Haplotype A1 Research Articles

Insights into the Genetic Determination of the Autotetraploid Potato Plant Height.

Plant height is an important characteristic, the modification of which can improve the ability of stress adaptation as well as the yield. In this study, genome-wide association analysis was performed for plant height traits in 370 potato cultivars using the tetraploid potato genome as a reference. A total of 92 significant single nucleotide polymorphism (SNP) loci for plant height were obtained, which were particularly significant in haplotypes A3 and A4 on chromosome 1 and A1, A2, and A4 on chromosome 5. Thirty-five candidate genes were identified that were mainly involved in the gibberellin and brassinolide signal transduction pathways, including the FAR1 gene, methyltransferase, ethylene response factor, and ubiquitin protein ligase. Among them, PIF3 and GID1a were only present on chromosome 1, with PIF3 in all four haplotypes and GID1a in haplotype A3. This could lead to more effective genetic loci for molecular marker-assisted selection breeding as well as more precise localization and cloning of genes for plant height traits in potatoes.

Spanish HTT gene study reveals haplotype and allelic diversity with possible implications for germline expansion dynamics in Huntington disease.

We aimed to determine the genetic diversity and molecular characteristics of the Huntington disease (HD) gene (HTT) in Spain. We performed an extended haplotype and exon one deep sequencing analysis of the HTT gene in a nationwide cohort of population-based controls (n = 520) and families with symptomatic individuals referred for HD genetic testing. This group included 331 HD cases and 140 carriers of intermediate alleles. Clinical and family history data were obtained when available. Spanish normal alleles are enriched in C haplotypes (40.1%), whereas A1 (39.8%) and A2 (31.6%) prevail among intermediate and expanded alleles, respectively. Alleles ≥ 50 CAG repeats are primarily associated with haplotypes A2 (38.9%) and C (32%), which are also present in 50% and 21.4%, respectively, of HD families with large intergenerational expansions. Non-canonical variants of exon one sequence are less frequent, but much more diverse, in alleles of ≥27 CAG repeats. The deletion of CAACAG, one of the six rare variants not observed among smaller normal alleles, is associated with haplotype C and appears to correlate with larger intergenerational expansions and early onset of symptoms. Spanish HD haplotypes are characterized by a high genetic diversity, potentially admixed with other non-Caucasian populations, with a higher representation of A2 and C haplotypes than most European populations. Differences in haplotype distributions across the CAG length range support differential germline expansion dynamics, with A2 and C showing the largest intergenerational expansions. This haplotype-dependent germline instability may be driven by specific cis-elements, such as the CAACAG deletion.

The Roles of Gut Microbiome and Plasma Metabolites in the Associations between ABO Blood Groups and Insulin Homeostasis: The Microbiome and Insulin Longitudinal Evaluation Study (MILES).

Non-O blood groups are associated with decreased insulin sensitivity and risk of type 2 diabetes. A recent study pinpointed the associations between ABO blood groups and gut microbiome, which may serve as potential mediators for the observed increased disease risks. We aimed to characterize associations between ABO haplotypes and insulin-related traits as well as potential mediating pathways. We assessed insulin homeostasis in African Americans (AAs; n = 109) and non-Hispanic whites (n = 210) from the Microbiome and Insulin Longitudinal Evaluation Study. The ABO haplotype was determined by six SNPs located in the ABO gene. Based on prior knowledge, we included 21 gut bacteria and 13 plasma metabolites for mediation analysis. In the white study cohort (60 ± 9 years, 42% male), compared to the O1 haplotype, A1 was associated with a higher Matsuda insulin sensitivity index, while a lower relative abundance of Bacteroides massiliensis and lactate levels. Lactate was a likely mediator of this association but not Bacteroides massiliensis. In the AAs group (57 ± 8 years, 33% male), we found no association between any haplotype and insulin-related traits. In conclusion, the A1 haplotype may promote healthy insulin sensitivity in non-Hispanic whites and lactate likely play a role in this process but not selected gut bacteria.

A continental-scale survey of Wolbachia infections in blue butterflies reveals evidence of interspecific transfer and invasion dynamics.

