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At least 19 recordsLinked to original sources
PubMed1976

Empirical relationship between the number of nucleotide substitutions and interspecific identity of amino acid sequences in some proteins.

There are three different methods of estimating the number of nucleotide substitutions between a pair of species from amino acid sequence data, i.e. the Poisson correction method, random evolutionary hit method, and counting the actual but minimum number of nucleotide substitutions. In this paper the relationships among the estimates obtained by these methods are studied empirically. The results obtained indicate that there is a high correlation among these estimates and in practice any of the three methods may be used for constructing evolutionary trees or relating nucleotide substitutions to evolutionary time. The effects of varying rates of nucleotide substition among different sites on the Poisson correction and random evolutionary hit methods are also studied mathematically. It is shown that these two methods are quite insensitive to the variation of the rate of nucleotide substitution.

Amino Acid Sequence↗
PubMed2025

Viral genome sequence datasets display pervasive evidence of strand-specific substitution biases that are best described using non-reversible nucleotide substitution models.

Most phylogenetic trees are inferred using time-reversible evolutionary models that assume that the relative rates of substitution for any given pair of nucleotides are the same regardless of the direction of the substitutions. However, there is no reason to assume that the underlying biochemical mutational processes that cause substitutions are similarly symmetrical. We consider two non-reversible nucleotide substitution models: (1) a 6-rate non-reversible model (NREV6) that is applicable to analyzing mutational processes in double-stranded genomes in that complementary substitutions occur at identical rates; and (2) a 12-rate non-reversible model (NREV12) that is applicable to analyzing mutational processes in single-stranded (ss) genomes in that all substitution types are free to occur at different rates. Using likelihood ratio and Akaike Information Criterion-based model tests, we show that, surprisingly, NREV12 provided a significantly better fit than the General Time Reversible (GTR) and NREV6 models to 21/31 dsRNA and 20/30 dsDNA datasets. As expected, however, NREV12 provided a significantly better fit to 24/33 ssDNA and 40/47 ssRNA datasets. We tested how non-reversibility impacts the accuracy with which phylogenetic trees are inferred. As simulated degrees of non-reversibility (DNR) increased, the tree topology inferences using both NREV12 and GTR became more accurate, whereas inferred tree branch lengths became less accurate. We conclude that while non-reversible models should be helpful in the analysis of mutational processes in most virus species, there is no pressing need to use these models for routine phylogenetic inference.

Models of evolution↗
PubMed1975

Effect of aza-substituted nucleotides on the starve-refeed response of rats.

Rat liver glucose 6-phosphate dehydrogenase (G6PD) and malic enzyme (ME) activities were increased by starvation-refeeding to levels above those found in rats fed ad libitum. The increases in enzyme activities above ad libitum-fed levels were prevented by 8-azaguanine and 6-azauridine, but not by 2-azauridine. Blood insulin levels were not affected at the time studied. Two aza analogs, 8-azaadenine and 5-azacytidine, proved to be too toxic in this type of studies. Since 8-azahypoxanthine, 8-azaxanthine and 5-azauracil were neither effective in preventing the enzyme overshoot, nor toxic to the animals, it was concluded that the toxiciyty to the animals of 8-azaadenine and 5-azacytidine is due to the compounds themselves rather than to the breakdown products.

Adenine↗
PubMed1979

Nucleotide sequence of the cro-cII-oop region of bacteriophage 434 DNA.

The nucleotide sequence of a 869 bp segment of phage 434 DNA including the regulatory genes cro and cII is presented and compared with the corresponding part of the phage lambda DNA sequence. The 434 cro protein as deduced from the DNA sequence is a highly basic protein of 71 amino acid residues with a calculated molecular weight of 8089. While the cro gene sequences of phage 434 and lambda DNA are very different, the nuleotide sequences to the right of the lambda imm434 boundary show differences only at 11 out of 512 positions. Nucleotide substitutions in the cII gene occur with one exception in the third positions of the respective codons and only one out of several DNA regulatory signals located in this region of the phage genomes is affected by these nucleotide substitutions.

Amino Acid Sequence↗
PubMed2025

Alternative splice acceptor site in MSH4 gene is responsible for male sterility conferred by ms5 in soybean.

