Alleles In Population Research Articles

Estimated birth prevalence of Menkes disease and ATP7A-related disorders based on the Genome Aggregation Database (gnomAD)

BackgroundPrevious estimates of the prevalence of Menkes disease, a lethal X-linked recessive disorder of copper metabolism, were based on confirmed clinical cases ascertained from specific populations and varied from 1 in 40,000 to 1 in 354,507. With newly available population-based allelic frequencies of DNA sequence variants, the expected birth prevalence of Menkes disease and other ATP7A-related phenotypes can be reconsidered using Hardy-Weinberg theoretical principles. MethodsWe reviewed the canonical ATP7A transcript in the current version of gnomAD (v2.1.1) to evaluate frequency of complete loss-of-function alleles in a diverse normal control population. As a comparator, we used the DMD locus, associated with Duchenne and Becker Muscular Dystrophy, another X-linked recessive trait. We applied Hardy-Weinberg theory and PolyPhen-2 in silico plus REVEL and CADD ensemble analyses to calculate estimated frequencies of normal and predicted deleterious ATP7A alleles. ResultsWe identified 1106 total ATP7A variants out of 205,523 alleles in gnomAD, with missense variants most common (43.4%). Complete loss-of-function variants were found in four ATP7A alleles (frequency = 0.0000194), including three frameshift/nonsense mutations and one canonical splice donor site defect. Assuming Hardy-Weinberg equilibrium, this frequency of pathogenic alleles predicts 1 in 34,810 live male births with Menkes disease or other ATP7A-related disorders each year in the US. The same analysis for DMD loss-of-function variants predicted 1 in 7246 newborn males with Duchenne (or Becker) muscular dystrophy. We also identified nine ATP7A missense variants in gnomAD predicted as deleterious by PolyPhen-2 and stringent REVEL/CADD criteria, comprising 12 more disease-causing alleles and raising the estimated birth prevalence to 1 in 8664 and predicting 225 newborns with Menkes disease or other ATP7A-related disorders per year in the US alone. ConclusionsAssuming Hardy-Weinberg equilibrium, the allelic frequency of deleterious ATP7A variants in a genomic database from a large diverse population predicts a birth prevalence of Menkes disease or ATP7A-related disorders as high as 1 in 8664 live male births. This genome-driven ascertainment of deleterious ATP7A alleles in the population implies a higher birth prevalence of Menkes disease and ATP7A-related conditions than previously appreciated. A population-based newborn screening pilot study for Menkes disease will be instrumental in confirming the prediction.

Association of STAT4 Gene Rs7574865, Rs10168266 Polymorphisms and Systemic Lupus Erythematosus Susceptibility: A Meta-analysis

ABSTRACT Association of signal transducer and activator of transcription 4 (STAT4) gene rs7574865, rs10168266 polymorphisms with systemic lupus erythematosus (SLE) risk remains unclear. A meta-analysis was conducted on the correlation between rs7574865, rs10168266 polymorphisms and SLE. Twenty-six studies were recruited in our study (17,389 patients and 29,273 controls). For rs7574865, results showed significant associations between T allele and SLE susceptibility in overall population, Asians and Europeans (OR=1.557, 95%CI: 1.505-1.611, P<0.001; OR=1.557, 95%CI: 1.498-1.661, P<0.001; OR=1.548, 95%CI: 1.474-1.625, P<0.001). Significant associations of genotypes TT, GT, TT+TG and SLE risk were observed in general subjects, Asians and Europeans (all P<0.001). Regarding rs10168266, increased T allele frequencies were detected in overall SLE cases and those from Asian origin (OR=1.532, 95%CI: 1.440-1.631, P<0.001; OR=1.575, 95%CI: 1.445-1.717, P<0.001). The overall data showed that TT genotype, CT genotype and TT+CT genotype were significantly correlated with SLE (all P < 0.001). In conclusion, the present study verified strong association of STAT4 gene rs7574865, rs10168266 polymorphisms and SLE susceptibility.

