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Although long-term survival in Rett syndrome (RTT) has been observed, limited information on older people with RTT exists. We hypothesized that increased longevity in RTT would be associated with genetic variants in MECP2 associated with milder severity, and that clinical features would not be static in older individuals. To address these hypotheses, we compared the distribution of MECP2 variants and clinical severity between younger individuals with Classic RTT (under 30 years old) and older individuals (over 30 years old). Contrary to expectation, enrichment of a severe MECP2 variant (R106W) was observed in the older cohort. Overall severity was not different between the cohorts, but specific clinical features varied between the cohorts. Overall severity from first to last visit increased in the younger cohort but not in the older cohort. While some specific clinical features in the older cohort were stable from the first to the last visit, others showed improvement or worsening. These data do not support the hypothesis that mild MECP2 variants or less overall severity leads to increased longevity in RTT but demonstrate that clinical features change with increasing age in adults with RTT. Additional work is needed to understand disease progression in adults with RTT. [ABSTRACT FROM AUTHOR]

Allergic respiratory diseases such as asthma might be considered multifactorial diseases, having a complex pathogenesis that involves environmental factors and the activation of a large set of immune response pathways and mechanisms. In addition, variations in genetic background seem to play a central role. The method developed for the analysis of the complexities, as association rule mining, nowadays may be applied to different research areas including genetic and biological complexities such as atopic airway diseases to identify complex genetic or biological markers and enlighten new diagnostic and therapeutic targets. A total of 308 allergic patients and 205 controls were typed for 13 single nucleotide polymorphisms (SNPs) of cytokine and receptors genes involved in type 1 and type 2 inflammatory response (IL-4 rs2243250 C/T, IL-4R rs1801275A/G, IL-6 rs1800795 G/C, IL-10 rs1800872 A/C and rs1800896 A/G, IL-10RB rs2834167A/G, IL-13 rs1800925 C/T, IL-18 rs187238G/C, IFNγ rs 24030561A/T and IFNγR2 rs2834213G/A), the rs2228137C/T of CD23 receptor gene and rs577912C/T and rs564481C/T of Klotho genes, using KASPar SNP genotyping method. Clinical and laboratory data of patients were analyzed by formal statistic tools and by a data-mining technique—market basket analysis—selecting a minimum threshold of 90% of rule confidence. Formal statistical analyses show that IL-6 rs1800795GG, IL-10RB rs2834167G positive genotypes, IL-13 rs1800925CC, CD23 rs2228137TT Klotho rs564481TT, might be risk factors for allergy. Applying the association rule methodology, we identify 10 genotype combination patterns associated with susceptibility to allergies. Together these data necessitate being confirmed in further studies, indicating that the heuristic approach might be a straightforward and useful tool to find predictive and diagnostic molecular patterns that might be also considered potential therapeutic targets in allergy. [ABSTRACT FROM AUTHOR]

Saussurea inversa is a perennial herb used in traditional Chinese medicine and is effective against rheumatoid arthritis. In this study, we sequenced the complete mitochondrial (mt) genome of S. inversa (GenBank accession number: ON584565.1). The circular mt genome of S. inversa was 335,372 bp in length, containing 62 genes, including 33 mRNAs, 22 tRNAs, 6 rRNAs, and 1 pseudogene, along with 1626 open reading frames. The GC content was 45.14%. Predictive analysis revealed substantial RNA editing, with ccmFn being the most abundantly edited gene, showing 36 sites. Gene migration between the mt and chloroplast (cp) genomes of S. inversa was observed through the detection of homologous gene fragments. Phylogenetic analysis revealed that S. inversa was clustered with Arctium tomentosum (Asteraceae). Our findings provide extensive information regarding the mt genome of S. inversa and help lay the foundation for future studies on its genetic variations, phylogeny, and breeding via the analysis of the mt genome. [ABSTRACT FROM AUTHOR]

The Krüppel-like factor (KLF) family represents a group of transcription factors (TFs) performing different biological processes that are crucial for proper neuronal function, including neuronal development, synaptic plasticity, and neuronal survival. As reported, genetic variants within the KLF family have been associated with a wide spectrum of neurodevelopmental and psychiatric symptoms. In a patient exhibiting attention deficit hyperactivity disorder (ADHD) combined with both neurodevelopmental and psychiatric symptoms, whole-exome sequencing (WES) analysis revealed a de novo heterozygous variant within the Krüppel-like factor 13 (KLF13) gene, which belongs to the KLF family and regulates axonal growth, development, and regeneration in mice. Moreover, in silico analyses pertaining to the likely pathogenic significance of the variant and the impact of the mutation on the KLF13 protein structure suggested a potential deleterious effect. In fact, the variant was localized in correspondence to the starting residue of the N-terminal domain of KLF13, essential for protein–protein interactions, DNA binding, and transcriptional activation or repression. This study aims to highlight the potential involvement of the KLF13 gene in neurodevelopmental and psychiatric disorders. Nevertheless, we cannot rule out that excluded variants, those undetectable by WES, or the polygenic risk may have contributed to the patient's phenotype given ADHD's high polygenic risk. However, further functional studies are required to validate its potential contribution to these disorders. [ABSTRACT FROM AUTHOR]

Current therapy in chronic myeloid leukemia (CML) has improved patient life expectancy close to that of healthy individuals. However, molecular alterations other than BCR::ABL1 fusion gene in CML are barely known. MicroRNAs are important regulators of gene expression, and variants in some of the components of microRNA biosynthesis pathways have been associated with genetic susceptibility to different types of cancer. Thus, the aim of this study was to evaluate the association of variants located in genes involved in the biogenesis of microRNAs with susceptibility to CML. Fifteen variants in eight genes involved in the biogenesis of miRNAs were genotyped in 296 individuals with CML and 485 healthy participants using TaqMan probes. The association of gene variants with CML and clinical variables was evaluated by a Chi-square test, and odds ratios and 95% confidence intervals were estimated by logistic regression. The variant rs13078 in DICER1 was significantly higher among CML individuals than in healthy participants. In addition, the variants rs7813 and rs2740349 were significantly associated with worse prognosis, according to their Hasford scores, whereas the rs2740349 variant was also associated with a later age at diagnosis. These findings suggest that variants in components of the microRNA biogenesis pathway could be involved in CML genetic risk. [ABSTRACT FROM AUTHOR]

The rapid advancement of high-throughput technologies, particularly next-generation sequencing (NGS), has revolutionized cancer research by enabling the investigation of genetic variations such as SNPs, copy number variations, gene expression, and protein levels. These technologies have elevated the significance of precision oncology, creating a demand for biomarker identification and validation. This review explores the complex interplay of oncology, cancer biology, and bioinformatics tools, highlighting the challenges in statistical learning, experimental validation, data processing, and quality control that underpin this transformative field. This review outlines the methodologies and applications of bioinformatics tools in cancer genomics research, encompassing tools for data structuring, pathway analysis, network analysis, tools for analyzing biomarker signatures, somatic variant interpretation, genomic data analysis, and visualization tools. Open-source tools and repositories like The Cancer Genome Atlas (TCGA), Genomic Data Commons (GDC), cBioPortal, UCSC Genome Browser, Array Express, and Gene Expression Omnibus (GEO) have emerged to streamline cancer omics data analysis. Bioinformatics has significantly impacted cancer research, uncovering novel biomarkers, driver mutations, oncogenic pathways, and therapeutic targets. Integrating multi-omics data, network analysis, and advanced ML will be pivotal in future biomarker discovery and patient prognosis prediction. [ABSTRACT FROM AUTHOR]

