Ancestral Haplotype Research Articles

Long contiguous stretches of homozygosity detected by chromosomal microarrays (CMA) in patients with neurodevelopmental disorders in the South of Brazil

BackgroundCurrently, chromosomal microarrays (CMA) are recommended as first-tier test in the investigation of developmental disorders to examine copy number variations. The modern platforms also include probes for single nucleotide polymorphisms (SNPs) that detect homozygous regions in the genome, such as long contiguous stretches of homozygosity (LCSH) also named runs of homozygosity (ROH). LCHS are chromosomal segments resulting from complete or segmental chromosomal homozygosity, which may be indicative of uniparental disomy (UPD), consanguinity, as well as replicative DNA repair events, however also are common findings in normal populations. Knowing common LCSH of a population, which probably represent ancestral haplotypes of low-recombination regions in the genome, facilitates the interpretation of LCSH found in patients, allowing to prioritize those with possible clinical significance. However, population records of ancestral haplotype derived LCSH by SNP arrays are still scarce, particularly for countries such as Brazil where even for the clinic, microarrays that include SNPs are difficult to request due to their high cost.MethodsIn this study, we evaluate the frequencies and implications of LCSH detected by Affymetrix CytoScan® HD or 750 K platforms in 430 patients with neurodevelopmental disorders in southern Brazil. LCSH were analyzed in the context of pathogenic significance and also explored to identify ancestral haplotype derived LCSH. The criteria for considering a region as LCSH was homozygosis ≥3 Mbp on an autosome.ResultsIn 95% of the patients, at least one LCSH was detected, a total of 1478 LCSH in 407 patients. In 2.6%, the findings were suggestive of UPD. For about 8.5% LCSH suggest offspring from first to fifth grade, more likely to have a clinical impact. Considering recurrent LCSH found at a frequency of 5% or more, we outline 11 regions as potentially representing ancestral haplotypes in our population. The region most involved with homozygosity was 16p11.2p11.1 (49%), followed by 1q21.2q21.3 (21%), 11p11.2p11.12 (19%), 3p21.31p21.2 (16%), 15q15 1q33p32.3 (12%), 2q11.1q12.1 (9%), 1p33p32.3 (6%), 20q11.21q11.23 (6%), 10q22.1q23.31 (5%), 6p22.2p22 (5%), and 7q11.22q11.23 (5%).ConclusionsIn this work, we show the importance and usefulness of interpreting LCSH in the results of CMA wich incorporate SNPs.

Increasing Levels of Serum Heat Shock Protein 70 Precede the Development of AIDS-Defining Non-Hodgkin Lymphoma Among Carriers of HLA-B8-DR3.

We hypothesized that carriage of presumably high Hsp70-producing gene variants on a specific human major histocompatibility complex haplotype, the 8.1 ancestral haplotype (8.1AH), may predispose HIV-infected individuals to AIDS-non-Hodgkin lymphoma (NHL). We compared serum Hsp70 levels in the years preceding the diagnosis of AIDS-NHL in a matched case-control study (n = 151 pairs) nested in the Multicenter AIDS Cohort Study. We tested the impact of 8.1AH-specific single-nucleotide polymorphism (SNP) and joint SNP-human leukocyte antigen extended haplotypes previously associated with AIDS-NHL in the Multicenter AIDS Cohort Study on the circulating Hsp70 levels in mixed linear models. We report elevated serum levels of Hsp70 in the 4 years preceding the diagnosis of AIDS-NHL in cases that carry 8.1AH, but not in noncarrier cases and not in carrier- or non-carrier-matched controls. The strongest predictor of higher serum Hsp70 was the haplotype A-G-A-C formed by SNPs rs537160(A) and rs1270942(G) in the complement factor CFB gene cluster, and rs2072633(A) and rs6467(C) in nearby RDBP and CYP21A2 located 70 Kb apart from the Hsp70 gene cluster. The association with A-G-A-C haplotype (beta = 0.718; standard error = 0.182; P = 0.0002) and with other 8.1AH-specific haplotypes including the high-producing tumor necrosis factor-alpha haplotype rs909253(G)-rs1800629(A) (beta = 0.308; standard error = 0.140; P = 0.032) were observed only with NHL identified as an AIDS-defining condition, but not as a post-AIDS condition, nor in combined AIDS and post-AIDS cases. Our combined genetic and functional approach suggests that the altered level of Hsp70 is a correlate of 8.1AH-mediated AIDS-NHL. Further investigation of the Hsp70 gene cluster and nearby loci that are tagged by A-G-A-C could better elucidate the genetic determinants of the malignancy.

