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Objectives GCA can be confirmed by temporal artery biopsy (TAB) but false negatives can occur. GCA may be overdiagnosed in TAB-negative cases, or if neither TAB nor imaging is done. We used HLA genetic association of TAB-positive GCA as an 'unbiased umpire' test to estimate historic overdiagnosis of GCA. Methods Patients diagnosed with GCA between 1990 and 2014 were genotyped. During this era, vascular imaging alone was rarely used to diagnose GCA. HLA region variants were jointly imputed from genome-wide genotypic data of cases and controls. Per-allele frequencies across all HLA variants with P  < 1.0 × 10−5 were compared with population control data to estimate overdiagnosis rates in cases without a positive TAB. Results Genetic data from 663 GCA patients were compared with data from 2619 population controls. TAB-negative GCA (n  = 147) and GCA without TAB result (n  = 160) had variant frequencies intermediate between TAB-positive GCA (n  = 356) and population controls. For example, the allele frequency of HLA-DRB1*04 was 32% for TAB-positive GCA, 29% for GCA without TAB result, 27% for TAB-negative GCA and 20% in population controls. Making several strong assumptions, we estimated that around two-thirds of TAB-negative cases and one-third of cases without TAB result may have been overdiagnosed. From these data, TAB sensitivity is estimated as 88%. Conclusions Conservatively assuming 95% specificity, TAB has a negative likelihood ratio of around 0.12. Our method for utilizing standard genotyping data as an 'unbiased umpire' might be used as a way of comparing the accuracy of different diagnostic pathways. [ABSTRACT FROM AUTHOR]

Objectives To efficiently detect somatic UBA1 variants and establish a clinical scoring system predicting patients with pathogenic variants in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Methods Eighty-nine Japanese patients with clinically suspected VEXAS syndrome were recruited [81 males and 8 females; median age of onset 69.3 years (interquartile range 62.1–77.6)]. Peptide nucleic acid–clamping PCR (PNA-PCR), regular PCR targeting exon 3 clustering UBA1 variants and subsequent Sanger sequencing were conducted for variant screening. Partitioning digital PCR or targeted amplicon deep sequencing was also performed to evaluate the variant allele frequency (VAF). We developed our clinical scoring system to predict UBA1 variant-positive and -negative patients and assessed the diagnostic value of our system using receiver operating characteristics (ROC) curve analysis. Results Forty patients (44.9%) with reported pathogenic UBA1 variants were identified, including a case having a variant with VAF of 1.7%, using a highly sensitive method. Our clinical scoring system considering age >50 years, cutaneous lesions, lung involvement, chondritis and macrocytic anaemia efficiently predicted patients with UBA1 variants (the area under the curve for the scoring total was 0.908). Conclusion Genetic screening with the combination of regular PCR and PNA-PCR detected somatic UBA1 variants with high sensitivity and specificity. Our scoring system could efficiently predict patients with UBA1 variants. [ABSTRACT FROM AUTHOR]

Simple Summary: Juvenile Myelomonocytic Leukemia (JMML) is a rare and clonal hematopoietic disorder of infancy and early childhood with myeloproliferative/myelodysplastic features resulting from germline or somatic mutations in the RAS pathway. Given its rarity, management is not standardized and varies widely, ranging from observation to bone marrow transplant depending on genomic and clinical features. We describe the course of JMML or Noonan Syndrome-associated Myeloproliferative Disorder in 22 pediatric patients treated at three institutions to provide guidance for monitoring versus intervention, including transplant, supported by patient outcomes. We provide additional insight into the expected time to spontaneous resolution in those with germline PTPN11 mutations and treatment approaches for patients with germline CBL mutations where no standard exists. Juvenile Myelomonocytic Leukemia (JMML) is a rare and clonal hematopoietic disorder of infancy and early childhood with myeloproliferative/myelodysplastic features resulting from germline or somatic mutations in the RAS pathway. Treatment is not uniform, with management varying from observation to stem cell transplant. The aim of our retrospective review is to describe the treatment and outcomes of a cohort of patients with JMML or Noonan Syndrome-associated Myeloproliferative Disorder (NS-MPD) to provide management guidance for this rare and heterogeneous disease. We report on 22 patients with JMML or NS-MPD managed at three institutions in the Texas Medical Center. Of patients with known genetic mutations and cytogenetics, 6 harbored germline mutations, 12 had somatic mutations, and 9 showed cytogenetic abnormalities. Overall, 14/22 patients are alive. Spontaneous clinical remission occurred in one patient with somatic NRAS mutation, as well as two with germline PTPN11 mutations with NS-MPD, and two others with germline PTPN11 mutations and NS-MPD remain under surveillance. Patients with NS-MPD were excluded from treatment analysis as none required chemotherapeutic intervention. All patients (5/5) treated with 5-azacitidine alone and one of the four treated with 6-mercaptopurine monotherapy had a reduction in mutant variant allele frequency. Transformation to acute myeloid leukemia was seen in two patients who both died. Among patients who received transplants, 7/13 are alive, and relapse post-transplant occurred in 3/13 with a median time to relapse of 3.55 months. This report provides insight into therapy responses and long-term outcomes across different genetic subsets of JMML and lends insight into the expected time to spontaneous resolution in patients with NS-MPD with germline PTPN11 mutations. [ABSTRACT FROM AUTHOR]

Pathogenic variations in the fused in sarcoma (FUS) gene are associated with rare and aggressive forms of amyotrophic lateral sclerosis (ALS). As FUS-ALS is a dominant disease, a targeted, allele-selective approach to FUS knockdown is most suitable. Antisense oligonucleotides (AOs) are a promising therapeutic platform for treating such diseases. In this study, we have explored the potential for allele-selective knockdown of FUS. Gapmer-type AOs targeted to two common neutral polymorphisms in FUS were designed and evaluated in human fibroblasts. AOs had either methoxyethyl (MOE) or thiomorpholino (TMO) modifications. We found that the TMO modification improved allele selectivity and efficacy for the lead sequences when compared to the MOE counterparts. After TMO-modified gapmer knockdown of the target allele, up to 93% of FUS transcripts detected were from the non-target allele. Compared to MOE-modified AOs, the TMO-modified AOs also demonstrated reduced formation of structured nuclear inclusions and SFPQ aggregation that can be triggered by phosphorothioate-containing AOs. How overall length and gap length of the TMO-modified AOs affected allele selectivity, efficiency and off-target gene knockdown was also evaluated. We have shown that allele-selective knockdown of FUS may be a viable therapeutic strategy for treating FUS-ALS and demonstrated the benefits of the TMO modification for allele-selective applications. [ABSTRACT FROM AUTHOR]

HLA alleles are representative of ethnicities and may play important roles in predisposition to hematological disorders. We analyzed DNA samples for HLA-A, -B, -C, -DRB1, and -DQB1 loci, from 1550 patients and 4450 potential related donors by PCR-SSO (Polymerase chain reaction sequence-specific oligonucleotides) and estimated allele frequencies in donors and patients from 1550 families who underwent bone marrow transplantation (BMT) in Egypt. We also studied the association between HLA allele frequencies and incidence of acute myeloid leukemia, acute lymphoblastic leukemia, and severe aplastic anemia. The most frequently observed HLA class I alleles were HLA- A*01:01 (16.9%), A*02:01 (16.1%), B*41:01 (8.7%), B*49:01 (7.3%), C*06:02 (25.1%), and C*07:01 (25.1%), and the most frequently observed class II alleles were HLA-DRB1*11:01 (11.8%), DRB1*03:01 (11.6%), DQB1*03:01 (27.5%), and DQB1*05:01 (18.9%). The most frequently observed haplotypes were A*33:01~B*14:02 ~ DRB1*01:02 (2.35%) and A*01:01~B*52:01~DRB1*15:01 (2.11%). HLA-DRB1*07:01 was associated with higher AML odds (OR, 1.26; 95% CI, 1.02–1.55; p = 0.030). Only HLA-B38 antigen showed a trend towards increased odds of ALL (OR, 1.52; 95% CI, 1.00–2.30; p = 0.049) HLA-A*02:01, -B*14:02, and -DRB1*15:01 were associated with higher odds of SAA (A*02:01: OR, 1.35; 95% CI, 1.07–1.70; p = 0.010; B*14:02: OR, 1.43; 95% CI, 1.06–1.93; p = 0.020; DRB1*15:01: OR, 1.32; 95% CI, 1.07–1.64; p = 0.011). This study provides estimates of HLA allele and haplotype frequencies and their association with hematological disorders in an Egyptian population. [ABSTRACT FROM AUTHOR]