The mitochondrial cytochrome c oxidase subunit I (COI) genes of six endangered goose breeds (Xupu, Yangjiang, Yan, Wuzong, Baizi, and Lingxian) were sequenced and compared to assess the genetic diversity of endangered goose breeds. By constructing phylogenetic trees and evolutionary maps of genetic relationships, the affinities and degrees of genetic variations among the six different breeds were revealed. A total of 92 polymorphic sites were detected in the 741 bp sequence of the mtDNA COI gene after shear correction, and the GC content of the processed sequence (51.11%) was higher than that of the AT content (48.89%). The polymorphic loci within the populations of five of the six breeds (Xupu, Yangjiang, Yan, Baizi, and Lingxian) were more than 10, the haplotype diversity > 0.5, and the nucleotide diversity (Pi) > 0.005, with the Baizi geese being the exception. A total of 35 haplotypes were detected based on nucleotide variation among sequences, and the goose breed haplotypes showed a central star-shaped dispersion; the FST values were −0.03781 to 0.02645, The greatest genetic differentiation (FST = 0.02645) was observed in Yan and Wuzong breeds. The most frequent genetic exchange (Nm > 15.00) was between the Wuzong and Yangjiang geese. An analysis of molecular variance showed that the population genetic variation mainly came from within the population; the base mismatch differential distribution analysis of the goose breeds and the Tajima's D and Fu's Fs neutral detection of the historical occurrence dynamics of their populations were negative (p > 0.10). The distribution curve of the base mismatches showed a multimodal peak, which indicated that the population tended to be stabilised. These results provide important genetic information for the conservation and management of endangered goose breeds and a scientific basis for the development of effective conservation strategies. [ABSTRACT FROM AUTHOR]

Genome-wide association study (GWAS) has identified numerous significant loci for boll number (BN) and boll weight (BW), which play an essential role in cotton (Gossypium spp.) yield. The North Carolina design II (NC II) genetic mating population exhibits a greater number of genetic variations than other populations, which may facilitate the identification of additional genes. Accordingly, the 3VmrMLM method was employed for the analysis of upland cotton (Gossypium hirsutum L.) in an incomplete NC II genetic mating population across three environments. A total of 204 quantitative trait nucleotides (QTNs) were identified, of which 25 (24.75%) BN and 30 (29.13%) BW QTNs were of small effect (<1%) and 24 (23.76%) BN and 20 (19.42%) BW QTNs were rare (<10%). In the vicinity of these QTNs, two BN-related genes and two BW-related genes reported in previous studies were identified, in addition to five BN candidate genes and six BW candidate genes, which were obtained using differential expression analysis, gene function annotation, and haplotype analysis. Among these, six candidate genes were identified as homologs of Arabidopsis genes. The present study addresses the limitation of heritability missing and uncovers several new candidate genes. The findings of this study can provide a basis for further research and marker-assisted selection in upland cotton. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy with respiratory distress type 1 (SMARD1; OMIM #604320, ORPHA:98920) is a rare autosomal recessive congenital motor neuron disease. It is caused by variants in the IGHMBP2 gene. Clinically, it presents with respiratory failure due to diaphragmatic paralysis, progressive muscle weakness starting in the distal parts of the limbs, dysphagia, and damage to sensory and autonomic nerves. Unlike spinal muscular atrophy (SMA), SMARD1 has a distinct genetic etiology and is not detected in the population newborn screening programs. Most children with SMARD1 do not survive beyond the first year of life due to progressive respiratory failure. Artificial ventilation can prolong survival, but no specific treatment is available. Therapy focuses on mechanical ventilation and improving the patient's quality of life. Research into gene therapy is ongoing. We report three female patients with SMARD1, including twins from a triplet pregnancy. In twin sisters (patient no. 1 and patient no. 2), two heterozygous variants in the IGHMBP2 gene were identified: c.595G>C/p.Ala199Pro and c.1615_1623del/p.Ser539_Tyr541del. In patient no. 3, a variant c.1478C>T/p.Thr493Ile and a variant c.439C>T/p.Arg147* in the IGHMBP2 gene were detected. Our findings underscore the variability of clinical presentations, even among patients sharing the same pathogenic variants in the IGHMBP2 gene, and emphasize the importance of early genetic diagnosis in patients presenting with respiratory failure, with or without associated diaphragmatic muscle paralysis. [ABSTRACT FROM AUTHOR]

The pink river dolphin, or bufeo, is one of the dolphins which lives in the rivers of the Orinoco and Amazon basins in South America. The Bolivian bufeo population is considered a differentiated species (Inia boliviensis) from the Amazon and Orinoco species (Inia geoffrensis). Until now, no study has completed an extensive population genetics analysis of the bufeo in Bolivian rivers. We analyzed 82 bufeos from different rivers from the Mamoré and Iténez (Guaporé) river basins for the mt control region (CR), nuclear microsatellites, and DQB-1 gene sequences to determine if the inner rapids of these Bolivian river basins have some influence on the genetic structure of this species. The first relevant result was that the genetic diversity for CR, and the microsatellites were substantially lower in the Bolivian bufeos than in the dolphins studied in other areas of the Amazon and Orinoco. However, the DQB-1 gene sequences yielded similar genetic diversity to those found in other areas. The second relevant result is the existence of some significant genetic heterogeneity among the bufeo populations within Bolivia, although in a small degree, but this differentiation is independent of the inner rapids of the Bolivian rivers we sampled. The third relevant result was the existence of significant isolation by distance for the CR, but not for microsatellites and DQB-1 gene sequences. This was related to differential gene flow capacity of females (philopatric) and males (less philopatric and more migrants) and, possibly, to different selective patterns affecting the molecular markers studied. The fourth relevant result was related to diverse demographic changes of these bufeos. At least two or three bottleneck events and one or two population expansions have occurred in the Bolivian bufeo population. The major part of these events occurred during the Pleistocene. [ABSTRACT FROM AUTHOR]

Understanding the correlation between genotype and phenotype remains challenging for modern genetics. Digenic network analysis may provide useful models for understanding complex phenotypes that traditional Mendelian monogenic models cannot explain. Clinical data, whole exome sequencing data, in silico, and machine learning analysis were combined to construct a digenic network that may help unveil the complex genotype–phenotype correlations in a child presenting with inherited seizures and thrombocytopenia. The proband inherited a maternal heterozygous missense variant in SCN1A (NM_001165963.4:c.2722G>A) and a paternal heterozygous missense variant in MYH9 (NM_002473.6:c.3323A>C). In silico analysis showed that these two variants may be pathogenic for inherited seizures and thrombocytopenia in the proband. Moreover, focusing on 230 epilepsy-associated genes and 35 thrombopoiesis genes, variant call format data of the proband were analyzed using machine learning tools (VarCoPP 2.0) and Digenic Effect predictor. A digenic network was constructed, and SCN1A and MYH9 were found to be core genes in the network. Further analysis showed that MYH9 might be a modifier of SCN1A, and the variant in MYH9 might not only influence the severity of SCN1A-related seizure but also lead to thrombocytopenia in the bone marrow. In addition, another eight variants might also be co-factors that account for the proband's complex phenotypes. Our data show that as a supplement to the traditional Mendelian monogenic model, digenic network analysis may provide reasonable models for the explanation of complex genotype–phenotype correlations. [ABSTRACT FROM AUTHOR]

Serum biochemical indicators serve as vital proxies that reflect the physiological state and functions of different organs. The genetic parameters and molecular mechanisms underlying serum biochemical indicators of sheep (Ovis aries) have not been well understood. Therefore, the aim of the present study was to identify the genetic architecture and genomic loci underlying ten serum biochemical indicators in sheep, including alanine transaminase, aspartate transferase, lactate dehydrogenase, cholesterol, glucose, phosphorus, calcium, creatinine, urea and total protein levels. We implemented genetic parameter estimations and GWASs for each trait in 422 Akkaraman lambs. Overall, low to moderate heritability estimates were found in the range of 0.14–0.55. Additionally, low to high genetic correlations were observed among traits. In total, 23 SNP loci were associated with serum biochemical indicators leading to 19 genes. These were SPTA1, MGST2, CACUL1, IGFBP7, PARD3, PHB1, SLC15A5, TRIM35, RGS6, NUP93, CNTNAP2, SLC7A11, B3GALT5, DPP10, HST2ST1, NRP1, LRP1B, MAP3K9 and ENSOARG00020040484.1, as well as LOC101103187, LOC101117162, LOC105611309 and LOC101118029. To our knowledge, these data provide the first associations between SPTA1 and serum cholesterol and between ENSOARG00020040484.1 and serum glucose. The current findings provide a comprehensive inventory of the relationships between serum biochemical parameters, genetic variants and disease-relevant characteristics. This information may facilitate the identification of therapeutic targets and fluid biomarkers and establish a strong framework for comprehending the pathobiology of complex diseases as well as providing targets for sheep genetic improvement programs. [ABSTRACT FROM AUTHOR]

