Journal of Genetics最新文献

The family Syngnathidae includes seahorses, sea dragons, and pipefishes. We sequenced the complete mitochondrial DNA (mtDNA) genome of the belly pipefish, Hippichthys heptagonus Bleeker, 1849. The genome is 16,646-bp long, and includes the standard complement for bony fishes of 13 protein-coding genes, 22 tRNA genes, two rRNA genes, and a control region, in the same order and strand distribution as other syngnathids. Maximum likelihood and Bayesian analysis of 58 complete mtDNA protein-coding sequences from 18 genera of Syngnathidae supports the inclusion of H. heptagonus with Phoxocampus in the tribe Leptonotini of the Syngnathinae, monophyly of the Nerophinae and Syngnathinae, and within the latter monophyly of the tribes Haliichthytini, Hippocampini, Leptonotini, Solegnathini, and Syngnathini. This is the first comprehensive mtDNA genome-based phylogenetic analysis of the evolutionary and systematic relationships within Syngnathidae.

Nonalcoholic fatty liver disease (NAFLD) occurs in a significant number of nonobese individuals, especially in Asian populations. Many genetic loci are associated with NAFLD. However, no exome-wide analysis of polymorphism data to identify asso- ciations with NAFLD is available for nonobese individuals from Asia. We have sought to fill this gap. With informed consent, we selected individuals from a defined population in India and assessed their liver fat-graded per international recommendations, and their demo- graphic and anthropometric data were collected. A set of 153 individuals were identified with high-grade liver fat. For each of these fatty- liver individuals (cases), two controls of the same sex with no or little liver fat were selected, the age and BMI of each control not exceeding 5 years and 5 kg/m², respectively, of the case. Whole-genome sequencing was done for each individual. For association analysis, we selected only nonsynonymous germline single-nucleotide polymorphisms (SNPs) in coding regions located on genes expressed in the liver. We removed SNPs and individuals with compromised quality and informativeness. We carried out association analysis in this high-quality data set and validated the results using a novel bootstrap procedure. On the basis of this high-stringency association analysis using exome- wideSNP data on 438 cases and controls, we identified 30 significant SNPs on 24 genes. Of these, 21 SNPs from 17 genes are hitherto unreported. We have determined that most of the significant SNPs are functionally relevant. Pathway analysis revealed that the genes on which these SNPs are located are involved in liver dysfunction.

Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration and loss of function due to the absence of dystrophin. In this study, we utilized a zebrafish model with a dmd gene knockout to explore the therapeutic potential of JAG1 overexpression in mitigating DMD-associated muscle dysfunction. Dystrophic zebrafish larvae displayed significant impairments in muscle function, evidenced by reduced swimming abilities, decreased birefringence, and disrupted β-dystroglycan localization, indicative of structural degeneration. Overexpression of JAG1, achieved via plasmid injection, partially restored muscle function, as reflected by improvements in stride length and total swimming distance. However, the structural integrity of slow oxidative muscle fibers remained largely unaffected, with a functional decline from 4 to 8 days post-fertilization (dpf) being more indicative of disease progression than structural changes. These findings suggest that the rescue effect of JAG1 overexpression may not be due to the preservation of slow oxidative fibers but rather through a mechanism that reduces susceptibility to contraction-induced injury. Notably, our study faced limitations related to the control of JAG1 expression levels and tissue specificity. Our results highlight the complexity of DMD pathology, where muscle structure and function do not always correlate, emphasizing the need for refined functional assays to better assess therapeutic outcomes. By incorporating functional recovery assessments at 8-10 dpf, zebrafish models can serve as more predictive preclinical tools, potentially enhancing the translational relevance of findings and reducing risks for patients in clinical trials. This study investigates how increasing the levels of a protein called JAG1 can help improve muscle function in a zebrafish model of DMD. By showing partial recovery of muscle activity, the findings suggest new therapeutic strategies that could potentially slow disease progression and improve patient outcomes.