Fungicide resistance is often conferred through the mutation of genes encoding fungicide targets or proteins that remove fungicides from cells, but mechanisms can vary widely between taxa. Discovering the specific resistance alleles present in pathogen populations is essential for monitoring the evolution and movement of resistant genotypes. In this study, we explored the genomic basis of demethylase inhibitor (DMI) resistance in Leptosphaeria maculans, the main pathogen of the canola crop Brassica napus. Using an international collection of over 200 genome‐sequenced isolates, we assayed in vitro sensitivity to the DMI tebuconazole and conducted a genome‐wide association study on a variant set including single‐nucleotide polymorphisms (SNPs), small indels and structural variants. The main resistance allele identified was a 237 bp remnant transposable element insertion in the promoter of the erg11/CYP51 DMI target gene in a large proportion of isolates from Europe, an allele known to confer DMI resistance in Australia. Several associated loci were identified, none of which are commonly linked to DMI resistance in other phytopathogens. We also found little to no relationship between DMI tolerance and baseline growth rate, suggesting minimal fitness effects of fungicide resistance in these isolates. This study indicates common DMI resistance alleles in L. maculans are shared across continents and erg11/CYP51 coding mutations, which are near‐ubiquitous in other fungal pathogens, may not underpin DMI resistance in this species. Furthermore, that resistance occurs frequently in numerous canola‐growing regions suggests management is essential for growers. [ABSTRACT FROM AUTHOR]

In this study, 38 elite breeding pepper lines were genetically analyzed using SRAP markers and tested for resistance to PVY, TSWV, and PMMoV viruses using molecular markers. In the virus resistance tests, 1 line (37-H–D-6) from the Three-lobs population was found to be resistant to all 3 viruses tested. The 19 SRAP primer combinations used for genetic diversity yielded a total of 85 bands, 57 of which were polymorphic among pepper lines. While 2–8 bands per primer were obtained, the number of polymorphic bands ranged from 1 to 6. The average polymorphism rate of the primers was 66.44%. The PIC values ranged from 0.06 to 0.40 (with a mean of 0.18). In addition, the average gene diversity, effective allele number, and Shannon information index values of the primers were 0.21, 1.34, and 0.31, respectively. STRUCTURE analysis showed that the pepper lines were grouped into 4 clusters. PCoA and Q-matrix plots supported the cluster distribution. Some lines of the Sivri and Three-lobs pepper populations were observed as outliers in the plots. Kapia and Three-lobs were more similar to each other. This study showed that SRAP markers can be successfully used for genetic diversity of pepper breeding lines. [ABSTRACT FROM AUTHOR]

This investigation aimed to explore the relationship between Chinese elite wrestlers and the polymorphic loci of explosive strength genes, and to further explore the feasibility of its application to athlete selection. The snapshot technique was used to resolve the polymorphic loci of explosive power genes in the wrestler group (59 elite wrestlers) and the control group (180 ordinary college students), and to analyze the genotype frequencies and allele frequencies of each group. A chi-square test was performed on the genotype and allele distribution data of each group to analyze the loci of explosive power genes that were associated with elite wrestlers. The loci that had an association with elite wrestlers were combined with the genotyping data, and the dominance ratios of the genotypes were calculated using the chi-square test to determine the dominant genotypes associated with elite wrestlers. The VDR gene rs2228570 locus exhibited statistically significant differences in genotype and allele distributions between elite wrestlers and the general population (p < 0.01). At the rs2228570 locus of the VDR gene, the difference between the CC genotype and other genotypes was statistically significant (p < 0.05). The rs2228570 locus of the VDR gene was identified as the locus associated with Chinese elite wrestlers. The polymorphism of the VDR gene can be used as a biomarker for Chinese wrestlers, and the CC genotype can be used as a molecular marker for the selection of Chinese elite athletes in this sport. However, expanding the sample size of elite athletes is necessary to further validate the scientific validity and feasibility of these findings. [ABSTRACT FROM AUTHOR]

Background: This study aimed to analyze genotype–phenotype correlations in children with Gitelman syndrome (GS). Methods: This multicenter retrospective study included 50 Korean children diagnosed with SLC12A3 variants in one or both alleles and the typical laboratory findings of GS. Genetic testing was performed using the Sanger sequencing except for one patient. Results: The median age at the diagnosis was 10.5 years (interquartile range, 6.8;14.1), and 41 patients were followed up for a median duration of 5.4 years (interquartile range, 4.1;9.6). A total of 30 different SLC12A3 variants were identified. Of the patients, 34 (68%) had biallelic variants, and 16 (32%) had monoallelic variants on examination. Among the patients with biallelic variants, those (n = 12) with the truncating variants in one or both alleles had lower serum chloride levels (92.2 ± 3.2 vs. 96.5 ± 3.8 mMol/L, P = 0.002) at onset, as well as lower serum potassium levels (3.0 ± 0.4 vs. 3.4 ± 0.3 mMol/L, P = 0.016), and lower serum chloride levels (96.1 ± 1.9 vs. 98.3 ± 3.0 mMol/L, P = 0.049) during follow-up than those without truncating variants (n = 22). Patients with monoallelic variants on examination showed similar phenotypes and treatment responsiveness to those with biallelic variants. Conclusions: Patients with GS who had truncating variants in one or both alleles had more severe electrolyte abnormalities than those without truncating variants. Patients with GS who had monoallelic SLC12A3 variants on examination had almost the same phenotypes, response to treatment, and long-term prognosis as those with biallelic variants. [ABSTRACT FROM AUTHOR]

The document titled "Nomenclature for factors of the HLA system, update January, February and March 2024" provides a list of newly assigned sequences and confirmations of previously reported sequences for the HLA system. The sequences have been submitted to the Nomenclature Committee and assigned official allele designations. Accession numbers are provided for each sequence, which can be used to retrieve the sequence files from data libraries. The document also mentions additional information and recent publications related to new HLA sequences. [Extracted from the article]

Background: Single nucleotide polymorphisms (SNPs) may influence pain susceptibility and impact treatment response in pain‐related temporomandibular disorders (TMDp). Objective: Explore the role of COMT (rs4646310, rs6269, rs4818, rs4680) and OPRM1 (rs1799971) genotypes in regulating treatment response. Methods: Sixty TMDp patients (55 females and 5 males), diagnosed with the Diagnostic Criteria for TMD (DC/TMD), underwent standardised treatment (information and education, home physical therapy, occlusal splint) for 6 months. Treatment outcomes included: pain intensity, pain‐free mouth opening, jaw functional limitation, depression, and anxiety. Genotyping for COMT and OPRM1 SNPs was performed using DNA from buccal mucosa swabs and TaqMan assays. Statistical analysis was carried out to compare the changes in treatment outcomes and the influence of genotypes on treatment response. Results: Significantly less pain reduction was observed in minor allele carriers of rs4646310, and rs4680 compared to dominant homozygous (p <.025). Minor allele carriers of rs1799971 and rs4646310 demonstrated worsening in pain‐free mouth opening while dominant homozygous exhibited improvement (p <.025). Significantly less anxiety reduction was observed in minor allele carriers of rs4646310 compared to dominant homozygous (p =.003). Of the all variables assessed in the regression model, carrying a minor allele of rs1799971 predicted a poorer treatment response considering pain‐free mouth opening while carrying a minor allele of rs4646310 predicted less pain and less anxiety reduction. Conclusion: Our findings indicate that certain SNP variants of the COMT and OPRM1 genes were associated with poorer treatment response and may therefore play a significant role in the classification of TMDp patients. Also, assessment of patient genotype could potentially aid in predicting treatment response. [ABSTRACT FROM AUTHOR]

Pharmacogenomics (PGx) investigates the influence of genetics on drug responses, enabling tailored treatments for personalized healthcare. This study assessed the accuracy of genotyping six genes using whole genome sequencing with four different computational tools and various sequencing depths. The effects of using different reference genomes (GRCh38 and GRCh37) and sequence aligners (BWA‐MEM and Bowtie2) were also explored. The results showed generally minor variations in tool performance across most genes; however, more notable discrepancies were observed in the analysis of the complex CYP2D6 gene. Cyrius, a CYP2D6‐specific tool, demonstrated the most robust performance, achieving the highest concordance rates for CYP2D6 in all instances, comparable to the consensus approach in most cases. There were rather small differences between the samples with 20× coverage depth and those with higher depth, but the decreased performance was more evident at lower depths, particularly at 5×. Additionally, variations in CYP2D6 results were observed when samples were aligned to different reference genomes using the same method, or to the same genome using different aligners, which led to reporting incorrect rare star alleles in several cases. These findings inform the selection of optimal PGx tools and methodologies as well as suggest that employing a consensus approach with two or more tools might be preferable for certain genes and tool combinations, especially at lower sequencing depths, to ensure accurate results. Additionally, we show how the upstream alignment can affect the performance of tools, an important factor to take into account. [ABSTRACT FROM AUTHOR]