Comprehension of the genetic basis of temperament has been improved by recent advances in the identification of genes and genetic variants. However, due to the complexity of the temperament traits, the elucidation of the genetic architecture of temperament is incomplete. A systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to analyze candidate genes related to bovine temperament, using bovine as the population, SNPs and genes as the exposure, and temperament test as the outcome, as principal search terms for population, exposure, and outcome (PEO) categories to define the scope of the search. The search results allowed the selection of 36 articles after removing duplicates and filtering by relevance. One hundred-two candidate genes associated with temperament traits were identified. The genes were further analyzed to construct an interaction network using the STRING database, resulting in 113 nodes and 346 interactions and the identification of 31 new candidate genes for temperament. Notably, the main genes identified were SST and members of the Kelch family. The candidate genes displayed interactions with pathways associated with different functions such as AMPA receptors, hormones, neuronal maintenance, protein signaling, neuronal regulation, serotonin synthesis, splicing, and ubiquitination activities. These new findings demonstrate the complexity of interconnected biological processes that regulate behavior and stress response in mammals. This insight now enables our targeted analysis of these newly identified temperament candidate genes in bovines. [ABSTRACT FROM AUTHOR]

Sorghum is an important C4 crop with various food and nonfood uses. Although improvements through hybridization and selection have been exploited, the introduction of genetic variation and the development of new genotypes in sorghum are still limited. Fast-neutron (FN) mutagenesis is a very effective method for gene functional studies and to create genetic variability. However, the full spectrum of FN-induced mutations in sorghum is poorly understood. To address this, we generated an FN-induced mutant population from the inbred line 'BTx623' and sequenced 40 M1 seedlings to evaluate the mutagenic effects of FNs on sorghum. The results show that each line had an average of 43.7 single-base substitutions (SBSs), 3.7 InDels and 35.15 structural variations (SVs). SBSs accounted for approximately 90.0% of the total number of small mutations. Among the eight treatment groups, FN irradiation at a dose of 19 Gy generated the highest number of mutations. The ratio of transition/transversion ranged from 1.77 to 2.21, and the G/C to A/T transition was the most common substitution in all mutant lines. The distributions of the identified SBSs and InDels were similar and uneven across the genome. An average of 3.63 genes were mutated in each mutant line, indicating that FN irradiation resulted in a suitable density of mutated genes, which can be advantageous for improving elite material for one specific or a few traits. These results provide a basis for the selection of the suitable dose of mutagen and new genetic resources for sorghum breeding. [ABSTRACT FROM AUTHOR]

CTNNB1 pathogenic variants are related to the improper functioning of the WNT/β-catenin pathway, promoting the development of different types of cancer of somatic origin. Bioinformatics analyses of genetic variation are a great tool to understand the possible consequences of these variants on protein structure and function and their probable implication in pathologies. The objective of this study is to describe the impact of the missense variants of uncertain significance (VUS) of the CTNNB1 gene on structure and function of the β-catenin protein. The CTNNB1 variants were obtained from the GnomAD v2.1.1 database; subsequently, a bioinformatic analysis was performed using the VarSome, UCSC Genome Browser, UniProt, the Kinase Library database, and DynaMut2 platforms to evaluate clinical significance, gene conservation, consensus sites for post-translational modifications, and the dynamics and stability of proteins. The GnomAD v2.1.1 database included 826 variants of the CTNNB1 gene, of which 385 were in exons and exon/intron boundaries. Among these variants, 214 were identified as missense, of which 146 were classified as VUS. Notably, 12 variants were in proximity to consensus sites for post-translational modifications (PTMs). The in silico analysis showed a slight tendency towards probably pathogenic for c.59C>T (p.Ala20Val) and c.983T>C (p.Met328Thr) missense VUS. These findings provide possible functional implications of these variants in some types of cancer. [ABSTRACT FROM AUTHOR]

During the expanded neonatal screening program conducted in 2023, we analyzed samples obtained from 1,227,130 out of 1,256,187 newborns in the Russian Federation in order to detect 5q spinal muscular atrophy (5q SMA). Within the 253-sample risk group formed based on the results of the first screening stage, 5 samples showed a discrepancy between the examination results obtained via various screening methods and quantitative MLPA (used as reference). The discrepancy between the results was caused by the presence of either a c.835-18C>T intronic variant or a c.842G>C p.(Arg281Thr) missense variant in the SMN1 gene, both of which are located in the region complementary to the sequences of annealing probes for ligation and real-time PCR. Three newborns had the c.835-18C>T variant in a compound heterozygous state with a deletion of exons 7–8 of the SMN1 gene, one newborn with two copies of the SMN1 gene had the same variant in a heterozygous state, and one newborn had both variants—c.835-18C>T and c.842G>C p.(Arg281Thr)—in a compound heterozygous state. Additional examination was carried out for these variants, involving segregation analysis in families, carriage analysis in population cohorts, and RNA analysis. Based on the obtained results, according to the ACMG criteria, the c.835-18C>T intronic variant should be classified as likely benign, and the c.842G>C p.(Arg281Thr) missense substitution as a variant of uncertain clinical significance. All five probands are under dynamic monitoring. No 5q SMA symptoms were detected in these newborns neonatally or during a 1-year follow-up period. [ABSTRACT FROM AUTHOR]

Dysfunction of some mitochondrial aminoacyl-tRNA synthetases (encoded by the KARS1, HARS2, LARS2 and NARS2 genes) results in a great variety of phenotypes ranging from non-syndromic hearing impairment (NSHI) to very complex syndromes, with a predominance of neurological signs. The diversity of roles that are played by these moonlighting enzymes and the fact that most pathogenic variants are missense and affect different domains of these proteins in diverse compound heterozygous combinations make it difficult to establish genotype–phenotype correlations. We used a targeted gene-sequencing panel to investigate the presence of pathogenic variants in those four genes in cohorts of 175 Spanish and 18 Colombian familial cases with non-DFNB1 autosomal recessive NSHI. Disease-associated variants were found in five cases. Five mutations were novel as follows: c.766C>T in KARS1, c.475C>T, c.728A>C and c.1012G>A in HARS2, and c.795A>G in LARS2. We provide audiograms from patients at different ages to document the evolution of the hearing loss, which is mostly prelingual and progresses from moderate/severe to profound, the middle frequencies being more severely affected. No additional clinical sign was observed in any affected subject. Our results confirm the involvement of KARS1 in DFNB89 NSHI, for which until now there was limited evidence. [ABSTRACT FROM AUTHOR]

Anderson–Fabry disease (AFD) is an X-linked multisystemic disorder with a heterogeneous phenotype, resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) and leading to globotriaosylceramide systemic accumulation. Lysosomal storage is not the unique player in organ failure and different mechanisms could drive tissue damage, including endoplasmic reticulum (ER) stress and its related signaling pathway's activation. We identified a new missense variant in the signal peptide of α-GLA gene, c.13 A/G, in a 55-year-old woman affected by chronic kidney disease, acroparesthesia, hypohidrosis, and deafness and exhibiting normal values of lysoGb3 and αGLA activity. The functional study of the new variant performed by its overexpression in HEK293T cells showed an increased protein expression of a key ER stress marker, GRP78, the pro-apoptotic BAX, the negative regulator of cell cycle p21, the pro-inflammatory cytokine, IL1β, together with pNFkB, and the pro-fibrotic marker, N-cadherin. Transmission electron microscopy showed signs of ER injury and intra-lysosomal inclusions. The proband's PBMC exhibited higher expression of TGFβ 1 and pNFkB compared to control. Our findings suggest that the new variant, although it did not affect enzymatic activity, could cause cellular damage by affecting ER homeostasis and promoting apoptosis, inflammation, and fibrosis. Further studies are needed to demonstrate the variant's contribution to cellular and tissue damage. [ABSTRACT FROM AUTHOR]

