UNASSIGNED: Nasopharyngeal cancer (NPC) is a complex cancer due to its unique genomic features and association with the Epstein-Barr virus (EBV). Despite therapeutic advancements, NPC prognosis remains poor, necessitating a deeper understanding of its genomics. Here, we present a comprehensive whole genome sequencing (WGS) view of NPC genomics and its correlation with the phenotype.
UNASSIGNED: This study involved WGS of a clinical NPC biopsy specimen. Sequencing was carried out using a long read sequencer from Oxford Nanopore. Analysis of the variants involved correlation with the phenotype of NPC.
UNASSIGNED: A loss of genes within chromosome 6 from copy number variation (CNV) was found. The lost genes included HLA-A, HLA-B, and HLA-C, which work in the antigen presentation process. This loss of the major histocompatibility complex (MHC) apparatus resulted in the tumour\'s ability to evade immune recognition. The tumour exhibited an immunologically \"cold\" phenotype, with mild tumour-infiltrating lymphocytes, supporting the possible etiology of loss of antigen presentation capability. Furthermore, the driver mutation PIK3CA gene was identified along with various other gene variants affecting numerous signaling pathways.
UNASSIGNED: Comprehensive WGS was able to detect various mutations and genomic losses, which could explain tumour progression and immune evasion ability. Furthermore, the study identified the loss of other genes related to cancer and immune pathways, emphasizing the complexity of NPC genomics. In conclusion, this study underscores the significance of MHC class I gene loss and its probable correlation with the cold tumour phenotype observed in NPC.

Fertility is an economically important trait in livestock. Poor fertility in dairy cattle can be due to loss-of-function variants affecting any essential gene that causes early embryonic mortality in homozygotes. To identify fertility-associated quantitative trait loci, we performed single-marker association analyses for 8 fertility traits in Holstein, Jersey, and Nordic Red Dairy cattle using imputed whole-genome sequence variants including SNPs, indels, and large deletion. We then performed stepwise selection of independent markers from GWAS loci using conditional and joint association analyses. From single-marker analyses for fertility traits, we reported genome-wide significant associations of 30,384 SNPs, 178 indels, and 3 deletions in Holstein; 23,481 SNPs, 189 indels, and 13 deletions in Nordic Red; and 17 SNPs in Jersey cattle. Conditional and joint association analyses identified 37 and 23 independent associations in Holstein and Nordic Red Dairy cattle, respectively. Fertility-associated GWAS loci were enriched for developmental and cellular processes (Gene Ontology enrichment, false discovery rate < 0.05). For these quantitative trait loci regions (top marker and 500 kb of surrounding regions), we proposed several candidate genes with functional annotations corresponding to embryonic lethality and various fertility-related phenotypes in mouse and cattle. The inclusion of these top markers in future releases of the custom SNP chip used for genomic evaluations will enable their validation in independent populations and improve the accuracy of genomic predictions.

After Salmonella Enteritidis and S. Typhimurium, S. 4,[5],12:i:- is the most reported serovar in human clinical cases. During the past 20 years, many tools have been used for its typing and second-phase flagellar deletion characterization. Currently, whole genome sequencing (WGS) and different bioinformatic programs have shown the potential to be more accurate than earlier tools. To assess this potential, we analyzed by WGS and in silico typing a selection of 42 isolates of S. 4,[5],12:i:- and S. Typhimurium with different in vitro characteristics. Comparative analysis showed that SeqSero2 does not differentiate fljB-positive S. 4,[5],12:i:- strains from those of serovar Typhimurium. Our results proved that the strains selected for this work were non-clonal S. 4,[5],12:i:- strains circulating in Spain. Using WGS data, we identified 13 different deletion types of the second-phase flagellar genomic region. Most of the deletions were generated by IS26 insertions, showing orientation-dependent conserved deletion ends. In addition, we detected S. 4,[5],12:i:- strains of the American clonal line that would give rise to the Southern European clone in Spain. Our results suggest that new S. 4,[5],12:i:- strains are continuously emerging from different S. Typhimurium strains via different genetic events, at least in swine products.

