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PubMed2026

Genetic Analysis of Genomic and Methylomic Variation and Identification of Multi-Trait Mutants in Rice Carried on Chang'e-5.

Global food security is facing challenges from population growth to diminishing arable land. Space mutation breeding holds promise for overcoming the variation limitations in conventional breeding; however, the mutagenic effects of the deep-space environment on rice and the transgenerational inheritance patterns of induced variations remain unclear. In this study, rice seeds carried by the Chang'e-5 spacecraft were used as materials. Whole-genome sequencing and whole-genome bisulfite sequencing were performed on the first (SP1) and second generations (SP2) of space-mutagenized plants after their return to Earth. The results showed that the number of genomic variants in the SP2 generation increased significantly compared with SP1, and SNPs, homozygous sites, and variants in coding regions were more heritable. The genome-wide methylation level was elevated in the SP2 generation, and among differentially methylated cytosines, those in the CG context exhibited the highest heritability. Furthermore, large-scale screening for nitrogen efficiency, tolerance to PEG-induced stress, and germination-stage cold resistant mutants was conducted in the SP2 generation, and phenotypic validation was performed in the third generation (SP3). By integrating multi-omics analyses of representative mutants to mine candidate genes, a number of heritable elite mutants were obtained, and seven candidate genes for key traits were identified. This study systematically elucidates the transgenerational inheritance patterns of deep-space-induced variation in rice. The multi-trait mutants obtained provide valuable germplasm resources for gene cloning and breeding applications in rice.

DNA methylation↗
PubMed1981

Genetics of the low density lipoprotein receptor: III. Evidence for multiple normal alleles at the low density lipoprotein receptor locus.

Fibroblast association (plasma membrane binding plus intracellular accumulation) and degradation of radioiodinated low density lipoprotein (125I-LDL) index plasma membrane LDL receptor activity. Cultured fibroblasts from 23 subjects affected with familial hypercholesterolemia (HC) and from 95 subjects without HC (non-HCs) were tested for 125I-LDL association and degradation. Both LDL receptor activity indices were twice as high in non-HC and HC heterozygous cell strains. This is compatible with a major gene effect on LDL receptor activity. However, a considerable overlap between non-HC and HC heterozygous values was found in the 125I-LDL association assay [median (range) 970 (330-2500), and 450 (250-490), respectively] and in the degradation assay [median (range) 810 (280-2020), and 470 (160-790), respectively]. The values are expressed as ng 125I-LDL X mg cell protein-1 X 4.5 h-1. These great overlaps in the LDL receptor activity indices support the view that the influence of LDL receptor activity on the HC phenotype may be smaller than believed previously. Furthermore, for the diagnosis of HC, these LDL receptor activity assays are far more expensive and have less sensitivity and specificity than simple serum cholesterol determination. The LDL receptor-dependent 125I-LDL association values for the HC heterozygous individuals clustered into four groups. Family data supported the hypothesis that this variation could be due to four different LDL receptor variants, each coded for by different alleles at the LDL receptor locus. If confirmed, this finding may have implications for the understanding of the variable expression of HC and also of the genetic impact on lipoprotein metabolism and susceptibility to atherosclerosis in non-HCs.

Adolescent↗
PubMedDate not supplied

A programme for computer-aided recognition of electrocardiographic patterns.

A programme for pattern recognition and automatic diagnosis on digitally converted electrocardiograms is described. Pattern recognition is carried out on the 12 classical leads and diagnosis is given in the Minnesota Code, 1968 variant. The programme was written in FORTRAN and tested in a FELIX C 256 computer.

Computers↗
PubMed2025

Identification of a novel non-coding deletion in Allan-Herndon-Dudley syndrome by long-read HiFi genome sequencing.

BACKGROUND: Allan-Herndon-Dudley syndrome (AHDS) is an X-linked disorder caused by pathogenic variants in the SLC16A2 gene. Although most reported variants are found in protein-coding regions or adjacent junctions, structural variations (SVs) within non-coding regions have not been previously reported. METHODS: We investigated two male siblings with severe neurodevelopmental disorders and spasticity, who had remained undiagnosed for over a decade and were negative from exome sequencing, utilizing long-read HiFi genome sequencing. We conducted a comprehensive analysis including short-tandem repeats (STRs) and SVs to identify the genetic cause in this familial case. RESULTS: While coding variant and STR analyses yielded negative results, SV analysis revealed a novel hemizygous deletion in intron 1 of the SLC16A2 gene (chrX:74,460,691 - 74,463,566; 2,876 bp), inherited from their carrier mother and shared by the siblings. Determination of the breakpoints indicates that the deletion probably resulted from Alu/Alu-mediated rearrangements between homologous AluY pairs. The deleted region is predicted to include multiple transcription factor binding sites, such as Stat2, Zic1, Zic2, and FOXD3, which are crucial for the neurodevelopmental process, as well as a regulatory element including an eQTL (rs1263181) that is implicated in the tissue-specific regulation of SLC16A2 expression, notably in skeletal muscle and thyroid tissues. CONCLUSIONS: This report, to our knowledge, is the first to describe a non-coding deletion associated with AHDS, demonstrating the potential utility of long-read sequencing for undiagnosed patients. Although interpreting variants in non-coding regions remains challenging, our study highlights this region as a high priority for future investigation and functional studies.