Winter survival is an essential trait for winter wheat (Triticum aestivum L.) cultivars grown in high latitude regions such as Eastern Canada. Indoor studies have identified that copy number variation of genes influencing freezing is an essential component. Although Canadian winter wheat is predominantly grown in Eastern Canada, the extent to which allele variation in freezing tolerance genes affects winter survival in this region remains unknown, as there are presently no studies characterizing such variation in Canadian winter wheat germplasm. In this study, we characterized a panel 415 Canadian winter wheat cultivars for haplotype diversity of the Frost Resistance-2 (Fr-A2) locus and copy number variation of Vernalization-A1 (Vrn-A1) and C-repeat binding factors-A14 (CBF-A14). Additionally, this study evaluates each gene's effect on winter survival across two locations and 2 years. We found that a combination of Vrn-A1 copy number and Fr-A2 haplotype accounted for 67.38% of the genotypic variance. Most of the cultivars tested (77.3%) carry the allele combination of three copies of Vrn-A1 and the Fr-A2-T haplotype, which was associated with the best winter survival. Interestingly, copy number of Vrn-A1 did not significantly affect heading time, therefore, selecting for higher copy number of Vrn-A1 would not affect maturity. [ABSTRACT FROM AUTHOR]

Pod shattering is a major production constraint of soybean [Glycine max (L.)]. The objectives of this study were to (i) estimate heritability for pod shattering resistance, (ii) determine the frequency of the pod shattering resistance allele pdh1 in the International Institute for Tropical Agriculture (IITA) soybean germplasm and Zambian commercial varieties, and (iii) determine the effectiveness of the DNA marker for the pod shattering resistance allele pdh1. A total of 59 genotypes were evaluated for pod shattering in field trials conducted in Malawi and Zambia and genotyped with a marker for pdh1. TGx2002‐8FM and TGx2002‐9FM were the most resistant among genotypes in early and medium maturity classes and can be used for genetic enhancement of pod shattering resistance in these specific maturity classes. Narrow sense heritability estimates for pod shattering ranged from 0.27 to 0.80. Of the 59 genotypes, 57 (96.6%) carried the resistance allele pdh1 while only two genotypes (3.6%) carried the susceptible allele, suggesting near‐fixation of the resistance allele pdh1 in the IITA germplasm. The marker for pdh1 was highly effective in selecting resistant genotypes. [ABSTRACT FROM AUTHOR]

Drought escape is an important wheat mechanism that triggers rapid growth development to complete the life cycle before drought occurrence. Earliness could reduce the risk of dehydration during heading date to physiological maturity. Three gene groups including vernalization (Vrn), photoperiod (Ppd), and earliness per se (Eps) control heading time in bread wheat. In the present research, isogenic lines for Vrn-B1 and Vrn-D1 were developed to assess the precise effect of Vrn genes on days to heading, grain yield, and important agronomic traits under well-watered and rain-fed conditions. It was assumed that spring habit alleles improve earliness in bread wheat. Here we showed for the first time that a winter growth habit allele on the B genome, vrn-B1, reduced days to heading by 5.47 days. The mentioned allele, significantly increased grain yield under well-watered conditions by 0.36 t/ha. Spring growth habit allele of the D genome, Vrn-D1a, decreased days to heading by 4.89 days and significantly improved grain yield under both well-watered and rain-fed conditions. This allele improved grain yield by 0.88 t/ha and 0.14 t/ha under well-watered and rain-fed conditions, respectively. The combination of vrn-B1 and Vrn-D1a decreased days to heading by 9.87 days and significantly increased grain yield by 1.24 and 0.15 t/ha under well-watered and rain-fed conditions, respectively. [ABSTRACT FROM AUTHOR]

PURPOSE: Several allelic variants of the gene DPYD encoding dihydropyrimidine dehydrogenase (DPD) are associated with impaired metabolism of the systemic fluoropyrimidine fluorouracil (5FU) and its oral prodrug, capecitabine, which elevates the risk for severe toxicity. Following a patient death related to capecitabine toxicity in which DPD deficiency was suspected, a multidisciplinary advisory panel was convened to develop an institution-wide approach to future patients planned for a systemic fluoropyrimidine. METHODS: The panel selected an opt-out testing strategy which focused on developing reliable processes to collect and report test results and targeted education. An electronic health record–based automated reminder was designed to activate when a 5FU- or capecitabine-containing chemotherapy regimen was ordered for a patient without prior exposure to either agent and without a prior DPYD sequencing test result. DPYD testing was standardized across all sites of care, and a closed loop reporting system for abnormal test results was created. Before implementation, targeted education was provided to providers, pharmacists, and nurses, and a failure mode and effects analysis was performed. Program rollout was staged over a 6-month period. RESULTS: At 10 months, the rate of preemptive testing increased from a baseline of 26% to a sustained rate of >90%. In the six network sites, the testing rate increased from 9% to 96%. A total of 1,043 patients have been tested preemptively; allelic variants have been identified in 43 (4.1%). Among 25 evaluable patients, dose reduction or change to a non–fluoropyrimidine-based regimen was accomplished in 96%. CONCLUSION: Preemptive DPYD testing is feasible, and high rates of testing can be achieved using an opt-out, reminder-based program. We provide the details of the implementation and encourage others to emulate it. [ABSTRACT FROM AUTHOR]

Objective of the study was to find the association of vitamin D receptor (VDR) polymorphisms (Fokl, Taql and Apal) with vitamin D levels in diabetic foot ulcer (DFU) patients in South India. In this case–control study, plasma vitamin D levels and VDR genotype frequencies of 70 cases (DFU patients) were compared with 70 diabetic (diabetes mellitus [DM] [non‐DFU]) patients and 70 apparently healthy controls (HC) from South India. Plasma vitamin D levels were measured using the ELISA technique, and genotyping of VDR polymorphisms was carried out using real‐time polymerase chain reaction. Logistic regression was used to find the association between DFU versus HC and DFU versus DM traits. Association analysis was performed based on additive, dominant and recessive models with age and gender as covariates. A 45.7% of DFU patients have sufficient vitamin D levels than 48.6% and 40% of DM patients and HC, respectively. Linkage disequilibrium analysis for DFU versus HC and DFU versus DM traits shows that single nucleotide polymorphisms (SNPs) Taq1 (rs731236) and Apal (rs7975232) are in strong linkage disequilibrium in DFU patients. The alleles and genotype frequencies were similar in all three groups. Although the additive model does not show statistical significance, age and sex correlate with the three SNPs (Fokl, Taql and Apal). No association was found between VDR gene polymorphisms and vitamin D levels in DFU patients in Southern India. On the other hand, age and sex correlate with the three SNPs. [ABSTRACT FROM AUTHOR]

Background: Single-nucleotide polymorphisms in LIN28B, critical regulators of female growth and puberty, have been linked to age at menarche. Methods: We assessed the association of rs7759938, rs314280, and rs314276 with menarcheal age in girls of Greek descent. We reviewed the records of 248 girls who had their first menstruation before 18 years and who attended the Greek Departments of Pediatric Endocrinology from January 2021 to July 2023. Genotyping was performed by standard DNA-based methods. Association analyses involved both parametric and non-parametric tests. Results: The average age of breast and pubic hair development was 9.95 years, and the age at menarche was 11.55 years. Menarche occurred ≤11 years (mean 10.24 years) in 108 girls (43.5%) and >11 years (mean 12.55 years) in 140 (56.5%). The girls' menarcheal age correlated significantly with that of their mothers (average 12.1 years, p-value < 0.0001, Spearman's r 0.350). The dominant rs7759938(TT) genotype was the most common (55.2%), followed by the dominant rs314276(CC) (53.2%) and dominant rs314280(TT) (14.5%) genotypes. Conclusions: There was no association between age at menarche and any of the polymorphism genotypes/alleles or between genotypes/alleles and birth weight, gestational week, mode of delivery, and maternal age at menarche. Future large sample studies are warranted to confirm these results. [ABSTRACT FROM AUTHOR]

Cultivated potatoes are incredibly diverse, ranging from diploid to pentaploid and encompass four different species. They are adapted to disparate environments and conditions and carry unique alleles for resistance to pests and pathogens. Describing how diversity is partitioned within and among these populations is essential to understanding the potato genome and effectively utilizing landraces in breeding. This task is complicated by the difficulty of making comparisons across cytotypes and extensive admixture within section petota. We genotyped 730 accessions from the US Potato genebank including wild diploids and cultivated diploids and tetraploids using Genotype-by-sequencing. This data set allowed us to interrogate population structure and diversity as well as generate core subsets which will support breeders in efficiently screening genebank material for biotic and abiotic stress resistance alleles. We found that even controlling for ploidy, tetraploid material exhibited higher observed and expected heterozygosity than diploid accessions. In particular group chilotanum material was the most heterozygous and the only taxa not to exhibit any inbreeding. This may in part be because group chilotanum has a history of introgression not just from wild species, but landraces as well. All group chilotanum, exhibits introgression from group andigenum except clones from Southern South America near its origin, where the two groups are not highly differentiated. Moving north, we do not observe evidence for the same level of admixture back into group andigenum. This suggests that extensive history of admixture is a particular characteristic of chilotanum. [ABSTRACT FROM AUTHOR]

