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Biomedical subjects

M Bulmer

Publications and source records attributed to M Bulmer.

15 recordsLinked to original sources
PubMed1991

Synonymous nucleotide substitution rates in mammalian genes: implications for the molecular clock and the relationship of mammalian orders.

Synonymous substitution rates have been estimated for 58 genes compared among primates, artiodactyls, and rodents. Although silent sites might be expected to be neutral, there is substantial rate variation among genes within each lineage. Some of the rate variation is associated with G + C content: genes with intermediate G + C values have the highest rates. Nevertheless, considerable heterogeneity remains after correcting for G + C content. Synonymous substitution rates also vary among lineages, but the relative rates of genes are well conserved in different lineages. Certain genes have also been sequenced in a fourth order (lagomorph or carnivore), and these data have been used to investigate mammalian phylogeny. Data on lagomorphs are consistent with a star phylogeny, but there is evidence that carnivores and artiodactyls are sister groups. Genes sequenced in both rat and mouse suggest that the increased substitution rate in rodents has occurred since the rat/mouse divergence.

Animals↗
PubMed1991

Strand symmetry of mutation rates in the beta-globin region.

It has been suggested that there may be inequalities in the types of substitution on the two DNA strands (in particular, in the frequencies of transversions from R to Y and from Y to R) due to a higher error rate on the lagging than the leading strand during replication. Reexamination of 11 kb of the beta-globin region sequenced in six primates fails to confirm this suggestion. Examination of the 73-kb beta-globin region sequenced in humans shows that the frequency of pyrimidines in different parts of this region is more variable than expected in a random sequence, but the pattern is more consistent with nonrandomness generated by DNA turnover mechanisms than with strand asymmetry due to a higher error rate on the lagging strand.

Animals↗
PubMed1991

The selection-mutation-drift theory of synonymous codon usage.

It is argued that the bias in synonymous codon usage observed in unicellular organisms is due to a balance between the forces of selection and mutation in a finite population, with greater bias in highly expressed genes reflecting stronger selection for efficiency of translation. A population genetic model is developed taking into account population size and selective differences between synonymous codons. A biochemical model is then developed to predict the magnitude of selective differences between synonymous codons in unicellular organisms in which growth rate (or possibly growth yield) can be equated with fitness. Selection can arise from differences in either the speed or the accuracy of translation. A model for the effect of speed of translation on fitness is considered in detail, a similar model for accuracy more briefly. The model is successful in predicting a difference in the degree of bias at the beginning than in the rest of the gene under some circumstances, as observed in Escherichia coli, but grossly overestimates the amount of bias expected. Possible reasons for this discrepancy are discussed.

Amino Acyl-tRNA Synthetases↗
PubMed1990

The effect of context on synonymous codon usage in genes with low codon usage bias.

The effect of neighbouring bases on the usage of synonymous codons in genes with low codon usage bias in yeast and E. coli is examined. The codon adaptation index is employed to identify a group of genes in each organism with low codon usage bias, which are likely to be weakly expressed. A similar pattern is found in complementary sequences with respect to synonymous usage of A vs G or of U vs C. It is suggested that this may reflect an effect of context on mutation rates in weakly expressed genes.

Base Sequence↗
PubMed1990

Analysis of the inheritance, selection and evolution of growth trajectories.

We present methods for estimating the parameters of inheritance and selection that appear in a quantitative genetic model for the evolution growth trajectories and other "infinite-dimensional" traits that we recently introduced. Two methods for estimating the additive genetic covariance function are developed, a "full" model that fully fits the data and a "reduced" model that generates a smoothed estimate consistent with the sampling errors in the data. By decomposing the covariance function into its eigenvalues and eigenfunctions, it is possible to identify potential evolutionary changes in the population's mean growth trajectory for which there is (and those for which there is not) genetic variation. Algorithms for estimating these quantities, their confidence intervals, and for testing hypotheses about them are developed. These techniques are illustrated by an analysis of early growth in mice. Compatible methods for estimating the selection gradient function acting on growth trajectories in natural or domesticated populations are presented. We show how the estimates for the additive genetic covariance function and the selection gradient function can be used to predict the evolutionary change in a population's mean growth trajectory.

Animals↗
PubMed1989

Codon usage and secondary structure of MS2 phage RNA.

MS2 is an RNA bacteriophage (3569 bases). The secondary structure of the RNA has been determined, and is known to play an important role in regulating translation. Paired regions of the genome have a higher G+C content than unpaired regions. It has been suggested that this reflects selection for high G+C content to encourage pairing, but a re-analysis of the data together with computer simulation suggest that it is an automatic consequence in any RNA sequence of the way it folds up to minimise its free energy. It has also been suggested that the three registers in which pairing can occur in a coding region are used differentially to optimise the use of the redundancy of the genetic code, but re-analysis of the data shows only weak statistical support for this hypothesis.

Base Composition↗
PubMed1989

Structural instability of models of sexual selection.

