) are autosomal recessive DNA repair disorders characterized by hypersensitivity to the mutagenic effects particularly to the ionisation and chemical agents. Individual incidence of SCI is rare, Louis-Bar syndrome of ataxia telangiectasia 1 : 30 000–40 000, Nijmegen breakage syndrome 1 : 70 000, Fanconi anemia 1 : 250 000 except of regions with malaria in Africa due to selective advantage of heterozytes, where is incidence so high as 1 : 22 000, Ligase I deficienty 1 : 1 milion, ligase IV deficiente 1 : 1 milion, Bloom syndrome 1 : 2 milion excerpt of Jewish and Japan population with ten times higher incidence of unknown reason, xeroderma pigmentosum 1 : 3 milions and Werner syndrome 1 : 5 milions. Common clinical symptomes of SCI are prenatal as well as postnatal growth retardation, cellular and humoral immunodeficiency with frequent infections particularly of respiratory tract, disturbance of sexual development and fertility, presenility, high risk of lymphoreticular malignancy in childhood and solid tumors without predilection in adulhood. Laboratory findings are increased genome instability, increased chromosomal breaks, hypersensitivity to mutagenit agents which is manifested in increased breakage and chromosomal rearrangements. The evoidance of ionisation and chemical mutagenes is necessary to prevent early onset of malignant process and particularly for modification of tumor therapy. The incidence of homozygote is low, but also heterozygote of SCI are hypersensitive to mutagens and have substantionally increased cancer risk in early adulthood. Heterozygotes of all SCI represent nearly 3 % of population. Their increased cancer risk could be controled by special regime with protection from mutagens, sufficient intake of antioxidants in food and monitoring of chromosomal instability for control of efficiency of protective regime. In our republic is available direct DNA diagnostics of mutations in ATM gene and NBN gene, responSouhrnsible for Louis-Bar and Nijmegen breakage syndromes. In case of another SCI we must cooperate with centres in abroad. Here we describe phenotypes of individual SCI and emphasize the signal features.

• MeSH
• Bloomův syndrom diagnóza   genetika   patofyziologie   MeSH
• chromozomální nestabilita * MeSH
• dítě MeSH
• Fanconiho anemie diagnóza   genetika   MeSH
• klinický obraz nemoci * MeSH
• lidé MeSH
• molekulární biologie MeSH
• nádory MeSH
• neurologické manifestace MeSH
• novorozenec MeSH
• přežití MeSH
• příznaky a symptomy MeSH
• riziko MeSH
• syndrom Nijmegen breakage diagnóza   genetika   patofyziologie   MeSH
• syndrom MeSH
• teleangiektatická ataxie diagnóza   patofyziologie   MeSH
• transplantace kostní dřeně MeSH
• vývojové poruchy u dětí MeSH
• xeroderma pigmentosum diagnóza   genetika   patofyziologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• ženské pohlaví MeSH

BACKGROUND: The swim-up and hyaluronan (HA)-binding methods are used for the selection of good quality spermatozoa to improve pregnancy rates and embryo quality and to reduce the number of miscarriages after IVF. We evaluated whether the processing of sperm by these methods reduces the frequency of spermatozoa with abnormal karyotypes and altered chromatin quality in balanced translocation carriers. METHODS: Semen samples of 12 carriers of balanced chromosomal translocations were analysed for the frequency of spermatozoa, which are chromosomally unbalanced due to the segregation of balanced translocations, aneuploidies for chromosomes 7, 8, 13, 18, 21, X or Y, diploid sperm or sperm with fragmented DNA and poorly condensed chromatin. Results obtained by fluorescence in situ hybridization (FISH) and sperm chromatin structure assay were compared between ejaculated (n = 12), swim-up (n = 12) and HA-binding processed (n = 6) semen samples of the translocation carriers and with the control group (n = 10). RESULTS: The mean frequencies of unbalanced segregation products were 17.5 and 16.5% in neat and swim-up processed samples from Robertsonian translocation carriers, and 55.4, 54.5 and 50.9% in neat, swim-up and HA-bound sperm samples from reciprocal translocation carriers. Significant decreases in the frequency of sperm showing chromosome 18 and XY disomy and of diploidy, and in the rates of high-density staining sperm were observed in the motile swim-up fractions. There were significantly more sperm showing fragmented chromatin in the group of translocation carriers than in the control group, but no differences in the aneuploidy and diploidy rates were observed. CONCLUSIONS: The swim-up method is suitable for selection of sperm with condensed chromatin and a lower frequency of some aneuploidies and of diploidy. The frequency of spermatozoa chromosomally unbalanced due to the segregation of reciprocal (but not Robertsonian) translocations is significantly lower in HA-bound sperm. However, the advantages of either method for selecting normal sperm are limited.