Evaluation of an HMGA2 variant for pleiotropic effects on height and metabolic traits in ponies.

BackgroundPonies are highly susceptible to metabolic derangements including hyperinsulinemia, insulin resistance, and adiposity.Hypothesis/ObjectivesGenetic loci affecting height in ponies have pleiotropic effects on metabolic pathways and increase the susceptibility to equine metabolic syndrome (EMS).AnimalsTwo hundred ninety‐four Welsh ponies and 529 horses.MethodsRetrospective study of horses phenotyped for metabolic traits. Correlations between height and metabolic traits were assessed by Pearson's correlation coefficients. Complementary genome‐wide analysis methods were used to identify a region of interest (ROI) for height and metabolic traits, determine the fraction of heritability contributed by the ROI, and identify candidate genes.ResultsThere was an inverse relationship between height and baseline insulin (−0.26) in ponies. Genomic signature of selection and association analyses for both height and insulin identified the same ~1.3 megabase region on chromosome 6 that contained a shared ancestral haplotype between these traits. The ROI contributed ~40% of the heritability for height and ~20% of the heritability for insulin. High‐mobility group AT‐hook 2 was identified as a candidate gene, and Sanger sequencing detected a c.83G>A (p.G28E) variant associated with height in Shetland ponies. In our cohort of ponies, the A allele had a frequency of 0.76, was strongly correlated with height (−0.75), and was low to moderately correlated with metabolic traits including: insulin (0.32), insulin after an oral sugar test (0.25), non‐esterified fatty acids (0.19), and triglyceride (0.22) concentrations.Conclusions and Clinical ImportanceThese data have important implications for identifying individuals at risk for EMS.

Genetic structure, phylogeography, and migration routes of Bouteloua gracilis (Kunth) Lag. ex Griffiths (Poaceae:Chloridoideae)

Blue grama grass (Bouteloua gracilis) populations are found in widely variable environments, tolerating drought, alkaline soils and different levels of grazing. Many ploidy levels have been reported for this species that is also considered to be phenotypically plastic and morphologically variable. Recently a decline in its cover and frequency in the North American shortgrass steppe and central Mexico has been reported although much about the biology of the species is unknown, including genetic diversity throughout its distribution. Genetic and phylogeographic structure and phylogenetic relationships among B. gracilis were estimated employing next generation sequencing of a high number of SNPs and loci. Population genetics and Structure analyses were performed. We compared the marginal likelihoods of different migration models using MIGRATE and obtained the best population model of migration for our data. Demographic expansion of B. gracilis was observed graphically with a mismatch distribution obtained in DNAsp. Bayesian and Maximum Likelihood methods were used to resolve phylogenetic relationships among B. gracilis and its closely related species as well as within B. gracilis populations. B. gracilis is sister to the B. chasei and B. herrera arrietae clade. Among the populations of the species two highly supported clades were resolved, grouping samples from Mexico and USA respectively. Allele frequencies determined three population clusters: CUSA from the Great Plains, MEX from central and southern Mexico, and WUSA-NMEX from northern Mexico and the western mountainous region of USA, the latter of which contains an allele admixture of the other two clusters. The haplotype network revealed an ancestral haplotype originating in Mexico, from which the rest of the haplotypes diversified to the north. Both evidence of gene flow and isolation among populations was observed. Genetic clusters are not genetically structured and variation is higher among populations. The genetic and morphological data do not support recognition of ecotypes or infraespecific taxa. However, the Great Plains populations are least diverse, making them most vulnerable to environmental change.