Association between Coronary Artery Disease and rs10757278 and rs1333049 Polymorphisms in 9p21 Locus in Iran.

Coronary arteries disease (CAD) has been recognized as one of the most common causes of death worldwide, with an estimated seven million deaths annually. Two hundred blood samples from Iranian CAD patients and normal healthy controls were collected. CAD and the 9p21 locus variants rs1333049 and rs10757278 were analyzed for potential associations. No significant differences in rs10757278 and rs1333049 polymorphisms were found between patients and controls, but a significant relationship was found between rs10757278 and rs1333049 in CAD patients at the genotype level (p= 0.0323). At the haplotype level and on the basis of diplotype analysis, a significant relationship was found between patients and controls (OR= 5.16, p= 0.047, 95% CI: 1.02-26.0). In CAD patients, rs10757278 and rs1333049 were associated at locus 9p21. The inconsistency between the results of this and other studies on different CAD populations may be due to high population, different ethnicities, low prevalence of some alleles in populations, and interactions of different genes.

Genetic Diversity Analysis of Five Egyptian Buffalo Populations Using Microsatellite Markers

For assessing the genetic diversity and genetic characterization of five Egyptian buffalo populations a total of 12 microsatellite markers were used. The total number of buffaloes sampled was 80, collected at random from five farms in five different governorates; Cairo, Kafr El-Sheikh, Shebeen El-Kom, Menoufia, and Beni Suef. The genetic parameters (allelic diversity, allelic frequencies, observed heterozygosity, unbiased expected heterozygosity, and polymorphic information content) were calculated using three different programs. All used microsatellites were polymorphic and ranged from four alleles (Loci; CSSM029, CSSM036, CSSM038, CSSM043, CSSM046, and ILSTS005) to nine alleles (Loci; BM1818 and CSSM047) with a total of 64 alleles in the whole population. Allelic richness for the whole population ranged between 3.297 (in locus CSSM029) and 6.806 (in locus CSSM047) with overall mean 4.574. Within populations, Kafr El-Sheikh population had the highest average of allelic richness (4.384). This indicates the potential of this population to adapt with environmental changes in future compared with other populations. BMC1013, BM1818, CSSM019, and CSSM047 showed the highest allelic richness. PIC estimates were high and ranged between 0.65 (in locus CSSM029) and 0.92 (in locus CSSM022) with an average of 0.82. Values of Ho were lower than values of HNb for all populations, which denoting depression of heterozygotes in these populations and may be attributable to existence of null alleles and inbreeding. This study as well proves the usefulness of heterologous bovine microsatellite markers in evaluation of the genetic variability in Egyptian buffalo populations due to high polymorphism, informativeness of these markers which can be used to develop future breeding strategies and conservation decisions on our indigenous breed.

The Metabolization Profile of the CYP2D6 Gene in Amerindian Populations: A Review

Background: the CYP2D6 gene is clinically important and is known to have a number of variants. This gene has four distinct metabolization profiles that are determined by the different allelic forms present in the individual. The relative frequency of these profiles varies considerably among human populations around the world. Populations from more isolated regions, such as Native Americans, are still relatively poorly studied, however. Even so, recent advances in genotyping techniques and increasing interest in the study of these populations has led to a progressive increase in publication rates. Given this, the review presented here compiled the principal papers published on the CYP2D6 gene in Amerindian populations to determine the metabolic profile of this group. Methods: a systematic literature review was conducted in three scientific publication platforms (Google Scholar, Science Direct, and Pubmed). The search was run using the keywords “CYP2D6 Amerindians” and “CYP2D6 native Americans”. Results: a total of 13 original papers met the inclusion criteria established for this study. All the papers presented frequencies of the different CYP2D6 alleles in Amerindian populations. Seven of the papers focused specifically on Amerindian populations from Mexico, while the others included populations from Argentina, Chile, Costa Rica, Mexico, Paraguay, Peru, and the United States. The results of the papers reviewed here showed that the extensive metabolization profile was the most prevalent in all Amerindian populations studied to date, followed by the intermediate, slow, and ultra-rapid, in that order. Conclusion: the metabolization profiles of the Amerindian populations reviewed in the present study do not diverge in any major way from those of other populations from around the world. Given the paucity of the data available on Amerindian populations, further research is required to better characterize the metabolization profile of these populations to ensure the development of adequate therapeutic strategies.