The neurite extension and migration factor (NEXMIF) encephalopathy is an X-linked disorder that is characterized by intellectual disability, behavioural abnormalities and seizures. The majority of pathogenic variants are de novo. Here, we report two siblings with NEXMIF encephalopathy exhibiting variable clinical presentations. The younger female sibling (proband) presented predominantly with refractory myoclonic and atonic epilepsy and milder intellectual disability, and the male sibling exhibited severe intellectual disability, and significant behavioural abnormalities without seizures. Exome sequencing in the proband revealed a novel heterozygous stop gain variant c.3206C>A p.(Ser1069Ter) in the NEXMIF gene, which was validated by Sanger sequencing. Targeted sequencing in the male sibling revealed the hemizygous nature of the variant. The asymptomatic mother was found to carry the wild-type allele, suggesting the possibility of gonadal mosaicism. This report represents the second documented case of NEXMIF encephalopathy associated with gonadal mosaicism.

Genomic biomarkers are essential aspects of personalized medicine. They offer an opportunity for early detection and appropriate intervention, thereby leading to improved patient outcomes and cost-effective treatment. However, different populations have varied genetic landscapes, and thus, may have unique biomarkers. Here we study the prevalence of mutation-specific oncogenic biomarkers in the Indian population and analyse their presence across disease cohorts. We annotate the IndiGen data obtained from whole genome sequencing of 1029 self-declared healthy Indian individuals with biomarker information obtained from the OncoKB knowledgebase, a repository of evidence-based information about somatic biomarkers and structural alterations in patient tumours. We further establish the utility of this study by analysing these biomarkers across GUaRDIAN, a nationwide multi-cohort database, and MUSTARD, a repository of mutation-specific therapies in cancer. In this study, we discovered 34 biomarker variants of therapeutic actionability across 16 genes linked to 23 unique drugs or drug combinations in 23 unique types of cancer. In all, we have found 52 biomarker variants with 172 different biomarker types including therapeutic, resistance, diagnostic, and prognostic. We establish that nearly 7% of the population were found to be carriers of at least one of the four evidence-based biomarkers. Finally, we also establish the prevalence of 42 biomarker variants across 23 genes in both AD and AR modes of inheritance. We have calculated the prevalence of cancer biomarkers of therapeutic, diagnostic and prognostic value in the globally underrepresented Indian population. The known biomarker landscape so established can be used for clinical advantage to improve patient care. Cancers without corresponding biomarker matches can also be further studied to discover biomarkers unique to Indian populations.

The father of sociobiology, Edward Wilson, described him as 'the most unpleasant human being I had ever met'. He was the first living laureate to auction his Nobel Prize. He said that because of some of his views and beliefs, he had become an 'unperson'. 'No one really wants to admit I exist.' 'Because I was an ''unperson'', I was fired from the boards of companies, so I have no income, apart from my academic income.' The 'unperson' is James Dewey Watson. He won the Nobel Prize at the age of 34, for the work he published in 1953, when he was only 25. The 1953 article in Nature, co-authored with Francis Crick, concluded with the famous understatement: 'It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.' Watson died on 6 November 2025 at the age of 97.

Duplications in the dystrophin gene (DMD) represent a common genetic variation associated with the onset of Duchenne and Becker muscular dystrophy. In this study, we reported a novel mRNA-derived DMD duplication identified by next-generation sequencing (NGS)-based expanded carrier screening (ECS) in a pregnant woman, which was not accurately detected by multiplex ligation probe amplification (MLPA) testing. The discrepancy was elucidated through the analysis of the duplication breakpoint via additional validation experiments. This variation was confirmed to originate from a partially reverse-transcribed intronless cDNA copy of a rare DMD gene transcript mRNA and reinserted into a noncoding region of chromosome 13. The variation was classified as benign because the DMD gene remained intact. We strongly recommend analysing the breakpoints before the pathogenicity assessment of DMD duplication variations, identified in ECS to improve the accuracy of clinical prediction and genetic counselling.

