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A Stoltzfus

Publications and source records attributed to A Stoltzfus.

12 recordsLinked to original sources
PubMed2005

Untangling the effects of codon mutation and amino acid exchangeability.

Determining the relative contributions of mutation and selection to evolutionary change is a matter of great practical and theoretical significance. In this paper, we examine relative contributions of codon mutation rates and amino acid exchangeability on the frequencies of each type of amino acid difference in alignments of distantly related proteins, alignments of closely related proteins, and among human SNPs, using a model that incorporates prior estimates of mutation and exchangeability parameters. For the operational exchangeability of amino acids in proteins, we use EX, a measure of protein-level effects from a recent statistical meta-analysis of nearly 10,000 experimental amino acid exchanges. EX is both free of mutational effects and more powerful than commonly used "biochemical distance" measures (1). For distant protein relationships, mutational effects (genetic code, transition/transversion bias) and operational exchangeability (EX) account for roughly equal portions of variance in off-diagonal values, the complete model accounting for R2 = 0.35 of the variance. For human/chimpanzee alignments representing closely related proteins relationships, mutational effects (including CpG bias) account for 0.52 of the variance; adding EX to the model increases this to 0.67. For natural variation in human proteins, the variance explained by mutational effects alone, and by mutational effects and operational exchangeability are, respectively, 0.66 and 0.70 for SNPs in HGVBase, and 0.56 and 0.60 for disease-causing missense variants in HGMD. Thus, exchangeability has a stronger relative effect for distant protein evolution than for the cases of closely related proteins or of population variation. A more detailed model for the hominid data suggests that 1) there is a threshold in EX below which substitutions are highly unlikely to be accepted, corresponding to roughly 30 % relative protein activity; 2) selection against missense mutants is a slightly convex function of protein activity, not changing much as long as protein activity is low; and 3) the probability of disease-causing effects decreases nearly linearly with EX.

Amino Acid Substitution↗
PubMed1999

On the possibility of constructive neutral evolution.

The neutral theory often is presented as a theory of "noise" or silent changes at an isolated "molecular level," relevant to marking the steady pace of divergence, but not to the origin of biological structure, function, or complexity. Nevertheless, precisely these issues can be addressed in neutral models, such as those elaborated here with regard to scrambled ciliate genes, gRNA-mediated RNA editing, the transition from self-splicing to spliceosomal splicing, and the retention of duplicate genes. All of these are instances of a more general scheme of "constructive neutral evolution" that invokes biased variation, epistatic interactions, and excess capacities to account for a complex series of steps giving rise to novel structures or operations. The directional and constructive outcomes of these models are due not to neutral allele fixations per se, but to these other factors. Neutral models of this type may help to clarify the poorly understood role of nonselective factors in evolutionary innovation and directionality.

Amino Acid Sequence↗
PubMed1997

Intron "sliding" and the diversity of intron positions.

Alignments of homologous genes typically reveal a great diversity of intron locations, far more than could fit comfortably in a single gene. Thus, a minority of these intron positions could be inherited from a single ancestral gene, but the larger share must be attributed to subsequent events of intron gain or intron "sliding" (movement from one position to another within a gene). Intron sliding has been argued from cases of discordant introns and from putative spatial clustering of intron positions. A list of 32 cases of discordant introns is presented here. Most of these cases are found to be artefactual. The spatial and phylogenetic distributions of intron positions from five published compilations of gene data, comprising 205 intron positions, have been examined systematically for evidence of intron sliding. The results suggest that sliding, if it occurs at all, has contributed little to the diversity of intron positions.

Animals↗
PubMed1995

Methods for evaluating exon-protein correspondences.