Improvements in self-pollinated crops rely on crosses between different genotypes. It has been suggested that the repeated use of "the best" genotypes may lead to the restriction of the genetic diversity of the crop. In wheat, the analysis of gliadin (storage protein) polymorphism has provided evidence that genetic diversity was high and stable throughout the 20th century. Moreover, a worldwide analysis of gliadin polymorphism shows that genetic diversity is structured spatially across countries and their regions. Therefore, the analysis of gliadin genotypes in a given grain sample can provide reliable information about the origin of grains in this sample. An unexpected finding is that many registered common wheat cultivars are genetically non-uniform and composed of authentic biotypes (genotypically related lines originated from the initial cross) in spite of current crop-registration rules that include a strict demand for each new cultivar to be genetically uniform (DUS rules). In summary, the results suggest that each cultivar is the fruit of joint effects of a breeder and of a region's environmental factors. We believe this finding will not be restricted to wheat and suggest there may be a need to re-evaluate relevant rules of cultivar registration for crop species in general. [ABSTRACT FROM AUTHOR]

Simple Summary: Tibetan sheep are integral to the ecosystems and livelihoods of the Tibetan Plateau; however, their breeding practices limit their production and growth. Candidate genes myostatin (MSTN)and Callipyge have been recognized as important for improving growth traits in livestock. This research examined the polymorphic loci of these genes in Tibetan sheep and their association with growth traits. The results indicated that SNP loci of MSTN could potentially be utilized as a molecular indicator for early growth traits in Tibetan sheep. Tibetan sheep are vital to the ecosystem and livelihood of the Tibetan Plateau; however, traditional breeding methods limit their production and growth. Modern molecular breeding techniques are required to improve these traits. This study identified a single nucleotide polymorphism (SNP) in myostatin (MSTN) and Callipyge in Tibetan sheep. The findings indicated notable associations between MSTN genotypes and growth traits including birth weight (BW), body length (BL), chest width (ChW), and chest circumference (ChC), as well as a particularly strong association with cannon circumference (CaC) at 2 months of age. Conversely, Callipyge polymorphisms did not have a significant impact on Tibetan sheep. Moreover, the analyses revealed a significant association between sex and BW or hip width (HW) at 2 months of age and ChW, ChC, and CaC at 4 months of age. Furthermore, the study's results suggested that the genotype of MSTN as a GA was associated with a notable sex effect on BW, while the genotype of Callipyge (CC) showed a significant impact of sex on CaC at 2 months of age. These results indicated that the SNP of MSTN could potentially serve as a molecular marker for early growth traits in Tibetan sheep. [ABSTRACT FROM AUTHOR]

Structural variation is a source of genetic variation that, in some cases, may trigger pathogenicity. Here, we describe two cases, a mother and son, with the same partial inverted duplication of the long arm of chromosome 8 [invdup(8)(q24.21q24.21)] of 17.18 Mb, showing different clinical manifestations: microcephaly, dorsal hypertrichosis, seizures and neuropsychomotor development delay in the child, and a cleft lip/palate, down-slanted palpebral fissures and learning disabilities in the mother. The deleterious outcome, in general, is reflected by the gain or loss of genetic material. However, discrepancies among the clinical manifestations raise some concerns about the genomic configuration within the chromosome and other genetic modifiers. With that in mind, we also performed a literature review of research published in the last 20 years about the duplication of the same, or close, chromosome region, seeking the elucidation of at least some relevant clinical features. [ABSTRACT FROM AUTHOR]

The Receptor Activator Nuclear of κB Ligand (RANKL) plays an important function in immune responses, activating osteoclast cells and unchanged bone resorption, which in turn leads to bone erosion and inflammation. Genetic variants in the promoter region of the RANKL gene could lead to a higher risk of rheumatoid arthritis (RA). Objective: To assess the association of rs9533155 (-693C>G) and rs9533156 (-643T>C) genetic variants with RA risk. Methods: A case–control study was carried out. A total of 94 patients with RA (RA group) and 134 subjects without any rheumatologic disease (control group) were included. Genetic DNA was extracted from peripheral white blood cells (leukocytes). Genetic variant rs9533155 (-693C>G) was screened by an approach based on Polymerase Chain Reaction–Restriction Fragment Length Polymorphism (PCR-RFLP), while rs9533156 (-643T>C) was screened using quantitative polymerase chain reaction (qPCR) with TaqMan probes. RANKL serum levels were measured by ELISA. Results: For rs9533155 (-693C>G), the polymorphic homozygous genotype frequencies (CC) were higher in the RA group (p = 0.006). Individuals carrying the risk genotype presented higher levels of serum RANKL. Carriers of the polymorphic homozygous genotype in the dominant model (CC vs. CG + GG) had an increased risk of developing RA (OR: 1.8, 95% CI 1.04 to 3.1). No association between rs9533156 (-643T>C) and the haplotypes with RA risk was observed. Conclusion: The rs9533155 (-693C>G) genetic variant exhibits a potential role in RA risk. The studied population had no association with the rs9533156 (-643T>C) genetic variant. [ABSTRACT FROM AUTHOR]

Rhodobryum giganteum (Bryaceae, Bryophyta), a rare medicinal bryophyte, is valued for its cardiovascular therapeutic properties in traditional Chinese medicine. This study presents the first complete chloroplast genome sequence of R. giganteum, including its assembly and annotation. The circular chloroplast genome of R. giganteum is 124,315 bp in length, displaying a typical quadripartite structure with 128 genes: 83 protein-coding genes, 37 tRNAs, and 8 rRNAs. Analyses of codon usage bias, repetitive sequences, and simple sequence repeats (SSRs) revealed an A/U-ending codon preference, 96 repetitive sequences, and 385 SSRs in the R. giganteum chloroplast genome. Nucleotide diversity analysis identified 10 high mutational hotspots. Ka/Ks ratio analysis suggested potential positive selection in rpl20, rps18, petG, and psbM genes. Phylogenetic analysis of whole chloroplast genomes from 38 moss species positioned R. giganteum within Bryales, closely related to Rhodobryum laxelimbatum. This study augments the chloroplast genomic data for Bryales and provides a foundation for molecular marker development and genetic diversity analyses in medicinal bryophytes. [ABSTRACT FROM AUTHOR]

Leucine-rich repeat kinase 2 (LRRK2) c.6055G>A (p.G2019S) is a frequent cause of Parkinson's disease (PD), accounting for >30% of Tunisian Arab-Berber patients. LRRK2 is widely expressed in the immune system and its kinase activity confers a survival advantage against infection in animal models. Here, we assess haplotype variability in cis and in trans of the LRRK2 c.6055G>A mutation, define the age of the pathogenic allele, explore its relationship to the age of disease onset (AOO), and provide evidence for its positive selection. [ABSTRACT FROM AUTHOR]

The cytoplasm of Aegilops kotschyi is known for the induction of male sterility and haploidy in wheat. Both systems originally appeared rather simple, but manipulation of the standard chromosome constitution of the nuclear genome revealed additional interactions. This study shows that while there is little or no allelic variation at the main fertility restorer locus Rfmulti on chromosome arm 1BS, additional genes may also be involved in the nuclear–mitochondrial genome interactions, affecting not only male fertility but also the growth rate, from pollen competition for fertilization and early endosperm divisions all the way to seed size and plant maturity. Some of these effects appear to be of a sporophytic nature; others are gametophytic. Induction of parthenogenesis by a rye inducer in conjunction with the Ae. kotschyi cytoplasm is well known. However, here we show that the cytoplasmic-nuclear interactions affect all aspects of double fertilization: producing maternal haploids from unfertilized eggs, diploids from fertilized eggs or synergids, embryo-less kernels, and fertilized eggs without fertilization of the double nucleus in the embryo sack. It is unclear how frequent the inducers of parthenogenesis are, as variation, if any, is obscured by suppressors present in the wheat genome. Genetic dissection of a single wheat accession revealed five distinct loci affecting the rate of maternal haploid production: four acting as suppressors and one as an enhancer. Only when the suppressing haplotypes are confirmed may it be possible to the identify genetic variation of haploidy inducers, map their position(s), and determine their nature and the mode of action. [ABSTRACT FROM AUTHOR]

