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PubMed2001

Genotype-phenotype correlation in gemistocytic astrocytomas.

OBJECTIVE: Gemistocytic astrocytomas often behave aggressively and carry the least favorable prognosis among diffuse astrocytomas. The frequency of p53 mutations has been reported to be significantly higher in the gemistocytic variant as compared with other astrocytomas. METHODS: Between 1985 and 1998, we selected 25 tumor samples from among 201 samples from patients with gemistocytic astrocytomas operated on at the Mayo Clinic. Exons 5 to 8 of the p53 gene were sequenced using an automated deoxyribonucleic acid sequencer. Morphometric characterization of individual gemistocytes was performed using an image analysis program. RESULTS: Of 25 tissue samples analyzed, 16 were found to carry a p53 missense mutation (three in exon 5, three in exon 6, one in exon 7, and nine in exon 8), and one sequence variant was synonymous. Mutations were clustered at codons 151 (2 of 17 mutations), 193 (3 of 17 mutations), and 273 (5 of 17 mutations) of the p53 gene. Patients whose tumors carried a p53 mutation were significantly younger than other patients, and their tumors tended to accumulate more p53 protein than those of other patients. Phenotype analysis of gemistocytes revealed that the sizes of tumor cell nuclei and of entire tumor cells in the same tissue area were positively correlated. Smaller tumor cell nuclei tended to be less circular or more atypical. In addition, more atypical gemistocytes were found in tumors lacking a wild-type p53 allele as well as in tissue from patients whose postoperative survival was shorter. CONCLUSION: Our data confirm that the frequency of p53 mutations is significantly higher (approximately twofold) in gemistocytic astrocytomas as compared with other astrocytoma subtypes. Whether the high frequency of p53 mutations contributes to the more aggressive behavior of gemistocytic astrocytomas, however, remains unclear.

Adult↗
PubMed2005

Polymerase chain reaction-single strand conformational polymorphism analysis of rearranged during transfection proto-oncogene in Chinese familial Hirschsprung's disease.

AIM: To investigate the relationship between mutations of rearranged during transfection (RET) proto-oncogene and Chinese patients with Hirschsprung's disease (HD), and to elucidate the genetic mechanism of familial HD patient at the molecular level. METHODS: Genomic DNA was extracted from venous blood of probands and their relatives in two genealogies. Polymerase chain reaction (PCR) products, which were amplified using specific primers (RET, exons 11, 13, 15 and 17), were electrophoresed to analyze the single-strand conformational polymorphism (SSCP) patterns. The positive amplified products were sequenced. Forty-eight sporadic HD patients and 30 normal children were screened for mutations of RET proto-oncogene simultaneously. RESULTS: Three cases with HD in one family were found to have a G heterozygous insertion at nucleotide 18,974 in exon 13 of RET cDNA (18,974insG), which resulted in a frameshift mutation. In another family, a heterozygosity for T to G transition at nucleotide 18,888 in the same exon which resulted in a synonymous mutation of Leu at codon 745 was detected in the proband and his father. Eight RET mutations were confirmed in 48 sporadic HD patients. CONCLUSION: Mutations of RET proto-oncogene may play an important role in the pathogenesis of Chinese patients with HD. Detection of mutated RET proto-oncogene carriers may be used for genetic counseling of potential risk for HD in the affected families.

Base Sequence↗
PubMed2026

Epistasis and the changing fitness landscapes of SARS-CoV-2.

Since its emergence in late 2019, millions of SARS-CoV-2 genomes have been generated as part of global efforts to monitor the evolution and spread of the virus. This unprecedented volume of data provides a unique opportunity to study viral evolution at unparalleled resolution. In particular, individual genomic sites can be observed to have mutated independently thousands of times. These mutation counts have been used to estimate site-specific mutation rates and fitness effects for most mutations across the viral genome. Here, we use these data to investigate how the landscape of mutational fitness costs has changed over the course of the pandemic. SARS-CoV-2 evolution over the past 6 years has been characterized by the emergence of distinct variants separated by long branches corresponding to evolutionary saltations involving up to 50 mutations. We compare inferred fitness landscapes of the Spike protein across these variants and find that shifts in the estimated effects of non-synonymous mutations are linked to genetic differences between them. Sites with altered fitness costs are enriched near positions where the genetic backgrounds differ. To explain the observed changes, we introduce a model with pairwise epistatic interactions between mutations and residues that differ between variants. This model is able to explain about half of the variance in the shifts of fitness effects and suggests that each mismatch between variants substantially alters mutation effects at typically 1 to 3 additional positions.