Models for sexual selection by the coevolution of female preference and a male trait have as a generic feature the existence of a neutrally stable line of equilibria up and down which the system can drift at random. However, this feature is structurally unstable since it is destroyed by introducing either mutation or weak direct selection on female preference into the model, to be replaced by a single equilibrium (or a finite set of disconnected equilibria). This process is investigated in detail under a simple but general population genetic model. It is concluded that the level of female preference is determined by mutation, selection, and genetic drift acting directly on it, and drags the male trait along with it along the line of equilibria. More attention should be paid to selective forces acting directly on female preference.

Biological Evolution↗
PubMed1989

Estimating the variability of substitution rates.

Suppose that amino acid or nucleotide data are available for a homologous gene in several species which diverged from a common ancestor at about the same time and that substitution rates between all pairs of species are calculated, correcting as necessary for multiple substitutions and for back and parallel substitutions. The variances and covariances of these corrected substitution rates are evaluated, and are used to construct a new test for uniformity (constancy of the molecular clock) and to find the best estimates of substitution rates in individual lineages with their standard errors. A substantial bias may arise if the effect of correcting the pairwise substitution rates is ignored.

Amino Acids↗
PubMed1988

Codon usage and intragenic position.

Data on codon usage bias in E. coli are re-examined with respect to intragenic position. The bias is less extreme near the beginning than in the rest of the gene, particularly in highly expressed genes. This is contrary to the previous finding that there is a linear decline in codon usage bias with position along weakly expressed genes but little or no change in bias along highly expressed genes. The effect is not confined to genes coding for proteins with leader peptides, as suggested earlier (Burns and Beacham, 1985). There is some evidence of a similar but smaller effect in yeast.

Codon↗
PubMed1988

Selective differences among translation termination codons.

The frequency of use of the three alternative translation termination codons has been examined in 165 Escherichia coli, 52 Bacillus subtilis and 106 Saccharomyces cerevisiae genes. Genes were first categorised according to their degree of bias in sense codon usage. In each species there is a very strong bias in favour of UAA (over UAG and UGA) in genes where sense codon usage is highly biased. This bias declines, principally with an increase in the use of UGA, in genes with lower sense codon bias. It appears that selection operating during translation may maintain the bias in stop codon usage. Such selection could result from the greater availability of UAA-cognate release factor(s), or from a lower frequency of translational readthrough at UAA.

Bacillus subtilis↗
PubMed1988

Sex ratio evolution in lemmings.

In the varying lemming, Dicrostonyx torquatus, numerous XY females occur due to the X-linked mutation X*. Gileva (1987) has shown that there is also segregation distortion in males, with the segregation ratio for Y sperm being about 0.56, which has a significant effect on the sex ratio and the frequency of XY females. A theoretical analysis shows that this degree of segregation distortion is expected to evolve in the Dicrostonyx system under random mating, provided that reproductive compensation for the loss of YY zygotes by XY females is largely an automatic process due to reduced competition between the surviving embryos. The evolution of segregation distortion makes it unlikely that X* is an adaptation to allow a female-biased sex ratio in response to population structure.

Animals↗
PubMed1987

A statistical analysis of nucleotide sequences of introns and exons in human genes.

DNA sequences of 56 human genes for which information on both exons and introns was available were examined. The variance in G+C content among genes is estimated and shown to be substantial. There is a high correlation in G+C content between exons and introns within the same gene. The dinucleotide frequencies of introns are similar to those of intergenic spacer regions and are in reasonable agreement with predictions from substitution rates estimated from pseudogenes, except that the observed deficiency of TA doublets is not predicted. Duplicated bases also show a frequency greater than the expectation under independence. There is marked variability among genes in the frequency of the doublet CG relative to its expectation under independence. This variation is evolutionarily conserved and is correlated with the G+C content. Pseudogenes behave as if they are in a low -G+C, CG-deficient part of the genome, although the genes from which they arose are variable in these respects.

Base Composition↗
PubMed1986

Neighboring base effects on substitution rates in pseudogenes.

Substitution rates in pseudogenes can be used to estimate the frequencies of different types of mutation on the assumption that pseudogenes are not subject to selective constraints. These rates are used here to investigate the effect of neighboring bases on mutation rates. There is a marked increase in the frequency of transitions, though not of transversions, from the doublet CG. There are also some smaller effects of neighboring bases on the frequencies of transitions from adenine and thymine. The results are used to predict dinucleotide frequencies in a stretch of DNA subject to no selective constraints and to investigate the possibility of non-randomness in the usage of stop codons.

Animals↗
PubMedDate not supplied

Coevolution of codon usage and transfer RNA abundance.

The use of synonymous codons is strongly biased in the bacterium Escherichia coli and yeast, comprising both bias between codons recognized by the same transfer RNA and bias between groups of codons recognized by different synonymous tRNAs. A major determinant of the second sort of bias is tRNA content, codons recognized by abundant tRNAs being used more often than those recognised by rare tRNAs, particularly in highly expressed genes, probably owing to selection at the level of translation against codons recognized by rare tRNAs. Conversely, codon usage is likely to exert selection pressure on tRNA abundance. Here I develop a model for the coevolution of codon usage and tRNA abundance which explains why there are unequal abundances of synonymous tRNAs leading to biased usage between groups of codons recognized by them in unicellular organisms.

Biological Evolution↗