In soybean breeding, using the recessive male-sterile ms5 gene, derived from fast neutron mutagenesis, for recurrent selection is advantageous because of the d2 locus, which controls cotyledon color in mature seeds and can be used as a phenotypic selection marker for ms5 male sterility. However, occasional self-fertilization occurs because of the elimination of d2 linkage and instability of male sterility. Elucidating the mechanism and the gene responsible for ms5 male sterility may resolve these problems. Using fine mapping with 15 simple sequence repeat (SSR) markers, we narrowed down the candidate ms5 locus to a 54-kbp region. Bulked-DNA analysis using next-generation sequencing revealed a deletion as a candidate variation in the region. This 15-bp deletion and a nucleotide substitution were identified in intron 1 of MutS homolog (GmMSH4), which modulates chromosomal recombination in meiosis. The ms5 transcript contained a novel exon with a premature termination codon. This exon originated from an alternative splice acceptor site caused by the deletion and nucleotide substitution, disrupting gene function. Co-segregation of male sterility with five independent mutations in GmMSH4 was confirmed using progeny of mutant lines. Mutations in GmMSH4 led to biased DNA partitioning during meiosis, resulting in collapsed or enlarged pollen and suggesting that ms5 male sterility is caused by the failure of pollen formation during meiosis due to the loss of function of GmMSH4. These findings could help explain the mechanism of instability of ms5 male sterility and improve the efficiency of recurrent selection using DNA markers in soybean breeding.

Glycine max↗
PubMed1979

A general approach to proving the minimality of phylogenetic trees illustrated by an example with a set of 23 vertebrates.

We have recently described a method of building phylogenetic trees and have outlined an approach for proving whether a particular tree is optimal for the data used. In this paper we describe in detail the method of establishing lower bounds on the length of a minimal tree by partitioning the data set into subsets. All characters that could be involved in duplications in the data are paired with all other such characters. A matching algorithm is then used to obtain the pairing of characters that reveals the most duplications in the data. This matching may still not account for all nucleotide substitutions on the tree. The structure of the tree is then used to help select subsets of three or more characters until the lower bound found by partitioning is equal to the length of the tree. The tree must then be a minimal tree since no tree can exist with a length less than that of the lower bound. The method is demonstrated using a set of 23 vertebrate cytochrome c sequences with the criterion of minimizing the total number of nucleotide substitutions. There are 131130 7045768798 96033440625 topologically distinct trees that can be constructed from this data set. The method described in this paper does identify 144 minimal tree variants. The method is general in the sense that it can be used for other data and other criteria of length. It need not however always be possible to prove a treee minimal but the method will give an upper and lower bound on the length of minimal trees.

Amino Acid Sequence↗
PubMed2025

Substitutions of nucleotides at the 3' ends of COL6A1/2/3 exons induce exon skipping associated with collagen VI-related muscular dystrophies and therapeutic strategies.

PURPOSE: Collagen VI-related muscular dystrophies, characterized by proximal muscle weakness and joint contractures, are caused by pathogenic variants in the genes, COL6A1 to COL6A3. A monoallelic variant at the last nucleotide of a COL6A1 exon was initially classified as a missense variant but acted as a splicing variant, resulting in exon skipping. Here, we evaluated whether single-nucleotide variants at the 3'-ends of COL6A1 to COL6A3 exons cause aberrant splicing. METHODS: Ten relevant variants were identified in patients from our repository or public databases, and their muscle COL6A1 to COL6A3 transcripts were analyzed. The effects of the variants on splicing were also analyzed by minigene assay and SpliceAI in silico prediction. RESULTS: Transcripts from muscles of individuals with suspected collagen VI-related phenotypes showed exon skipping (skipping rate >12%). Findings of minigene assay and in silico prediction experiments supported these findings. Two therapeutic approaches, splicing correction of pre-messenger RNA or gene silencing of mature messenger RNA were assessed. Among them, gene silencing using short interfering RNAs targeting the skipped transcripts proved to be effective in restoring collagen VI in cells containing the pathogenic variant. CONCLUSION: Single-nucleotide variants at the 3'-ends of exons can lead to aberrant splicing, and allele-specific gene silencing targeting such variants is a promising therapeutic strategy.

Humans↗
PubMed1975

Study of double and triple simultaneous substitutions of amino acids in cytochromes C.

A statistical analysis aimed at obtaining some informations on a possible correlation between simultaneous amino acid substitutions is proposed. This method is applied to a set of cytochrome C, at the level of tandem and triple substitutions separated along the peptide chain by 1 to 15 peptide bonds. Monte-Carlo simulations are performed and the results are compared. We find a significant occurrence of three adjacent amino acid substitutions in which the first replacement requires a two nucleotide substitution. A possible explanation of this fact is proposed on the basis of covarions.

Amino Acid Sequence↗
PubMed2026

The shape of fitness functions and the distribution of mutational effect sizes jointly limit adaptation by regulatory mutations.