SARS-CoV-2↗
PubMed2004

[Analysis on FUT1 and FUT2 gene of 10 para-Bombay individuals in China].

OBJECTIVE: This is a study on the allele composing of ABO, FUT1 and FUT2 gene loci of 10 para-Bombay individuals in China. METHODS: Ten samples coming from different districts of China were suspected of para-Bombay phenotype by primary serology tests. Routine and absorb-elution tests were conducted to identify their ABO type, and duplex polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied to getting their ABO genotype. Most of them were submitted to a test of their Lewis type as well. Then through direct DNA sequencing with PCR products of FUT1 and FUT2 genes, the genotypes of their H and SE gene loci were analyzed. RESULTS: It can be confirmed that the 10 samples are para-Bombay. All of their ABO genotypes are consistent with the serological absorb-elution results and the substances detected results in saliva. Seven out of 10 have recessive homozygous gene at their H locus. Each phenotype of h1h1 (nt547-552Deltaag), h2h2 (nt880-882Deltatt) and h4h4 (nt35 t-->c) are ascertained in 2 individuals; moreover, h3h3 (nt 658 c-->t) is identified in one individual. The rest are hh heterozygous individuals: one is h3/h(new-1); the other is h2/h(new-2); the last one is h1/h2. The h(new-1) (nt586 c-->t) allele has a point mutation at nt 586 C to T, which leads a nonsense mutation Gln(CAG) to stop (TAG).The second h (new-2) (nt328 g-->a) has an nt328 G to A missense mutation,which leads Ala (GCC),was replaced by Thr (ACC) at 110 amino acid position. All the 10 samples have Se (nt357 c-->t) synonymous mutation. One Bm(h) (B/O) individual with h4h4 phenotype has a Se(w)(nt357 c-->t; nt385 a-->t) allele, whose Lewis type is Le(a+b+). Moreover, the authors detected a (nt716 g-->a) mutation in two samples' Se gene. CONCLUSION: Four kinds of known h alleles (h1-h4), 2 kinds of novel non-functional FUT1 alleles, a Se(w) allele, and a novel SeG716A polymorphism in Chinese para-Bombay individuals were detected. At the same time, the authors noticed that all the 10 samples have the nt357 c-->t mutation in their FUT2 gene.

ABO Blood-Group System↗
PubMed1998

Brain-derived HIV-1 tat sequences from AIDS patients with dementia show increased molecular heterogeneity.

HIV-1 infection results in a dementing illness affecting 20% of patients with AIDS. Several HIV-1 genes have been implicated in the pathogenesis of HIV-induced neurological disease. To search for distinct HIV-1 sequences associated with the development of dementia, brain-derived tat, env, and pol sequences were examined from AIDS patients defined pre-mortem as demented (HIV-D)[n=5] or non-demented (HIV-ND)[n=5]. Estimations of evolutionary distances and frequency of non-synonymous mutation rates revealed significant differences between brain-derived tat, env, and pol-encoded reverse transcriptase sequences. However, established zidovudine-associated resistance mutations in reverse transcriptase sequences were identified in only one HIV-D and one HIV-ND patient despite prolonged treatment of some patients. Non-synonymous/synonymous substitution rates among the tat sequences derived from patients with HIV-D were significantly higher compared to the HIV-ND group (P < 0.001). The ratios of transversions to transitions were also significantly higher among the HIV-D tat sequences (P< 0.01). Phylogenetic analyses showed clustering of sequences from each clinical group among the brain-derived tat and env sequences. These studies indicated that differing selective forces act on individual HIV-1 genes in the brain which may influence the development of dementia.