• MeSH
• analýza spermatu metody   MeSH
• dospělí MeSH
• heterozygot MeSH
• hybridizace in situ fluorescenční MeSH
• kyselina hyaluronová analýza   MeSH
• lidé MeSH
• segregace chromozomů MeSH
• spermie abnormality   MeSH
• translokace genetická MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The village and street dogs represent a unique model of canine populations. In the absence of selective breeding and veterinary care, they are subject mostly to natural selection. Their analyses contribute to understanding general mechanisms governing the genetic diversity, evolution and adaptation. In this study, we analyzed the genetic diversity and population structure of African village dogs living in villages in three different geographical areas in Northern Kenya. Data obtained for neutral microsatellite molecular markers were compared with those computed for potentially non-neutral markers of candidate immunity-related genes. The neutral genetic diversity was similar to other comparable village dog populations studied so far. The overall genetic diversity in microsatellites was higher than the diversity of European pure breeds, but it was similar to the range of diversity observed in a group composed of many European breeds, indicating that the African population has maintained a large proportion of the genetic diversity of the canine species as a whole. Microsatellite marker diversity indicated that the entire population is subdivided into three genetically distinct, although closely related subpopulations. This genetical partitioning corresponded to their geographical separation and the observed gene flow well correlated with the communication patterns among the three localities. In contrast to neutral microsatellites, the genetic diversity in immunity-related candidate SNP markers was similar across all three subpopulations and to the European group. It seems that the genetic structure of this particular population of Kenyan village dogs is mostly determined by geographical and anthropogenic factors influencing the gene flow between various subpopulations rather than by biological factors, such as genetic contribution of original migrating populations and/or the pathogen-mediated selection. On the other hand, the study of oldest surviving dogs suggested a biological mechanism, i.e. a possible advantage of the overal heterozygosity marked by the the microsatellite loci analyzed.

• MeSH
• analýza hlavních komponent MeSH
• fenotyp MeSH
• genetická variace * MeSH
• genetické lokusy MeSH
• genetické markery MeSH
• haplotypy genetika   MeSH
• heterozygot MeSH
• hlavní histokompatibilní komplex genetika   MeSH
• imunita genetika   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• jezera MeSH
• mikrosatelitní repetice genetika   MeSH
• populační genetika * MeSH
• psi genetika   imunologie   MeSH
• software MeSH
• zeměpis MeSH
• zvířata MeSH
• Check Tag
• psi genetika   imunologie   MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH
• Keňa MeSH

Rhesus-positive and Rhesus-negative persons differ in the presence-absence of highly immunogenic RhD protein on the erythrocyte membrane. The biological function of the RhD molecule is unknown. Its structure suggests that the molecular complex with RhD protein transports NH3 or CO2 molecules across the erythrocyte cell membrane. Some data indicate that RhD positive and RhD negative subjects differ in their tolerance to certain biological factors, including, Toxoplasma infection, aging and fatique. Present cross sectional study performed on 3,130 subjects) showed that Rhesus negative subjects differed in many indices of their health status, including incidences of many disorders. Rhesus negative subjects reported to have more frequent allergic, digestive, heart, hematological, immunity, mental health, and neurological problems. On the population level, a Rhesus-negativity-associated burden could be compensated for, for example, by the heterozygote advantage, but for Rhesus negative subjects this burden represents a serious problem.

