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Microbial Genomics Apr 2023Malarial parasites exhibit extensive genomic plasticity, which induces the antigen diversification and the development of antimalarial drug resistance. Only a few...
Malarial parasites exhibit extensive genomic plasticity, which induces the antigen diversification and the development of antimalarial drug resistance. Only a few studies have examined the genome maintenance mechanisms of parasites. The study aimed at elucidating the impact of a mutation in a DNA mismatch repair gene on genome stability by maintaining the mutant and wild-type parasites through serial cultures for approximately 400 days and analysing the subsequent spontaneous mutations. A P513T mutant of the DNA mismatch repair protein PfMSH2-1 from 3D7 was created. The mutation did not influence the base substitution rate but significantly increased the insertion/deletion (indel) mutation rate in short tandem repeats (STRs) and minisatellite loci. STR mutability was affected by allele size, genomic category and certain repeat motifs. In the mutants, significant telomere healing and homologous recombination at chromosomal ends caused extensive gene loss and generation of chimeric genes, resulting in large-scale chromosomal alteration. Additionally, the mutant showed increased tolerance to N-methyl-N'-nitro-N-nitrosoguanidine, suggesting that PfMSH2-1 was involved in recognizing DNA methylation damage. This work provides valuable insights into the role of PfMSH2-1 in genome stability and demonstrates that the genomic destabilization caused by its dysfunction may lead to antigen diversification.
Topics: Humans; Plasmodium falciparum; MutS Homolog 2 Protein; Mutation; Genomic Instability; Phenotype
PubMed: 37083479
DOI: 10.1099/mgen.0.001003 -
Genome Research Apr 2023Understanding the impact of DNA variation on human traits is a fundamental question in human genetics. Variable number tandem repeats (VNTRs) make up ∼3% of the human...
Understanding the impact of DNA variation on human traits is a fundamental question in human genetics. Variable number tandem repeats (VNTRs) make up ∼3% of the human genome but are often excluded from association analysis owing to poor read mappability or divergent repeat content. Although methods exist to estimate VNTR length from short-read data, it is known that VNTRs vary in both length and repeat (motif) composition. Here, we use a repeat-pangenome graph (RPGG) constructed on 35 haplotype-resolved assemblies to detect variation in both VNTR length and repeat composition. We align population-scale data from the Genotype-Tissue Expression (GTEx) Consortium to examine how variations in sequence composition may be linked to expression, including cases independent of overall VNTR length. We find that 9422 out of 39,125 VNTRs are associated with nearby gene expression through motif variations, of which only 23.4% are accessible from length. Fine-mapping identifies 174 genes to be likely driven by variation in certain VNTR motifs and not overall length. We highlight two genes, and , that have expression associated with motif variation, showing the utility of RPGG analysis as a new approach for trait association in multiallelic and highly variable loci.
Topics: Humans; Minisatellite Repeats; Phenotype; Haplotypes; Gene Expression; Adenosine Triphosphatases; Ubiquitin-Protein Ligases
PubMed: 37037626
DOI: 10.1101/gr.276768.122 -
Journal, Genetic Engineering &... Apr 2023Gymnema sylvestre (Retz.) R. Br. ex Schult. is a well-known medicinal plant against diabetes in India. There is as such no organized cultivation in India, and the plant...
BACKGROUND
Gymnema sylvestre (Retz.) R. Br. ex Schult. is a well-known medicinal plant against diabetes in India. There is as such no organized cultivation in India, and the plant is still being collected from the wild for their therapeutic uses. It is, therefore, important to estimate the genetic diversity and population genetic structure of G. sylvestre to ascertain the genetically diverse germplasm. The present study, therefore, was undertaken to analyze the genetic variability in 118 accessions belonging to 11 wild populations of G. sylvestre using directed amplification of minisatellite-region DNA (DAMD) and inter simple sequence repeats (ISSR).
RESULTS
The present genetic analyses of 11 populations with 25 markers (8 DAMD and 17 ISSR) revealed significant genetic diversity (H = 0.26, I = 0.40, PPL = 80.89%) at a species level, while the average genetic diversity at the population level was low. Among the 11 populations studied, PCH and UTK populations showed maximum genetic diversity, followed by KNR and AMB, while TEL population revealed the lowest genetic diversity. AMOVA and G values (0.18) revealed that most of the genetic variations are found within populations and very less among populations, and higher gene flow (N = 2.29) was found to be responsible for the genetic homogenization of the populations. The clustering pattern resulting from the UPGMA dendrogram was in congruence with STRUCTURE and PCoA, segregating all the 11 populations into two main genetic clusters: cluster I (populations of North and Central India) and cluster II (populations of South India). The clustering patterns obtained from all three statistical methods indicate that the genetic structure in G. sylvestre populations corresponds to the geographical diversity of the populations and represents a strong genetic structure.