RDL mutations in Guangxi Anopheles sinensis populations along the China\u2013Vietnam border: distribution frequency and evolutionary origin of A296S resistance allele

BackgroundMalaria is a deadly vector-borne disease in tropical and subtropical regions. Although indigenous malaria has been eliminated in Guangxi of China, 473 confirmed cases were reported in the Northern region of neighbouring Vietnam in 2014. Considering that frequent population movement occurs across the China–Vietnam border and insecticide resistance is a major obstacle in disease vector control, there is a need to know the genotype and frequency of insecticide resistance alleles in Anopheles sinensis populations along the China–Vietnam border and to take action to prevent the possible migration of insecticide resistance alleles across the border.MethodsTwo hundred and eight adults of An. sinensis collected from seven locations in Guangxi along the China–Vietnam border were used in the investigation of individual genotypes of the AsRDL gene, which encodes the RDL gamma-aminobutyric acid (GABA) receptor subunit in An. sinensis. PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) analysis was deployed to genotype codon 345, while direct sequencing of PCR products was conducted to clarify the genotypes for codons 296 and 327 of the AsRDL gene. The genealogical relation of AsRDL haplotypes was analyzed using Network 5.0.ResultsThree putative insecticide resistance related mutations (A296S, V327I and T345S) were detected in all the seven populations of An. sinensis in Guangxi along the China–Vietnam border. The resistance-conferring A296S mutation was found to be widely distributed and present at notably high frequencies (78.8% to 100%). Relatively lower frequencies of mutations V327I (26.9% to 53.2%) and T345S (0% to 28.8%) were observed. The V327I or T345S always occurred in the presence of A296S. Evolutionary analysis of 21 AsRDL haplotypes indicated multiple origins of the A296S and V327I mutations.ConclusionThe resistance A296S allele was present at high frequencies in the An. sinensis populations along the China–Vietnam border, indicating a risk of resistance to insecticides targeting RDL. The double mutations (A296S + V327I) may have evolved from alleles carrying the A296S mutation by scaffolding the additional mutation V327I, and A296S allele may have multiple evolutionary origins. These findings will help inform strategies for vector control and malaria prevention.

Molecular and computational analysis of 45 samples with a serologic weak D phenotype detected among 132,479 blood donors in northeast China

BackgroundRH1 is one of the most clinically important blood group antigens in the field of transfusion and in the prevention of fetal incompatibility. The molecular analysis and characterization of serologic weak D phenotypes is essential to ensuring transfusion safety.MethodsBlood samples from a northeastern Chinese population were randomly screened for a serologic weak D phenotype. The nucleotide sequences of all 10 exons, adjacent flanking intronic regions, and partial 5′ and 3′ untranslated regions (UTRs) were detected for RHD genes. Predicted deleterious structural changes in missense mutations of serologicl weak D phenotypes were analyzed using SIFT, PROVEAN and PolyPhen2 software. The protein structure of serologic weak D phenotypes was predicted using Swiss-PdbViewer 4.0.1.ResultsA serologic weak D phenotype was found in 45 individuals (0.03%) among 132,479 blood donors. Seventeen distinct RHD mutation alleles were detected, with 11 weak D, four partial D and two DEL alleles. Further analyses resulted in the identification of two novel alleles (RHD weak D 1102A and 399C). The prediction of a three-dimensional structure showed that the protein conformation was disrupted in 16 serologic weak D phenotypes.ConclusionsTwo novel and 15 rare RHD alleles were identified. Weak D type 15, DVI Type 3, and RHD1227A were the most prevalent D variant alleles in a northeastern Chinese population. Although the frequencies of the D variant alleles presented herein were low, their phenotypic and genotypic descriptions add to the repertoire of reported RHD alleles. Bioinformatics analysis on RhD protein can give us more interpretation of missense variants of RHD gene.