Infections by maternally inherited bacterial endosymbionts, especially Wolbachia, are common in insects and other invertebrates but infection dynamics across species ranges are largely under studied. Specifically, we lack a broad understanding of the origin of Wolbachia infections in novel hosts, and the historical and geographical dynamics of infections that are critical for identifying the factors governing their spread. We used Genotype-by-Sequencing data from previous population genomics studies for range-wide surveys of Wolbachia presence and genetic diversity in North American butterflies of the genus Lycaeides. As few as one sequence read identified by assembly to a Wolbachia reference genome provided high accuracy in detecting infections in host butterflies as determined by confirmatory PCR tests, and maximum accuracy was achieved with a threshold of only 5 sequence reads per host individual. Using this threshold, we detected Wolbachia in all but 2 of the 107 sampling localities spanning the continent, with infection frequencies within populations ranging from 0% to 100% of individuals, but with most localities having high infection frequencies (mean = 91% infection rate). Three major lineages of Wolbachia were identified as separate strains that appear to represent 3 separate invasions of Lycaeides butterflies by Wolbachia. Overall, we found extensive evidence for acquisition of Wolbachia through interspecific transfer between host lineages. Strain wLycC was confined to a single butterfly taxon, hybrid lineages derived from it, and closely adjacent populations in other taxa. While the other 2 strains were detected throughout the rest of the continent, strain wLycB almost always co-occurred with wLycA. Our demographic modeling suggests wLycB is a recent invasion. Within strain wLycA, the 2 most frequent haplotypes are confined almost exclusively to separate butterfly taxa with haplotype A1 observed largely in Lycaeides melissa and haplotype A2 observed most often in Lycaeides idas localities, consistent with either cladogenic mode of infection acquisition from a common ancestor or by hybridization and accompanying mutation. More than 1 major Wolbachia strain was observed in 15 localities. These results demonstrate the utility of using resequencing data from hosts to quantify Wolbachia genetic variation and infection frequency and provide evidence of multiple colonizations of novel hosts through hybridization between butterfly lineages and complex dynamics between Wolbachia strains.

Hydrophilic But Not Hydrophobic Surfactant Protein Genetic Variants Are Associated With Severe Acute Respiratory Syncytial Virus Infection in Children.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection-related hospitalization in the first year of life. Surfactant dysfunction is central to pathophysiologic mechanisms of various pulmonary diseases including RSV. We hypothesized that RSV severity is associated with single nucleotide polymorphisms (SNPs) of surfactant proteins (SPs). We prospectively enrolled 405 RSV-positive children and divided them into moderate and severe RSV disease. DNA was extracted and genotyped for sixteen specific SP gene SNPs. SP-A1 and A2 haplotypes were assigned. The association of RSV severity with SP gene SNPs was investigated by multivariate logistic regression. A likelihood ratio test was used to test the goodness of fit between two models (one with clinical and demographic data alone and another that included genetic variants). p ≤ 0.05 denotes statistical significance. A molecular dynamics simulation was done to determine the impact of the SFTPA2 rs1965708 on the SP-A behavior under various conditions. Infants with severe disease were more likely to be younger, of lower weight, and exposed to household pets and smoking, as well as having co-infection on admission. A decreased risk of severe RSV was associated with the rs17886395_C of the SFTPA2 and rs2243639_A of the SFTPD, whereas an increased risk was associated with the rs1059047_C of the SFTPA1. RSV severity was not associated with SNPs of SFTPB and SFTPC. An increased risk of severe RSV was associated with the 1A0 genotype of SFTPA2 in its homozygous or heterozygous form with 1A3. A molecular dynamic simulation study of SP-A variants that differ in amino acid 223, an important amino acid change (Q223K) between 1A0 and 1A3, showed no major impact on the behavior of these two variants except for higher thermodynamic stability of the K223 variant. The likelihood ratio test showed that the model with multi-allelic variants along with clinical and demographic data was a better fit to predict RSV severity. In summary, RSV severity was associated with hydrophilic (but not with hydrophobic) SPs gene variants. Collectively, our findings show that SP gene variants may play a key role in RSV infection and have a potential role in prognostication.

Are H1 and H3 haplotypes of endothelial protein C receptor (PROCR) an important factor in contracting COVID‐19?