Phylogeography of Asian sockeye salmon (Oncorhynchus nerka) based on the analysis of mtDNA D-loop polymorphism

Phylogeography of Asian sockeye salmon (Oncorhynchus nerka) based on the analysis of mtDNA D-loop polymorphism

Increased MHC Matching by C4 Gene Compatibility in Unrelated Donor Hematopoietic Stem Cell Transplantation.

HLA matching is a prerequisite for successful allogeneic hematopoietic stem cell transplantation (HSCT) because it lowers the occurrence and severity of graft-versus-host disease (GVHD). However, matching a few alleles of the classic HLA genes only may not ensure matching of the entire MHC region. HLA haplotype matching has been reported to be beneficial in HSCT because of the variation relevant to GVHD risk in the non-HLA region. Because polymorphism in the MHC is highly population specific, we hypothesized that donors from the Finnish registry are more likely to be matched at a higher level for the Finnish patients than donors from other registries. In the present study we determined 25 single nucleotide polymorphisms (SNPs) of the complement component 4 (C4) gene in the γ-block segment of MHC from 115 Finnish HSCT patients and their Finnish (n = 201) and non-Finnish (n = 280) donor candidates. Full matching of HLA alleles and C4 SNPs, independently or additively, occurred more likely in the Finnish-Finnish group as compared with the Finnish-non-Finnish group (P < .003). This was most striking in cases with HLA haplotypes typical of the Finnish population. Patients with ancestral HLA haplotypes (AH) were more likely to find a full HLA and C4 matched donor, regardless of donor origin, as compared with patients without AH (P < .0001). Despite the clear differences at the population level, we could not find a statistical association between C4 matching and clinical outcome. The results suggest that screening C4 SNPs can be advantageous when an extended MHC matching or HLA haplotype matching in HSCT is required. This study also supports the need for small population-specific stem cell registries.

When type 1 diabetes meets celiac disease.

Type1 diabetes (T1D) and celiac disease (CD) may occur together. HLA-DQ8 and DQ2 are key genetic risk factors in both. Overall, the patients with co-existing T1D and CD (T1D+CD) were shown to have HLA profile more similar to patients with T1D than those with CD. Slovenian patients with both diseases had the frequency of DQB1*02:01 (86.5%) very similar to patients with CD (83.8%) in contrast to the significantly different frequency of the same allele in patients with T1D (52.24%). The DQ2 conveyed higher risk for developing both T1D and CD in the same individual than DQ8. Additionally, the A1-B8-DR3-DQ2-MICA*008 ancestral haplotype (8.1AH) was over-represented in Slovenian (T1D+CD) patients, where B*08 was the most significant independent risk factor. Moreover, C*07, that is also present in the 8.1AH, could have an impact on the innate immunity rout of this susceptibility through interaction with KIRs. In the genotype context, the CD risk in T1D patients was associated with DR3-DQ2/DR3-DQ2, whereas the risk for T1D in CD patients was associated with DR3-DQ2/DR4-DQ8. Less frequent screening for the second disease related antibodies could be considered in patients with the first disease and low risk genotype for obtaining the second-one. Individuals carrying high risk DR3-DQ2/DR3-DQ2 or DR3-DQ2/DR4DQ8 are more likely to develop both autoimmune diseases together than individuals carrying any other HLA genotypes.

Structural Variation within the Beta-Globin Gene Cluster Among HbS Haplotype Groups