Narrow-leafed lupin (Lupinus angustifolius L.) is a moderate-yielding legume crop known for its high grain protein content and contribution to soil improvement. It is cultivated under photoperiods ranging from 9 to 17 h, as a spring-sown (in colder locations) or as an autumn-sown crop (in warmer regions). Wild populations require a prolonged cold period, called vernalization, to induce flowering. The key achievement of L. angustifolius domestication was the discovery of two natural mutations (named Ku and Jul) conferring vernalization independence. These mutations are overlapping deletion variants in the promoter of LanFTc1, a homolog of the Arabidopsis thaliana FLOWERING LOCUS T (FT) gene. The third deletion, named here as Pal, was recently found in primitive germplasm. In this study, we genotyped L. angustifolius germplasm that differs in domestication status and geographical origin for LanFTc1 alleles, which we then phenotyped to establish flowering time and vernalization responsiveness. The Ku and Jul lines were vernalization-independent and early flowering, wild (ku) lines were vernalization-dependent and late flowering, whereas the Pal line conferred intermediate phenotype. Three lines representing ku, Pal, and Ku alleles were subjected to gene expression surveys under 8- and 16-h photoperiods. FT homologs (LanFTa1, LanFTa2, LanFTc1, and LanFTc2) and some genes selected by recent expression quantitative trait loci mapping were analyzed. Expression profiles of LanFTc1 and LanAGL8 (AGAMOUS-like 8) matched observed differences in flowering time between genotypes, highlighted by high induction after vernalization in the ku line. Moreover, these genes revealed altered circadian clock control in Pal line under short days. LanFD (FD) and LanCRLK1 (CALCIUM/CALMODULIN-REGULATED RECEPTOR-LIKE KINASE 1) were negatively responsive to vernalization in Ku and Pal lines but positively responsive or variable in ku, whereas LanUGT85A2 (UDP-GLUCOSYL TRANSFERASE 85A2) was significantly suppressed by vernalization in all lines. Such a pattern suggests the opposite regulation of these gene pairs in the vernalization pathway. LanCRLK1 and LanUGT85A2 are homologs of A. thaliana genes involved in the FLOWERING LOCUS C (FLC) vernalization pathway. Lupins, like many other legumes, do not have any FLC homologs. Therefore, candidate genes surveyed in this study, namely LanFTc1, LanAGL8, LanCRLK1, and LanUGT85A2, may constitute anchors for further elucidation of molecular components contributing to vernalization response in legumes.

Cardiovascular disease (CVD), one of the main mortality causes worldwide is considered to be affected by general oxidative stress and inadequacy antioxidant system. Superoxide dismutase 1 (SOD1), a cytosolic antioxidant enzyme has a key role in neutralizing the excessive prooxidant by scavenging the super oxide anions. SOD1 polymorphic variants exhibit the altered activity properties. In the current study, we are aimed to investigate the association between the SOD1 polymorphism and CVD prevalence. A 6-years case control follow up study was designed to genotype the 526 participants (311 controls and 215 cases) for studying the 50 bp INS/DEL polymorphism at SOD1 promoter gene and analyze their blood lipid profile and anthropometric characteristics. Among the two possible alleles of the SOD1 gene (Wild [W] and Mutant [M]) the meaningful association was detected between the Mutants\' frequency and the prevalence of CVD patients (p-value <.001). The W and M allele refer to inserted and deleted 50 bp in the polymorphic site of the SOD1 promoter, respectively. The WM and MM genotypes\' frequency which indicate the wild heterozygotes and Mutant homozygotes, respectively, were significantly correlated with the prevalence of cardiovascular disease (p-value <.001). The present study has the potential to introduce the 50 bp INS/DEL polymorphism of SOD1 genotyping as a novel unique diagnostic approach for screening the high risk CVD.

Angelman syndrome (AS) is a neurodevelopmental disorder that is caused by maternal genetic deficiency of a gene that encodes E6-AP ubiquitin-protein ligase (gene symbol UBE3A) mapping to chromosome 15q11-q13. AS leads to stiff and jerky gait, excess laughter, seizures, and severe intellectual disability. In some parts of the brain, the paternally inherited UBE3A gene is subject to genomic imprinting by the action of the UBE3A-antisense transcript (UBE3A-ATS) on the paternally inherited allele. Consequently, only the maternally inherited UBE3A gene is expressed in mature neurons. AS occurs due to deletions of the maternal 15q11 - 13 region, paternal uniparental disomy (UPD), imprinting center defects, mutations in the maternal UBE3A gene, or other unknown genetic malfunctions that result in a silenced maternal UBE3A gene in the specific imprinted regions of the brain.
A potential treatment strategy for AS is to increase methylation of UBE3A-ATS to promote expression of the paternal UBE3A gene and thus ameliorate the clinical phenotypes of AS. We treated two sets of male identical twins with class I deletions with a 1 year treatment trial of either betaine and folic acid versus placebo. We found no statistically significant changes in the clinical parameters tested at the end of the 1 year trial, nor did we find any significant adverse events.
This study tested the hypothesis that by increasing the methylation of the UBE3A-antisense transcript in Angelman syndrome to promote expression of the silenced paternal UBE3A gene we may ameliorate the clinical phenotypes of AS. We treated two sets of identical twins with placebo versus betaine and folic acid. Although this study represented a novel approach to treating Angelman syndrome, the differences in the developmental testing results was not significant. This paper also discusses the value of monozygotic twin studies in minimizing confounding variables and its utility in conducting small treatment studies.
NCT00348933 . Registered 6 July 2006.