Humans↗
PubMed1984

A mutation in actin associated with neoplastic transformation.

A new protein was recognized in a chemically transformed human fibroblast cell line when its proteins labeled with [35S]methionine were compared with those from normal human fibroblasts by two-dimensional gel electrophoresis. The new protein was found in the Triton-insoluble cytoskeletal fraction as well as in the Triton-soluble fraction, and it migrated very closely to beta- and gamma-actins on the gels. This new protein was identified as a variant form of actin by its reaction with antiactin antibody and its tryptic peptide pattern, which was identical to actin. mRNA coding for the variant actin was detected only in this particular transformed line. The size and cross- hybridizability with Dictyostelium actin cDNA of mRNA coding for the variant actin and complete amino acid sequence of the variant actin indicate that the new variant actin is the product of a mutated beta-actin gene. Only a single amino acid (glycine) at position 244 was replaced by aspartic acid. This substitution corresponds to a GC----AT transition, a point mutation. On the other hand, a highly malignant cell variant was isolated from the transformed line. The mutated beta-actin was further altered in this highly malignant subclone: it showed a more negative charge, rapid synthetic rate, and a short half-life in the cells. Incorporation into the cytoskeleton was significantly reduced in the mutated beta-actin. A hypothesis on the relationship between a mutation in the actin gene and oncogenic transformation was proposed.

4-Nitroquinoline-1-oxide↗
PubMed1988

[Two allelic genes of human p53 code for proteins differing with respect to amino acid sequence].

Two allelic p53 genes were investigated. The allelic gene with BgIII site in the first intron codes for faster p53 protein variant, the other allelic gene coding for slower p53 protein variant (according to the mobility in SDS-PAAG). Exons and flanked regions of introns were sequenced. In coding regions allelic genes only differ by second nucleotides of codon 72 (G----C), which leads to the change in amino acid sequence (Arg----Pro). The relationship of these changes and the function of p53 is discussed.

Alleles↗
PubMed2025

Federated learning for the pathogenicity annotation of genetic variants in multi-site clinical settings.

MOTIVATION: Rare diseases collectively affect 5% of the population. However, fewer than 50% of rare disease patients receive a molecular diagnosis after whole genome sequencing. Supervised machine learning is a valuable approach for the pathogenicity scoring of human genetic variants. However, existing methods are often trained on curated but limited central repositories, resulting in poor accuracy when tested on external cohorts. Yet, large collections of variants generated at hospitals and research institutions remain inaccessible to machine-learning purposes because of privacy and legal constraints. Federated learning (FL) algorithms have been recently developed enabling institutions to collaboratively train models without sharing their local datasets. RESULTS: Here, we present a proof-of-concept study evaluating the effectiveness of FL for the clinical classification of genetic variants. A comprehensive array of diverse FL strategies was assessed for coding and non-coding Single Nucleotide Variants as well as Copy Number Variants. Our results showed that federated models generally achieved comparable or superior performance to traditional centralized learning. In addition, federated models reached a robust generalization to independent sets with smaller data fractions as compared to their centralized model counterparts. Our findings support the adoption of FL to establish secure multi-institutional collaborations in human variant interpretation. AVAILABILITY AND IMPLEMENTATION: All source code required to reproduce the results presented in this article, implemented in Python, is available under the GNU General Public License v3 at https://github.com/RausellLab/FedLearnVar.

Humans↗
PubMed1986

Mung bean nuclease cleaves preferentially at the boundaries of variant surface glycoprotein gene transpositions in trypanosome DNA.