CONCLUSION
The genetically diverse populations identified during the present study could be a potential genetic resource for further prospecting and conserving this important plant resource.
PubMed: 37022506
DOI: 10.1186/s43141-023-00497-7 -
Frontiers in Cellular and Infection... 2023The epidemiological situation of tuberculosis (TB) in Poland urges for its continuous and scrupulous monitoring. The objective of this study was to explore the genetic...
INTRODUCTION
The epidemiological situation of tuberculosis (TB) in Poland urges for its continuous and scrupulous monitoring. The objective of this study was to explore the genetic diversity of multidrug-resistant (MDR) and drug-susceptible (DS) isolates from Poland with a combination of spoligotyping and high-resolution mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) analysis. The results were placed in the Northern and Eastern Europe context.
METHODS
The study included 89 (39 MDR and 50 DS) isolates collected from as many patients between 2018 and 2021 in Poland. The analysis was done using spoligotyping, and MIRU-VNTR typing at 24 standard loci. The data were compared to those available on Poland and neighbors and global datasets.
RESULTS
The main identified families were Beijing (28.1%) and Haarlem (16.8%) while 34.8% of isolates were in the heterogeneous L4-unclassified group. Although the Beijing family was the most prevalent (61.5%) among MDR-TB cases, it accounted for only 2% of DS isolates. Among foreign-born patients, a higher ratio of MDR isolates were observed when compared with those who Poland-born (64.3% vs. 40%). Furthermore, all patients from the Former Soviet Union (FSU) countries were infected with MDR-TB.
DISCUSSION
Whereas DS population in Poland is dominated by L4 isolates, MDR isolates are mostly of the Beijing genotype. The rise in the prevalence of the Beijing isolates in Poland, coupled with high proportion of the Beijing genotype among foreign-born TB patients may reflect an ongoing transmission of this family, imported to Poland mainly from FSU countries.
Topics: Humans; Mycobacterium tuberculosis; Phylogeny; Beijing; Poland; Tuberculosis; Tuberculosis, Multidrug-Resistant; Genotype; Minisatellite Repeats
PubMed: 37009494
DOI: 10.3389/fcimb.2023.1161905 -
Communications Biology Mar 2023SINE-VNTR-Alu (SVA) retrotransposons arose and expanded in the genome of hominoid primates concurrent with the slowing of brain maturation. We report genes with intronic...
SINE-VNTR-Alu (SVA) retrotransposons arose and expanded in the genome of hominoid primates concurrent with the slowing of brain maturation. We report genes with intronic SVA transposons are enriched for neurodevelopmental disease and transcribed into long non-coding SVA-lncRNAs. Human-specific SVAs in microcephaly CDK5RAP2 and epilepsy SCN8A gene introns repress their expression via transcription factor ZNF91 to delay neuronal maturation. Deleting the SVA in CDK5RAP2 initiates multi-dimensional and in SCN8A selective sodium current neuronal maturation by upregulating these genes. SVA-lncRNA AK057321 forms RNA:DNA heteroduplexes with the genomic SVAs and upregulates these genes to initiate neuronal maturation. SVA-lncRNA AK057321 also promotes species-specific cortex and cerebellum-enriched expression upregulating human genes with intronic SVAs (e.g., HTT, CHAF1B and KCNJ6) but not mouse orthologs. The diversity of neuronal genes with intronic SVAs suggest this hominoid-specific SVA transposon-based gene regulatory mechanism may act at multiple steps to specialize and achieve neoteny of the human brain.
Topics: Animals; Humans; Retroelements; RNA, Long Noncoding; Minisatellite Repeats; Short Interspersed Nucleotide Elements; Primates; Chromatin Assembly Factor-1; NAV1.6 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Cell Cycle Proteins
PubMed: 36997626
DOI: 10.1038/s42003-023-04683-8 -
PloS One 2023Enterohemorrhagic Escherichia coli O157 (O157) strains can be subdivided into clades based on their single-nucleotide polymorphisms, but such analysis using conventional...
Another advantage of multi-locus variable-number tandem repeat analysis that can putatively subdivide enterohemorrhagic Escherichia coli O157 strains into clades by maximum a posteriori estimation.