The development of cardiovascular disease shows increase after contracting coronavirus 2019(COVID-19) disease and myocardial damage is observed in patients who have had the disease severely. The relationship between genetic cardiovascular risk factors with COVID-19infection was investigated in our study.One hundred thirty-five patients, 27 of whom were COVID-19 (-) and 108 were COVID-19 (+) patients, were included in the study. Patients were divided into three groups ([COVID-19[-], COVID-19[+]asymptomatic, and COVID-19 [+]symptomatic + patients with pulmonary involvement]). Genetic cardiovascular risk factors were examined in blood samples taken from the patients with new generation sequencing analysis.In the clinical classification, there were no significant differences between the three groups in fibrinogen beta chain-455G>A, human platelet antigen 1 (HPA1b)/platelet receptor GPIIIa/(ITGB3)(HPA1a/b; GpIIIa; integrin beta 3 L33P), ACE I/D, AGT (M268T), AGTR1 (1166A>C), Apo E (E2/E3/E4) (rs7412, rs429358), eNOS (786T>C), eNOS (894G>T) genes (p > 0.05). However, significant differences were observed in PROCR H3 haplotype/G (endothelial protein C receptor gene[EPCR] 4600A>G [A3 haplotype]), PROCR H1 haplotype/C (EPCR 4678G>C [A1 haplotype])genes (p < 0.05). When COVID-19 (+) and COVID-19 (-) groups were compared, it was observed that the infection was more common in people with PROCR H1 haplotype/C and PROCR H3 haplotype/G genotypes (p < 0.05).PROCR H1 and PROCR H3 haplotypes may be an important factor in contracting COVID-19 disease. In people with COVID-19 disease, revealing PROCR genetic differences and measuring sEPCR levels will be beneficial in the follow-up of the disease.

Morphometric and mitochondrial variation of Apis mellifera L. and its relationship with geographical variables in parts of West and Central Africa

In order to investigate the geographical distribution of morphological and mitochondrial variation of the Western honey bee in West and Central Africa, 175 colonies, sampled from 44 localities (or a subset therefrom), were subjected to geometric morphometric (GM), traditional morphometric (TM) and mitochondrial DNA analyses. The shape of the forewing differed significantly between the three ecological zones (rainforest, savanna and Sahel) and significantly correlated with latitude, longitude and altitude. A one-way ANOVA revealed a highly significant difference between the ecological zones in respect of the size of the forewing. Based on TM, no clear geographic clustering was observed, and the samples could not be unambiguously assigned to reference data of A. m. adansonii or A. m. jemenitica. However, a conspicuous geographic pattern was observed, with bees increasing in size northward in the west of the area, but southward in the east. Four mitochondrial haplotypes, previously reported from Africa, were found: A1 (n = 60), A4 (n = 58), A4′ (n = 14) and A14 (n = 1). The overall haplotype diversity was low (h = 0.485 ± S. E. 0.062) and small bees were found to bear the A1 haplotype while large bees had either A4 or A4′ haplotype.

No effect of abscisic and p-coumaric acids as food supplements and stimulants of the immunological system of Africanized hybrids of Apis mellifera

Bee colonies determined as Apis mellifera scutellata haplotype A1 were administered with a food supplement of sugar syrup mixed with p-coumaric acid (CUM), to test its supposed antioxidant effects; abscisic acid (ABA), to test whether it promotes innate immunity in bees, the combination of both (ABACUM), and syrup as a control. During three months, the number of cells with brood, honey and pollen reserves, as well as the concentration of hemocytes in worker bees were counted. Besides, Varroa destructor and Nosema ceranae were monitored. At the concentrations used, ABA and CUM had no effect on oviposition; however, there was a significant increase in the number of cells with brood or with honey and pollen reserves between the beginning and the end of the study. Regarding the monitoring of V. destructor, there were no significant differences between treatments; this mite did not cause obvious damage, seemingly because the experimental (Africanized) bees are considered tolerant to its infestation. There were no significant differences between treatments in infection by N. ceranae; however, there was a significant decrease in intensity, prevalence, and abundance of spores between the beginning and the end of the study, which was associated with the fact that the bees collected nectar and this resulted in the development of colonies. The number of hemocytes did not show a significant difference between treatments, but there was a significant increase between the first and the last evaluation. Neither ABA, CUM or ABACUM produced the predicted effects on the experimental bees.