Protective Resistance by Human G6PD Enzyme Deficiency and Hemoglobin Variants Against Malaria and Natural Selection: Further Evidence from Review of New Studies

Main objective of this article is to review and evaluate recent red cell variant studies for protection against malaria and natural selection. Malaria is a parasitic disease highly widespread in tropical and subtropical regions of the world. It is also one of the leading causes of death worldwide and genes involved in malaria resistance are the most important for natural selection in human populations. Multiple red cell variants, which evolved probably to counter the lethal effects of malaria and confer protection against malaria through different mechanisms, show high frequencies in malaria endemic vulnerable populations. Different natural protective/resistance mechanisms including hampering of parasite growth, invasion related immunological responses or rapidly elimination of malaria parasite from the infected erythrocytes of host have briefly been discussed, evaluated, and reviewed. Conclusions drawn have been projected here. High frequency of inherited hemoglobin disorders including thalassemias, and red cell G6PD enzyme deficiency, which seemed to evolve simultaneously in relation to malaria, and high mortality caused by Plasmodium falciparum malaria in different vulnerable populations of tropical and subtropical parts of world, confirm that the natural selection is certainly operating against malaria in one way or another; and human population genetics have distinctly played a significant role in the co-evolution of host and malaria. The inverse relationship between sickle cell trait and G6PD deficiency and vice versa, revealed by allele frequencies distribution shown in our previous studies, is a testimony of disequilibrium, as sickle cell allele being replaced by G6PD deficiency allele in populations of central India. Positive natural selection plays a definite role against malaria for maintaining balance in high frequency endemic populations.

Associations between paraoxonase-1 and systemic lupus erythematosus.

The objective of this analysis was to explore associations between paraoxonase-1 levels, gene polymorphisms and systemic lupus erythematosus. Meta-analyses of paraoxonase-1 levels and Q192R and L55M and polymorphisms in systemic lupus erythematosus were conducted. Nine articles were incorporated in our meta-analysis, which uncovered that the paraoxonase-1 level was decreased in systemic lupus erythematosus compared to control (standard mean difference = -1.626, 95% confidence interval = -2.829--0.424, p = 0.008). Ethnicity-specific meta-analysis demonstrated a relation tendency between decreased paraoxonase-1 activity and lupus in Europeans (standard mean difference = -1.236, 95% confidence interval = -2.634-0.163, p = 0.083). Paraoxonase-1 activity was reduced in systemic lupus erythematosus in a single Arab and African population. Decreased paraoxonase-1 activity was found in a small sample of systemic lupus erythematosus patients (standard mean difference = -1.642, 95% confidence interval = -3.076--0.247, p = 0.021). Ethnicity-specific analysis indicated a relationship between the paraoxonase-1 55 M allele in the Arab systemic lupus erythematosus population. However, a lack of association with systemic lupus erythematosus and the paraoxonase-1 192 R allele was observed. Meta-analyses revealed reduced paraoxonase-1 activity in patients with systemic lupus erythematosus and found possible associations between systemic lupus erythematosus and paraoxonase-1 L55M polymorphism in a specific ethnic group.

Future Preventive Gene Therapy of Polygenic Diseases from a Population Genetics Perspective.