Celiac disease (CD) is a complicated autoimmune disease that is caused by gluten sensitivity. It was commonly believed that CD only affected white Europeans, but recent findings show that it is also prevailing in some other racial groups, like South Asians, Caucasians, Africans, and Arabs. Genetics plays a profound role in increasing the risk of developing CD. Genetic Variations in non-HLA genes such as LPP, ZMIZ1, CCR3, and many more influence the risk of CD in various populations. This study aimed to explore the association between LPP rs1464510 and ZMIZ1 rs1250552 and CD in the Punjabi Pakistani population. For this, a total of 70 human subjects were selected and divided into healthy controls and patients. Genotyping was performed using an in-house-developed tetra-amplification refractory mutation system polymerase chain reaction. Statistical analysis revealed a significant association between LPP rs1464510 (χ2 = 4.421, p = 0.035) and ZMIZ1 rs1250552 (χ2 = 3.867, p = 0.049) and CD. Multinomial regression analysis showed that LPP rs1464510 A allele reduces the risk of CD by ~52% (OR 0.48, CI: 0.24–0.96, 0.037), while C allele-carrying subjects are at ~2.6 fold increased risk of CD (OR 3.65, CI: 1.25–10.63, 0.017). Similarly, the ZMIZ1 rs1250552 AG genotype significantly reduces the risk of CD by 73% (OR 0.26, CI: 0.077–0.867, p = 0.028). In summary, Genetic Variations in the LPP and ZMIZ1 genes influence the risk of CD in Punjabi Pakistani subjects. LPP rs1464510 A allele and ZMIZ1 AG genotype play a protective role and reduce the risk of CD. [ABSTRACT FROM AUTHOR]

This study involved 45 Holstein and 60 Holstein-Charolaise steers, tailored with specific diets according to breed and rearing systems. DNA genotyping was conducted for DGAT1, LEP, SCD1, SREBF1, and TG genes to investigate their impact on carcass conformation traits, beef quality traits, and sensory quality traits. The results showed associations between the genetic variants and the analyzed traits. Specifically, DGAT1 was found to affect drip loss, meat brightness, and color saturation. The TG gene was associated with marbling and meat color. LEP influenced trim fat and pH levels, while SCD1 was linked to metabolic energy live weight gains, and pH levels. SREBF1 was related to fatness. [ABSTRACT FROM AUTHOR]

Background: Brugada syndrome (BrS) is an inherited primary channelopathy syndrome associated with the risk of ventricular fibrillation (VF) and sudden cardiac death in a structurally normal heart. Aim of the Study: The aim of this study was to clinically and genetically evaluate a large family with severe autosomal dominant Brugada syndrome. Methods: Clinical and genetic studies were performed. Genetic analysis was conducted with NGS technologies (WES) using the Illumina instrument. According to the standard procedure, variants found by WES were confirmed in all available families by Sanger sequencing. The effect of the variants was studied by using in silico prediction of pathogenicity. Results: The proband was a 52-year-old man who was admitted to the emergency department for syncope at rest. WES of the index case identified a heterozygous VUS CASQ2, c.532T>C, p.(Tyr178His). We studied the segregation of the variation in all pedigree members. All the patients were heterozygous for the variation CASQ2 p.(Tyr178His), whereas the remaining healthy individuals in the family were homozygous for the normal allele. Structural analysis of CASQ2 p.(Tyr178His) was performed and revealed an important effect of the missense variation on monomer stability. The CASQ2 Tyr180 residue is located inside the sarcoplasmic reticulum (SR) junctional face membrane interaction domain and is predicted to disrupt filamentation. Conclusions: Our data suggest that the p.Tyr178His substitution is associated with BrS in the family investigated, affecting the stability of the protein, disrupting filamentation at the interdimer interface, and affecting the subsequent formation of tetramers and polymers that contain calcium-binding sites. [ABSTRACT FROM AUTHOR]

Cowpeas (Vigna unguiculata L. Walp) have been credible constituents of nutritious food and forage in human and animal diets since the Neolithic era. The modern technique of Diversity Array Technology (DArTseq) is both cost-effective and rapid in producing thousands of high-throughputs, genotyped, single nucleotide polymorphisms (SNPs) in wide-genomic analyses of genetic diversity. The aim of this study was to assess the heterogeneity in cowpea genotypes using DArTseq-derived SNPs. A total of 92 cowpea genotypes were selected, and their fourteen-day-old leaves were freeze-dried for five days. DNA was extracted using the CTAB protocol, genotyped using DArTseq, and analysed using DArTsoft14. A total of 33,920 DArTseq-derived SNPs were recalled for filtering analysis, with a final total of 16,960 SNPs. The analyses were computed using vcfR, poppr, and ape in R Studio v1.2.5001-3 software. The heatmap revealed that the TVU 9596 (SB26), Orelu (SB72), 90K-284-2 (SB55), RV 403 (SB17), and RV 498 (SB16) genotypes were heterogenous. The mean values for polymorphic information content, observed heterozygosity, expected heterozygosity, major allele frequency, and the inbreeding coefficient were 0.345, 0.386, 0.345, 0.729, and 0.113, respectively. Moreover, they validated the diversity of the evaluated cowpea genotypes, which could be used for potential breeding programmes and management of cowpea germplasm. [ABSTRACT FROM AUTHOR]

Germline variants in the phosphatidylinositol glycan class A (PIGA) gene, which is involved in glycosylphosphatidylinositol (GPI) biosynthesis, cause multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) with X-linked recessive inheritance. The available literature has described a pattern of almost 100% X-chromosome inactivation in mothers carrying PIGA variants. Here, we report a male infant with MCAHS2 caused by a novel PIGA variant inherited from his mother, who has a non-skewed pattern of X inactivation. Phenotypic evidence supporting the pathogenicity of the variant was obtained by flow-cytometry tests. We propose that the assessment in neutrophils of the expression of GPI-anchored proteins (GPI-APs), especially CD16, should be considered in cases with variants of unknown significance with random X-inactivation in carrier mothers in order to clarify the pathogenic role of PIGA or other gene variants linked to the synthesis of GPI-APs. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated the essential role of the Kisspeptin/Neurokinin B/Dynorphin A (KNDy) pathway in female reproductive biology by regulating the activity of the hypothalamic–pituitary–gonadal axis. Identified loss-of-function mutations in these genes are linked to various reproductive disorders. This study investigated genetic disorders linked to mutations in the KNDy genes related to premature ovarian insufficiency (POI). A cohort of 14 Mexican POI patients underwent genetic screening using PCR-SSCP and Sanger sequencing, assessing the genetic variations' impact on protein function thereafter using multiple in silico tools. The PCR excluded extensive deletions, insertions, and duplications, while SSCP detected five genetic variants. Variations occurred in the KISS1 (c.58G>A and c.242C>G), KISS1R (c.1091A>T), PDYN (c.600C>T), and OPRK1 (c.36G>T) genes, whereas no genetic anomalies were found in NK3/NK3R genes. Each single-nucleotide variant underwent genotyping using PCR-SSCP in 100 POI-free subjects. Their allelic frequencies paralleled the patient group. These observations indicate that allelic variations in the KNDy genes may not contribute to POI etiology. Hence, screening for mutations in KNDy genes should not be a part of the diagnostic protocol for POI. [ABSTRACT FROM AUTHOR]

Cardiomyopathies (CMs), one of the main causes of sudden death among the young population, are a heterogeneous group of myocardial diseases, usually with a genetic cause. Next-Generation Sequencing (NGS) has expanded the genes studied for CMs; however, the yield is still around 50%. The systematic study of Copy Number Variants (CNVs) could contribute to improving our diagnostic capacity. These alterations have already been described as responsible for cardiomyopathies in some cases; however, their impact has been rarely assessed. We analyzed the clinical significance of CNVs in cardiomyopathies by studying 11,647 affected patients, many more than those considered in previously published studies. We evaluated the yield of the systematic study of CNVs in a production context using NGS and a novel CNV detection software tool v2.0 that has demonstrated great efficacy, maximizing sensitivity and avoiding false positives. We obtained a CNV analysis yield of 0.8% that fluctuated depending on the type of cardiomyopathy studied (0.29% HCM, 1.41% DCM, 1.88% ARVC, 1.8% LVNC, 1.45% RCM), and we present the frequency of occurrence for 18 genes that agglutinate the 95 pathogenic/likely pathogenic CNVs detected. We conclude the importance of including in diagnostic tests a systematic study of these genetic alterations for the different cardiomyopathies. [ABSTRACT FROM AUTHOR]