At the major vernalization locus 'Vrn-D1', the spring allele, Vrn-D1a, and two winter alleles, Vrn-D1b and vrn-D1, have been identified in wheat. We conducted field trials to determine the effects of alleles on growth and yield-related traits, using near-isogenic lines developed in the genetic background of spring type wheat cultivars, 'Abukumawase' and 'Asakazekomugi', both of which carry the Vrn-D1a allele. Although maturity date of three alleles was same, the panicle development occurred earlier in the following order of genotype: Vrn-D1a > Vrn-D1b > vrn-D1. There was a significant difference in panicle development even between two winter type alleles vrn-D1 and Vrn-D1b. Grain yield and the spikelet number per spike of the original spring type cultivars were lower than those of the winter type NILs. In addition, while the young panicle development of the tillers in the spring type cultivars was found to be two weeks to one month later in the tillers than that in the main stem, young panicle development of the main stem and tillers in the winter type NILs were almost identical. Hence, winter type wheat bearing vrn-D1 which exhibit later panicle development than that bearing Vrn-D1b, was elucidated to might be more useful especially in areas with high risk of frost damage. Spring type wheat had a lower sink capacity and grain yield, meanwhile that was considered to prevent severe frost damage by allowing late-developed tillers to survive. [ABSTRACT FROM AUTHOR]

Since the introduction of next generation sequencing technologies, the field of epigenomics has evolved rapidly. However, most commonly used assays are enrichment-based methods and thus only semi-quantitative. Nucleosome occupancy and methylome sequencing (NOMe-seq) allows for quantitative inference of chromatin states with single locus resolution, but this requires high sequencing depth and is therefore prohibitively expensive to routinely apply to organisms with large genomes. To overcome this limitation, we introduce guidedNOMe-seq, where we combine NOMe profiling with large scale sgRNA synthesis and Cas9-mediated region-of-interest (ROI) liberation. To facilitate quantitative comparisons between multiple samples, we additionally develop an R package to standardize differential analysis of any type of NOMe-seq data. We extensively benchmark guidedNOMe-seq in a proof-of-concept study, dissecting the interplay of ChAHP and CTCF on chromatin. In summary we present a cost-effective, scalable, and customizable target enrichment extension to the existing NOMe-seq protocol allowing genome-scale quantification of nucleosome occupancy and transcription factor binding at single allele resolution. [ABSTRACT FROM AUTHOR]

Background: Antiretroviral drugs in people living with HIV-1 (PLHIV-1) often trigger side effects which may lead to discontinuation or failure of treatment. Human Leukocyte Antigen B*57:01 (HLA-B*57:01) allele is known to predict hypersensitivity reactions to Abacavir. Very few data are available on the prevalence of HLA-B*57:01 allele in PLHIV-1 in African countries. This study aimed to screen for HLA-B*57:01 allele in PLHIV-1 in Benin. Methods: This pilot study was carried out on one hundred ten PLHIV-1 enrolled in two health facilities in Benin. Socio-demographic and clinical data were collected. Biological data were determined and HLA-B*57:01 allele was genotyped, using Single Specific Primer-Polymerase Chain Reaction in blood samples. Results: 70% of participants were female. PLHIV-1 were under TDF + 3TC + DTG (47.2%) or TDF + 3TC + EFV (57.3%). Their median age was 41 [36-48.75] years and the average CD4 + T cell count was 249 [130-381.25] cells/µl. The average viral load in treatment failure PLHIV-1 was 4.7 [3.9–5.2] Log10. At the inclusion date, twenty-nine (26.4%) PLHIV-1 under TDF + 3TC + EFV have developed hypersensitivity reactions. None of 110 patients had shown HLA-B*5701 allele. Conclusion: Our study revealed that HLA-B*57:01 allele was very rare in PLHIV-1 in Benin, suggesting that its screening before starting the Abacavir regimen did not seem necessary. [ABSTRACT FROM AUTHOR]

Background: There is evidence suggesting that Notch1 signaling pathway contributes to the development of hand, foot, and mouth disease (HFMD); however, the role of Notch1 gene polymorphisms in the severity of coxsackievirus A6 (CVA6)-related HFMD remains unclear. This study aimed to investigate the correlation between Notch1 gene polymorphisms and the severity of CVA6-related HFMD. Methods: A total of 196 patients (Chinese Han population) diagnosed with CVA6-related HFMD through nucleic acid testing were included in this study. Among them, 97 patients were classified as severe cases, while 99 cases were categorized as mild. The mRNA levels of Notch1 in the peripheral blood leukocytes of HFMD patients were detected by quantitative real-time polymerase chain reaction (qRT-PCR), and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was utilized for genotyping of rs3124599, rs3124603, and rs3124591. Results: The frequencies of rs3124599 alleles were G (39.0%) and A (61.0%), while the frequencies of rs3124599 genotypes were GG (12.2%), GA (53.6%), and AA (34.2%), respectively. In the recessive model, the frequency of rs3124599 AA genotypes significantly increased in severe patients, compared to mild patients (P < 0.05). Due to the low frequency of alleles for rs3124591 and rs3124603 in patients, as well as the absence of any difference in their distribution between the two groups (P > 0.05), no additional statistical analysis was performed. After adjusting for age and sex, patients with rs3124599 AA genotype had a significantly higher risk of severe HFMD in comparison to G allele carriers (GA/GG), with an odds ratio (95% confidence interval) of 2.010 (1.094, 3.691). Meanwhile, the mRNA levels of Notch1 were found to be significantly higher in severe patients compared to mild patients (P < 0.05), and a positive correlation was observed between Notch1 mRNA levels and the peripheral blood monocyte count (r = 0.42, P < 0.001). Additionally, there were significant differences observed in Notch1 mRNA levels and peripheral blood monocyte counts between patients with the AA genotype of rs3124599 and those with the GA genotype or G allele carriers (P < 0.05). Conclusion: In the Chinese Han population, there is a strong correlation between the Notch1 rs3124599 allele and the severity of CVA6-related HFMD. This correlation may be attributed to genetic polymorphism of rs3124599 regulating Notch1 transcription levels. These findings reveal the important role of Notch1 gene polymorphism in CVA6 infection, establishing a scientific foundation for the precise control of severe HFMD. [ABSTRACT FROM AUTHOR]

Cephalosporin antibiotics are widely used in clinical settings, but they can cause hypersensitivity reactions, which may be influenced by genetic factors such as the expression of Human leukocyte antigen (HLA) molecules. This study aimed to investigate whether specific HLA alleles were associated with an increased risk of adverse reactions to cephalosporins among individuals in the Taiwanese population. This retrospective case–control study analyzed data from the Taiwan Precision Medicine Initiative (TPMI) on 27,933 individuals who received cephalosporin exposure and had HLA allele genotyping information available. Using logistic regression analyses, we examined the associations between HLA genotypes, comorbidities, allergy risk, and severity. Among the study population, 278 individuals had cephalosporin allergy and 2780 were in the control group. Our results indicated that certain HLA alleles, including HLA-B*55:02 (OR = 1.76, 95% CI 1.18–2.61, p = 0.005), HLA-C*01:02 (OR = 1.36, 95% CI 1.05–1.77, p = 0.018), and HLA-DQB1*06:09 (OR = 2.58, 95% CI 1.62–4.12, p < 0.001), were significantly associated with an increased risk of cephalosporin allergy reactions. Additionally, the HLA-C*01:02 allele genotype was significantly associated with a higher risk of severe allergy (OR = 2.33, 95% CI 1.05–5.15, p = 0.04). This study identified significant associations between HLA alleles and an increased risk of cephalosporin allergy, which can aid in early detection and prediction of adverse drug reactions to cephalosporins. Furthermore, our study highlights the importance of HLA typing in drug safety and expanding our knowledge of drug hypersensitivity syndromes. [ABSTRACT FROM AUTHOR]