Defensive Behavior and Morphometric Variation in Apis mellifera Colonies From Two Different Agro-Ecological Zones of North-Western Argentina

European lineages of Apis mellifera were first introduced into America for beekeeping purposes. A subsequent introduction and accidental release of A. m. scutellata resulted in hybridization events that gave rise to Africanized populations that rapidly spread throughout the continent. In Argentina, Africanized honey bees (AHBs) have been mostly detected in northern regions of the territory, and represent a valuable genetic resource for the selection of stocks with advantageous characteristics for beekeeping. The objective of the present study was to profile honey bee colonies of wild origin with potential beneficial traits for apiculture using morphological, molecular and behavioral traits. Honey bee colonies chosen for evaluation were located in two different agro-ecological regions in north-western Argentina (Tucumán province): The Chaco Depressed Plain (Leales apiary) and the Piedmont (Famaillá apiary). Each apiary was surveyed three times during the 2017–2018 season (mid-season, wintertime, and early spring) for: brood population, phoretic Varroa level and defensive behavior (run, fly, sting, and hang). At the midpoint of the beekeeping season colonies were also characterized by morphometry (45 variables) and mitochondrial haplotypes (COI–COII intergenic region). Apiaries studied showed similar patterns throughout the beekeeping season, for most of the characteristics monitored. However, significant variation in defensive behavior parameters was found between apiaries at the different times of evaluation. Twelve of 45 morphometric variables also showed significant differences between apiaries. The mitochondrial haplotype analysis revealed a high representation of African A4 and A1 haplotypes (91%) in both apiaries. Haplotype variation was associated with morphometric and behavioral traits. Multivariate analyses [principal component analysis (PCA) and principal coordinate analysis (PCoA)] including morphometric and behavior variables explained 65.3% (PCA) and 48.1% (PCoA) of the variability observed between colonies in the first two components. Several morphometric parameters and “fly” behavior were mainly associated with the separation of the colonies. The results from this study point to a possible association between morphometric and behavioral variation and the adaptation of honey bee colonies to differential agro-ecological conditions. We discuss how the detected variation between apiaries can be used for the selection and preservation of honey bee ecotypes in regional breeding programs.

Genetic susceptibility to multiple sclerosis in African Americans.

ObjectiveTo explore the nature of genetic-susceptibility to multiple sclerosis (MS) in African-Americans.BackgroundRecently, the number of genetic-associations with MS has exploded although the MS-associations of specific haplotypes within the major histocompatibility complex (MHC) have been known for decades. For example, the haplotypes HLA-DRB1*15:01~HLA-DQB1*06:02, and HLA-DRB1*03:01~ HLA-DQB1*02:01 have odds ratios (ORs) for an MS-association orders of magnitude stronger than many of these newly-discovered associations. Nevertheless, all these haplotypes are part of much larger conserved extended haplotypes (CEHs), which span both the Class I and Class II MHC regions. African-Americans are at greater risk of developing MS compared to a native Africans but at lesser risk compared to Europeans. It is the purpose of this manuscript to explore the relationship between MS-susceptibility and the CEH make-up of our African-American cohort.Design/methodsThe African-American (AA) cohort consisted of 1,305 patients with MS and 1,155 controls, who self-identified as being African-American. For comparison, we used the 18,492 controls and 11,144 MS-cases from the predominantly European Wellcome Trust Case Control Consortium (WTCCC) and the 28,557 phased native Africans from the multinational “Be the Match” registry. The WTCCC and the African-Americans were phased at each of five HLA loci (HLA-A, HLA-C, HLA-B, HLA-DRB1 and HLA-DQB1) and the at 11 SNPs (10 of which were in non-coding regions) surrounding the Class II region of the DRB1 gene using previously-published probabilistic phasing algorithms.ResultsOf the 32 most frequent CEHs, 18 (56%) occurred either more frequently or exclusively in Africans) whereas 9 (28%) occurred more frequently or exclusively in Europeans. The remaining 5 CEHs occurred in neither control group although, likely, these were African in origin. Eight of these CEHs carried the DRB1*15:03~DQB1*06:02~a36 haplotype and three carried the DRB1*15:01~DQB1*06:02~a1 haplotype. In African Americans, a single-copy of the European CEH (03:01_07:02_07:02_15:01_06:02_a1) was associated with considerable MS-risk (OR = 3.30; p = 0.0001)–similar to that observed in the WTCCC (OR = 3.25; p<10−168). By contrast, the MS-risk for the European CEH (02:01_07:02_07:02_15:01_06:02_a1) was less (OR = 1.49; ns)–again, similar to the WTCCC (OR = 2.2; p<10−38). Moreover, four African haplotypes were “protective” relative to a neutral reference, to three European CEHs, and also to the five other African CEHs.ConclusionsThe common CEHs in African Americans are divisible into those that are either African or European in origin, which are derived without modification from their source population. European CEHs, linked to MS-risk, in general, had similar impacts in African-Americans as they did in Europeans. By contrast, African CEHs had mixed MS-risks. For a few, the MS-risk exceeded that in a neutral-reference group whereas, for many others, these CEHs were “protective”–perhaps providing a partial rationale for the lower MS-risk in African-Americans compared to European-Americans.