• MeSH
• dítě MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• incidence MeSH
• krevní skupiny - systém Rh-Hr genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• polymorfismus genetický MeSH
• průřezové studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• věkové rozložení MeSH
• zdravotní stav MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The high incidence of cystic fibrosis (CF) is due to the frequency of the c.1521_1523delCTT variant in the cystic fibrosis transmembrane conductance regulator (CFTR), but its age and origin are uncertain. This gap limits attempts to shed light on the presumed heterozygote selective advantage that accounts for the variant's high prevalence among Caucasian Europeans and Europe-derived populations. In addition, explaining the nature of heterozygosity to screened individuals with one c.1521_1523delCTT variant is challenging when families raise questions about these issues. To address this gap, we obtained DNA samples from 190 patients bearing c.1521_1523delCTT and their parents residing in geographically distinct European populations plus a Germany-derived population in the USA. We identified microsatellites spanning CFTR and reconstructed haplotypes at 10 loci to estimate the time/age of the most recent common ancestor (tMRCA) with the Estiage program. We found that the age estimates differ between northwestern populations, where the mean tMRCA values vary between 4600 and 4725 years, and the southeastern populations where c.1521_1523delCTT seems to have been introduced only about 1000 years ago. The tMRCA values of Central Europeans were intermediate. Thus, our data resolve a controversy by establishing an early Bronze Age origin of the c.1521_1523delCTT allele and demonstrating its likely spread from northwest to southeast during ancient migrations. Moreover, taking the archeological record into account, our results introduce a novel concept by suggesting that Bell Beaker folk were the probable migrating population responsible for the early dissemination of c.1521_1523delCTT in prehistoric Europe.

• MeSH
• cystická fibróza epidemiologie   genetika   MeSH
• lidé MeSH
• migrace lidstva MeSH
• mikrosatelitní repetice MeSH
• populace genetika   MeSH
• protein CFTR genetika   MeSH
• rodokmen * 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

Cytochrome-c oxidase (COX) deficiency is one of the common childhood mitochondrial disorders. Mutations in genes for the assembly factors SURF1 and SCO2 are prevalent in children with COX deficiency in the Slavonic population. Molecular diagnosis is difficult because of the number of genes involved in COX biogenesis and assembly. The aim of this study was to screen for mutations in 15 nuclear genes that encode the 10 structural subunits, their isoforms and two assembly factors of COX in 60 unrelated Czech children with COX deficiency. Nine novel variants were identified in exons and adjacent intronic regions of COX4I2, COX6A1, COX6A2, COX7A1, COX7A2 and COX10 using high-resolution melting (HRM) analysis. Online bioinformatics servers were used to predict the importance of the newly identified amino-acid substitutions. The newly characterized variants updated the contemporary spectrum of known genetic sequence variations that are present in the Czech population, which will be important for further targeted mutation screening in Czech COX-deficient children. HRM and predictive bioinformatics methodologies are advantageous because they are low-cost screening tools that complement large-scale genomic studies and reduce the required time and effort.

• MeSH
• buněčné jádro genetika   MeSH
• deficit cytochrom-c-oxidázy epidemiologie   genetika   patologie   MeSH
• dítě MeSH
• endokrinní disruptory MeSH
• exony MeSH
• genetická predispozice k nemoci MeSH
• genetické testování metody   MeSH
• genom lidský MeSH
• genotypizační techniky metody   MeSH
• heterozygot MeSH
• introny MeSH
• jednonukleotidový polymorfismus MeSH
• kojenec MeSH
• lidé MeSH
• missense mutace MeSH
• předškolní dítě MeSH
• respirační komplex IV genetika   metabolismus   MeSH
• senzitivita a specificita MeSH
• substituce aminokyselin MeSH
• výpočetní biologie metody   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

"Genetics and Genomics in Medicine is a new textbook written for undergraduate and graduate students, as well as medical researchers, which explains the science behind the uses of genetics and genomics in medicine today. It is not just about rare inherited and chromosomal disorders, but how genetics affects the whole spectrum of human health and disease. DNA technologies are explained, with emphasis on the modern techniques that have revolutionized the use of genetic information in medicine and are indicating the role of genetics in common complex diseases. The detailed, integrative coverage of genetic approaches to treatment and prevention includes pharmacogenomics and the prospects for personalized medicine. Cancers are essentially genetic diseases and are given a dedicated chapter that includes new insights from cancer genome sequencing. Clinical disorders are covered throughout and there are extensive end-of-chapter questions and problems"--Provided by publisher.