Telomere-linked genes coding for the variant surface glycoproteins (VSGs) of African trypanosomes have been difficult to clone because their flanking regions frequently lack restriction sites. Therefore, we constructed a genomic DNA library of fragments generated by digestion of purified trypanosome DNA with mung bean nuclease, an enzyme that cleaves before and after genes in Plasmodium falciparum DNA (McCutchan, T. F., Hansen, J. L., Dame, J. B., and Mullins, J. A. (1984) Science 225, 625-628). Southern hybridizations with several gene probes showed that under the appropriate conditions mung bean nuclease produces discrete trypanosome DNA fragments that are as clearly resolved on an agarose gel as restriction fragments. The majority of VSG genes are on fragments of about 1.7 kilobase pairs. To examine the sites of mung bean nuclease cleavage, the insert boundary sequences of eight recombinant clones in the library containing VSG genes were determined. In general, mung bean nuclease cleaved 300-800 base pairs in front of the VSG start codon and within 50 base pairs on either side of the termination codon. These regions also form the boundaries of VSG gene conversion events indicating that the enzyme recognizes, in part, a conformational structure rather than a specific sequence. The analyzed clones included both telomere-linked and interior basic copy VSG genes indicating that the library potentially contains all of the telomere-linked VSG genes in the genome.

Animals↗
PubMed2026

Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios.

The genetic architecture of sporadic Early-Onset Alzheimer Disease (sEOAD, onset ≤65 years) remains largely unknown. To assess the de novo mutation (DNM) hypothesis, we performed a nationwide recruitment of 37 novel sEOAD patients-unaffected parents trios. After assessing known monogenic genes, we performed trio-based exome sequencing and jointly analyzed novel trios with 12 previously reported ones. Of these, we selected 16 trios for genome sequencing. We identified three patients with a pathogenic DNM in APP or PSEN1. Then, from the 46 remaining trios, we identified 38 non-synonymous coding DNM and 4 de novo copy number variants (CNVs) in exome data. Four DNM (2 novel, in SPHK2 and DDR1) and bi-allelic inherited variants in two genes affected Alzheimer disease-related genes. No significant burden of rare coding variants in exome/genome data from 5643 EOAD cases and 16097 controls was identified using nested windows centered on each DNM position, at the transcript level. From genome data, one non-coding DNM was predicted to affect splicing in an AD-associated gene, PINX1. Overall, 48% probands carried ≥1 inherited risk factor with odds ratio (OR) > 1.5 and GWAS-defined Genetic Risk Scores (GRS) distribution was more consistent with random distribution than enrichment in higher scores in probands. We confirm that DNMs in known monogenic genes explain sEOAD in a minority of cases, while candidate DNMs in other genes might account for a small proportion of additional cases. The majority of sEOAD patients may have a complex etiology including multiple inherited variants, however, GRS might not explain most of its genetic component.

Humans↗
PubMedDate not supplied

An H1 histone gene from rainbow trout (Salmo gairdnerii).

A 1.7-kbp DNA region from the 10.2-kb cluster containing the five rainbow trout histone genes has been subcloned in pBR322 and completely sequenced. It contains a trout histone H1 gene together with its 5' and 3' flanking sequences. This H1 gene codes for a H1 variant different from the major trout testis H1 previously sequenced by Macleod et al. (1977). Northern blots of total RNA from trout testis, kidney, and liver indicate that this H1 gene is expressed in all three tissues but that the level of H1 mRNA is much higher in testis than in other tissues. The lack of heterogeneity in the sizes and 5' initiation sites of trout H1 mRNAs is surprising in view of the substantial heterogeneity of H1 variant proteins observed previously. The coding sequence of the H1 gene shows strong evidence of repeated partial duplications of a hexapeptide motif of the form Ala.Ala.Ala.Lys.Lys.Pro and of a pentapeptide phosphorylation-site sequence, Lys.Ser.Pro.Lys.Lys, during its evolution. Comparisons are drawn between this gene and the coding sequences of other vertebrate H1 genes from chicken and Xenopus, and a strong homology is seen in the region of amino acids 22-101, which form the hydrophobic "head" of the H1 molecule. The 5' and 3' regulatory signals in the trout H1 are also compared with those of H1 genes from other sequences.

Amino Acid Sequence↗
PubMed1979

The genetic and cytogenetic localization of the three structural genes coding for the major protein of drosophila larval serum.

The alpha, beta and gamma polypeptides that make up Drosophila Larval Serum Protein-1 seem to be coded for by genes that have evolved by duplication of a common ancestral gene. We have found variants of all three polypeptides, and these are variants of the coding sequences. The alpha-chain variant mapped to 39.5 on the X chromosome and to the polytene interval 11A7-11B9. The beta-chain variant mapped to 1.9 on chromosome 2L and to 21D2-22A1. The gamma-chain variant was mapped as 0.13 map units from the tip of chromosome 3L or to --1.41 with respect to ru, which has been defined as 0.0, and to 61A1-61A6.