BACKGROUNDThe severity of sickle cell anemia (SCA) has been associated with five specific haplotypes in the beta globin cluster, identifiable by distinct patterns of restriction fragment length polymorphism (RFLP). These RFLP-defined haplotypes, named according to the region where they were first discovered - Central Africa region (CAR), Benin, Senegal, Arabic-Indian, and Cameroon - suggested that the sickle cell mutation arose recently at least four independent times in Africa, each time on a different genetic background, and again in India - the Multi-centric Sickle Cell Model. The beta-globin locus, however, is prone to extensive structural rearrangements, and alongside observations of ancestral sequence haplotypes extending several hundreds of kilobases beyond the beta globin cluster, it has been suggested that there is more cis-variation in the beta-globin gene cluster than is evident from RFLP analyses, and current definitions of RFLP haplotypes may not accurately reflect the ancestral origin of the sickle mutation. This undescribed cis-variation is important to understanding inter-individual phenotype variation associated with the different haplotypes.To better define this variation, we have undertaken extended, long-range molecular haplotyping of the beta-globin cluster on differing RFLP haplotype backgrounds using real time single molecule sequencing (SMS). The SMS approach generates long, unbroken reads with uniform coverage, thereby allowing for detailed molecular phasing of RFLP haplotypes and identification of local structural variation that would otherwise be hidden within the complex repetitive elements of the beta-globin cluster. In so doing, we plan to evaluate the molecular evidence for a single origin for the sickle cell allele and identify potential cis-acting, disease-modifying, candidate variants within the beta globin cluster.METHODSDNA from 200 SCA patients from three countries in sub-Saharan Africa - Nigeria, Cameroon, and Kenya - were collected after informed consent. RFLP analysis revealed the majority of the patients to be homozygous for the Benin and CAR haplotypes, with a smaller sampling of Cameroon, Senegal, and Atypical haplotypes. From this group we selected 40 samples - representing the four main classical RFLP haplotypes in sub-Saharan Africa - were selected for SMS. PCR was used to tile barcoded amplicons across the cluster. SMS was performed on a Sequel machine (Pacific Biosciences). The resulting FASTQ sequences were de-multiplexed, read quality control filters were applied, and mapped to human reference genome Hg38, prior to annotation and calling of single nucleotide variants (SNV) and structural variants (SV).RESULTSAnalyses have so far identified 227 insertions, 18 deletions, 7 duplications, 76 inversions and 13 translocations from long-read analyses of the initial 40 samples; the vast majority of these variants are not described in public variant databases. Atypical haplotypes demonstrated more translocation and duplication events than other haplotypes. Insertions ~48 kb upstream of the beta-globin locus control region and 1.3 kb upstream of gamma globin gene 2 (HBG2) were observed on 50% of Senegal and 45% of CAR haplotypes. Also, recurrent insertions ranging between 32bp and 1,184bp in length, 2.3 kb downstream of the beta globin gene (HBB), were seen on 50% of the Benin and 54% of the CAR haplotypes, but only once on Senegal haplotypes.CONCLUSIONSOur findings suggest there are more cis-SVs within the beta-globin gene cluster than previously described. Work to validate these SVs using orthogonal methods and complete similar analyses of SNVs is ongoing. Variation outside of the gene cluster will also be integrated with RFLP and within-cluster molecular haplotypes to investigate the ancestral origin of the mutation, and validated cis-acting variants will be used to identify markers associated with proxies of SCA disease modification. DisclosuresNo relevant conflicts of interest to declare.

Time estimations by network of beta globin gene cluster haplotypes linked with Hb D-Los Angeles [β121 (GH4) Glu→Gln GAA→CAA] mutation in the world populations.

Backgroundβ‐Globin gene cluster haplotypes associated with the Hb D‐Los Angeles mutation have been reported in many different locations in different populations including Italy, Iran, Thailand, Belgium, Mexico, Holland, and Turkey. In this study, we have identified genetic relationships and formation periods between the haplotypes reported in the world regarding the Hb D‐Los Angeles.MethodsWe comparatively analyzed the RFLP (restriction fragment length polymorphism) data in Denizli region and world populations using Arlequin 3.5 statistical software program. The data obtained from the Arlequin software were then entered into the Phylogenetic Network software to calculate the age estimates and to discover possible links between the haplotypes.ResultsWe observed the frequencies of the β‐globin gene haplotypes for the seven polymorphic restriction sites around the world and calculated the estimated time of haplotypes using Network software on the basis of ancestral haplotypes. We performed the phylogenetic network analysis of the haplotypes linked with Hb D‐Los Angeles mutation by processing the data of frequency and age estimations with Network software.ConclusionOur period of time results suggests that HAP1 was formed before modern human migration to Asia and/or independent origin of the Hb D‐Los Angeles mutation from other populations. Considering that the population in Denizli region started the Hb D‐Los Angeles mutation past about 40,000 years ago, it can be said that HAP1, HAP15, and HAP21 belong to the gene pool with an external effect. Our period of time results of HAP6 is compatible with published dating results.