With the accumulation of scientific knowledge of the genetic causes of common diseases and continuous advancement of gene-editing technologies, gene therapies to prevent polygenic diseases may soon become possible. This study endeavored to assess population genetics consequences of such therapies. Computer simulations were used to evaluate the heterogeneity in causal alleles for polygenic diseases that could exist among geographically distinct populations. The results show that although heterogeneity would not be easily detectable by epidemiological studies following population admixture, even significant heterogeneity would not impede the outcomes of preventive gene therapies. Preventive gene therapies designed to correct causal alleles to a naturally-occurring neutral state of nucleotides would lower the prevalence of polygenic early- to middle-age-onset diseases in proportion to the decreased population relative risk attributable to the edited alleles. The outcome would manifest differently for late-onset diseases, for which the therapies would result in a delayed disease onset and decreased lifetime risk; however, the lifetime risk would increase again with prolonging population life expectancy, which is a likely consequence of such therapies. If the preventive heritable gene therapies were to be applied on a large scale, the decreasing frequency of risk alleles in populations would reduce the disease risk or delay the age of onset, even with a fraction of the population receiving such therapies. With ongoing population admixture, all groups would benefit over generations.

MEFV Gene Variant Alleles in Normal Population of Northwest of Iran, Which Is Near to Mediterranean Sea.

Background and Objective MEFV gene codes the pyrine protein that has major role in FMF as an autoinflammatory disorder. FMF is more often seen in the people of the Mediterranean area. Considering the significant role of MEFV gene in many rheumatologic diseases and even nonrheumatologic disorders, it is necessary to identify different variations of these mutations in the healthy and normal population of this area. Methods 224 healthy (unaffected or control) people based on the Cochran formula entered this study. The blood samples were screened for the 12 common MEFV gene variants polymorphisms according to manufacturer's instructions (FMF Strip Assay, Vienna lab, Vienna, Austria). They filled a questionnaire containing required information. All healthy control cases initially were evaluated for FMF symptoms and signs in themselves and their first-degree relatives based on clinical criteria. All data were analyzed by simple statistical method. Results Among 224 healthy control cases, 113 (50.4%) were male and 111 (49.6%) female. There were MEFV variants alleles in 57 patients (25%): 28 were male (49.1%) and 29 female (50.9%). The most frequent variants were E148Q (18.3%), followed by P369S (3.1%), V726A (2.2%), A744S (1.3%), and F479L, M694V, and R761H (0.8%), and eventually K695R (0.4%), respectively. Some variants such as M694I, M680I (G/C), M680I (G/A), and I692del were not seen in these samples. There were compound heterozygote variations of E148Q/P369S, E148Q/V726A, E148Q/P369S, and P369S/F479L in normal population without any findings in favor of FMF. Conclusion Twenty-five percent of the normal populations of the northwest of Iran are carrying MEFV gene variants, and the most common mutation is E148Q (18.3%). The presence of M694I, M680I (G/C), M680I (G/A), I692del mutations in the normal population can be interpreted cautiously, while particular compound heterozygote mutations can be considered as normal variants.

On estimating evolutionary probabilities of population variants

BackgroundThe evolutionary probability (EP) of an allele in a DNA or protein sequence predicts evolutionarily permissible (ePerm; EP ≥ 0.05) and forbidden (eForb; EP < 0.05) variants. EP of an allele represents an independent evolutionary expectation of observing an allele in a population based solely on the long-term substitution patterns captured in a multiple sequence alignment. In the neutral theory, EP and population frequencies can be compared to identify neutral and non-neutral alleles. This approach has been used to discover candidate adaptive polymorphisms in humans, which are eForbs segregating with high frequencies. The original method to compute EP requires the evolutionary relationships and divergence times of species in the sequence alignment (a timetree), which are not known with certainty for most datasets. This requirement impedes a general use of the original EP formulation. Here, we present an approach in which the phylogeny and times are inferred from the sequence alignment itself prior to the EP calculation. We evaluate if the modified EP approach produces results that are similar to those from the original method.ResultsWe compared EP estimates from the original and the modified approaches by using more than 18,000 protein sequence alignments containing orthologous sequences from 46 vertebrate species. For the original EP calculations, we used species relationships from UCSC and divergence times from TimeTree web resource, and the resulting EP estimates were considered to be the ground truth. We found that the modified approaches produced reasonable EP estimates for HGMD disease missense variant and 1000 Genomes Project missense variant datasets. Our results showed that reliable estimates of EP can be obtained without a priori knowledge of the sequence phylogeny and divergence times. We also found that, in order to obtain robust EP estimates, it is important to assemble a dataset with many sequences, sampling from a diversity of species groups.ConclusionWe conclude that the modified EP approach will be generally applicable for alignments and enable the detection of potentially neutral, deleterious, and adaptive alleles in populations.