Objective: Recent studies have indicated that HOTTIP and MEG3 are associated with the initiation and progression of various types of tumors, including nasopharyngeal carcinoma (NPC). This investigation aimed to elucidate the impact of HOTTIP and MEG3 polymorphisms on the susceptibility and clinicopathologic characteristics of NPC. Methods: This research employed next-generation sequencing and multiplex PCR to assess the polymorphisms of HOTTIP rs1859168 and MEG3 rs7158663 in 200 NPC and 200 healthy individuals respectively. HOTTIP and MEG3 expression were assessed via qRT-PCR assessment. Furthermore, the genotypes and alleles frequency of rs1859168 and rs7158663 were compared between healthy and NPC individuals to elucidate their influence on NPC susceptibility and relation with clinicopathologic characteristics. Results: In comparison with the healthy cohort, the presence of HOTTIP rs1859168 CC genotype and the C allele were markedly linked with increased NPC incidence (p < 0.05). Furthermore, the MEG3 rs7158663 AA genotype and the A allele also indicated an increased risk of NPC (p < 0.05). The subgroup analysis of age, EBV infection, gender, nationality, smoking, and drinking status revealed no marked association between rs1859168 and rs7158663 genotypes and these potential confounding factors. Moreover, it was observed that rs1859168 CC and rs7158663 AA genotypes were related to local tumor invasion and lymph node metastasis. Additionally, HOTTIP indicated a marked elevation, while MEG3 substantially reduced in NPC samples than the normal nasopharyngeal biospecimens. Patients who carried CC or CA genotypes rather than the HOTTIP rs1859168 AA genotype, had substantially higher HOTTIP levels, while patients with rs7158663 AA or GA genotypes indicated notably lower expression of MEG3 than GG genotype carriers. Conclusion: Individuals with genetic variants of HOTTIP rs1859168 and MEG3 rs7158663 might have an increased risk of NPC susceptibility and related clinicopathologic characteristics, potentially by affecting the expression of HOTTIP and MEG3. [ABSTRACT FROM AUTHOR]

Background: Identification of human leukocyte antigen (HLA) types from DNA-sequenced human samples is important in organ transplantation and cancer immunotherapy and remains a challenging task considering sequence homology and extreme polymorphism of HLA genes. Results: We present Orthanq, a novel statistical model and corresponding application for transparent and uncertainty-aware quantification of haplotypes. We utilize our approach to perform HLA typing while, for the first time, reporting uncertainty of predictions and transparently observing mutations beyond reported HLA types. Using 99 gold standard samples from 1000 Genomes, Illumina Platinum Genomes and Genome In a Bottle projects, we show that Orthanq can provide overall superior accuracy and shorter runtimes than state-of-the-art HLA typers. Conclusions: Orthanq is the first approach that allows to directly utilize existing pangenome alignments and type all HLA loci. Moreover, it can be generalized for usages beyond HLA typing, e.g. for virus lineage quantification. Orthanq is available under https://orthanq.github.io. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial cancer is a common cancer among women worldwide. In rare occasions, it can be caused by mutations in genes that can be inherited, and, mostly, as part of the Lynch syndrome that can also increase the risk of developing other cancers, mostly colorectal. In this study, we analyzed genetic alterations in 130 Arab patients with endometrial cancer. Among the whole group, 18 (13.8%) patients had positive mutations in MLH1, PMS2, MSH2, ATM, MUTYH, and BRCA2. Such mutations were more common in younger patients and in patients with specific endometrial cancers like carcinosarcoma and clear cell carcinoma. Most of endometrial cancers are sporadic, with 5% or less being attributed to inherited pathogenic germline mutations and mostly related to the Lynch syndrome. To our knowledge, this is the first study to investigate patterns and frequencies of germline mutations in patients with endometrial cancer in an Arab region. Consecutive patients with endometrial cancer (n = 130), regardless of their age and family history, were enrolled. Germline genetic testing, using an 84-gene panel, was performed on all. Almost half of the patient population (n = 64, 49.2%) was tested based on international guidelines, while the remaining patients (n = 66, 50.8%) were tested as part of an ongoing universal germline genetic testing program. Among the whole group, 18 (13.8%) patients had positive pathogenic or likely pathogenic (P/LP) germline variants. The most common variants encountered were in MLH1 (n = 4, 22.2%), PMS2 (n = 3, 16.7%), ATM, MSH2, MUTYH, and BRCA2 (n = 2, 11.1% each). In addition, three (2.3%) patients were found to have an increased risk allele of the APC gene. P/LP variants were more common among patients with carcinosarcoma and clear cell carcinoma, younger patients (age ≤ 50 years), and in patients with a non-metastatic disease. We conclude that germline genetic variants, mostly in genes related to the Lynch syndrome, are relatively common among Arab patients with endometrial cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the relationship between specific gene polymorphisms (TRAF2, TAB2, IKBKB) and protein levels and pituitary adenomas (PAs). The research included 459 participants, divided into a control group and a PA group. The key findings include significant differences in TRAF2 genotypes between the groups, with the G allele being less common in the PA group. The presence of the G allele and GG genotype were linked to a reduced risk of developing PAs, particularly microadenomas and macroadenomas. These results indicate a protective effect of the TRAF2 G allele against pituitary tumors. Aim: The aim of this study was to determine associations of TRAF2 (rs867186), TAB2 (rs237025), IKBKB (rs13278372) gene polymorphisms and TRAF2, TAB2, IKBKB protein levels with clinical and morphological features of pituitary adenomas (PAs). Methods: This case–control study included 459 individuals divided into two groups: a control group (n = 320) and a group of individuals with PAs (n = 139). DNA from peripheral blood leukocytes was isolated using salt precipitation and column method. Real-time PCR was used for TRAF2 (rs867186), TAB2 (rs237025), and IKBKB (rs13278372) SNP genotyping, and TRAF2, TAB2, IKBKB protein concentration measurements were performed by immunoenzymatic analysis tests using a commercial ELISA kit according to the manufacturer's recommendations. The labeling index Ki-67 was determined by immunohistochemical analysis using a monoclonal antibody (clone SP6; Spring Bioscience Corporation). Statistical data analysis was performed using the programs "IMB SPSS Statistics 29.0". Results: We found significant differences in TRAF2 (rs867186) genotypes (AA, AG, GG) between groups: 79.1%, 17.3%, 3.6% vs. 55.3%, 20.9%, 23.8% (p < 0.001). The G allele was less frequent in the PA group than in controls (12.2% vs. 34.2%, p < 0.001). The AG and GG genotypes reduced PA occurrence by 1.74-fold and 9.43-fold, respectively, compared to AA (p < 0.001). In the dominant model, GG and AG genotypes reduced PA odds by 3.07-fold, while in the recessive model, the GG genotype reduced PA odds by 8.33-fold (p < 0.001). Each G allele decreased PA odds by 2.49-fold in the additive model (p < 0.001). Microadenomas had significant genotype differences compared to controls: 81.3%, 18.8%, 0.0% vs. 55.3%, 20.9%, 23.8% (p < 0.001), with the G allele being less frequent (9.4% vs. 34.2%, p < 0.001). In macroadenomas, genotype differences were 78%, 16.5%, 5.5% vs. 55.3%, 20.9%, 23.8% (p < 0.001), and the G allele was less common (13.7% vs. 34.2%, p < 0.001). The dominant model showed that GG and AG genotypes reduced microadenoma odds by 3.5-fold (p = 0.001), and each G allele reduced microadenoma odds by 3.1-fold (p < 0.001). For macroadenomas, the GG genotype reduced odds by 6.1-fold in the codominant model (p < 0.001) and by 2.9-fold in GG and AG genotypes combined compared to AA (p < 0.001). The recessive model indicated the GG genotype reduced macroadenoma odds by 5.3-fold (p < 0.001), and each G allele reduced odds by 2.2-fold in the additive model (p < 0.001). Conclusions: The TRAF2 (rs867186) G allele and GG genotype are significantly associated with reduced odds of pituitary adenomas, including both microadenomas and macroadenomas, compared to the AA genotype. These findings suggest a protective role of the G allele against the occurrence of these tumors. [ABSTRACT FROM AUTHOR]

Pre-treatment genotyping of four well-characterized toxicity risk-variants in the dihydropyrimidine dehydrogenase gene (DPYD) has been widely implemented in Europe to prevent serious adverse effects in cancer patients treated with fluoropyrimidines. Current genotyping practices are largely limited to selected commonly studied variants and are unable to determine phasing when more than one variant allele is detected. Recent evidence indicates that common DPYD variants modulate the functional impact of deleterious variants in a phase-dependent manner, where a cis- or a trans-configuration translates into different toxicity risks and dosing recommendations. DPYD is a large gene with 23 exons spanning nearly a mega-base of DNA, making it a challenging candidate for full-gene sequencing in the diagnostic setting. Herein, we present a time- and cost-efficient long-read sequencing approach for capturing the complete coding region of DPYD. We demonstrate that this method can reliably produce phased genotypes, overcoming a major limitation with current methods. This method was validated using 21 subjects, including two cancer patients, each of whom carried multiple DPYD variants. Genotype assignments showed complete concordance with conventional approaches. Furthermore, we demonstrate that the method is robust to technical challenges inherent in long-range sequencing of PCR products, including reference alignment bias and PCR chimerism. [ABSTRACT FROM AUTHOR]