Comparative systematics and phylogeography of Quercus Section Cerris in western Eurasia: inferences from plastid and nuclear DNA variation.

Oaks (Quercus) comprise more than 400 species worldwide and centres of diversity for most sections lie in the Americas and East/Southeast Asia. The only exception is the Eurasian sect. Cerris that comprises about 15 species, most of which are confined to western Eurasia. This section has not been comprehensively studied using molecular tools. Here, we assess species diversity and provide a first comprehensive taxonomic and phylogeographic scheme of western Eurasian members of sect. Cerris using plastid (trnH-psbA) and nuclear (5S-IGS) DNA variation with a dense intra-specific and geographic sampling. Chloroplast haplotypes primarily reflected phylogeographic patterns originating from interspecific cytoplasmic gene flow within sect. Cerris and its sister section Ilex. We identified two widespread and ancestral haplotypes, and locally restricted derived variants. Signatures shared with Mediterranean species of sect. Ilex, but not with the East Asian Cerris oaks, suggest that the western Eurasian lineage came into contact with Ilex only after the first (early Oligocene) members of sect. Cerris in Northeast Asia had begun to radiate and move westwards. Nuclear 5S-IGS diversification patterns were more useful for establishing a molecular-taxonomic framework and to reveal hybridization and reticulation. Four main evolutionary lineages were identified. The first lineage is comprised of Q. libani, Q. trojana and Q. afares and appears to be closest to the root of sect. Cerris. These taxa are morphologically most similar to the East Asian species of Cerris, and to both Oligocene and Miocene fossils of East Asia and Miocene fossils of western Eurasia. The second lineage is mainly composed of the widespread Q. cerris and the narrow endemic species Q. castaneifolia, Q. look, and Q. euboica. The third lineage comprises three Near East species (Q. brantii, Q. ithaburensis and Q. macrolepis), well adapted to continental climates with cold winters. The forth lineage appears to be the most derived and comprises Q. suber and Q. crenata. Q. cerris and Q. trojana displayed high levels of variation; Q. macrolepis and Q. euboica, previously treated as subspecies of Q. ithaburensis and Q. trojana, likely deserve independent species status. A trend towards inter-specific crosses was detected in several taxa; however, we found no clear evidence of a hybrid origin of Q. afares and Q. crenata, as currently assumed.

Screening and characterization of BRCA2 c.156_157insAlu in Brazil: Results from 1380 individuals from the South and Southeast

Portuguese immigration to Brazil occurred in several waves and greatly contributed to the genetic composition of current Brazilian population. In this study, we evaluated the frequency of a Portuguese founder Alu insertion in BRCA2 exon 3 (c.156_157insAlu) among individuals fulfilling Hereditary Breast and Ovarian Cancer (HBOC) syndrome criteria in 1,380 unrelated families originated from three distinct Brazilian States. We identified the c.156_157insAlu BRCA2 mutation in nine (9/1,380; 0.65%) probands analised. In carrier probands, European ancestry had the highest proportion (80%), followed by the African (10%) and Amerindian and in most families with the rearrangement, haplotype analyses were compatible with the Portuguese ancestral haplotype. In conclusion, the present study reports a low albeit relevant frequency of the Portuguese BRCA2 founder mutation c.156_157insAlu in Brazilian patients at-risk for HBOC Brazilian population.

Sweet Sorghum Originated through Selection of Dry, a Plant-Specific NAC Transcription Factor Gene.

Sorghum (Sorghum bicolor) is the fifth most popular crop worldwide and a C4 model plant. Domesticated sorghum comes in many forms, including sweet cultivars with juicy stems and grain sorghum with dry, pithy stems at maturity. The Dry locus, which controls the pithy/juicy stem trait, was discovered over a century ago. Here, we found that Dry gene encodes a plant-specific NAC transcription factor. Dry was either deleted or acquired loss-of-function mutations in sweet sorghum, resulting in cell collapse and altered secondary cell wall composition in the stem. Twenty-three Dry ancestral haplotypes, all with dry, pithy stems, were found among wild sorghum and wild sorghum relatives. Two of the haplotypes were detected in domesticated landraces, with four additional dry haplotypes with juicy stems detected in improved lines. These results imply that selection for Dry gene mutations was a major step leading to the origin of sweet sorghum. The Dry gene is conserved in major cereals; fine-tuning its regulatory network could provide a molecular tool to control crop stem texture.