Gender differences in prognostic value of immune-related biomarkers in colon cancer patients randomized to surgery or surgery and adjuvant chemotherapy treatment.

3603 Background: HLA-A*02, a common allele in the Scandinavian population, is a negative prognostic factor in epithelial ovarian cancer. It is a strong predictor of patient outcome, only inferior to clinical staging. This prognostic trait in epithelial ovarian cancer is stronger by the presence of the gene compared with the expression of its protein, MHC class I. Microsatellite instability (MSI) is used as a biomarker for prognosis and is suggested an increased tumor mutational burden which can make the tumor more susceptible for T cell mediated immunotherapy. Our aim was to analyze the prognostic markers HLA-A*02 genotype, MHC class I on tumor cells, the CD8+ lymphocyte infiltration and MSI status in colon cancer patients with randomized treatment. Methods: Clinical information and primary tumors were collected from 520 colon cancer patients and followed for overall survival for 120 months. Patients hade stage II and III colon cancer and were randomized to surgery alone or surgery and adjuvant chemotherapy. HLA-A*02 genotype was determined by conventional PCR. MHC class I, MSI status and CD8+ lymphocyte infiltration were determined by immunohistochemistry. Results: Female patients with a stage III tumor and HLA-A*02 genotype had a better outcome if they had received adjuvant chemotherapy instead of just surgery (p = 0.03), whereas this was not the case for patients with other HLA-A genotypes or in the male patients where HLA-type did not correlate to outcome. MHC class I expression did not act as a prognostic factor, however the presence of CD8+ lymphocytes in the invasive margin and inside the tumor was a positive prognostic factor for overall survival (p = 0.01), although only statistically significant in the male patients (p = 0.03). 21% patients had a tumor with MSI (23% of the female and 19% of the male patients respectively). MSI tumors had a slightly better outcome and this was irrespective of gender and HLA-type. Conclusions: The prognostic traits of HLA-A*02 appear in this colon cancer cohort to act differently in male and female patients. Also CD8+ infiltration is different between genders. These findings suggest that men and women may have two different immune responses to malignancy.

Detection of alleles associated with resistance to chemical insecticide in the malaria vector Anopheles arabiensis in Santiago, Cabo Verde

BackgroundMosquitoes of the Anopheles gambiae complex are the main malaria vectors worldwide. Due to the lack of a vaccine to prevent malaria, the principal way to reduce the impact of this disease relies on the use of chemical insecticides to control its vectors. However, the intensive use of such compounds has led to the emergence of insecticide resistance in several Anopheles populations in Africa. This study aimed to investigate the presence of resistance alleles in an Anopheles arabiensis population from the City of Praia, capital of the Archipelago Cabo Verde, one of the countries on the World Health Organization list of countries that are on a path to eliminate local transmission of malaria.MethodsLarvae from the Anopheles genus were collected using a one-pint dipper in three areas of City of Praia. Larvae were fed and maintained until the emergence of adult mosquitoes, and these were morphologically identified. In addition, molecular identification was performed using IGS markers and all An. arabiensis samples were subjected to PCR to screen for mutations associated to resistance in the Ace-1, Nav and GSTE2 genes.ResultsFrom a total of 440 mosquitoes collected, 52.3% were morphologically identified as An. gambiae sensu lato (s.l.) and 46.7% as Anopheles pretoriensis. The molecular identification showed that 100% of the An. gambiae s.l. were An. arabiensis. The mutations G119S in the Ace-1 gene and L119F in the GSTE2 gene were screened but not found in any sample. However, sequencing analysis for GSTE2 revealed the presence of 37 haplotypes, 16 polymorphic sites and a high genetic diversity (π = 2.67). The L1014S mutation in the Nav (voltage-gated sodium channel gene) was detected at a frequency of 7.3%.ConclusionThis is the first study to investigate the circulation of insecticide resistance alleles in An. arabiensis from Cabo Verde. The circulation of the L1014S allele in the population of An. arabiensis in the city of Praia suggests that pyrethroid resistance may arise, be quickly selected, and may affect the process of malaria elimination in Cabo Verde. Molecular monitoring of resistance should continue in order to guide the development of strategies to be used in vector control in the study region.