AIDS Dementia Complex↗
PubMed1992

A germ line mutation within the coding sequence for the putative 5-phosphoribosyl-1-pyrophosphate binding site of hypoxanthine-guanine phosphoribosyltransferase (HPRT) in a Lesch-Nyhan patient: missense mutations within a functionally important region probably cause disease.

Lesch-Nyhan syndrome caused by a complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT) is the result of a heterogeneous group of germ line mutations. Identification of each mutant gene provides valuable information as to the type of mutation that occurs spontaneously. We report here a newly identified HPRT mutation in a Japanese patient with Lesch-Nyhan syndrome. This gene, designated HPRT Tokyo, had a single nucleotide change from G to A, as identified by sequencing cDNA amplified by the polymerase chain reaction. Allele specific oligonucleotide hybridization analysis using amplified genomic DNA showed that the mutant gene was transmitted from the maternal germ line. This mutation would lead to an amino acid substitution of Asp for Gly at the amino acid position 140 located within the putative 5-phosphoribosyl-1-pyrophosphate (PRPP) binding region. Missense mutations in human HPRT deficient patients thus far reported tend to accumulate in this functionally active region. However, a comparison of the data suggested that both missense and synonymous mutations can occur at any coding sequence of the human germ line HPRT gene, but that a limited percentage of all the missense mutations cause disease. The probability that a mutation will cause disease tends to be higher when the missense mutation is within a functionally important sequence.

Amino Acid Sequence↗
PubMed2004

The human serotonin receptor 2B: coding region polymorphisms and association with vulnerability to illegal drug abuse.

OBJECTIVE AND METHODS: 5-Hydroxytryptamine (serotonin) receptor 2B (HTR2B) is involved in brain development. Although expressed in the human brain, HTR2B has not been investigated much for its role in higher brain functions. Here we describe a genome-scan with 391 simple sequence repeat markers in 300 Caucasians, identifying HTR2B gene as a candidate for drug abuse vulnerability. RESULTS: From DNA re-sequencing of 110 subjects, we discovered three novel single nucleotide polymorphisms (SNPs), two of which confer a double-mutant of the receptor protein in a drug-abusing population. Arg6, a conserved basic residue, and the conserved acidic Glu42 are mutated simultaneously into Gly, termed R6G/E42G. Furthermore, this double-mutant tends to associate with drug abuse (P = 0.08 by chi2 test). The third SNP that is a synonymous mutation in the codon of Gln11 showed significant association with drug abuse (P = 0.0335 by Fisher's exact test). CONCLUSION: Our data are the first suggesting that HTR2B contributes to brain architecture and pathways that are involved in illegal drug reward.

Adult↗
PubMed2005

Spread of vaccine-derived poliovirus from a paralytic case in an immunodeficient child: an insight into the natural evolution of oral polio vaccine.

Sabin strains used in the manufacture of oral polio vaccine (OPV) replicate in the human organism and can give rise to vaccine-derived polioviruses. The increased neurovirulence of vaccine derivatives has been known since the beginning of OPV use, but their ability to establish circulation in communities has been recognized only recently during the latest stages of the polio eradication campaign. This important observation called for studies of their emergence and evolution as well as extensive surveillance to determine the scope of this phenomenon. Here, we present the results of a study of vaccine-derived isolates from an immunocompromised poliomyelitis patient, the contacts, and the local sewage. All isolates were identified as closely related and slightly evolved vaccine derivatives with a recombinant type 2/type 1 genome. The strains also shared several amino acid substitutions including a mutation in the VP1 protein that was previously shown to be associated with the loss of attenuation. Another mutation in the VP3 protein resulted in altered immunological properties of the isolates, possibly facilitating virus spread in immunized populations. The patterns and rates of the accumulation of synonymous mutations in isolates collected from the patient over the extended period of excretion suggest either a substantially nonuniform rate of mutagenesis throughout the genome, or, more likely, the strains may have been intratypic recombinants between coevolving derivatives with different degrees of divergence from the vaccine parent. This study provides insight into the early stages of the establishment of circulation by runaway vaccine strains.