Genetics and expression of anthocyanin pathway genes in the major skin-pigmented Portuguese cultivar ‘Vinhão’ developing berries

‘Vinhão’ is an autochthonous Portuguese cultivar with an intense black-bluish skin color, highly appreciated due to this feature. This study aimed to give the first insights into the genetic background that may be responsible for the skin color properties of cv. ‘Vinhão’. For this purpose, the allelic composition of MYBA1 and MYBA2 genes was investigated, along with quantification of the expression levels of structural and regulatory genes involved in the anthocyanin biosynthetic pathway via qRT-PCR. The molecular characterization of MYBA1 and MYBA2 loci revealed that cv. ‘Vinhão’ is homozygous for the functional allele in both genes, corresponding to the most ancestral haplotype, which is consistent with the high colored phenotype that characterizes this cultivar. There were no differences in the DNA sequence of the MYBA1 promoter region between cv. ‘Vinhão’ and the grapevine reference genome Pinot Noir. The expression patterns of genes playing key functional roles in anthocyanin biosynthesis was analyzed in four developmental stages. The dynamics occurring throughout grape berry development revealed the involvement of these genes in the progression of key development events, mainly from veraison to mature berries. These findings provide the first molecular characterization focused on the skin color feature of cv. ‘Vinhão’ to improve our understanding of the genetics behind its intense skin pigmentation.

Small mutation screening in the DMD gene by whole exome sequencing of an Argentine Duchenne/Becker muscular dystrophies cohort

Dystrophinopathies are neuromuscular X-linked recessive diseases caused by mutations in the DMD gene. This study aimed to identify DMD gene small mutations by Whole Exome Sequencing (WES), in order to confirm clinical diagnosis, identify candidates for Ataluren treatment and perform carrier status testing. Furthermore, was our goal to characterize the DMD sequence variants and identify ancestral haplotypes. We analyzed 40 non-related individuals (38 affected boys with dystrophinopathy presumptive clinical diagnosis and 2 at-risk women) with negative MLPA results. Pathogenic DMD variants were found in 32 boys. Surprisingly, in another 4 patients with absence/deficiency of dystrophin in muscle biopsy, pathogenic variants were found in Limb-girdle muscular dystrophy genes. Therefore, the WES detection rate resulted ∼94% (36/38). We could identify 15 Ataluren candidates and exclude 2 at-risk women. The characterization of the occurrence and diversity of DMD sequence variants from our cohort and from LOVD database, revealed no hotspots but showed exons/introns unlikely to carry small molecular alterations and exons presenting a greater mutagenic abundance than others. Also, we have detected the existence of 2 co-segregating haplotypes blocks. Finally, this work represents the first DMD gene small mutations screening applying WES in an argentine cohort, contributes with the characterization of our population and collaborates with the DMD small mutation’s knowledge.

OR25. The highly polymorphic HLA-DRA Gene: conserved and diverse regions within the HLA-DRA gene imply haplotypes of DRA[formula omitted]DRB3/4/5[formula omitted]DRB1[formula omitted]DQB1

