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IUBMB Life Jan 2000From a population standpoint, two main features characterize the replication of RNA viruses and viruses that use RNA as a replicative intermediate: high genetic... (Review)
Review
From a population standpoint, two main features characterize the replication of RNA viruses and viruses that use RNA as a replicative intermediate: high genetic variability, and enormous fluctuations in population size. Their genetic variability mainly reflects a lack of the proof-reading and post-replicative error correction mechanisms that operate during cellular DNA replication, but recombination and segment exchange can also play an important role. Viral population size can change tremendously as a consequence of transmission between hosts or between different tissues within an infected host. A new infection can be initiated with very few particles that subsequently expand many trillion-fold. Repeated bottleneck events can lead to drastic fitness losses or even to viral extinction, whereas continuously large population sizes result in fitness gains and adaptation. Here we review experimental evidence for the effects of mutation, selection, and genetic drift on the adaptation and extinction of RNA viruses.
Topics: Adaptation, Physiological; Evolution, Molecular; Gene Frequency; Models, Genetic; Mutation; Point Mutation; RNA Viruses; Recombination, Genetic; Selection, Genetic; Virus Replication
PubMed: 10772334
DOI: 10.1080/713803585 -
Briefings in Bioinformatics Mar 2022Predicting the difference in thermodynamic stability between protein variants is crucial for protein design and understanding the genotype-phenotype relationships. So...
Predicting the difference in thermodynamic stability between protein variants is crucial for protein design and understanding the genotype-phenotype relationships. So far, several computational tools have been created to address this task. Nevertheless, most of them have been trained or optimized on the same and 'all' available data, making a fair comparison unfeasible. Here, we introduce a novel dataset, collected and manually cleaned from the latest version of the ThermoMutDB database, consisting of 669 variants not included in the most widely used training datasets. The prediction performance and the ability to satisfy the antisymmetry property by considering both direct and reverse variants were evaluated across 21 different tools. The Pearson correlations of the tested tools were in the ranges of 0.21-0.5 and 0-0.45 for the direct and reverse variants, respectively. When both direct and reverse variants are considered, the antisymmetric methods perform better achieving a Pearson correlation in the range of 0.51-0.62. The tested methods seem relatively insensitive to the physiological conditions, performing well also on the variants measured with more extreme pH and temperature values. A common issue with all the tested methods is the compression of the $\Delta \Delta G$ predictions toward zero. Furthermore, the thermodynamic stability of the most significantly stabilizing variants was found to be more challenging to predict. This study is the most extensive comparisons of prediction methods using an entirely novel set of variants never tested before.
Topics: Mutation; Point Mutation; Protein Stability; Proteins; Thermodynamics
PubMed: 35021190
DOI: 10.1093/bib/bbab555 -
Orphanet Journal of Rare Diseases Sep 2014We report a 6.5 year-old female with a homozygous missense mutation in ZFYVE20, encoding Rabenosyn-5 (Rbsn-5), a highly conserved multi-domain protein implicated in...
BACKGROUND
We report a 6.5 year-old female with a homozygous missense mutation in ZFYVE20, encoding Rabenosyn-5 (Rbsn-5), a highly conserved multi-domain protein implicated in receptor-mediated endocytosis. The clinical presentation includes intractable seizures, developmental delay, microcephaly, dysostosis, osteopenia, craniofacial dysmorphism, macrocytosis and megaloblastoid erythropoiesis. Biochemical findings include transient cobalamin deficiency, severe hypertriglyceridemia upon ketogenic diet, microalbuminuria and partial cathepsin D deficiency.
METHODS AND RESULTS
Whole exome sequencing followed by Sanger sequencing confirmed a rare (frequency:0.003987) homozygous missense mutation, g.15,116,371 G > A (c.1273G > A), in ZFYVE20 resulting in an amino acid change from Glycine to Arginine at position 425 of the Rbsn protein (p.Gly425Arg), as the only mutation segregating with disease in the family. Studies in fibroblasts revealed expression and localization of Rbsn-5G425R in wild-type manner, but a 50% decrease in transferrin accumulation, which is corrected by wild-type allele transfection. Furthermore, the patient's fibroblasts displayed an impaired proliferation rate, cytoskeletal and lysosomal abnormalities.