Enterohemorrhagic Escherichia coli O157 (O157) strains can be subdivided into clades based on their single-nucleotide polymorphisms, but such analysis using conventional methods requires intense effort by laboratories. Although multi-locus variable-number tandem repeat analysis (MLVA), which can be performed with low laboratory burden, has been used as a molecular epidemiological tool, it has not been evaluated whether MLVA can be used the clade subdivision of O157 strains like it can for that of other pathogenic bacteria. This study aimed to establish a method for subdividing O157 strains into clades using MLVA data. The standardized index of association, ISA, for O157 strains isolated in Chiba prefecture, Japan (Chiba isolates) revealed the presence of unique tandem repeat patterns in each major clade (clades 2, 3, 7, 8, and 12). A likelihood database of tandem repeats for these clades was then constructed using the Chiba isolates, and a formula for maximum a posteriori (MAP) estimation was constructed. The ratio of the number of O157 strains putatively subdivided into a clade by MAP estimation from MLVA data relative to the number of O157 strains subdivided using single-nucleotide polymorphism analysis (designated as the concordance ratio [CR]) was calculated using the Chiba isolates and O157 strains isolated in Yamagata prefecture (Yamagata isolates). The CRs for the major Chiba and Yamagata isolate clades, other than clade 2, were 89%-100%. Although the CR for clade 2 Chiba isolates was >95%, that of the Yamagata isolates was only 78.9%. However, these clade 2 CRs were not significantly different from one another, indicating that clade 2 strains can be subdivided correctly by MAP estimation. In conclusion, this study expands the utility of MLVA, previously applied predominantly for molecular epidemiological analysis, into a low-laboratory-burden tool for subdividing O157 strains into phylogenetic groups.
Topics: Humans; Escherichia coli O157; Enterohemorrhagic Escherichia coli; Phylogeny; Escherichia coli Infections; Minisatellite Repeats; Tandem Repeat Sequences
PubMed: 36996016
DOI: 10.1371/journal.pone.0283684 -
Asian Pacific Journal of Cancer... Mar 2023Breast cancer recurrence and metastasis are associated with alterations in the cellular stress responses that influence tumour signalling. Sirtuin3 (SIRT3), a...
BACKGROUND
Breast cancer recurrence and metastasis are associated with alterations in the cellular stress responses that influence tumour signalling. Sirtuin3 (SIRT3), a mitochondrial deacetylase is the regulator of mitochondrial metabolism and oxidative stress affecting tumour cell responses. Genetic variants or dysregulation of SIRT3 was known to associate with poor prognosis of recurrence and relapse in few cancers.
METHODS
The current case-control study was conducted in Hyderabad, India. A total of 200 primary female breast cancer cases were recruited, irrespective of age and clinical subtype. However, secondary or recurrent breast cancer cases were excluded from the study. A total of 202 age and gender-matched healthy controls without any familial inheritance of either breast or other cancer and having similar ethnicity as cases were recruited. The blood samples of both cases and controls were collected from Nizam's Institute of Medical Sciences (NIMS), Hyderabad. Our study is an attempt to evaluate the association of SIRT3 VNTR polymorphism in intron 5 with the development and progression of breast cancer by PCR-based genotyping. Result: The statistical analysis of the results with respect to epidemiological and clinical phenotypes revealed significant association of 0R allele and 0R/0R genotype with breast cancer risk (p<0.01). The odds ratios also were found to be significant i.e., 0R/0R [OR(CI): 2.67(1.54-4.65); p=0.000005] genotype. Also, the epidemiological and clinical variables have shown significant association with the risk of onset of the disease. Therefore, the influence of lack of repeats at intron 5 harbouring enhancer site on altered expression of SIRT3 might confer increased susceptibility to breast cancer.
CONCLUSION
The VNTR polymorphism in the intron 5 region of SIRT3 gene could serve as a molecular marker for detection of breast cancer onset. Further studies are warranted to study the prognostic and therapeutic significance of this SIRT3 polymorphism.
Topics: Female; Humans; Breast Neoplasms; Case-Control Studies; Genetic Predisposition to Disease; Genotype; Introns; Minisatellite Repeats; Neoplasm Recurrence, Local; Polymorphism, Genetic; Sirtuin 3
PubMed: 36974538
DOI: 10.31557/APJCP.2023.24.3.859 -
BMC Infectious Diseases Mar 2023Mycobacterium tuberculosis genotyping has been crucial to determining the distribution and impact of different families on disease clinical presentation. The aim of the...
BACKGROUND
Mycobacterium tuberculosis genotyping has been crucial to determining the distribution and impact of different families on disease clinical presentation. The aim of the study was to evaluate the associations among sociodemographic and clinical characteristics and M. tuberculosis lineages from patients with pulmonary tuberculosis in Orizaba, Veracruz, Mexico.
METHODS
We analyzed data from 755 patients whose isolates were typified by 24-loci mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTR). The associations among patient characteristics and sublineages found were evaluated using logistic regression analysis.