Animals↗
PubMed1982

Characterization of the DNA duplication-transposition that controls the expression of two genes for variant surface glycoproteins in Trypanosoma brucei.

The genome of Trypanosoma brucei carries over a hundred genes coding for different variants of the major surface glycoprotein. Activation of some of these genes is accompanied by a duplication and transposition of the gene (the basic copy) to another region in the genome where it is transcribed. We present here physical maps of the basic and transposition-activated genes for two surface glycoproteins of Trypanosoma brucei, stock 427. In both cases the transposed segment starts 1-2 kb in front of the coding region and ends within the 3'-terminal region of the gene. The DNA segments flanking both transposed genes are indistinguishable and share a 6-kb stretch upstream and a 8-kb stretch downstream of the transposed segment not cut by several restriction endonucleases. The 5' borders of the two transposed segments are homologous and contain sequences present in many copies in the genome. A different repeated sequence has previously been found at the 3' edge of the transposed segment. The replicative transposition may, therefore, involve a unidirectional gene conversion initiated by base pairing between the edges of the transposed sequence and a single expression site elsewhere in the genome.

Animals↗
PubMed2025

Improved diagnosis of patients with rare diseases through the application of constrained coding region annotation and de novo status.

PURPOSE: Identifying the pathogenic variant in a patient with rare disease (RD) is the first step in ending their diagnostic odyssey. De novo (Dn) variants affecting protein-coding DNA are a well-established cause of Mendelian disorders in patients with RD. Constrained coding regions (CCRs) are specific segments of coding DNA that are devoid of functional variants in healthy individuals. METHODS: We evaluated the diagnostic utility of incorporating combined Dn/CCR status into the variant prioritization cascade for patients with RD that have undergone genomic sequencing. Using the Genomics England 100,000 Genomes Project v12, we selected 3090 trios that have undergone diagnostic evaluation and been analyzed with an advanced Dn identification pipeline. RESULTS: Our analysis shows that the diagnostic rate increased from 71% in the full cohort to 87% for Dn/CCR variants. Of note, manual evaluation of the Dn/CCR variants from undiagnosed patients with clinical follow-up revealed a diagnosis for 13 further patients. This outcome increases the diagnostic rate for Dn/CCR variants to 91% and suggests that the application of this metric can prioritize diagnostic variants in undiagnosed patients. CONCLUSION: We demonstrate the potential clinical utility of performing bespoke Dn analyses of patients with RD and for incorporating CCR information into the filtering cascade to prioritize pathogenic variants.

Humans↗
PubMed1992

Cytotoxic T lymphocytes (CTL) against a transforming gene product select for transformed cells with point mutations within sequences encoding CTL recognition epitopes.

The 94-kD large tumor (T) antigen specified by simian virus 40 (SV40) is sufficient to induce cell transformation. T antigen contains four H-2Db-restricted cytotoxic T lymphocyte (CTL) recognition epitopes that are targets for CTL clones Y-1, Y-2, Y-3, and Y-5. These epitopes have been mapped to T antigen amino acids 207-215 (site I), 223-231 (sites II and III), and 489-497 (site V), respectively. Antigenic site loss variant cells that had lost one or more CTL recognition epitopes were previously selected by coculturing SV40-transformed H-2Db cells with the site-specific Db-restricted CTL clones. The genetic bases for T antigen CTL recognition epitope loss from the variant cells were identified by DNA amplification and direct sequencing of epitope-coding regions from variant cell DNAs. Cells selected for resistance to CTL clone Y-1 (K-1; K-1,4,5; K-3,1) carry deleted SV40 genomes lacking site I, II, and III coding sequences. Point mutations present within the site II/III coding region of Y-2-/Y-3-resistant cell lines specify the substitution of asparagine for lysine as T antigen amino acid 228 (K-2) or phenylalanine for tyrosine at position 230 (K-3). Point mutations identified within independently selected Y-5 resistant populations (K-5 and K-1,4,5) direct the substitution of isoleucine for asparagine at position 496 (K-5) or the substitution of phenylalanine for isoleucine at position 491 (K-1,4,5) of T antigen. Each substitution causes loss of the relevant CTL recognition epitope, apparently by compromising CTL T cell receptor recognition. These experiments identify specific amino acid changes within a transforming protein that facilitate transformed cell escape from site-specific CTL clones while allowing maintenance of cellular transformation. This experimental model system provides unique opportunities for studying mechanisms of transformed cell escape from active immunosurveillance in vivo, and for analysis of differential host immune responses to wild-type and mutant cell-transforming proteins.