Aim HLA-DRA is highly conserved compared to the other HLA genes. The gene is represented in IPD-IMGT/HLA by 7 alleles encoding two distinct proteins, and we observed that the known DRA alleles have two deletions in intron 4, forming 3 characteristic patterns. We are interested in elucidating the polymorphism of DRA in relation to DR-DQ haplotypes using full-length genomic sequencing. Methods Our laboratory performed full-length DRA sequencing on 70 samples, using MinION and confirming novel SNPs with Sanger SBT. Full-length reads were aligned against reference sequences from IPD-IMGT/HLA to identify sequence polymorphisms and deletion patterns. These polymorphisms were analyzed in the context of HLA-DRB1, -DRB3,4,5, and -DQB1 alleles. Results HLA-DRA alleles represented in IPD-IMGT/HLA are a underestimation of the diversity in the sequence polymorphism. More than 40 novel DRA alleles were identified based on intronic polymorphisms, but exon 2 remains remarkably conserved. Polymorphisms in exons 3 and 4 were confirmed, but no new exonic polymorphism was identified. 19 previously unrepresented SNP positions were identified within the 5711bp region represented in IPD-IMGT/HLA, and the remaining SNPs are combinations of the 61 known polymorphisms. HLA-DRB1 alleles were correlated with the observed intronic deletion patterns. Specifically, DRA alleles corresponding to DRB1∗04, DRB1∗07, and DRB1∗11 groups are correlated with one deletion pattern. DRA deletion patterns that are linked with the DRB1∗03 and DRB1∗13 were correlated with specific DRB3 and DQB1 alleles. Similarly, DRA deletion patterns correlated with DRB1∗15 alleles were also correlated with DRB5 and DQB1. Conclusions HLA-DRA is highly polymorphic, but has conserved exons, suggesting the gene plays a crucial role in immune responses. The observed polymorphism patterns suggest the existence of recombination site(s) within DRA, and the intron deletions give clues about the DRA ∼ DRB3/4/5 ∼ DRB1 ∼ DQB1 haplotypes. Patterns in polymorphisms may represent different evolutionary lineages, suggesting different origins of the DRA genes in the ancestral haplotypes. Extending the samples for further analysis by computational haplotyping will elucidate the origin of the DRA genes in this haplotype.

Genetic Diversity of Echinococcus granulosus Genotype G1 in Xinjiang, Northwest of China.

Cystic echinococcosis (CE) caused by E. granulosus is a serious helminthic zoonosis in humans, livestock and wildlife. Xinjiang is one of high endemic province for CE in China. A total of 55 sheep and cattle livers containing echinococcal cysts were collected from slaughterhouses in Changji and Yining City, northern region of Xinjiang. PCR was employed for cloning 2 gene fragments, 12S rRNA and CO1 for analysis of phylogenetic diversity of E. granulosus. The results showed that all the samples collected were identified as G1 genotype of E. granulosus. Interestingly, YL5 and CJ75 strains were the older branches compared to those strains from France, Argentina, Australia. CO1 gene fragment showed 20 new genotype haploids and 5 new genotype haplogroups (H1-H5) by the analysis of Network 5.0 software, and the YLY17 strain was identified as the most ancestral haplotype. The major haplotypes, such as CJ75 and YL5 strains, showed identical to the isolates from Middle East. The international and domestic trade of livestock might contribute to the dispersal of different haplotypes for E. granulosus evolution.

Autoimmune diseases and 8.1 ancestral haplotype: An update.

The aim of the present review is to provide an update of the current research into the pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype. This is a common Caucasoid haplotype carried by most people who type for HLA-B8, DR3. Numerous genetic studies reported that individuals with certain HLA alleles have a higher risk of specific autoimmune disorders than those without these alleles. However, much remains to be learned about the heritability of autoimmune conditions. Recently, progress and advances in the field of genome-wide-association studies have revolutionized the capacity to perform large, economically feasible, and statistically robust analyses of HLA within 8.1 ancestral haplotype, and understand its contribute to autoimmune events. In this paper, the characteristic features of this haplotype that might give rise to diverse autoimmune phenotypes are reviewed, focusing on the contribution of the HLA-DRB1 gene, the most polymorphic sequence within the HLA II region.