According to the exon theory of genes, protein-coding genes evolved originally by combinatorial assembly of mini-gene precursors of modern exons. If so, then exons should tend to encode discrete bits of protein structure, as first suggested by C.C.F. Blake. In order to assess the evidence for Blake's conjecture, we have developed methods for evaluating the significance of correspondences between split gene structure and protein structure, using computer programs for measuring observed correspondences and comparing them to random expectations. Initial results of applying these methods to data on ancient proteins have been presented elsewhere. Here we describe the algorithms in detail, and demonstrate their effectiveness in finding correlations in idealized test cases. The likely effects of deletion and putative displacement ('sliding') of introns on the ability to detect correlations are also examined.

Algorithms↗
PubMed1994

Testing the exon theory of genes: the evidence from protein structure.

A tendency for exons to correspond to discrete units of protein structure in protein-coding genes of ancient origin would provide clear evidence in favor of the exon theory of genes, which proposes that split genes arose not by insertion of introns into unsplit genes, but from combinations of primordial mini-genes (exons) separated by spacers (introns). Although putative examples of such correspondence have strongly influenced previous debate on the origin of introns, a general correspondence has not been rigorously proved. Objective methods for detecting correspondences were developed and applied to four examples that have been cited previously as evidence of the exon theory of genes. No significant correspondence between exons and units of protein structure was detected, suggesting that the putative correspondence does not exist and that the exon theory of genes is untenable.

Alcohol Dehydrogenase↗
PubMed1988

Molecular evolution of the Escherichia coli chromosome. I. Analysis of structure and natural variation in a previously uncharacterized region between trp and tonB.

We present the sequence of a 3500-bp region of the Escherichia coli strain K12 chromosome lying between the tryptophan operon and the tonB gene. Analysis of the sequence yields six open reading frames that have properties characteristic of genes for proteins. The reading frames are closely spaced, and putative transcription units and control sites compose over 95% of the DNA. The sequences of several wild strains of E. coli have been determined for a large segment of the region described. Comparison of these sequences reveals the effects of base substitutions, DNA rearrangements, and recombination. In the regions presumably expressed as polypeptides, most of the natural variation results from synonymous substitutions. However, the DNA rearrangements identified have end points within the open reading frames and disrupt them in a variety of ways. The effects of genetic recombination between strains, recently found to be significant on a large scale in E. coli, are also apparent in the region between trp and tonB.

Base Sequence↗
PubMed1988

Molecular evolution of the Escherichia coli chromosome. II. Clonal segments.

Remarkable sequence similarities in the trp region among Escherichia coli strains of diverse natural origins imply the existence of worldwide clones of very recent origin. This in turn implies a low rate of fixation of new universally favorable alleles, which carry adjacent stretches of chromosome to high frequency. These clonal segments begin as entire chromosomes; recombination shortens them progressively by substituting less closely related homologous DNA. The rate of this recombination, comprising the introduction of a homologous chromosomal fragment to a cell and the replacement of part of the original chromosome, is estimated from observations.

Biological Evolution↗
PubMedDate not supplied

Molecular evolution: recent cases of spliceosomal intron gain?

The 'introns-late' theory holds that spliceosomal introns have been added to genes during eukaryotic evolution. Few clear examples of recent intron gains have been well documented, but two such cases have now been reported, one with possible identification of the source of the intron.

Animals↗
PubMedDate not supplied

Bias in the introduction of variation as an orienting factor in evolution.

According to New Synthesis doctrine, the direction of evolution is determined by selection and not by "internal causes" that act by way of propensities of variation. This doctrine rests on the theoretical claim that because mutation rates are small in comparison to selection coefficients, mutation is powerless to overcome opposing selection. Using a simple population-genetic model, this claim is shown to depend on assuming the prior availability of variation, so that mutation may act only as a "pressure" on the frequencies of existing alleles, and not as the evolutionary process that introduces novelty. As shown here, mutational bias in the introduction of novelty can strongly influence the course of evolution, even when mutation rates are small in comparison to selection coefficients. Recognizing this mode of causation provides a distinct mechanistic basis for an "internalist" approach to determining the contribution of mutational and developmental factors to evolutionary phenomena such as homoplasy, parallelism, and directionality.

Alleles↗