UNASSIGNED: The gene encoding glucose transporter 3 (GLUT3, SLC2A3) is present in the human population at variable copy number. An overt disease phenotype of SLC2A3 copy number variants has not been reported; however, deletion of SLC2A3 has been previously reported to protect carriers from rheumatoid arthritis, implicating GLUT3 as a therapeutic target in rheumatoid arthritis. Here we aim to perform functional analysis of GLUT3 copy number variants in immune cells, and test the reported protective association of the GLUT3 copy number variants for rheumatoid arthritis in a genetic replication study.
UNASSIGNED: Cells from genotyped healthy controls were analyzed for SLC2A3/GLUT3 expression and glycolysis capacity. We genotyped the SLC2A3 copy number variant in four independent cohorts of rheumatoid arthritis and controls and one cohort of multiple sclerosis and controls.
UNASSIGNED: Heterozygous deletion of SLC2A3 correlates directly with expression levels of GLUT3 and influences glycolysis rates in the human immune system. The frequency of the SLC2A3 copy number variant is not different between rheumatoid arthritis, multiple sclerosis and control groups.
UNASSIGNED: Despite a robust SLC2A3 gene copy number dependent phenotype, our study of large groups of rheumatoid arthritis cases and controls provides no evidence for rheumatoid arthritis disease protection in deletion carriers. These data emphasize the importance of well powered replication studies to confirm or refute genetic associations, particularly for relatively rare variants.

Chromosome 16p13.11 microdeletion syndrome is a rare copy number variant that carries increased risks for complications in the neonatal period and throughout the life span. Clinical manifestations and associated defects known to present in the neonatal period include motor delay, facial dysmorphisms, microcephaly, gastroesophageal reflux disease (GERD), and congenital heart defects. Management in the neonatal period focuses on associated comorbidities, including motor delay with or without GERD, which commonly manifests as feeding difficulties. Life span implications of chromosome 16p13.11 microdeletion syndrome include developmental, speech, and language delay; psychiatric and behavioral problems; seizure disorders; and, less commonly, obesity. Nursing assessment is critical to the early identification of nonspecific abnormalities associated with de novo genetic disorders. Early identification and diagnosis of chromosome 16p13.11 microdeletion syndrome are critical to optimizing outcomes throughout infancy and across the life span. We present a case report of an infant diagnosed with chromosome 16p13.11 microdeletion. A discussion of genetic influences, associated clinical manifestations, diagnostics, management, and health promotion strategies are presented to establish core knowledge of chromosome 16p13.11 microdeletion.

Glucocerebrosidase gene (GBA) variants are associated with Parkinson\'s disease (PD) and dementia with Lewy bodies (DLB). The molecular mechanisms underlying these diseases with GBA variants, however, are not well understood. In order to determine the effect of a deletion mutation in GBA, we performed a neuroimaging, genetic, and enzymatic study in a Japanese family with a gross deletion of exons 3 to 11 in GBA.
We performed [123I] FP-CIT SPECT and [123I] N-isopropyl-p-iodoamphetamine SPECT (IMP-SPECT), and determined GBA expression and glucocerebrosidase (GCase) activity in leukocytes in two GBA-associated PD patients and nine unaffected individuals (including four mutation carriers) in a Japanese family with a heterozygous gross deletion mutation in the GBA gene.
The two PD patients and two of the four clinically unaffected carriers showed decreased [123I] FP-CIT uptake. IMP-SPECT showed a pattern like that in DLB in one patient. When we compared PD patients with GBA mutations with clinically unaffected carriers, there was a poor correlation between the development of PD and the expression level of GBA or GCase activity.
We confirmed the gross deletion mutation in the GBA gene, which appeared to be associated with the PD or reduced [123I] FP-CIT in this family. However, since we cannot conclude whether a reduction of GCase activity is directly correlated with the pathogenesis of PD or not, longitudinal follow-up of this family is needed.

BACKGROUND: Pseudomonas aeruginosa is a common bacterium which is recognized for its association with hospital-acquired infections and its advanced antibiotic resistance mechanisms. Tuberculosis, one of the major causes of mortality, is initiated by the deposition of Mycobacterium tuberculosis. Accessory sequences shared by a subset of strains of a species play an important role in a species\' evolution, antibiotic resistance and infectious potential.
RESULTS: Here, with a multiple sequence aligner, we segmented 25 P. aeruginosa genomes and 28 M. tuberculosis genomes into core blocks (include sequences shared by all the input genomes) and dispensable blocks (include sequences shared by a subset of the input genomes), respectively. For each input genome, we then constructed a scaffold consisting of its core and dispensable blocks sorted by blocks\' locations on the chromosomes. Consecutive dispensable blocks on these scaffold formed instable regions. After a comprehensive study of these instable regions, three characteristics of instable regions are summarized: instable regions were short, site specific and varied in different strains. Three DNA elements (directed repeats (DRs), transposons and integrons) were then studied to see whether these DNA elements are associated with the variation of instable regions. A pipeline was developed to search for DR pairs on the flank of every instable sequence. 27 DR pairs in P. aeruginosa strains and 6 pairs in M. tuberculosis strains were found to exist in the instable regions. On the average, 14% and 12% of instable regions in P. aeruginosa strains covered transposase genes and integrase genes, respectively. In M. tuberculosis strains, an average of 43% and 8% of instable regions contain transposase genes and integrase genes, respectively.
CONCLUSIONS: Instable regions were short, site specific and varied in different strains for both P. aeruginosa and M. tuberculosis. Our experimental results showed that DRs, transposons and integrons may be associated with variation of instable regions.