In humans, the transient receptor potential vanilloid 1 (TRPV1) gene is activated by exogenous (e.g., high temperatures, irritating compounds such as capsaicin) and endogenous (e.g., endocannabinoids, inflammatory factors, fatty acid metabolites, low pH) stimuli. It has been shown to be involved in several processes including nociception, thermosensation, and energy homeostasis. In this study, we investigated the association between TRPV1 gene variants, sensory perception (to capsaicin and PROP), and body composition (BMI and bioimpedance variables) in human populations. By comparing sequences deposited in worldwide databases, we identified two haplotype blocks (herein referred to as H1 and H2) that show strong stabilizing selection signals (MAF approaching 0.50, Tajima's D > +4.5) only in individuals with sub-Saharan African ancestry. We therefore studied the genetic variants of these two regions in 46 volunteers of sub-Saharan descent and 45 Italian volunteers (both sexes). Linear regression analyses showed significant associations between TRPV1 diplotypes and body composition, but not with capsaicin perception. Specifically, in African women carrying the H1-b and H2-b haplotypes, a higher percentage of fat mass and lower extracellular fluid retention was observed, whereas no significant association was found in men. Our results suggest the possible action of sex-driven balancing selection at the non-coding sequences of the TRPV1 gene, with adaptive effects on water balance and lipid deposition. [ABSTRACT FROM AUTHOR]

Worldwide molecular research of economically important Phalaris arundinacea (Poaceae) is mainly focused on the invasions of this species from Europe to North America. Until the present study, the genetic diversity of the P. arundinacea had not been studied across the Baltic countries. The objective of this research is to evaluate the diversity of Lithuanian populations of P. arundinacea at simple sequence repeat (SSR) loci comparatively among populations of the Baltic countries, Luxembourg, and the Russian Far East (Eurasian), evaluating differentiation between Lithuanian populations and ornamental accessions, and relating these with environmental features. For six selected Lithuanian river basin populations, GBS low density SNPs were used to determine genetic diversity. Bayesian analysis showed that Eurasian populations of Phalaris arundinacea consist of two gene clusters. Statistically significant genetic differentiation among European and Eurasian populations was documented. Lithuanian genotypes growing naturally along rivers are genetically distinct from cultivated ornamentals. GBS-SNPs divided the six selected Nemunas river basins into three distinct groups with one, two, or three rivers in separate groupings for genetic diversity. Genetic diversity is primarily within, rather than among, Lithuanian, eastern European, and Eurasian populations of P. arundinacea across the continent. Thus, restoration efforts would benefit from local population seed origination. [ABSTRACT FROM AUTHOR]

Fritillaria cirrhosa and its relatives have been utilized in traditional Chinese medicine for many years and are under priority protection in China. Despite their medicinal and protective value, research on their phylogeny, genetic diversity, and divergence remains limited. Here, we investigate the chloroplast genome variation architecture of 46 samples of F. cirrhosa and its relatives collected from various regions, encompassing the majority of wild populations across diverse geographical areas. The results indicate abundant variations in 46 accessions including 1659 single-nucleotide polymorphisms and 440 indels. Six variable markers (psbJ, ndhD, ycf1, ndhG, trnT-trnL, and rpl32-trnL) were identified. Phylogenetic and network analysis, population structure analysis, and principal component analysis showed that the 46 accessions formed five clades with significant divergence, which were related to their geographical distribution. The regions spanning from the southern Hengduan Mountains to the Qinghai–Tibet Plateau exhibited the highest levels of genetic diversity. F. cirrhosa and its relatives may have suffered a genetic bottleneck and have a relatively low genetic diversity level. Moreover, geographical barriers and discrete patches may have accelerated population divergence. The study offers novel perspectives on the phylogeny, genetic diversity, and population structure of F. cirrhosa and its relatives, information that can inform conservation and utilization strategies in the future. [ABSTRACT FROM AUTHOR]

Sesamum indicum L. (Pedaliaceae) is one of the most economically important oil crops in the world, thanks to the high oil content of its seeds and its nutritional value. It is cultivated all over the world, mainly in Asia and Africa. Well adapted to arid environments, sesame offers a good opportunity as an alternative subsistence crop for farmers in Africa, particularly Niger, to cope with climate change. For the first time, the variation in genome size among 75 accessions of the Nigerien germplasm was studied. The sample was collected throughout Niger, revealing various morphological, biochemical and phenological traits. For comparison, an additional accession from Thailand was evaluated as an available Asian representative. In the Niger sample, the 2C DNA value ranged from 0.77 to 1 pg (753 to 978 Mbp), with an average of 0.85 ± 0.037 pg (831 Mbp). Statistical analysis showed a significant difference in 2C DNA values among 58 pairs of Niger accessions (p-value < 0.05). This significant variation indicates the likely genetic diversity of sesame germplasm, offering valuable insights into its possible potential for climate-resilient agriculture. Our results therefore raise a fundamental question: is intraspecific variability in the genome size of Nigerien sesame correlated with specific morphological and physiological traits? [ABSTRACT FROM AUTHOR]

Numerous studies have tried to evaluate the potential role of thrombophilia-related genes in retinal vein occlusion (RVO); however, there is limited research on genes related to different pathophysiological mechanisms involved in RVO. In view of the strong contribution of oxidative stress and inflammation to the pathogenesis of RVO, the purpose of the present study was to investigate the association of inflammation- and oxidative-stress-related polymorphisms from three different genes [apolipoprotein E (APOE), paraoxonase 1 (PON1) and stromal cell-derived factor 1 (SDF-1)] and the risk of RVO in a Greek population. Participants in this case-control study were 50 RVO patients (RVO group) and 50 healthy volunteers (control group). Blood samples were collected on EDTA tubes and genomic DNA was extracted. Genotyping of rs854560 (L55M) and rs662 (Q192R) for the PON1 gene, rs429358 and rs7412 for the APOE gene and rs1801157 [SDF1-3′G(801)A] for SDF-1 gene was performed using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method. Multiple genetic models (codominant, dominant, recessive, overdominant and log-additive) and haplotype analyses were performed using the SNPStats web tool to assess the correlation between the genetic polymorphisms and the risk of RVO. Binary logistic regression analysis was used for the association analysis between APOE gene variants and RVO. Given the multifactorial nature of the disease, our statistical analysis was adjusted for the most important systemic risk factors (age, hypertension and diabetes mellitus). The dominant genetic model for the PON1 Q192R single nucleotide polymorphism (SNP) of the association analysis revealed that there was a statistically significant difference between the RVO group and the control group. Specifically, after adjusting for age and hypertension, the PON1 192 R allele (QR + RR) was found to be associated with a statistically significantly higher risk of RVO compared to the QQ genotype (OR = 2.51; 95% CI = 1.02–6.14, p = 0.04). The statistically significant results were maintained after including diabetes in the multivariate model in addition to age and hypertension (OR = 2.83; 95% CI = 1.01–7.97, p = 0.042). No statistically significant association was revealed between the other studied polymorphisms and the risk of RVO. Haplotype analysis for PON1 SNPs, L55M and Q192R, revealed no statistically significant correlation. In conclusion, PON1 192 R allele carriers (QR + RR) were associated with a statistically significantly increased risk of RVO compared to the QQ homozygotes. These findings suggest that the R allele of the PON1 Q192R is likely to play a role as a risk factor for retinal vein occlusion. [ABSTRACT FROM AUTHOR]

Azoospermia is a form of male infertility characterized by a complete lack of spermatozoa in the ejaculate. Sertoli cell-only syndrome (SCOS) is the most severe form of azoospermia, where no germ cells are found in the tubules. Recently, FANCM gene variants were reported as novel genetic causes of spermatogenic failure. At the same time, FANCM variants are known to be associated with cancer predisposition. We performed whole-exome sequencing on a male patient diagnosed with SCOS and a healthy father. Two compound heterozygous missense mutations in the FANCM gene were found in the patient, both being inherited from his parents. After the infertility assessment, the patient was diagnosed with diffuse astrocytoma. Immunohistochemical analyses in the testicular and tumor tissues of the patient and adequate controls showed, for the first time, not only the existence of a cytoplasmic and not nuclear pattern of FANCM in astrocytoma but also in non-mitotic neurons. In the testicular tissue of the SCOS patient, cytoplasmic anti-FANCM staining intensity appeared lower than in the control. Our case report raises a novel possibility that the infertile carriers of FANCM gene missense variants could also be prone to cancer development. [ABSTRACT FROM AUTHOR]