Genetic variation inLUMAN/CREB3and association with stress and meat quality traits in Yorkshire pigs

LUMAN/CREB3 is a stress regulatory gene that affects the activity of the hypothalamic–pituitary–adrenal axis in mice and presents a promising avenue for exploring variable stress-responsiveness in pigs. Pigs with similar characteristics to LUMAN-deficient mice, including greater resilience to stress and receptivity to human handling, would be valuable in the pork industry from animal welfare and production efficiency perspectives. We previously identified eight genetic variations and five haplotypes throughout the LUMAN locus in Yorkshire pigs. In this study, we analysed associations between LUMAN variations with behavioural stress response during three tests (open field test, novel object test, and human approach test), physiological stress responsiveness (cortisol), and carcass/meat quality measurements from purebred Yorkshire pigs. Haplotypes A1 and A2 were associated with decreased activity levels in novel environments and greater plasma cortisol concentrations at slaughter. Haplotype A1 was associated with lower carcass scratch scores and meat with lower cooking losses and greater tenderness. Haplotypes B1 and B2 were associated with the opposite traits including increased activity levels in novel environments and characteristics for lower meat quality including greater cooking losses, lower marbling, and paler coloured meat. We conclude that DNA variations in the LUMAN locus could potentially be used as genetic markers for stress resistance and meat quality in pig breeding.

The nature of genetic and environmental susceptibility to multiple sclerosis.

To understand the nature of genetic and environmental susceptibility to multiple sclerosis (MS) and, by extension, susceptibility to other complex genetic diseases. Certain basic epidemiological parameters of MS (e.g., population-prevalence of MS, recurrence-risks for MS in siblings and twins, proportion of women among MS patients, and the time-dependent changes in the sex-ratio) are well-established. In addition, more than 233 genetic-loci have now been identified as being unequivocally MS-associated, including 32 loci within the major histocompatibility complex (MHC), and one locus on the X chromosome. Despite this recent explosion in genetic associations, however, the association of MS with the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 (H+) haplotype has been known for decades. We define the "genetically-susceptible" subset (G) to include everyone with any non-zero life-time chance of developing MS. Individuals who have no chance of developing MS, regardless of their environmental experiences, belong to the mutually exclusive "non-susceptible" subset (G-). Using these well-established epidemiological parameters, we analyze, mathematically, the implications that these observations have regarding the genetic-susceptibility to MS. In addition, we use the sex-ratio change (observed over a 35-year interval in Canada), to derive the relationship between MS-probability and an increasing likelihood of a sufficient environmental exposure. We demonstrate that genetic-susceptibitly is confined to less than 7.3% of populations throughout Europe and North America. Consequently, more than 92.7% of individuals in these populations have no chance whatsoever of developing MS, regardless of their environmental experiences. Even among carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, far fewer than 32% can possibly be members the (G) subset. Also, despite the current preponderance of women among MS patients, women are less likely to be in the susceptible (G) subset and have a higher environmental threshold for developing MS compared to men. Nevertheless, the penetrance of MS in susceptible women is considerably greater than it is in men. Moreover, the response-curves for MS-probability in susceptible individuals increases with an increasing likelihood of a sufficient environmental exposure, especially among women. However, these environmental response-curves plateau at under 50% for women and at a significantly lower level for men. The pathogenesis of MS requires both a genetic predisposition and a suitable environmental exposure. Nevertheless, genetic-susceptibility is rare in the population (< 7.3%) and requires specific combinations of non-additive genetic risk-factors. For example, only a minority of carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype are even in the (G) subset and, thus, genetic-susceptibility to MS in these carriers must result from the combined effect this haplotype together with the effects of certain other (as yet, unidentified) genetic factors. By itself, this haplotype poses no MS-risk. By contrast, a sufficient environmental exposure (however many events are involved, whenever these events need to act, and whatever these events might be) is common, currently occurring in, at least, 76% of susceptible individuals. In addition, the fact that environmental response-curves plateau well below 50% (especially in men), indicates that disease pathogenesis is partly stochastic. By extension, other diseases, for which monozygotic-twin recurrence-risks greatly exceed the disease-prevalence (e.g., rheumatoid arthritis, diabetes, and celiac disease), must have a similar genetic basis.