Immune escape and immune camouflage may reduce the efficacy of RTS,S vaccine in Malawi

ABSTRACTThe RTS,S/AS01 malaria vaccine will undergo a pilot vaccination study in sub-Saharan Africa beginning in 2019. RTS,S/AS01 Phase III trials reported an efficacy of 28.3% (children 5–17 months) and 18.3% (infants 6–12 weeks), with substantial variability across study sites. We postulated that the relatively low efficacy of the RTS,S vaccine and variability across sites may be due to lack of T-cell epitopes in the vaccine antigen, and due to the HLA distribution of the vaccinated population, and/or due to ‘immune camouflage’, an immune escape mechanism. To examine these hypotheses, we used immunoinformatics tools to compare T helper epitopes contained in RTS,S vaccine antigens with Plasmodium falciparum circumsporozoite protein (CSP) variants isolated from infected individuals in Malawi. The prevalence of epitopes restricted by specific HLA-DRB1 alleles was inversely associated with prevalence of the HLA-DRB1 allele in the Malawi study population, suggesting immune escape. In addition, T-cell epitopes in the CSP of strains circulating in Malawi were more often restricted by low-frequency HLA-DRB1 alleles in the population. Furthermore, T-cell epitopes that were highly conserved across CSP variants in Malawi possessed TCR-facing residues that were highly conserved in the human proteome, potentially reducing T-cell help through tolerance. The CSP component of the RTS,S vaccine also exhibited a low degree of T-cell epitope relatedness to circulating variants. These results suggest that RTS,S vaccine efficacy may be impacted by low T-cell epitope content, reduced presentation of T-cell epitopes by prevalent HLA-DRB1, high potential for human-cross-reactivity, and limited conservation with the CSP of circulating malaria strains.

APPLICATION OF THE TARGETED MULTIGENE SEQUENCING FOR THE SEARCH OF HEREDITARY BREAST CANCER MUTATIONS IN RUSSIAN PATIENTS

Understanding of the molecular-genetic pathogenesis of hereditary cancer syndrome is extremely important for developing of personal therapeutic approaches and for improving the effectiveness of preventive measures. Today, the optimal solution for the search of causative germ-line mutations in hereditary breast cancer (BC) patients is the next-generation sequencing-based multigene mutational screening. The authors have assembled a targeted panel of 31 genes, based on their potential involvement in the cancer susceptibility and taking into account the frequency of pathogenic alleles in the Russian population. It includes the “canonical” genes of hereditary breast cancer (BRCA1, BRCA2, BRIP1, PALB2, TP53, ATM, NBN), the recently identified “novel” genes (BLM, FANCD2, POLE, FANCM, RAD51C, MRE11A, RECQL, as well as some other genes involved in DNA repair, apoptosis and genome stability maintenance. 94 patients with hereditary BC of unknown genetic etiology were subjected to targeted sequencing. As a result, causative germ-line mutations were identified in 21/94 (22.3%) patients. Importantly, 19 patients harbored rare non-founder BRCA1 and BRCA2 mutations. In the remaining two cases, the functions of the ATM (p.Glu73fs) and POLE (p.Leu1171fs) genes were disrupted. The obtained data are of evident clinical importance; they argue for the expanding of diagnostic panels for monitoring at-risk individuals and for moving the standards of routine clinical diagnostics towards the targeted next-generation sequencing of multigene panels.