Evolution, Molecular↗
PubMedDate not supplied

[Molecular bases of evolution].

The general notions of the theory of evolution are listed. The unity of the "engineering principles" of the living nature is emphasized. The generalists and specialists species are discussed. The estimation of their evolution rates must be different if it is expressed by the number of species or by the morphological changes. The principles of "protein engineering" of the organisms and the role of metals in protein evolution are discussed. It is suggested that in the presence of ions of transition metals and zinc the Fox's proteinoids can possess more specific forms of enzymatic activity. In the evolution of language the horizontal transfer plays a much more important role than in the biological evolution. However in this case also the initial basis of the language remains. The random drift is considered and it is shown that in concordance with the neutralist theory there are no grounds to replace the calculation of the rates of mutational changes per time unity by the calculation per generation. The molecular drive is the main source of the evolutionary novelties. The drive is connected with drift. The synonymic mutations and the mutations in non-functional DNA are evolutionary important. The future mathematical theory of evolution must be based on the theory of Markov's chains with the stochastic matrix changing along the chain and containing the set of the non-diagonal members equal to zero. The results obtained in the theory of ontogeny are presented. The evolution of species is the evolution of ontogenies, the formation of the molecular theory of evolution can be possible only on the basis of the molecular theory of ontogeny. The internal causes of extinction of species reduce the accumulation of neutral and pseudo-neutral mutations.

Animals↗
PubMed1998

Characterization of the mitochondrial genome in childhood multiple sclerosis. III. Multiple sclerosis without optic neuritis and the non-LHON-associated genes.

The higher maternal transmission of multiple sclerosis in familial cases and the coincidence of a MS-like phenotype with mitochondrial point mutations in patients with Leber's hereditary optic neuropathy has inspired a detailed assessment of the mitochondrial genome as an etiological factor in the pathogenesis of MS. To further elucidate the contribution of maternally transmitted mutations to MS susceptibility, we sequenced five protein- and all RNA-coding genes of the mtDNA from thirteen children with MS and twenty unaffected individuals. After excluding several synonymous mutations and common polymorphisms, a total of ten ambiguous missense or protein synthesis mutations were selected and analysed. By defining minimal criteria for pathogenity--incidence, location and degree of evolutionary conservation--we conclude that sequence variations in COII, ATPase6 and 8, ND3, or ND4L subunits of oxidative phosphorylation as well as in rRNA and tRNA genes are unlikely to increase susceptibility for the development of MS.

Adolescent↗
PubMed2002

Distinguishing between selection and population expansion in an experimental lineage of bacteriophage T7.

Experimental evolution of short-lived organisms offers the opportunity to study the dynamics of polymorphism over time in a controlled environment. Here, we characterize DNA polymorphism data over time for four genes in bacteriophage T7. Our experiment ran for 2500 generations and populations were sampled after 500, 2000, and 2500 generations. We detect positive selection, purifying ("negative") selection, and population expansion in our experiment. We also present a statistical test that is able to distinguish demographic from selective events, processes that are hard to identify individually because both often produce an excess of rare mutations. Our "heterogeneity test" modifies common statistics measuring the frequency spectrum of polymorphism (e.g., Fu and Li's D) by looking for processes producing different patterns on nonsynonymous and synonymous mutations. Test results agree with the known conditions of the experiment, and we are therefore confident that this test offers a tool to evaluate natural populations. Our results suggest that instances of segregating deleterious mutations may be common, but as yet undetected, in nature.

Bacteriophage T7↗
PubMed2004

Three novel missense mutations of WNK4, a kinase mutated in inherited hypertension, in Japanese hypertensives: implication of clinical phenotypes.