Association between ABO haplotypes and the risk of venous thrombosis: impact on disease risk estimation

AbstractGenetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, ∼1.2), the A1 and B haplotypes are associated with an ∼1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, ∼0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.

Genetic and Environmental Susceptibility to Multiple Sclerosis

OBJECTIVE: To explore the nature and basis of environmental and genetic susceptibility to multiple sclerosis (MS). BACKGROUND Susceptibility to multiple sclerosis (MS) is complex but clearly involves both environmental events and genetic factors. Certain epidemiological observations regarding MS (e.g., proportion of women among MS patients, population-prevalence of MS, impact of birth-month and migration patterns on the likelihood of MS, recurrence-risks for MS in siblings and twins, and time-dependent changes in MS-prevalence and the female to male sex-ratio) are well-established. DESIGN/METHODS: We define the “genetically-susceptible” subset (G) to include everyone with any non-zero life-time chance of developing MS. Individuals who have no chance of developing MS, regardless of their environmental experiences, belong to the mutually exclusive “non-susceptible” subset (G–). We consider the implications that these well-established epidemiological observations have regarding the genetic and environmental basis of susceptibility to MS. In addition, we use the change in the female to male sex ratio, observed over a 35-year interval in Canada, to construct the response curves relating an increasing likelihood of MS to an increasing probability of a susceptible individual experiencing an environmental exposure sufficient to cause MS. RESULTS: Environmental susceptibility to MS requires at least three different events – one occurring during the intrauterine or early post-natal period, another during childhood or adolescence, and a third (or more) many years later. Vitamin D deficiency and Epstein-Barr viral infections are likely involved. Moreover, we demonstrate that only a very small fraction of the general populations throughout Europe and North America is susceptible to MS. The vast majority of individuals in these populations has no chance whatsoever of developing MS, regardless of their environmental experiences. Even among carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, only a small minority can possibly be members the (G) subset. Also, despite the preponderance of women among MS patients, compared to men, women are less likely to be susceptible and have a higher environmental threshold for developing MS. Nevertheless, the penetrance of MS in susceptible women is substantially greater than it is in men. Moreover, MS-probability in susceptible individuals increases with an increasing likelihood of a sufficient environmental exposure, especially among women. However, these response-curves plateau at under 50% for women and at a significantly lower level for men. CONCLUSIONS: The pathogenesis of MS requires both a genetic predisposition and a suitable environmental exposure. Nevertheless, genetic-susceptibility is rare in the population and requires specific combinations of non-additive genetic risk-factors. By contrast, a sufficient environmental exposure (however many events are involved, whenever these events need to act, and whatever these events might be) is common, currently occurring in, at least, 76% of susceptible individuals. In addition, the environmental response-curves (especially in men) plateau well below 50%, which indicates that disease pathogenesis is partially stochastic.

Characterization of glycerol-3-phosphate acyltransferase 9 (AhGPAT9) genes, their allelic polymorphism and association with oil content in peanut (Arachis hypogaea L.)

GPAT, the rate-limiting enzyme in triacylglycerol (TAG) synthesis, plays an important role in seed oil accumulation. In this study, two AhGPAT9 genes were individually cloned from the A- and B- genomes of peanut, which shared a similarity of 95.65%, with 165 site differences. The overexpression of AhGPAT9 or the knock-down of its gene expression increased or decreased the seed oil content, respectively. Allelic polymorphism analysis was conducted in 171 peanut germplasm, and 118 polymorphic sites in AhGPAT9A formed 64 haplotypes (a1 to a64), while 94 polymorphic sites in AhGPAT9B formed 75 haplotypes (b1 to b75). The haplotype analysis showed that a5, b57, b30 and b35 were elite haplotypes related to high oil content, whereas a7, a14, a48, b51 and b54 were low oil content types. Additionally, haplotype combinations a62/b10, a38/b31 and a43/b36 were associated with high oil content, but a9/b42 was a low oil content haplotype combination. The results will provide valuable clues for breeding new lines with higher seed oil content using hybrid polymerization of high-oil alleles of AhGPAT9A and AhGPAT9B genes.

Distribution of the HTT Gene A1 and A2 Haplotypes Worldwide: A Systematic Review.