CONCLUSION
These results are consistent with a functional defect in the early endocytic pathway resulting from mutation in Rbsn-5, which secondarily disrupts multiple cellular functions dependent on endocytosis, leading to a severe multi-organ disorder.
Topics: Child; Endocytosis; Female; Humans; Point Mutation; Protein Transport; Seizures; Vesicular Transport Proteins
PubMed: 25233840
DOI: 10.1186/s13023-014-0141-5 -
Genes Dec 2023Missense variation in genomes can affect protein structure stability and, in turn, the cell physiology behavior. Predicting the impact of those variations is relevant,...
Missense variation in genomes can affect protein structure stability and, in turn, the cell physiology behavior. Predicting the impact of those variations is relevant, and the best-performing computational tools exploit the protein structure information. However, most of the current protein sequence variants are unresolved, and comparative or ab initio tools can provide a structure. Here, we evaluate the impact of model structures, compared to experimental structures, on the predictors of protein stability changes upon single-point mutations, where no significant changes are expected between the original and the mutated structures. We show that there are substantial differences among the computational tools. Methods that rely on coarse-grained representation are less sensitive to the underlying protein structures. In contrast, tools that exploit more detailed molecular representations are sensible to structures generated from comparative modeling, even on single-residue substitutions.
Topics: Point Mutation; Computational Biology; Proteins; Protein Stability; Amino Acid Sequence
PubMed: 38137050
DOI: 10.3390/genes14122228 -
Blood Jun 2020
Topics: Hematologic Neoplasms; Humans; Leukemia; Point Mutation
PubMed: 32526020
DOI: 10.1182/blood.2020005296 -
Eastern Mediterranean Health Journal =... Nov 1999It has been 20 years since DNA analysis was first used in the detection of sickle-cell anaemia. Here, techniques for detecting human mutations are reviewed. We describe... (Review)
Review
It has been 20 years since DNA analysis was first used in the detection of sickle-cell anaemia. Here, techniques for detecting human mutations are reviewed. We describe direct detection of mutations using restriction enzyme analysis and polymerase chain reaction amplification to detect gene deletions, rearrangements and point mutations. Indirect detection of mutations include the use of DNA polymorphisms in linkage analysis.
Topics: Chromosome Mapping; DNA Mutational Analysis; Gene Deletion; Gene Rearrangement; Point Mutation; Polymerase Chain Reaction; Polymorphism, Genetic; Restriction Mapping
PubMed: 11924102
DOI: No ID Found -
Epileptic Disorders : International... Sep 2003Classification is a creative activity that helps us understand relationships. The traditional classifications of central nervous system malformations was based... (Review)
Review
Classification is a creative activity that helps us understand relationships. The traditional classifications of central nervous system malformations was based exclusively upon descriptive morphology, but these criteria must now be integrated with molecular genetic data to enable an etiological classification that also remains useful to the clinician, radiologist and pathologist, who rely upon imaging and tissue examination for diagnosis. Many cerebral malformations previously thought to be a single disorder are now known to be common end-results of several independent genetic mutations. Examples are holoprosencephaly and lissencephaly. Gradients of genetic expression along the axes of the neural tube, established at the time of gastrulation, may explain many varieties or anatomical and clinical manifestations of cerebral malformations, including the involvement of non-neural tissues such as in midfacial hypoplasia, that may be attributed to abnormal neural crest migration. Genes of cellular lineage and of symmetry may explain some hamartomatous malformations, such as tuberous sclerosis and hemimegalencephaly. Modern classification should be applicable to the entire CNS as well as regions; schemes that attempt to artificially isolate the cerebral cortex for a "regional classification" may be erroneous even though the genetic defect primarily affects cortical structures because genetic gradients in the neuraxis are excluded and some involve a more subtle but still important expression in subcortical structures.