RESULTS
Among M. tuberculosis isolates, 730/755 (96.6%) were assigned to eight sublineages of lineage 4 (Euro-American). Alcohol consumption (adjusted odds ratio [aOR] 1.528, 95% confidence interval (CI) 1.041-2.243; p = 0.030), diabetes mellitus type 2 (aOR 1.625, 95% CI 1.130-2.337; p = 0.009), sputum smear positivity grade (3+) (aOR 2.198, 95% CI 1.524-3.168; p < 0.001) and LAM sublineage isolates (aOR 1.023, 95% CI 1.023-2.333; p = 0.039) were associated with the presence of cavitations. Resistance to at least one drug (aOR 25.763, 95% CI 7.096-93.543; p < 0.001) and having isolates other than Haarlem and LAM sublineages (aOR 6.740, 95% CI 1.704-26.661; p = 0.007) were associated with treatment failure. In a second model, multidrug resistance was associated with treatment failure (aOR 31.497, 95% CI 5.119-193.815; p < 0.001). Having more than 6 years of formal education was not associated with treatment failure.
CONCLUSIONS
Knowing M. tuberculosis genetic diversity plays an essential role in disease development and outcomes, and could have important implications for guiding treatment and improving tuberculosis control.
Topics: Humans; Mycobacterium tuberculosis; Tuberculosis, Pulmonary; Tuberculosis; Minisatellite Repeats; Phylogeny; Genotype
PubMed: 36918814
DOI: 10.1186/s12879-023-08055-9 -
Genes Feb 2023(1) Background/aims: To examine potential genetic modifiers of disease penetrance in -associated retinitis pigmentosa 11 (RP11). (2) Methods: Blood samples from...
(1) Background/aims: To examine potential genetic modifiers of disease penetrance in -associated retinitis pigmentosa 11 (RP11). (2) Methods: Blood samples from individuals (n = 37) with variants believed to be disease-causing were used for molecular genetic testing and, in some cases (n = 23), also for mRNA expression analyses. Medical charts were used to establish if individuals were symptomatic (RP) or asymptomatic non-penetrant carriers (NPC). RNA expression levels of and were measured on peripheral whole blood using quantitative real-time PCR normalized to . Copy number variation of minisatellite repeat element 1 (MSR1) was performed with DNA fragment analysis. (3) Results: mRNA expression analyses on 22 individuals (17 with RP and 5 non-penetrant carriers) revealed no statistically significant differences in or mRNA expression levels between individuals with RP and non-penetrant carriers. Among 37 individuals, we found that all three carriers of a 4-copy MSR1 sequence on their wild-type (WT) allele were non-penetrant carriers. However, copy number variation of MSR1 is not the sole determinant factor of non-penetrance, as not all non-penetrant carriers carried a 4-copy WT allele. A 4-copy MSR1 mutant allele was not associated with non-penetrance. (4) Conclusions: In this Danish cohort, a 4-copy MSR1 WT allele was associated with non-penetrance of retinitis pigmentosa caused by variants. The level of mRNA expression in peripheral whole blood was not a useful indicator of disease status.
Topics: Humans; DNA Copy Number Variations; Transcription Factors; Retinitis Pigmentosa; RNA, Messenger; Denmark; RNA; Eye Proteins
PubMed: 36833363
DOI: 10.3390/genes14020435 -
Life Science Alliance Apr 2023The dopamine transporter gene, , has received substantial attention in genetic association studies of various phenotypes. Although some variable number tandem repeats...
The dopamine transporter gene, , has received substantial attention in genetic association studies of various phenotypes. Although some variable number tandem repeats (VNTRs) present in have been tested in genetic association studies, results have not been consistent. VNTRs in that have not been examined genetically were characterized. The Tandem Repeat Annotation Library was used to characterize the VNTRs of 64 unrelated long-read haplotype-phased sequences. Sequence similarity of each repeat unit of the five VNTRs is reported, along with the correlations of SNP-SNP, SNP-VNTR, and VNTR-VNTR alleles across the gene. One of these VNTRs is a novel hyper-VNTR (hyVNTR) in intron 8 of , which contains a range of 3.4-133.4 repeat copies and has a consensus sequence length of 38 bp, with 82% G+C content. The 38-base repeat was predicted to form G-quadruplexes in silico and was confirmed by circular dichroism spectroscopy. In addition, this hyVNTR contains multiple putative binding sites for PRDM9, which, in combination with low levels of linkage disequilibrium around the hyVNTR, suggests it might be a recombination hotspot.
Topics: Alleles; Dopamine Plasma Membrane Transport Proteins; Haplotypes; Introns; Minisatellite Repeats; Humans
PubMed: 36754567
DOI: 10.26508/lsa.202201677