Amino Acid Sequence↗
PubMed2025

Non-coding single-nucleotide and structural variants affecting the EYS putative promoter cause autosomal recessive retinitis pigmentosa.

PURPOSE: Variants in untranslated genomic regions are difficult to identify as pathogenic but are capable of causing disease by interfering with gene expression. This study aimed to characterize the effect of variants identified in the 5'-untranslated region of EYS in patients with autosomal recessive retinitis pigmentosa (RP). METHODS: Variant screening included gene panels, Sanger, exome, and genome sequencing. Functional validation included an electrophoretic mobility shift assay and various luciferase assays. RESULTS: Patients with RP from 6 EYS biallelic Arab-Muslim families harbored a 5' noncoding EYS variant, c.-453G>T, and 4 harbored a structural variant affecting the 5' noncoding exons. Electrophoretic mobility shift assay analysis revealed an effect on binding of transcription factors for c.-453G>T and a neighboring variant c.-454G>T. Dual luciferase assays using overexpression of various transcription factors showed distinct effects on expression. c.-453G>T was associated with higher luciferase expression with CRX overexpression and c.-454G>C with OTX2 overexpression. In addition, the 2 variants were found to influence translation by affecting upstream initiation codons. Interestingly, visual function of EYS RP patients who harbor c.-453G>T are better than those with biallelic null EYS variants. CONCLUSION: Our analysis revealed both single-nucleotide and structural variants in the EYS promoter as the cause of autosomal recessive RP. These variants may affect EYS expression via a dual mechanism by altering transcription factor binding affinity at the EYS promoter and by affecting upstream open reading frames.

Humans↗
PubMed1992

Mutations away from splice site recognition sequences might cis-modulate alternative splicing of goat alpha s1-casein transcripts. Structural organization of the relevant gene.

alpha s1-Casein variants F and D, synthesized in goat milk at lower levels than variant A, essentially differ from it by internal deletions of 37 and 11 amino acid residues, respectively. Northern blot analysis of mRNAs encoding alpha s1-casein F and A and sequencing of the relevant cloned cDNAs, as well as sequencing of in vitro amplified genomic fragments, revealed multiple alternatively processed transcripts, from the F allele. Although correctly spliced messengers were identified, most of the FmRNAs lacked three exons. These exons, further identified as exons 9, 10, and 11, together encode the 37 amino acid residues present in alpha s1-casein variant A but missing in variant F. Exon 9 codes for the sequence present in variant A but deleted in variant D. A single nucleotide deletion in exon 9 and two insertions, 11 and 3 base pairs in length, in the downstream intron, were identified as mutations potentially responsible for the alternative skipping of these 3 exons. From a computer-predicted secondary structure it appeared that the 11-base pair insertion might be involved in base-pairing interactions with the intron 5' splice site which might consequently be less accessible to U1 snRNA. We also report here the complete structural organization of the goat alpha s1-casein transcription unit, deduced from polymerase chain reaction experiments. It contains 19 exons scattered within a nucleotide stretch nearly 17-kilobase pairs long.

Amino Acid Sequence↗
PubMedDate not supplied

Allotypes of the a series and their variants in rabbit immunoglobulins.

Six allotypic specificities of the a series are found on rabbit immunoglobulins: a1, a2 and a3 are found both in domestic and wild rabbits Oryctolagus cuniculus; a100, a101 and a102 seem to be present only in wild rabbits. Each of these specificities is a family of variants always present together in a given serum. These variants can be studied through the cross-reactivities detected between the patterns of the a series. The results of studies of cross-reactivities between a1, a3 and the two specificities a100, and a102 and also the cross-reactivity between a2 and a minor variant of the a1 specificity suggested a hypothetical scheme. This hypothesis attempts to take into account the evolution of the specificities of the a series and their variants. This hypothesis also postulates the existence of a set of closely linked genes which control the synthesis of the variants of a given specificity. One could suppose that primordial allelic genes might have appeared from an ancestor gene. By duplication each allele would have led to the appearance of a set of genes coding for a given specificity. These genes might have evolved through mutations and recombinations. In wild rabbits, the observation of an allotype which seems to result from a recombination between the group of genes coding for the a2 variants and the group of genes coding for a3 variants argues in favors of the genetic recombination mechanism.

Animals↗