The genome-wide landscape of small insertion and deletion mutations in Monopterus albus

Insertion and deletion (indel) mutations, which can trigger single nucleotide substitutions on the flanking regions of genes, may generate abundant materials for disease defense, reproduction, species survival and evolution. However, genetic and evolutionary mechanisms of indels remain elusive. We establish a comparative genome-transcriptome-alignment approach for a large-scale identification of indels in Monopterus population. Over 2000 indels in 1738 indel genes, including 1–21 bp deletions and 1–15 bp insertions, were detected. Each indel gene had ∼1.1 deletions/insertions, and 2–4 alleles in population. Frequencies of deletions were prominently higher than those of insertions on both genome and population levels. Most of the indels led to in frame mutations with multiples of three and majorly occurred in non-domain regions, indicating functional constraint or tolerance of the indels. All indel genes showed higher expression levels than non-indel genes during sex reversal. Slide window analysis of global expression levels in gonads showed a significant positive correlation with indel density in the genome. Moreover, indel genes were evolutionarily conserved and evolved slowly compared to non-indel genes. Notably, population genetic structure of indels revealed divergent evolution of Monopterus population, as bottleneck effect of biogeographic isolation by Taiwan Strait, China.

Faulty kinase purged by tuberculosis?

Tuberculosis Rare mutations in genes involved in interferon-γ–dependent immunity underpin human genetic susceptibility to severe mycobacterial diseases, including primary tuberculosis. Boisson-Dupuis et al. investigated whether two common missense variants of the TYK2 Janus kinase that have impaired catalytic activity conferred an increased risk of tuberculosis. Individuals homozygous for the P1104A (proline to alanine substitution at residue 1104) variant of TYK2 are markedly predisposed to developing primary tuberculosis, defining a common monogenic etiology for the “white plague.” The current frequency of the P1104A allele in European populations is significantly decreased compared with its frequency in ancient European DNA samples. These findings suggest that negative selection against the TYK2 P1104A allele by endemic tuberculosis in Europe may have contributed to a slow genetic purge of this susceptibility allele during recent millennia. Sci. Immunol. 3 , eaau8714 (2018).

Analysis of the ABCA4 c.[2588G>C;5603A>T] Allele in the Australian Population.

Inherited retinal diseases (IRDs) are genetically and phenotypically diverse, and they cause significant morbidity worldwide. Importantly, IRDs may be amenable to precision medicine strategies, and thus the molecular characterisation of causative variants is becoming increasingly important with the promise of personalised therapies on the horizon. ABCA4, involved in the translocation of visual cycle derivatives, is a well-established, frequent cause of IRDs worldwide, with pathogenic variants implicated in phenotypically diverse diseases. Identification of causative ABCA4 variants in some individuals, however, has been enigmatic, and resolution of this issue is currently a hotbed of research. Recent evidence has indicated that hypomorphic alleles, which cause disease under certain conditions, may account for some of the missing causal variants. It has been postulated that the ABCA4 c.5603A>T (p.Asn1868Ile) variant, previously considered benign, be reclassified as hypomorphic when in cis configuration with c.2588G>C (p.Gly863Ala/Gly863del), a variant previously considered to be pathogenic in its own right. We are exploring this relationship within an Australian cohort to test this theory.

HLA allele and haplotype diversity in the Croatian population: State of the art.

The aim of this report was to compare our data with data presented in the European Federation for Immunogenetics (EFI) catalogue (version 1.0) and to evaluate whether or not current (CUR) HLA alleles found in the Croatian population fall into the same categories of common (COM) or well-documented (WD) HLA alleles as those listed in the EFI catalogue. Among 237 HLA-A, -B, -DRB1 alleles observed in the Croatian population so far, 181 alleles were observed ≥3 times. According to our criteria, 36 alleles at HLA-A locus, 71 alleles at HLA-B locus and 51 alleles at HLA-DRB1 locus were characterised as CUR in Croatia (COM or WD in EFI catalogue), while 23 local HLA alleles are not listed at all among COM or WD alleles in EFI catalogue.