Tandem repeats (TRs) are highly polymorphic low complexity regions present in all the genomes. The length variation in TRs, particularly that of short TRs (STRs), is associated with several cellular functions such as gene expression and genome organization. In humans, an abnormal expansion of a few STR loci is linked to neurodegenerative diseases. Despite their importance, limitations and gaps in reference genomes prohibit the comprehensive analysis of TRs. Recent advances in high-throughput sequencing technologies have enabled the generation of gapless, telomere-to-telomere (T2T) genomes of humans and other ape species. Here, we report the TR landscape of seven primate T2T genomes, including humans. Our analysis indicates that TRs of 1-100 nucleotide (nt) motifs cover 3.5-6.9% of large primate genomes, with the highest density observed in gorilla (69 kb per Mbp). Large motif size TRs are prevalent and contribute abundantly to higher-order repeats. As an example, we describe a species-specific 32 nt A/T rich motif that contributes to subtelomeric repeats. Finally, we present the motif decomposition and substructure of pentameric repeats in Y chromosomes of six ape species. Our work illutrates the dynamics of TRs in large genomes, and showcases the utility of complete genomes for better understanding the role of low complexity sequences.

Smith-Magenis syndrome (SMS) is a complex genetic disorder characterized by developmental delay and a typical behavioral phenotype. Interstitial 17p11.2 deletions, which include the RAI1 gene are detected in >90% of patients, while single nucleotide variants (SNVs) are detected in the rest. The RAI1 gene is encoded from exons 3 onwards, while exons 1-2 are noncoding. It is unclear whether genetic variants preceding exon 3 cause SMS. We evaluated a 15-month-old infant for developmental delay and infantile spasms who was found to carry a deletion encompassing exons 1-2 of RAI. To determine whether the deletion of the noncoding exons 1-2 of the RAI1 gene is associated with SMS and to elucidate the underlying mechanism of this association. A singleton exome-based gene panel was performed, followed by chromosomal-microarray (CMA) to confirm the results. Real time quantitative PCR (RT-qPCR) analysis was conducted to evaluate RAI1 mRNA expression. CMA confirmed a de novo 737.8 kbp deletion on 17p11.2, which includes exons 1-2 of RAI1 but spares exons 3 onwards. RT-qPCR analysis on RNA extracted from the patient, father and three unrelated controls revealed that the patient has RAI1 haploinsufficiency. We show that deletion of the RAI1 noncoding exons 1-2, which spares the gene's coding region, causes RAI1 haploinsufficiency by eliminating regulatory elements, including the gene promoter, thus causing SMS and expanding the mutational spectrum of SMS.

N-glycanase1 (NGLY1) deficiency, an autosomal recessive disorder identified a decade ago, is categorized as a congenital disorder of deglycosylation (CDDG). This disorder arises from bi-allelic variants in the NGLY1 gene, leading to impaired protein deglycosylation. Phenotypically, individuals with NGLY1 deficiency present with intellectual disability, movement disorders, liver dysfunction, muscular hypotonia, etc., termed as NGLY1-CDDG, its diagnosis relies primarily on next generation sequencing (NGS) and till date, it has been diagnosed in over 100 patients. However, there are no previous reports on this from India. We report the first two NGLY1 cases from India in this study. These patients presented with developmental delay, movement disorder, microcephaly, hypotonia and suspicion of congenital disorder of glycosylation (CDG) and were assessed for glycosylation defect using the high pressure liquid chromatography (HPLC) based transferrin isoform analysis and whole exome sequencing (WES). Both patients exhibited a normal transferrin isoform pattern and harboured variants in NGLY1 gene. The variants, NM_018297.4:c.571C[T; p.Gln191Ter and NM_018297.4:c.707G[A; p.Trp236Ter on exons 4 and 5, respectively, identified in our patients are bi-allelic loss of function homozygous variants that have not been previously reported. These variants are inferred as pathogenic in view of genotype-phenotype correlation, parental segregation analysis, in-silico analyses, and absence of other genetic disorders. We have also summarized literature reports on NGLY1-CDDG and compared the phenotype and variants of our patients with the reported cases. These cases contribute to the clinical, biochemical, and molecular understanding of NGLY1 deficiency among Indians, thereby elucidating the presence of NGLY1-CDDG in India.