The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+ and CD8+ memory T-cells

Tyrosine kinase 2 (TYK2) belongs to the Janus kinase (JAK) family of tyrosine kinases, which transmit signals from activated cytokine receptors. GWAS have consistently implicated TYK2 in psoriasis susceptibility. We performed an in-depth association analysis of TYK2 using GWAS and resequencing data. Strong genetic association of three nonsynonymous variants in the exonic regions of the TYK2 gene (rs34536443, rs12720356, and rs2304256) were found. rs12720356 encoding I684S is predicted to be deleterious based on its location in the pseudokinase domain. We analyzed PBMCs from 29 individuals representing the haplotypes containing each of the significantly associated signals. STAT4 phosphorylation was evaluated by phospho-flow cytometry after CD3/CD28 activation of cells followed by IL-12 stimulation. Individuals carrying the protective I684S variant manifested significantly reduced p-STAT4 levels in CD4 + CD25 + CD45RO+ (mean Stimulation Index (S.I.) 48.08, n = 10) and CD8 + CD25 + CD45RO + cells (S.I. 55.71, n = 10), compared to controls homozygous for the ancestral haplotype (S.I. 68.19, n = 10 (p = 0.002) and 76.76 n = 10 (p = 0.0008) respectively). Reduced p-STAT4 levels were also observed in skin-homing, cutaneous lymphocyte associated antigen (CLA)-positive CD4 and CD8 cells from I684S carriers. No significant changes in p-STAT4 for the psoriasis-associated variant rs34536443 was found. These data establish the functional significance of the TYK2 I684S variant in psoriasis susceptibility.

Unveiling the origin of Quercus serrata subsp. mongolicoides found in Honshu, Japan, by using genetic and morphological analyses

AbstractQuercus mongolica is a tree found in temperate deciduous forests in east Asia. In Japan, Q. mongolica var. crispula is commonly found; moreover, an oak whose morphology is similar to that of Q. mongolica var. mongolica of the Asian continent has been found in certain areas of Honshu and Hokkaido. Recently, the oak found in Honshu was described as Q. serrata subsp. mongolicoides (QSM). However, genetic comparison between this oak and Q. mongolica var. mongolica of the Asian continent has not been performed; the origin of QSM is thus unknown. Therefore, we aimed to determine the origin of QSM by conducting nuclear microsatellite (nSSR), chloroplast DNA (cpDNA) and leaf morphology analyses for the three taxa, as well as other congeners. The cpDNA variation overlapped among the three taxa, suggesting low discrimination ability for these taxa. Although morphological congruency was found between QSM and Q. mongolica var. mongolica, results of nSSR analyses showed that QSM contained a genetic admixture of Q. mongolica var. mongolica of the Asian continent and Q. mongolica var. crispula of Japan, bolstering an admixture hypothesis. The nSSR and cpDNA analyses suggested that Q. mongolica var. crispula can be the progenitor of Q. mongolica var. mongolica and harbors the ancestral cpDNA haplotypes. Therefore, we concluded that QSM might have been created by an admixture that likely occurred within Japan between Q. mongolica var. crispula and putative relict Q. mongolica var. mongolica, which might have diverged in or around Japan from Q. mongolica var. crispula during the late Pleistocene.

Seasonal dynamics, geographical range size, hosts, genetic diversity and phylogeography of Amblyomma sculptum in Argentina

The aim of this work was to generate knowledge on ecological aspects of Amblyomma sculptum in Argentina, such as seasonal dynamics, geographical range size, hosts, genetic diversity and phylogeography. Adult and immature A. sculptum ticks were collected in different localities of Argentina to know the geographical range size and hosts. The genetic diversity of this tick was studied through analyses of 16S rDNA sequences. To describe the seasonal dynamics, free-living ticks were monthly collected from October 2013 to October 2015. A. sculptum shows a marked ecological preference for Chaco Húmedo eco-region and “Albardones” forest of the great rivers in the wetlands in the Chaco Biogeographical Province, and for Selvas Pedemontanas and Selva Montana in the Yungas Biogeographical Province. This species has low host specificity, and it has large wild and domestic mammals as principal hosts to both immature and adult stages. Amblyomma sculptum is characterized by a one-year life cycle. Larvae peak in early winter, nymphs peaked during mid-spring, and adults during late summer and mid-summer. The genetic divergence was low and the total genetic variability was attributable to differences among populations. This fact could be associated to stochastics process linked to micro-habitat variations that could produce a partial restriction to gene flow among populations. The geographic regions do not contribute much to explain the A. sculptum population genetic structure, with an ancestral haplotype present in most populations, which gives rise to the rest of the haplotypes denoting a rapid population expansion.