The integration of target capture systems with next-generation sequencing has emerged as an efficient tool for exploring specific genetic regions with a high resolution and facilitating the rapid discovery of novel alleles. Despite these advancements, the application of targeted sequencing methodologies, such as the myBaits technology, in polyploid oat species remains relatively unexplored. In this study, we utilized the myBaits target capture method offered by Daicel Arbor Biosciences to detect variants and assess their reliability for variant detection in oat genomics and breeding. Ten oat genotypes were carefully chosen for targeted sequencing, focusing on specific regions on chromosome 2A to detect variants. The selected region harbors 98 genes. Precisely designed baits targeting the genes within these regions were employed for the target capture sequencing. We employed various mappers and variant callers to identify variants. After the identification of variants, we focused on the variants identified via all variants callers to assess the applicability of the myBaits sequencing methodology in oat breeding. In our efforts to validate the identified variants, we focused on two SNPs, one deletion and one insertion identified via all variant callers in the genotypes KF-318 and NOS 819111-70 but absent in the remaining eight genotypes. The Sanger sequencing of targeted SNPs failed to reproduce target capture data obtained through the myBaits technology. Similarly, the validation of deletion and insertion variants via high-resolution melting (HRM) curve analysis also failed to reproduce target capture data, again suggesting limitations in the reliability of the myBaits target capture sequencing using short-read sequencing for variant detection in the oat genome. This study shed light on the importance of exercising caution when employing the myBaits target capture strategy for variant detection in oats. This study provides valuable insights for breeders seeking to advance oat breeding efforts and marker development using myBaits target capture sequencing, emphasizing the significance of methodological sequencing considerations in oat genomics research. [ABSTRACT FROM AUTHOR]

The incidence of ulcerative colitis (UC) has increased globally. As a complex disease, the genetic predisposition for UC could be estimated by the polygenic risk score (PRS), which aggregates the effects of a large number of genetic variants in a single quantity and shows promise in identifying individuals at higher lifetime risk of UC. Here, based on a cohort of 2869 UC cases and 2900 controls with genotype array datasets, we used PRSice-2 to calculate PRS, and systematically analyzed factors that could affect the power of PRS, including GWAS summary statistics, population stratification, and impact of variants. After leveraging a stepwise condition analysis, we eventually established the best PRS model, achieving an AUC of 0.713. Meanwhile, samples in the top 20% of the PRS distribution had a risk of UC more than ten times higher than samples in the lowest 20% (OR = 10.435, 95% CI 8.571–12.703). Our analyses demonstrated that including population-enriched, more disease-associated SNPs and using GWAS summary statistics from similar ethnic background can improve the power of PRS. Strictly following the principle of focusing on one population in all aspects of generating PRS can be a cost-effective way to apply genotype-array-derived PRS to practical risk estimation. [ABSTRACT FROM AUTHOR]

Keratins are the main structural protein components of wool fibres, and variation in them and their genes (KRTs) is thought to influence wool structure and characteristics. The PCR–single strand conformation polymorphism technique has been used previously to investigate genetic variation in selected coding and intron regions of the type II sheep keratin gene KRT81, but no variation was identified. In this study, we used the same technique to explore the 5′ untranslated region of KRT81 and detected three sequence variants (A, B and C) that contain four single nucleotide polymorphisms. Among the 389 Merino × Southdown cross sheep investigated, variant B was linked to a reduction in clean fleece weight, while C was associated with an increase in both greasy fleece weight and clean fleece weight. No discernible effects on staple length or mean-fibre-diameter-related traits were observed. These findings suggest that variation in ovine KRT81 might influence wool growth by changing the density of wool follicles in the skin, the density of individual fibres, or the area of the skin producing fibre, as opposed to changing the rate of extrusion of fibres or their diameter. [ABSTRACT FROM AUTHOR]

X-linked hypophosphatemia (XLH) is a rare inherited disorder of renal phosphate wasting with a highly variable phenotype caused by loss-of-function variants in the PHEX gene. The diagnosis of individuals with mild phenotypes can be challenging and often delayed. Here, we describe a three-generation family with a very mild clinical presentation of XLH. The diagnosis was unexpectedly found in a 39-year-old woman who was referred for genetic testing due to an unclear childhood diagnosis of a tubulopathy. Genetic testing performed by next-generation sequencing using a kidney disease gene panel identified a novel non-canonical splice site variant in the PHEX gene. Segregation analysis detected that the consultand's father, who presented with hypophosphatemia and decreased tubular phosphate reabsorption, and the consultand's son also carried this variant. RNA studies demonstrated that the non-canonical splice site variant partially altered the splicing of the PHEX gene, as both wild-type and aberrant splicing transcripts were detected in the two male members with only one copy of the PHEX gene. In conclusion, this case contributes to the understanding of the relationship between splicing variants and the variable expressivity of XLH disease. The mild phenotype of this family can be explained by the coexistence of PHEX transcripts with aberrant and wild-type splicing. [ABSTRACT FROM AUTHOR]

Rubinstein–Taybi syndrome (RTS) is a rare genetic disorder characterized by intellectual disability, facial dysmorphisms, and enlarged thumbs and halluces. Approximately 55% of RTS cases result from pathogenic variants in the CREBBP gene, with an additional 8% linked to the EP300 gene. Given the close relationship between these two genes and their involvement in epigenomic modulation, RTS is grouped into chromatinopathies. The extensive clinical heterogeneity observed in RTS, coupled with the growing number of disorders involving the epigenetic machinery, poses a challenge to a phenotype-based diagnostic approach for these conditions. Here, we describe the first case of a patient clinically diagnosed with RTS with a CREBBP truncating variant in mosaic form. We also review previously described cases of mosaicism in CREBBP and apply clinical diagnostic guidelines to these patients, confirming the good specificity of the consensus. Nonetheless, these reports raise questions about the potential underdiagnosis of milder cases of RTS. The application of a targeted phenotype-based approach, coupled with high-depth NGS, may enhance the diagnostic yield of whole-exome sequencing (WES) in mild and mosaic conditions. [ABSTRACT FROM AUTHOR]

Lysine acetyltransferase 8, also known as KAT8, is an enzyme involved in epigenetic regulation, primarily recognized for its ability to modulate histone acetylation. This review presents an overview of KAT8, emphasizing its biological functions, which impact many cellular processes and range from chromatin remodeling to genetic and epigenetic regulation. In many model systems, KAT8's acetylation of histone H4 lysine 16 (H4K16) is critical for chromatin structure modification, which influences gene expression, cell proliferation, differentiation, and apoptosis. Furthermore, this review summarizes the observed genetic variability within the KAT8 gene, underscoring the implications of various single nucleotide polymorphisms (SNPs) that affect its functional efficacy and are linked to diverse phenotypic outcomes, ranging from metabolic traits to neurological disorders. Advanced insights into the structural biology of KAT8 reveal its interaction with multiprotein assemblies, such as the male-specific lethal (MSL) and non-specific lethal (NSL) complexes, which regulate a wide range of transcriptional activities and developmental functions. Additionally, this review focuses on KAT8's roles in cellular homeostasis, stem cell identity, DNA damage repair, and immune response, highlighting its potential as a therapeutic target. The implications of KAT8 in health and disease, as evidenced by recent studies, affirm its importance in cellular physiology and human pathology. [ABSTRACT FROM AUTHOR]