SUMMARY: Several dwarf and semi‐dwarf genes have been identified in barley. However, only a limited number have been effectively utilized in breeding programs to cultivate lodging resistant varieties. This is due to the common association of dwarf and semi‐dwarf traits with negative effects on malt quality. In this study, we employed gene editing to generate three new haplotypes of sdw1/denso candidate gene gibberellin (GA) 20‐oxidase2 (GA20ox2). These haplotypes induced a dwarfing phenotype and enhancing yield potential, and promoting seed dormancy, thereby reducing pre‐harvest sprouting. Moreover, β‐amylase activity in the grains of the mutant lines was significantly increased, which is beneficial for malt quality. The haplotype analysis revealed significant genetic divergence of this gene during barley domestication and selection. A novel allele (sdw1.ZU9), containing a 96‐bp fragment in the promoter region of HvGA20ox2, was discovered and primarily observed in East Asian and Russian barley varieties. The 96‐bp fragment was associated with lower gene expression, leading to lower plant height but higher germination rate. In conclusion, HvGA20ox2 can be potentially used to develop semi‐dwarf barley cultivars with high yield and improved malt quality. Significance Statement: Gene editing of HvGA20ox2 led to reduced plant height, improved yield potential, and pre‐harvest sprouting in barley. A novel allele sdw1.ZU9 containing a 96‐bp fragment located in the promoter region of HvGA20ox2 results in suppression of the gene expression, leading to reduced plant height and increased germination rate. [ABSTRACT FROM AUTHOR]

Female breast cancer is the most common and the fifth deadliest cancer worldwide. It is influenced by a combination of genetic, hormonal, and environmental factors. The excision repair cross‐complementation group 3 gene (ERCC3) has recently been identified as a breast cancer susceptibility gene in various cohorts of different geographical and ethnic origin. To explore the role of ERCC3 mutations in breast cancer development and pathological diagnosis, genetic analysis was conducted in 291 patients and 291 controls from mainland China. Bioinformatic analysis and immunohistochemistry (IHC) were performed. A novel ERCC3 mutation p.Y116X was identified in a breast cancer family, while no frequency bias for the genotype and allele of rs754010782 and rs371627165 was observed (all P > 0.05). Bioinformatic analysis revealed that ERCC3 expression was negatively associated with estrogen receptor (ER), progesterone receptor (PR), nontriple‐negative status, and nodal status of breast cancers. ERCC3 amplifications and deep deletions primarily occurred in breast invasive cancer not otherwise specified (NOS) and metaplastic breast cancer, respectively. The decreased ERCC3 expression in tumor tissues of patient with p.Y116X mutation was found by IHC. The ERCC3 mutation p.Y116X may increase breast cancer risk in the Han‐Chinese population. ERCC3 exhibits potential as a biomarker for the pathological diagnosis of breast cancer. [ABSTRACT FROM AUTHOR]

The evolution of separate sexes from cosexuality requires at least two mutations: a feminizing allele to cause female development and a masculinizing allele to cause male development. Classically, the double mutant is assumed to be sterile, which leads to two-factor sex determination where male and female sex chromosomes differ at two loci. However, several species appear to have one-factor sex determination where sexual development depends on variation at a single locus. We show that one-factor sex determination evolves when the double mutant develops as a male or a female. The feminizing allele fixes when the double mutant is male, and the masculinizing allele fixes when the double mutant is female. The other locus then gives XY or ZW sex determination based on dominance: for example, a dominant masculinizer becomes a Y chromosome. Although the resulting sex determination system differs, the conditions required for feminizers and masculinizers to spread are the same as in classical models, with the important difference that the two alleles do not need to be linked. Thus, we reveal alternative pathways for the evolution of sex determination and discuss how they can be distinguished using new data on the genetics of sex determination. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Current core cerebrospinal fluid (CSF) AD biomarkers, widely employed for diagnosis, require a lumbar puncture to be performed, making them impractical as screening tools. Considering the role of sleep disturbances in AD, recent research suggests quantitative sleep electroencephalography features as potential non-invasive biomarkers of AD pathology. However, quantitative analysis of comprehensive polysomnography (PSG) signals remains relatively understudied. PSG is a non-invasive test enabling qualitative and quantitative analysis of a wide range of parameters, offering additional insights alongside other biomarkers. Machine Learning (ML) gained interest for its ability to discern intricate patterns within complex datasets, offering promise in AD neuropathology detection. Therefore, this study aims to evaluate the effectiveness of a multimodal ML approach in predicting core AD CSF biomarkers. Methods: Mild-moderate AD patients were prospectively recruited for PSG, followed by testing of CSF and blood samples for biomarkers. PSG signals underwent preprocessing to extract non-linear, time domain and frequency domain statistics quantitative features. Multiple ML algorithms were trained using four subsets of input features: clinical variables (CLINVAR), conventional PSG parameters (SLEEPVAR), quantitative PSG signal features (PSGVAR) and a combination of all subsets (ALL). Cross-validation techniques were employed to evaluate model performance and ensure generalizability. Regression models were developed to determine the most effective variable combinations for explaining variance in the biomarkers. Results: On 49 subjects, Gradient Boosting Regressors achieved the best results in estimating biomarkers levels, using different loss functions for each biomarker: least absolute deviation (LAD) for the Aß42, least squares (LS) for p-tau and Huber for t-tau. The ALL subset demonstrated the lowest training errors for all three biomarkers, albeit with varying test performance. Specifically, the SLEEPVAR subset yielded the best test performance in predicting Aß42, while the ALL subset most accurately predicted p-tau and t-tau due to the lowest test errors. Conclusions: Multimodal ML can help predict the outcome of CSF biomarkers in early AD by utilizing non-invasive and economically feasible variables. The integration of computational models into medical practice offers a promising tool for the screening of patients at risk of AD, potentially guiding clinical decisions. [ABSTRACT FROM AUTHOR]

Accurately reconstructing the reticulate histories of polyploids remains a central challenge for understanding plant evolution. Although phylogenetic networks can provide insights into relationships among polyploid lineages, inferring networks may be hindered by the complexities of homology determination in polyploid taxa. We use simulations to show that phasing alleles from allopolyploid individuals can improve phylogenetic network inference under the multispecies coalescent by obtaining the true network with fewer loci compared with haplotype consensus sequences or sequences with heterozygous bases represented as ambiguity codes. Phased allelic data can also improve divergence time estimates for networks, which is helpful for evaluating allopolyploid speciation hypotheses and proposing mechanisms of speciation. To achieve these outcomes in empirical data, we present a novel pipeline that leverages a recently developed phasing algorithm to reliably phase alleles from polyploids. This pipeline is especially appropriate for target enrichment data, where the depth of coverage is typically high enough to phase entire loci. We provide an empirical example in the North American Dryopteris fern complex that demonstrates insights from phased data as well as the challenges of network inference. We establish that our pipeline (PATÉ: Phased Alleles from Target Enrichment data) is capable of recovering a high proportion of phased loci from both diploids and polyploids. These data may improve network estimates compared with using haplotype consensus assemblies by accurately inferring the direction of gene flow, but statistical nonidentifiability of phylogenetic networks poses a barrier to inferring the evolutionary history of reticulate complexes. [ABSTRACT FROM AUTHOR]

Heading date determines rice seasonal and regional adaptation, while plant height is an important trait related to rice lodging resistance. In this study, a recombinant inbred line population was used to detect quantitative trait loci (QTLs) for both traits in long-day (LD) and short-day (SD) environments. Three and two QTLs for heading date were detected in LD and SD environments, respectively. Notably, qHD8 and qHD10 were commonly detected in both environments. Five and four QTLs for plant height were identified in LD and SD environments, respectively. Among them, qPH3, qPH5 and qPH6 showed no pleiotropic effects on heading date and were detected in both environments. These three QTLs are considered to be the primary targets for improving rice plant height. Additionally, two genomic regions exhibited pleiotropic effects on both heading date and plant height. The alleles delayed the heading date while simultaneously increasing plant height. This study indicated that most QTLs for heading date are sensitive to photoperiod and have pleiotropic effects on plant height, thereby complicating their application in breeding programs. These findings provide useful information for the breeding of rice varieties with desired heading dates and plant heights. [ABSTRACT FROM AUTHOR]

Chakhao is a popular pigmented black rice variety with remarkably high anthocyanin content. Due to its susceptibility to various biotic and abiotic stresses, its production has remained low. Here, two genes, Pi54 blast-resistant and OsSPL14, high-yielding genes of rice, were pyramided in a Chakhao landrace by crossing with CR Dhan 307. From a total of 147 F4 lines developed, 32 were identified with the positive alleles of both genes, of which 16 were black grain coloured, and their total anthocyanin content ranged from 30.19±2.19 to 240.31±2.62 mg 100 g-1 dried weight. Among these, ChM 68 F4 line had the highest anthocyanin content (240.31 ± 2.62 mg 100 g-1 of powdered grain) with more 118.96 mg 100 g-1 anthocyanin than the recipient parent, CHK13 (121.35±3.32 mg 100 g-1), making it a promising line to be released as a highyielding and durable blast-resistant Chakhao variety in Manipur [ABSTRACT FROM AUTHOR]