Huntington's disease (HD)(MIM:143100) is an severe autosomal dominant neurodegenerative disease caused by the dynamic expansion of CAG trinucleotides (> 35) in the HTT gene [Genomic Coordinates- (GRCh38):4:3,074,680-3,243,959]. The aim of this systematic review was to investigate the reported associations between the frequencies of the A1 and A2 haplotypes in HD-affected and non-affected populations from different countries on different continents, in order to demonstrate the overall profile of these haplotypes worldwide, pointing towards the most frequent haplotypes that could be useful for HTT mutant-specific allele silencing in different populations. Publications in MEDLINE (PubMed) and Embase from the last 10 years (PROSPERO CRD42018115282) were assessed. A total of 20 articles from 113 were selected for evaluation in their entirety, and eight were eligible for this study. Regardless of the size of the CAG tract, the articles included in this review demonstrate that populations with high HD prevalence present higher frequencies of the A1 or A2 haplotypes than populations exhibiting low HD prevalence, even when similar average CAG numbers are noted. Based on the presented articles, we suggest that the haplotypic profile is more closely related to the ancestral origin than to the size of the CAG tract. The identification of populations presenting a higher frequency of high-risk genotypes can contribute to more accurate genetic counseling, in addition to providing knowledge on HD epidemiology. According to the continued progress in the development of specific genetic silencing therapies by different research groups and pharmaceutical companies, such as haplotype targeting strategies for allele-specific HTT suppression, we conclude that the definition of haplotypes in phase with CAG expansions will contribute to the design of gene-silencing drugs specific for different populations worldwide.

TP53 p.Arg337His geographic distribution correlates with adrenocortical tumor occurrence.

BackgroundThe p.Arg337His mutation of the TP53 is the most frequent germline missense variant associated with cancer described so far in this gene. It is mainly found in the South and Southeastern regions of Brazil, where it has been associated with a high incidence of pediatric adrenocortical (ACT) and choroid plexus tumors. The frequency and geographic distribution of this mutation is largely unknown, except for the Parana State, where a mean prevalence of 0.27% was reported. In the present study, we developed a high‐throughput method for p.Arg337His genotyping, what allowed us to determine the frequency and geographic distribution of this mutation in a cohort from the most populous state in Brazil.MethodsConsecutive samples from 31,612 newborns from São Paulo State were screened for p.Arg337His. The allelic discrimination was done by real‐time polymerase chain reaction (PCR) and the presence of haplotype A3 in carriers was examined by using allele‐specific oligonucleotide PCR, followed by nested‐PCR to detect the SNP rs9894946.ResultsWe found 67 (0.21%) samples positive for this mutation. The highest p.Arg337His frequencies were found in the cities close to the boundary between São Paulo and Minas Gerais State. No association could be found between p.Arg337His and gender, ethnicity, premature birth or twinning. Remarkably, a trend was found between the geographic distribution of p.Arg337His carriers and occurrence of ACT.ConclusionWe presented for the first time the p.Arg337His frequency among individuals unselected for any disease from a subset of the São Paulo State, the most populous in Brazil. The allele discrimination assay we presented here has proven to be a reliable and efficient method for high‐throughput genotyping. ACT was found to be a good sentinel cancer to suppose p.Arg337His presence in our region.

Genetic diversity of Echinococcus multilocularis and Echinococcus granulosus sensu lato in Kyrgyzstan: The A2 haplotype of E. multilocularis is the predominant variant infecting humans.