BACKGROUND: Mutations in serine-threonine kinase WNK4 with no lysine (K) at a key catalytic residue cause familial hypertension known as pseudohypoaldosteronism type II (PHAII). The objective of this study was to test whether more subtle changes of WNK4 could be implicated in hypertension or renal failure. METHODS: We screened 956 Japanese patients with hypertension or renal failure for mutations in exons 7 and 17 in the WNK4 gene where the mutations were identified in patients with PHAII. RESULTS: We identified three novel missense mutations, Met546Val (n = 2) and Pro556Thr (n = 2) in exon 7, and Pro1173Thr (n = 1) in exon 17, in a heterozygous state in addition to four single nucleotide polymorphisms including one synonymous mutation (Ala547Ala). Results of genotyping Met546Val and Pro556Thr mutations indicated that these mutations were not present in a Japanese general population (n = 1875). CONCLUSIONS: The present study indicated that a systematic screening of WNK4 in a large set of patients with hypertension or renal failure detected some rare genetic variants. Although substantial contribution of three novel missense mutations in exons 7 and 17 of WNK4 to the genetics of hypertension or renal failure is still unclear, these mutations in the WNK4 gene identified in Japanese hypertensives but not in a general population may contribute to hypertension and progression of hypertensive complications to some extent.

Aged↗
PubMed2000

Mutation analysis of the N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) in schizophrenia.

Dysfunction of N-methyl-D-aspartate (NMDA) type ionotropic glutamate receptors has been implicated in the etiology of schizophrenia based on psychotomimetic properties of the antagonist phencyclidine (PCP) and observation that mice expressing low levels of the N-methyl-D-aspartate receptor NR1 subunit exhibit behavioral alterations that may be ameliorated by neuroleptic drugs. Based on the hypothesis that some schizophrenic patients have functionally deficient mutation(s) of the gene encoding N-methyl-D-aspartate receptor NR1 subunit (GRIN1), we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the GRIN1 gene. Four variants, IVS2-22T>C, IVS2-12G>A, IVS4-34C>T, and 1719G/A (Pro516Pro), were identified. No non-synonymous mutation was detected. No significant association was suggested by case-control comparisons. Results indicate that genomic variations of the GRIN1 gene are not likely to be involved substantially in the etiology of schizophrenia.

Adult↗
PubMed2004

Genotype 2a hepatitis C virus subgenomic replicon can replicate in HepG2 and IMY-N9 cells.

A hepatitis C virus genotype 2a subgenomic replicon, JFH-1 replicon, was previously established using the consensus sequence of clone JFH-1 from a patient with fulminant hepatitis and, in a previous report, was indicated to replicate efficiently in Huh7. Here the replication of JFH-1 replicon was tested in HepG2, a human hepatocyte-derived cell line, and in IMY-N9, a cell line developed by fusing human hepatocytes and HepG2 cells. Following transfection with in vitro transcribed replicon RNA and selection by cultivation with G418, colonies formed in both cell lines although at efficiencies substantially lower than those of Huh7. The H2476L mutation identified in the Huh7 replicon in our previous study increased the colony formation efficiencies of the JFH-1 replicon in HepG2 and IMY-N9 cells. Higher amounts of replicon RNA were detected in IMY-N9 clones than in HepG2 clones by real time detection reverse transcription-PCR, and replicon RNA replication and viral protein expression were confirmed by Northern and Western blotting in isolated clones. Sequencing of replicon RNAs revealed that mutations found in hepatitis C virus-derived regions were not identical and that two of nine HepG2 clones and three of nine IMY-N9 clones had no or one synonymous mutation. This system with the JFH-1 replicon and three cell lines is useful not only for estimating the cellular factors affecting viral activity but also for clarifying the common gene response of the host.

Blotting, Northern↗
PubMed1997

Sequence variations and viral genomic state of human papillomavirus type 16 in penile carcinomas from Ugandan patients.