Maize is considered one of the most important cereal fodder crops. Many studies on morphological diversity in fodder maize have been helpful in obtaining good heterotic hybrids. The current study focused on analysing diversity of 28 fodder maize inbreds with 30 SSR markers, which revealed total of 110 alleles; and their polymorphic information content (PIC) values ranged from 0.064 to 0.745. Population structure analysis revealed four subpopulation groups with the ΔK value of 132.70. Clustering based on the pairwise dissimilarity coefficient grouped the genotypes into two major and four sub-clusters. The high dissimilarity (0.777) observed between DM 84 and UMI 1221 indicated that these two were highly divergent. Principal coordinate analysis also showed diverse nature of inbreds and corroborated the clustering pattern. Parental diversity and their heterosis performance revealed that parents with average or narrow divergence could be useful in obtaining hybrids with medium/early flowering and moderate/high crude protein content. [ABSTRACT FROM AUTHOR]

The escalating rates of gonorrhea globally are associated with higher numbers of disseminated gonococcal infection (DGI). Expression of the PorB1A allele of the major outer membrane porin protein, PorB, is associated with DGI. This meta-analysis shows that the odds of PorB1A strains to disseminate is 20.53 compared to PorB1B isolates. [ABSTRACT FROM AUTHOR]

Motivation The alignment of sequencing reads is a critical step in the characterization of ancient genomes. However, reference bias and spurious mappings pose a significant challenge, particularly as cutting-edge wet lab methods generate datasets that push the boundaries of alignment tools. Reference bias occurs when reference alleles are favoured over alternative alleles during mapping, whereas spurious mappings stem from either contamination or when endogenous reads fail to align to their correct position. Previous work has shown that these phenomena are correlated with read length but a more thorough investigation of reference bias and spurious mappings for ancient DNA has been lacking. Here, we use a range of empirical and simulated palaeogenomic datasets to investigate the impacts of mapping tools, quality thresholds, and reference genome on mismatch rates across read lengths. Results For these analyses, we introduce AMBER, a new bioinformatics tool for assessing the quality of ancient DNA mapping directly from BAM-files and informing on reference bias, read length cut-offs and reference selection. AMBER rapidly and simultaneously computes the sequence read mapping bias in the form of the mismatch rates per read length, cytosine deamination profiles at both CpG and non-CpG sites, fragment length distributions, and genomic breadth and depth of coverage. Using AMBER, we find that mapping algorithms and quality threshold choices dictate reference bias and rates of spurious alignment at different read lengths in a predictable manner, suggesting that optimized mapping parameters for each read length will be a key step in alleviating reference bias and spurious mappings. Availability and implementation AMBER is available for noncommercial use on GitHub (https://github.com/tvandervalk/AMBER.git). Scripts used to generate and analyse simulated datasets are available on Github (https://github.com/sdolenz/refbias_scripts). [ABSTRACT FROM AUTHOR]

• The novelty is that MTHFR genotype may modulate the response to betaine intake. • Betaine concentrations increase more in TT/CT compared to CC. • Betaine supplementation decreases serum homocysteine concentration. • Betaine does not affect amino acid profile in healthy, athletic males. • The effect of betaine was not dose dependent. Betaine supplementation is used by athletes, but its mechanism of action is still not fully understood. We hypothesized that betaine supplementation would increase betaine concentration and alter amino acid profiles in relation to MTHFR genotype and dose in physically active males. The study followed a randomized placebo-controlled cross-over design. Blood samples were collected before and after each supplementation period. Serum was analyzed for amino acid profile, homocysteine, betaine, choline, and trimethylamine N-oxide (TMAO) concentrations. For the washout analysis, only participants starting with betaine were included (n = 20). Statistical analysis revealed no differences in the amino acid profile after betaine supplementation. However, betaine concentration significantly increased after betaine supplementation (from 4.89 ± 1.59 µg/mL to 17.31 ± 9.21 µg/mL, P <.001), with a greater increase observed in MTHFR (C677T, rs180113) T-allele carriers compared to CC (P =.027). Betaine supplementation caused a decrease in homocysteine concentration (from 17.04 ± 4.13 µmol/L to 15.44 ± 3.48 µmol/L, P =.00005) and a non-significant increase in TMAO concentrations (from 0.27 ± 0.20 µg/ml to 0.44 ± 0.70 µg/ml, P =.053), but had no effect on choline concentrations. Serum betaine concentrations were not significantly different after the 21-day washout from the baseline values (baseline: 4.93 ± 1.87 µg/mL and after washout: 4.70 ± 1.70 µg/mL, P = 1.000). In conclusion, betaine supplementation increased betaine and decreased homocysteine concentrations, but did not affect the amino acid profile or choline concentrations in healthy active males. Betaine concentrations may be dependent on MTHFR genotype. This was a randomized cross-over study of betaine supplementation in healthy athletic males. We showed that the increase in serum betaine concentrations was dependent on MTHFR genotype. Specifically, T-allele carriers experienced greater increase in betaine concentrations than CC homozygotes. Homocysteine concentration decreased with betaine supplementation. Abbreviations: BET, betaine; Hcy, homocysteine; MTHFR, methylenetatrahydrofolate; PL, placebo; WO, washout. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: Systemic lupus erythematosus (SLE), an autoimmune disease with incompletely understood etiology, has a strong genetic component. Although genome‐wide association studies (GWASs) have revealed multiple SLE susceptibility loci and associated single‐nucleotide polymorphisms (SNPs), the precise causal variants, target genes, cell types, tissues, and mechanisms of action remain largely unknown. Methods: Here, we report a comprehensive post‐GWAS analysis using extensive bioinformatics, molecular modeling, and integrative functional genomic and epigenomic analyses to optimize fine‐mapping. We compile and cross‐reference immune cell–specific expression quantitative trait loci (cis– and trans–expression quantitative trait loci) with promoter capture high‐throughput capture chromatin conformation (PCHi‐C), allele‐specific chromatin accessibility, and massively parallel reporter assay data to define predisposing variants and target genes. We experimentally validate a predicted locus using CRISPR/Cas9 genome editing, quantitative polymerase chain reaction, and Western blot. Results: Anchoring on 452 index SNPs, we selected 9,931 high linkage disequilibrium (r2 > 0.8) SNPs and defined 182 independent non‐human leukocyte antigen (HLA) SLE loci. The 3,746 SNPs from 143 loci were identified as regulating 564 unique genes. Target genes are enriched in lupus‐related tissues and associated with other autoimmune diseases. Of these, 329 SNPs (106 loci) showed significant allele‐specific chromatin accessibility and/or enhancer activity, indicating regulatory potential. Using CRISPR/Cas9, we validated reference SNP identifier 57668933 (rs57668933) as a functional variant regulating multiple targets, including SLE‐risk gene ELF1 in B cells. Conclusion: We demonstrate and validate post‐GWAS strategies for using multidimensional data to prioritize likely causal variants with cognate gene targets underlying SLE pathogenesis. Our results provide a catalog of significantly SLE‐associated SNPs and loci, target genes, and likely biochemical mechanisms to guide experimental characterization. [ABSTRACT FROM AUTHOR]

Gregor Mendel developed the principles of segregation and independent assortment in the mid-1800s based on his detailed analysis of several traits in pea plants. Those principles, now called Mendel's laws, in fact, explain the behavior of genes and alleles during meiosis and are now understood to underlie "Mendelian inheritance" of a wide range of traits and diseases across organisms. When asked to give examples of inheritance that do NOT follow Mendel's laws, in other words, examples of non-Mendelian inheritance, students sometimes list incomplete dominance, codominance, multiple alleles, sex-linked traits, and multigene traits and cite as their sources the Khan Academy, Wikipedia, and other online sites. Against this background, the goals of this Perspective are to (1) explain to students, healthcare workers, and other stakeholders why the examples above, in fact, display Mendelian inheritance, as they obey Mendel's laws of segregation and independent assortment, even though they do not produce classic Mendelian phenotypic ratios and (2) urge individuals with an intimate knowledge of genetic principles to monitor the accuracy of learning resources and work with us and those resources to correct information that is misleading. [ABSTRACT FROM AUTHOR]

Characterizing spatial patterns in allele frequencies is fundamental to evolutionary biology because these patterns contain evidence of underlying processes. However, the spatial scales at which gene flow, changing selection, and drift act are often unknown. Many of these processes can operate inconsistently across space, causing nonstationary patterns. We present a wavelet approach to characterize spatial pattern in allele frequency that helps solve these problems. We show how our approach can characterize spatial patterns in relatedness at multiple spatial scales, i.e. a multilocus wavelet genetic dissimilarity. We also develop wavelet tests of spatial differentiation in allele frequency and quantitative trait loci (QTL). With simulation, we illustrate these methods under different scenarios. We also apply our approach to natural populations of Arabidopsis thaliana to characterize population structure and identify locally adapted loci across scales. We find, for example, that Arabidopsis flowering time QTL show significantly elevated genetic differentiation at 300–1,300 km scales. Wavelet transforms of allele frequencies offer a flexible way to reveal geographic patterns and underlying evolutionary processes. [ABSTRACT FROM AUTHOR]