Alveolar and cystic echinococcosis (AE, CE) caused by E. multilocularis and E. granulosus s.l., respectively, are considered emerging zoonotic diseases in Kyrgyzstan with some of the world highest regional incidences. Little is known regarding the molecular variability of both species in Kyrgyzstan. In this study we provide molecular data from a total of 72 parasite isolates derived from humans (52 AE and 20 CE patients) and 43 samples from dogs (23 infected with E. multilocularis and 20 with E. granulosus s.l.).Genetic variability in E. multilocularis was studied using the concatenated complete sequences of the cob, nad2 and cox1 mitochondrial genes adding a total of 3,558bp per isolate. The cob/nad2/cox1 A2 haplotype was identified in 63.4% of the human and in 65.2% of the dog samples. This haplotype was originally described in samples from Kazakhstan and St. Lawrence Island (Alaska, USA). We also describe here 16 non-previously defined variants of E. multilocularis (called A11-A26). All haplotypes cluster together within the Asian group in the haplotype network. Based on Fst values, low level of genetic differentiation was found between the populations of E. multilocularis isolated from different regions within the country. However, high degree of differentiation was found when all the concatenated sequences from Kyrgyzstan are considered as a single population and compared with the population of the parasite from the neighbouring country China. In the case of E. granulosus s.l. the analysis was based in 1,609bp of the cox1 gene. One isolate from a dog was identified as E. equinus, while all the other sequences were identified belonging to E. granulosus s.s. In total, 24 cox1 haplotypes of E. granulosus s.s. were identified including the already described variants: Eg01 (in 6 samples), Eg33 (in 4 samples), EgCl04 (in 2 samples), Eg03 (in 1 sample) and Eg32 (in 1 sample). From the twenty-five other isolates of E. granulosus s.s. a total of 19 non-previously described cox1 haplotypes were identified and named as EgKyr1 to EgKyr19. The most common haplotype infecting human is the EgKyr1 which was found in 5 isolates.The cob/nad2/cox1 A2 haplotype of E. multilocularis is responsible for the majority of human infections in Kyrgyzstan and is also found in the majority of dogs included in this study. Further similar studies in different parts of Asia could elucidate if it is also the most common variant infecting humans in other countries. It remains unknown if this particular haplotype presents differences in virulence which could have contributed to the emergency of alveolar echinococcosis in Kyrgyzstan. In the case of E. granulosus s.s. it seems that there is no dominant haplotype infecting humans in Kyrgzstan. Further characterization of biological or antigenic features of dominant mitochondrial haplotypes could help to elucidate if they present differences which could be relevant in the diagnostic, pathogenicity or in the host/parasite interaction when infecting humans.

A Comprehensive Haplotype-Targeting Strategy for Allele-Specific HTT Suppression in Huntington Disease

Huntington disease (HD) is a fatal neurodegenerative disorder caused by a gain-of-function mutation in HTT. Suppression of mutant HTT has emerged as a leading therapeutic strategy for HD, with allele-selective approaches targeting HTT SNPs now in clinical trials. Haplotypes associated with the HD mutation (A1, A2, A3a) represent panels of allele-specific gene silencing targets for efficient treatment of individuals with HD of Northern European and indigenous South American ancestry. Here we extend comprehensive haplotype analysis of the HD mutation to key populations of Southern European, South Asian, Middle Eastern, and admixed African ancestry. In each of these populations, the HD mutation occurs predominantly on the A2 HTT haplotype. Analysis of HD haplotypes across all affected population groups enables rational selection of candidate target SNPs for development of allele-selective gene silencing therapeutics worldwide. Targeting SNPs on the A1 and A2 haplotypes in parallel is essential to achieve treatment of the most HD-affected subjects in populations where HD is most prevalent. Current allele-specific approaches will leave a majority of individuals with HD untreated in populations where the HD mutation occurs most frequently on the A2 haplotype. We further demonstrate preclinical development of potent and selective ASOs targeting SNPs on the A2 HTT haplotype, representing an allele-specific treatment strategy for these individuals. On the basis of comprehensive haplotype analysis, we show the maximum proportion of HD-affected subjects that may be treated with three or four allele targets in different populations worldwide, informing current allele-specific HTT silencing strategies.

HTT haplogroups in Finnish patients with Huntington disease.

ObjectiveTo study genetic causes of the low frequency of Huntington disease (HD) in the Finnish population, we determined HTT haplogroups in the population and patients with HD and analyzed intergenerational Cytosine-Adenosine-Guanosine (CAG) stability.MethodsA national cohort of patients with HD was used to identify families with mutant HTT (mHTT). HTT haplogroups were determined in 225 archival samples from patients and from 292 population samples. CAG repeats were phased with HTT haplotypes using data from parent-offspring pairs and other mHTT carriers in the family.ResultsThe allele frequencies of HTT haplotypes in the Finnish population differed from those in 411 non-Finnish European subjects (p < 0.00001). The frequency of haplogroup A was lower than that in Europeans and haplogroup C was higher. Haplogroup A alleles were significantly more common in patients than in controls. Among patients with HD haplotypes A1 and A2 were more frequent than among the controls (p = 0.003). The mean size of the CAG repeat change was +1.38 units in paternal transmissions being larger than that (−0.17) in maternal transmissions (p = 0.008). CAG repeats on haplogroup A increased by 3.18 CAG units in paternal transmissions, but only by 0.11 units in maternal transmissions (p = 0.008), whereas haplogroup C repeat lengths decreased in both paternal and maternal transmissions.ConclusionsThe low frequency of HD in Finland is partly explained by the low frequency of the HD-associated haplogroup A in the Finnish population. There were remarkable differences in intergenerational CAG repeat dynamics that depended on HTT haplotype and parent gender.