Mutations in gene regulatory regions have been shown to play a role in rapid adaptation, but the factors determining their contribution are largely unknown. Here, using the metabolic enzyme cytosine deaminase of budding yeast, we examine whether adaptation to 5-fluorocytosine, which requires reduced cytosine deamination and can readily arise from amino acid substitutions, may be reached by single promoter mutations. We generated all single-nucleotide substitutions and indels in the FCY1 promoter and assayed the resulting mutants in presence of 5-fluorocytosine. This revealed that no promoter mutation is sufficient for adaptation to occur. We next investigated how this inaccessibility of adaptation arises by combining large-scale expression measurements with the experimental characterization of the corresponding expression-fitness function. These experiments showed that the shape of this function precludes single promoter mutations from being adaptive. Although 24% of mutations significantly affect expression, the fitness curve is flat around wild-type level. As such, adaptation can only emerge from a severe reduction of expression, which cannot occur from a single mutation in the promoter. Our results show that the contribution of regulatory mutations to rapid adaptation depends not only on the distribution of mutational effect sizes on expression level but also on the shape of the function linking fitness to expression levels.

Promoter Regions, Genetic↗
PubMed2025

Taxogenomic analysis of Pichia senei sp. nov. and new insights into hybridization events in the Pichia cactophila species complex.

Three strains of a novel yeast species were isolated from necrotic cactus tissues of Cereus saddianus and Micranthocereus dolichospermaticus and from phytotelmata of Bromelia karatas. DNA sequence analysis of the Internal Transcribed Spacer (ITS) region and D1/D2 domains of the large subunit ribosomal RNA, along with whole genome phylogenomic analysis, showed that this yeast is most closely related to Pichia insulana, Pichia cactophila, and Pichia inconspicua. The new species differs by 10-13 nucleotide substitutions from these species in D1/D2 sequences and exhibits <90% genome-wide average nucleotide identity to them. The name Pichia senei sp. nov. is proposed for the novel species, which is homothallic and produces asci with one to four hat-shaped ascospores. The holotype is CBS 16311 (MycoBank MB 858723). Taxogenomic analyses of the P. cactophila species complex, including P. senei, provide new insights about the hybridizations events that shaped this group. Pichia insulana and P. inconspicua are identified as the parental lineages that originated P. cactophila, and P. senei also appears closely related to one of the progenitors of P. inconspicua. We assess phylogeny, heterozygosity, and ploidy to explore the processes shaping diversity, showing how genomic data support yeast species delimitation and reveal complex hybridization.

Phylogeny↗
PubMed1978

Mutagenesis during in vitro DNA synthesis.

The error frequency of in vitro DNA synthesis using a natural DNA template has been measured with a biological assay for nucleotide substitutions. phiX174 DNA containing an amber mutation was copied in vitro by Escherichia coli DNA polymerase I, and the reversion frequency of the progeny DNA was determined by transfection of E. coli spheroplasts. E. coli polymerase I makes less than 1 mistake at the am3 locus for every 7700 nucleotides incorporated under standard reaction conditions. Substitution of Mn2+ for Mg2+ and unequal concentrations of deoxynucleoside triphosphate substrates raises this mutation frequency to greater than 1 in 1000. Thus, E. coli DNA polymerase I can copy natural DNA templates with high fidelity and its accuracy can be affected by alterations in reaction conditions.

Coliphages↗
PubMed1979

The structure and transcription of four linked rabbit beta-like globin genes.

Rabbit chromosomal DNA contains a cluster of four linked beta-like globin genes arranged in the orientation 5'-beta 4-(8kb)-beta 3-(5 kb)-beta 2-(7-kb)-beta 1-3'. Determination of the nucleotide sequence of gene beta 1 confirms that this gene corresponds to the second type of two common co-dominant alleles encoding the adult beta-globin chain. With the exception of two nucleotide substitutions in the large intervening sequence (intron), the intron and flanking sequences are identical with the nucleotide sequence of the first type determined by Weissmann et al. (1979). A 14S polyadenylated transcript containing large intron sequences (possibly a mRNA precursor) is detected in the bone marrow cells of anemic rabbits. Gene beta 2 has limited sequence homology to adult and embryonic beta-globin probes and lacks a detectable mRNA transcript in the erythropoietic tissues examined. It contains at least one intervening sequence analogous to the large intron in gene beta 1. Genes beta 3 and beta 4 both contain an intron of 0.8 kb. Partial DNA sequence analysis indicates that the large intron in beta 4 is located between codons for amino acids lysine and leucine in an analogous position to that of the large intron in beta 1. In addition, a second smaller intron interrupts the 5' coding sequences of gene beta 4. Both genes beta 3 and beta 4 are transcribed in embryonic globin-producing cells. Their DNA sequence homology is limited, however, to a segment of approximately 0.2 kb located on the 5' side of the large intron.

Animals↗