Pathogenic variants in the Crumbs homolog 1 (CRB1) gene lead to severe, childhood-onset retinal degeneration leading to blindness in early adulthood. There are no approved therapies, and traditional adeno-associated viral vector-based gene therapy approaches are challenged by the existence of multiple CRB1 isoforms. Here, we describe three CRB1 variants, including a novel, previously unreported variant that led to retinal degeneration. We offer a CRISPR-Cas-mediated DNA base editing strategy as a potential future therapeutic approach. This study is a retrospective case series. Clinical and genetic assessments were performed, including deep phenotyping by retinal imaging. In silico analyses were used to predict the pathogenicity of the novel variant and to determine whether the variants are amenable to DNA base editing strategies. Case 1 was a 24-year-old male with cone–rod dystrophy and retinal thickening typical of CRB1 retinopathy. He had a relatively preserved central outer retinal structure and a best corrected visual acuity (BCVA) of 60 ETDRS letters in both eyes. Genetic testing revealed compound heterozygous variants in exon 9: c.2843G>A, p.(Cys948Tyr) and a novel variant, c.2833G>A, p.(Gly945Arg), which was predicted to likely be pathogenic by an in silico analysis. Cases 2 and 3 were two brothers, aged 20 and 24, who presented with severe cone–rod dystrophy and a significant disruption of the outer nuclear layers. The BCVA was reduced to hand movements in both eyes in Case 2 and to 42 ETDRS letters in both eyes in Case 3. Case 2 was also affected with marked cystoid macular lesions, which are common in CRB1 retinopathy, but responded well to treatment with oral acetazolamide. Genetic testing revealed two c.2234C>T, p.(Thr745Met) variants in both brothers. As G-to-A and C-to-T variants, all three variants are amenable to adenine base editors (ABEs) targeting the forward strand in the Case 1 variants and the reverse strand in Cases 2 and 3. Available PAM sites were detected for KKH-nSaCas9-ABE8e for the c.2843G>A variant, nSaCas9-ABE8e and KKH-nSaCas9-ABE8e for the c.2833G>A variant, and nSpCas9-ABE8e for the c.2234C>T variant. In this case series, we report three pathogenic CRB1 variants, including a novel c.2833G>A variant associated with early-onset cone–rod dystrophy. We highlight the severity and rapid progression of the disease and offer ABEs as a potential future therapeutic approach for this devastating blinding condition. [ABSTRACT FROM AUTHOR]

Genetic variation facilitates the evolution, environmental adaptability, and biodiversity of organisms. Danish Large White (LW) pigs have more desirable phenotypes compared with local Chinese pigs, which have difficulty adapting to the modern swine industry. However, the genome-wide mutational differences between these pig breeds are yet to be evaluated. Therefore, this study aimed to evaluate genomic variation and identify breed-specific SNPs in Danish LW pigs. Here, 43 LW, 15 Diqing Tibetan (DQZ), and 15 Diannan small-ear (DN) pigs whose genomes were re-sequenced with 5× depth were selected. This was followed by a conjoined analysis of our previous resequencing data of 24 Anqing six-end white (AQ) and six Asian wild (SS) pigs. In total, 39,158,378 SNPs and 13,143,989 insertion–deletions were obtained in all breeds. The variation number of LW pigs was the lowest, with 287,194 breed-specific and 1289 non-synonymous SNPs compared with Chinese breeds. Functional analysis of the breed-specific non-synonymous SNPs indicated that these mutations were mainly associated with the reproductive performance, feed intake, and feed conversion ratio of LW pigs. These findings provide a theoretical basis for genetic improvements in the Chinese swine industry. [ABSTRACT FROM AUTHOR]

Background: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is an inherited disease caused by pathogenic biallelic variants in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. This disease is characterized by slowly progressive spastic gait, cerebellar symptoms, and leukoencephalopathy with brainstem and spinal cord involvement. Case Presentation: Peripheral blood samples were collected from four patients from four unrelated families to extract genomic DNA. All patients underwent partial exon analysis of the DARS2 gene using Sanger sequencing, which detected the c.228-21_228-20delinsC variant in a heterozygous state. Further DNA from three patients was analyzed using a next-generation sequencing-based custom AmpliSeq™ panel for 59 genes associated with leukodystrophies, and one of the patients underwent whole genome sequencing. We identified a novel pathogenic variant c.1675-1256_*115delinsGCAACATTTCGGCAACATTCCAACC in the DARS2 gene. Three patients (patients 1, 2, and 4) had slowly progressive cerebellar ataxia, and two patients (patients 1 and 2) had spasticity. In addition, two patients (patients 2 and 4) showed signs of axonal neuropathy, such as decreased tendon reflexes and loss of distal sensitivity. Three patients (patients 1, 2, and 3) also had learning difficulties. It should be noted the persistent presence of characteristic changes in brain MRI in all patients, which emphasizes its importance as the main diagnostic tool for suspicion and subsequent confirmation of LBSL. Conclusions: We found a novel indel variant in the DARS2 gene in four patients with LBSL and described their clinical and genetic characteristics. These results expand the mutational spectrum of LBSL and aim to improve the laboratory diagnosis of this form of leukodystrophy. [ABSTRACT FROM AUTHOR]

Many organisms facultatively produce different phenotypes depending on their environment, yet relatively little is known about the genetic bases of such plasticity in natural populations. In this study, we describe the genetic variation underlying an extreme form of plasticity––resource polyphenism––in Mexican spadefoot toad tadpoles, Spea multiplicata. Depending on their environment, these tadpoles develop into one of two drastically different forms: a carnivore morph or an omnivore morph. We collected both morphs from two ponds that differed in which morph had an adaptive advantage and performed genome-wide association studies of phenotype (carnivore vs. omnivore) and adaptive plasticity (adaptive vs. maladaptive environmental assessment). We identified four quantitative trait loci associated with phenotype and nine with adaptive plasticity, two of which exhibited signatures of minor allele dominance and two of which (one phenotype locus and one adaptive plasticity locus) did not occur as minor allele homozygotes. Investigations into the genetics of plastic traits in natural populations promise to provide novel insights into how such complex, adaptive traits arise and evolve. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate gene regulation of the developing fetal brain from congenic or inbred mice strains that differed in longevity. Gene expression and alternative splice variants were analyzed in a genome-wide manner in the fetal brain of C57BL/6J mice (long-lived) in comparison to B6.Cg-Cav1tm1Mls/J (congenic, short-lived) and AKR/J (inbred, short-lived) mice on day(d) 12, 15, and 17 of gestation. The analysis showed a contrasting gene expression pattern during fetal brain development in these mice. Genes related to brain development, aging, and the regulation of alternative splicing were significantly differentially regulated in the fetal brain of the short-lived compared to long-lived mice during development from d15 and d17. A significantly reduced number of splice variants was observed on d15 compared to d12 or d17 in a strain-dependent manner. An epigenetic clock analysis of d15 fetal brain identified DNA methylations that were significantly associated with single-nucleotide polymorphic sites between AKR/J and C57BL/6J strains. These methylations were associated with genes that show epigenetic changes in an age-correlated manner in mice. Together, the finding of this study suggest that fetal brain development and longevity are epigenetically linked, supporting the emerging concept of the early-life origin of longevity. [ABSTRACT FROM AUTHOR]

Rett Syndrome (RTT) is a severe neurodevelopmental disorder predominately diagnosed in females and primarily caused by pathogenic variants in the X-linked gene Methyl-CpG Binding Protein 2 (MECP2). Most often, the disease causing the MECP2 allele resides on the paternal X chromosome while a healthy copy is maintained on the maternal X chromosome with inactivation (XCI), resulting in mosaic expression of one allele in each cell. Preferential inactivation of the paternal X chromosome is theorized to result in reduced disease severity; however, establishing such a correlation is complicated by known MECP2 genotype effects and an age-dependent increase in severity. To mitigate these confounding factors, we developed an age- and genotype-normalized measure of RTT severity by modeling longitudinal data collected in the US Rett Syndrome Natural History Study. This model accurately reflected individual increase in severity with age and preserved group-level genotype specific differences in severity, allowing for the creation of a normalized clinical severity score. Applying this normalized score to a RTT XCI dataset revealed that XCI influence on disease severity depends on MECP2 genotype with a correlation between XCI and severity observed only in individuals with MECP2 variants associated with increased clinical severity. This normalized measure of RTT severity provides the opportunity for future discovery of additional factors contributing to disease severity that may be masked by age and genotype effects. [ABSTRACT FROM AUTHOR]