Sequence variations in the E6/E7 (nt 34-880) and the L1-(nt 6584-7035) ORFs, and in the long control region (LCR) (nt 7289-93) of human papillomavirus type 16 (HPV-16) were analysed in five penile carcinoma biopsies obtained from Ugandan patients. Uganda is a country with a high incidence of genital cancers. All five isolates were classified as members of African-1 lineage (Af1) by phylogenetic analysis based on LCR sequences. The E6 gene phylogenetic analysis, however, showed that four isolates fell into a new subclass designated Af1-u. This subclass, characterized by three point mutations located at the 5' end of the E6 gene with resulting changes in amino acids at positions 10 and 14, is distinguishable from the Af1 class by the absence of synonymous mutations at nt 286 and 289. The nonsynonymous substitution at nt 335 was present in three out of five samples. The E6 Af1 mutation pattern was present in only a single Ugandan HPV-16 isolate. Nucleotide sequence analysis of the E7 and L1 regions did not allow any Af1 subclass identification. The physical state of the viral DNA in these samples was characterized by PCR and Southern blot analysis. Oligonucleotides which enable amplification of the full length E2 region (nt 2734-3872) failed to amplify the target sequence in four out of five samples, suggesting disruption of the E2 ORF and integration of the HPV genome into the human DNA. Southern blot analysis confirmed the virus integration status. Our results contribute to the characterization of the HPV-16 'African lineages' with the identification of the Af1-u subclass; furthermore, this is also the first report showing that in male genital cancers HPV-16 is integrated into the human genome with disruption of the E2 ORF.

Carcinoma, Squamous Cell↗
PubMed2006

Analyses on mutation patterns, detection of population bottlenecks, and suggestion of deleterious-compensatory evolution among members of the genus Potyvirus.

Viruses of the family Potyviridae exhibited a robust single-nucleotide polymorphism profile at the between-species level, conforming to the neutral theory rule. However, the ratios of nonsynonymous to synonymous mutations (Ka/Ks) were relatively greater between-species than within-species in viral cistrons examined from members of the genus Potyvirus, indicating a relaxation on constraint. Judged by the McDonald and Kreitman's test, the fixation frequencies for nonsynonymous mutations across the genomes of closely related potyviruses were greater than expected, suggesting population bottlenecks at speciation. These mutation patterns are best explained by a deleterious-compensatory model.

Animals↗
PubMed2003

Failure to find causal mutations in the GABA(A)-receptor gamma2 subunit (GABRG2) gene in Japanese febrile seizure patients.

Recently, mutations in the GABA(A)-receptor gamma2 subunit (GABRG2) gene were identified in two families with generalized epilepsy with febrile seizures plus (GEFS+) and two families with childhood absence epilepsy (CAE) and febrile seizures (FS). We tested the hypothesis that genetic variations in the GABRG2 gene confer susceptibility to FS in the Japanese population. We performed a systematic search for mutations in 94 unrelated Japanese patients with FS and detected six variants (-158C>T, 315C>T, 588T>C, IVS5-55C>T, IVS7+20G>A, and IVS7-141T>A). No non-synonymous mutation was detected. We genotyped three exonic polymorphisms and performed a case control study and a transmission disequilibrium test using 55 independent complete trios with FS and 106 control subjects. None of these polymorphic alleles were significantly associated with FS. Our results indicate that genomic variations of GABRG2 are not likely to be substantially involved in the etiology of FS in the Japanese population.

Alleles↗
PubMed2006

Preliminary assessment of the impact of microRNA-mediated regulation on coding sequence evolution in mammals.

Despite prior claims to the contrary, several lines of evidence suggest that selection acts on synonymous mutations in mammals. What might be the mechanisms for such selection? Here I attempt to quantify the constraints on the evolution of the coding sequence resulting from regulation of mRNA by microRNAs (miRNAs) that antisense-bind to the coding region of mRNAs. I employ a set of genes recently experimentally verified to be the target of a miRNA, all with putative antisense pairing domains within the coding sequence. Although very small ( approximately 22 nucleotides), 2 of 13 pairing domains show evidence of significantly slow sequence evolution. This, along with evidence that these genes are regulated by the miRNA under consideration, provides the first good candidate domains for intra-CDS pairing of a miRNA in mammals. When analyzed en masse, the putative pairing domains have a significantly reduced rate of synonymous evolution (approximately 35% lower than null). However, given the size and rarity of pairing domains within the coding sequence, the effects that such constraint has on estimates of the mutation rate are small enough to be ignored (probably less than 1% reduction). The pairing sites also have low Ka values and the selection on the synonymous sites is unlikely to lead to misleading reports of localized high Ka/Ks ratios.

3' Untranslated Regions↗