Sex-biased demography, including sex-biased survival or migration, can alter allele frequency changes across the genome. In particular, we can expect different patterns of genetic variation on autosomes and sex chromosomes due to sex-specific differences in life histories, as well as differences in effective population size, transmission modes, and the strength and mode of selection. Here, we demonstrate the role that sex differences in life history played in shaping short-term evolutionary dynamics across the genome. We used a 25-year pedigree and genomic dataset from a long-studied population of Florida Scrub-Jays (Aphelocoma coerulescens) to directly characterize the relative roles of sex-biased demography and inheritance in shaping genome-wide allele frequency trajectories. We used gene dropping simulations to estimate individual genetic contributions to future generations and to model drift and immigration on the known pedigree. We quantified differential expected genetic contributions of males and females over time, showing the impact of sex-biased dispersal in a monogamous system. Due to female-biased dispersal, more autosomal variation is introduced by female immigrants. However, due to male-biased transmission, more Z variation is introduced by male immigrants. Finally, we partitioned the proportion of variance in allele frequency change through time due to male and female contributions. Overall, most allele frequency change is due to variance in survival and births. Males and females make similar contributions to autosomal allele frequency change, but males make higher contributions to allele frequency change on the Z chromosome. Our work shows the importance of understanding sex-specific demographic processes in characterizing genome-wide allele frequency change in wild populations. [ABSTRACT FROM AUTHOR]

Inversions have been proposed to facilitate local adaptation, by linking together locally coadapted alleles at different loci. Prior work addressing this question theoretically has considered the spread of inversions in "continent-island" scenarios in which there is a unidirectional flow of maladapted migrants into the island population. In this setting, inversions capturing locally adaptive haplotypes are most likely to invade when selection is weak, because stronger local selection (i) more effectively purges maladaptive alleles and (ii) generates linkage disequilibrium between adaptive alleles, thus lessening the advantage of inversions. We show this finding only holds under limited conditions by studying the establishment of inversions in a more general two-deme model, which explicitly considers the dynamics of allele frequencies in both populations linked by bidirectional migration. In this model, the level of symmetry between demes can be varied from complete asymmetry (continent-island) to complete symmetry. For symmetric selection and migration, strong selection increases the allele frequency divergence between demes thereby increasing the frequency of maladaptive alleles in migrants, favoring inversions—the opposite of the pattern seen in the asymmetric continent-island scenario. We also account for the likelihood that a new inversion captures an adaptive haplotype in the first instance. When considering the combined process of capture and invasion in "continent island" and symmetric scenarios, relatively strong selection increases inversion establishment probability. Migration must also be low enough that the inversion is likely to capture an adaptive allele combination, but not so low as to eliminate the inversion's advantage. Overall, our analysis suggests that inversions are likely to harbor larger effect alleles that experience relatively strong selection. [ABSTRACT FROM AUTHOR]

The accurate segregation of homologous chromosomes during the Meiosis I reductional division in most sexually reproducing eukaryotes requires crossing over between homologs. In baker's yeast approximately 80% of meiotic crossovers result from Mlh1 – Mlh3 and Exo1 acting to resolve double-Holliday junction intermediates in a biased manner. Little is known about how Mlh1 – Mlh3 is recruited to recombination intermediates to perform its role in crossover resolution. We performed a gene dosage screen in baker's yeast to identify novel genetic interactors with Mlh1 – Mlh3. Specifically, we looked for genes whose lowered dosage reduced meiotic crossing over using sensitized mlh3 alleles that disrupt the stability of the Mlh1 – Mlh3 complex and confer defects in mismatch repair but do not disrupt meiotic crossing over. To our surprise we identified genetic interactions between MLH3 and DMC1 , the recombinase responsible for recombination between homologous chromosomes during meiosis. We then showed that Mlh3 physically interacts with Dmc1 in vitro and in vivo. Partial complementation of Mlh3 crossover functions was observed when MLH3 was expressed under the control of the CLB1 promoter (NDT80 regulon), suggesting that Mlh3 function can be provided late in meiotic prophase at some functional cost. A model for how Dmc1 could facilitate Mlh1 – Mlh3 's role in crossover resolution is presented. [ABSTRACT FROM AUTHOR]

Gene duplication is an important substrate for the evolution of new gene functions, but the impacts of gene duplicates on their own activities and on the developmental networks in which they act are poorly understood. Here, we use a natural experiment of lin-12 /Notch gene duplication within the nematode genus Caenorhabditis , combined with characterization of loss- and gain-of-function mutations, to uncover functional distinctions between the duplicate genes in 1 species (Caenorhabditis briggsae) and their single-copy ortholog in Caenorhabditis elegans. First, using improved genomic sequence and gene model characterization, we confirm that the C. briggsae genome includes 2 complete lin-12 genes, whereas most other genes encoding proteins that participate in the LIN-12 signaling pathway retain a one-to-one orthology with C. elegans. We use CRISPR-mediated genome editing to introduce alleles predicted to cause gain-of-function (gf) or loss-of-function (lf) into each C. briggsae gene and find that the gf mutations uncover functional distinctions not apparent from the lf alleles. Specifically, Cbr-lin-12.1 (gf) , but not Cbr-lin-12.2 (gf) , causes developmental defects similar to those observed in Cel-lin-12 (gf). In contrast to Cel-lin-12 (gf) , however, the Cbr-lin-12.1 (gf) alleles do not cause dominant phenotypes as compared to the wild type, and the mutant phenotype is observed only when 2 gf alleles are present. Our results demonstrate that gene duplicates can exhibit differential capacities to compensate for each other and to interfere with normal development, and uncover coincident gene duplication and evolution of developmental sensitivity to LIN-12 /Notch activity. [ABSTRACT FROM AUTHOR]

The major loci for the large primary ribosomal RNA (rRNA) genes (35S rRNAs) exist as hundreds to thousands of tandem repeats in all organisms and dozens to hundreds in Drosophila. The highly repetitive nature of the ribosomal DNA (rDNA) makes it intrinsically unstable, and many conditions arise from the reduction in or magnification of copy number, but the conditions under which it does so remain unknown. By targeted DNA damage to the rDNA of the Y chromosome, we created and investigated a series of rDNA alleles. We found that complete loss of rDNA leads to lethality after the completion of embryogenesis, blocking larval molting and metamorphosis. We find that the resident retrotransposons— R1 and R2 —are regulated by active rDNA such that reduction in copy number derepresses these elements. Their expression is highest during the early first instar, when loss of rDNA is lethal. Regulation of R1 and R2 may be related to their structural arrangement within the rDNA , as we find they are clustered in the flanks of the nucleolus organizing region (NOR ; the cytological appearance of the rDNA). We assessed the complex nucleolar dominance relationship between X - and Y -linked rDNA using a histone H3.3–GFP reporter construct and incorporation at the NOR and found that dominance is controlled by rDNA copy number as at high multiplicity the Y -linked array is dominant, but at low multiplicity the X -linked array becomes derepressed. Finally, we found that multiple conditions that disrupt nucleolar dominance lead to increased rDNA magnification, suggesting that the phenomena of dominance and magnification are related, and a single mechanism may underlie and unify these two longstanding observations in Drosophila. [ABSTRACT FROM AUTHOR]

Wheat (Triticum aestivum L.) has inflorescences made up of multiple spikelets arranged along a central rachis, with each spikelet producing between one and four grains. The Grain Number Increase 1 (GNI‐A1) gene wheat directly influences grain number per spikelet and grain size. Three naturally occurring alleles have been described previously: GNI‐A1‐105N, 105Y, and 105K. This project's goal was to characterize the impact of these alleles within hard red spring wheat cultivars in Montana, where each of the alleles is common. The 105N allele and the 105K allele were compared through analysis of an F5 Vida by Spring‐Yellowstone recombinant inbred line (RIL) population, and with near isogenic lines (NILs) derived from the same population. The 105N allele and the 105Y allele were compared with NILs derived from an F4 Lanning by Egan RIL population. We analyzed the impact of each of the three alleles and compared their effects on inflorescence architecture, grain size, grain yield, grain quality, and milling quality under Bozeman, MT, field conditions. Data show that either loss‐of‐function alleles (105Y and 105K) increased grain number per spikelet by 5% when compared to the more functional allele (105N) across all years and environments tested. Overall grain size was not significantly reduced and there was also not a significant increase in overall grain yield. Core Ideas: The wheat Grain Number Increase 1 gene increases grain number per spikelet.Grain Number Increase 1 missense alleles increased grain number per inflorescence by 5%.Grain Number Increase 1 missense alleles did not increase grain yield. [ABSTRACT FROM AUTHOR]