Topics: Brain Diseases; Central Nervous System; Gene Expression; Humans; Point Mutation
PubMed: 14617419
DOI: No ID Found -
Molecular Genetics & Genomic Medicine Dec 2019Pathogenic variants of ANKRD11 have been reported to cause KBG syndrome characterized by short stature, characteristic facial appearance, intellectual disability,...
BACKGROUND
Pathogenic variants of ANKRD11 have been reported to cause KBG syndrome characterized by short stature, characteristic facial appearance, intellectual disability, macrodontia, and skeletal anomalies. However, the direct clinical relevance of ANKRD11 mutation with short stature is yet unknown.
METHODS
Here, we report a Chinese boy with idiopathic short stature (ISS) based on clinical and genetic characteristics. Comprehensive medical evaluations were performed including metabolic studies, endocrine function tests, bone X-rays, and echocardiography. Whole-exome and Sanger sequencing was used to detect and confirm genetic mutations associated with short stature in this patient, respectively. The pathogenicity of the variant was further predicted by several in silico prediction tools and repositories of sequence variation. Twenty-four months follow-up was performed to observe the growth rate of the patient treated with recombinant human growth hormone (GH).
RESULTS
One heterozygous point mutation (c.2579C>T) was confirmed in the ANKRD11 gene of the patient and inherited from his mother. This mutation site was located within the highly conservative region of ANKRD11 protein and predicted to be possibly damaging in several in silico prediction programs and repositories of sequence variation. Additionally, patient underwent GH replacement therapy for 24 months exhibited good response to the treatment.
CONCLUSION
A heterozygous point mutation of AKNRD11 gene was identified in a Chinese patient with short stature phenotype. The patient was treated effectively with GH supplementation.
Topics: Adult; Asian People; Child; China; Dwarfism; Family; Female; Genetic Association Studies; Heterozygote; High-Throughput Nucleotide Sequencing; Humans; Male; Pedigree; Phenotype; Point Mutation; Polymorphism, Single Nucleotide; Receptors, Glutamate; Repressor Proteins
PubMed: 31566922
DOI: 10.1002/mgg3.988 -
Trends in Biotechnology Nov 1997Advances in capillary electrophoresis technology over the past three years have been rapid. Capillary electrophoresis offers high-throughput, high-resolution, automatic... (Review)
Review
Advances in capillary electrophoresis technology over the past three years have been rapid. Capillary electrophoresis offers high-throughput, high-resolution, automatic operation and on-line detection with automatic data acquisition, and this has stimulated its application to the analysis of DNA mutations. Many different PCR-based DNA-mutation assays have been developed for unknown and known mutations. This article compares conventional PCR-based mutation-detection assays with the methods developed for use with capillary electrophoresis. Future trends for mutation detection using capillary electrophoresis are also assessed, with a special emphasis on totally integrated, microchip capillary-electrophoresis-based mutation-detection systems.
Topics: DNA; Electrophoresis, Capillary; Point Mutation; Polymerase Chain Reaction; Polymorphism, Genetic
PubMed: 9369028
DOI: 10.1016/S0167-7799(97)01117-7 -
The Psychiatric Clinics of North America Mar 2010Autism spectrum disorders (ASDs) are highly heritable. Gene discovery promises to help illuminate the pathophysiology of these syndromes, yielding opportunities for the... (Review)
Review
Autism spectrum disorders (ASDs) are highly heritable. Gene discovery promises to help illuminate the pathophysiology of these syndromes, yielding opportunities for the development of novel treatments and understanding of their natural history. Although the underlying genetic architecture of ASDs is not yet known, the literature demonstrates that it is not a monogenic disorder with mendelian inheritance, rather a group of complex genetic syndromes with risk deriving from genetic variations in multiple genes. This article reviews the origins of the common versus rare variant debate, highlights recent findings in the field, and addresses the clinical implications of common and rare variant discoveries.
Topics: Abnormalities, Multiple; Alleles; Autistic Disorder; Gene Expression; Genetic Association Studies; Genetic Variation; Humans; Karyotyping; Point Mutation; Social Behavior
PubMed: 20159341
DOI: 10.1016/j.psc.2009.12.002