Parasitology. A game of cat and mouth.
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Animals↗
Biomedical subjects
Daniel L Hartl
Publications and source records attributed to Daniel L Hartl.
Bayesian analysis suggests that most amino acid replacements in Drosophila are driven by positive selection.
One of the principal goals of population genetics is to understand the processes by which genetic variation within species (polymorphism) becomes converted into genetic differences between species (divergence). In this transformation, selective neutrality, near neutrality, and positive selection may each play a role, differing from one gene to the next. Synonymous nucleotide sites are often used as a uniform standard of comparison across genes on the grounds that synonymous sites are subject to relatively weak selective constraints and so may, to a first approximation, be regarded as neutral. Synonymous sites are also interdigitated with nonsynonymous sites and so are affected equally by genomic context and demographic factors. Hence a comparison of levels of polymorphism and divergence between synonymous sites and amino acid replacement sites in a gene is potentially informative about the magnitude of selective forces associated with amino acid replacements. We have analyzed 56 genes in which polymorphism data from D. simulans are compared with divergence from a reference strain of D. melanogaster. The framework of the analysis is Bayesian and assumes that the distribution of selective effects (Malthusian fitnesses) is Gaussian with a mean that differs for each gene. In such a model, the average scaled selection intensity (gamma = N(e)s) of amino acid replacements eligible to become polymorphic or fixed is -7.31, and the standard deviation of selective effects within each locus is 6.79 (assuming homoscedasticity across loci). For newly arising mutations of this type that occur in autosomal or X-linked genes, the average proportion of beneficial mutations is 19.7%. Among the amino acid polymorphisms in the sample, the expected average proportion of beneficial mutations is 47.7%, and among amino acid replacements that become fixed the average proportion of beneficial mutations is 94.3%. The average scaled selection intensity of fixed mutations is +5.1. The presence of positive selection is pervasive with the single exception of kl-5, a Y-linked fertility gene. We find no evidence that a significant fraction of fixed amino acid replacements is neutral or nearly neutral or that positive selection drives amino acid replacements at only a subset of the loci. These results are model dependent and we discuss possible modifications of the model that might allow more neutral and nearly neutral amino acid replacements to be fixed.
Amino Acid Substitution↗
Evidence for S. cerevisiae fermentation in ancient wine.
Saccharomyces cerevisiae is the principal yeast used in modern fermentation processes, including winemaking, breadmaking, and brewing. From residue present inside one of the earliest known wine jars from Egypt, we have extracted, amplified, and sequenced ribosomal DNA from S. cerevisiae. These results indicate that this organism was probably responsible for wine fermentation by at least 3150 B.C. This inference has major implications for the evolution of bread and beer yeasts, since it suggests that S. cerevisiae yeast, which occurs naturally on the surface bloom of grapes, was also used as an inoculum to ferment cereal products.
Base Sequence↗
Conservation, relocation and duplication in genome evolution.
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Animals↗
Maximum likelihood and Bayesian methods for estimating the distribution of selective effects among classes of mutations using DNA polymorphism data.
Maximum likelihood and Bayesian approaches are presented for analyzing hierarchical statistical models of natural selection operating on DNA polymorphism within a panmictic population. For analyzing Bayesian models, we present Markov chain Monte-Carlo (MCMC) methods for sampling from the joint posterior distribution of parameters. For frequentist analysis, an Expectation-Maximization (EM) algorithm is presented for finding the maximum likelihood estimate of the genome wide mean and variance in selection intensity among classes of mutations. The framework presented here provides an ideal setting for modeling mutations dispersed through the genome and, in particular, for the analysis of how natural selection operates on different classes of single nucleotide polymorphisms (SNPs).
Bayes Theorem↗
Genetic diversity in yeast assessed with whole-genome oligonucleotide arrays.
The availability of a complete genome sequence allows the detailed study of intraspecies variability. Here we use high-density oligonucleotide arrays to discover 11,115 single-feature polymorphisms (SFPs) existing in one or more of 14 different yeast strains. We use these SFPs to define regions of genetic identity between common laboratory strains of yeast. We assess the genome-wide distribution of genetic variation on the basis of this yeast population. We find that genome variability is biased toward the ends of chromosomes and is more likely to be found in genes with roles in fermentation or in transport. This subtelomeric bias may arise through recombination between nonhomologous sequences because full-gene deletions are more common in these regions than in more central regions of the chromosome.
Chromosome Mapping↗
Horizontal acquisition of divergent chromosomal DNA in bacteria: effects of mutator phenotypes.
We examine the potential beneficial effects of the expanded access to environmental DNA offered by mutators on the adaptive potential of bacterial populations. Using parameters from published studies of recombination in E. coli, we find that the presence of mutators has the potential to greatly enhance bacterial population adaptation when compared to populations without mutators. In one specific example, for which three specific amino acid substitutions are required for adaptation to occur in a 300-amino-acid protein, we found a 3500-fold increase in the rate of adaptation. The probability of a beneficial acquisition decreased if more amino acid changes, or integration of longer DNA fragments, were required for adaptation. The model also predicts that mutators are more likely than nonmutator phenotypes to acquire genetic variability from a more diverged set of donor bacteria. Bacterial populations harboring mutators in a sequence heterogeneous environment are predicted to acquire most of their DNA conferring adaptation in the range of 13-30% divergence, whereas nonmutator phenotypes become adapted after recombining with more homogeneous sequences of 7-21% divergence. We conclude that mutators can accelerate bacterial adaptation when desired genetic variability is present within DNA fragments of up to approximately 30% divergence.
Data Interpretation, Statistical↗
Genetic dissection of hybrid incompatibilities between Drosophila simulans and D. mauritiana. I. Differential accumulation of hybrid male sterility effects on the X and autosomes.
The genetic basis of hybrid incompatibility in crosses between Drosophila mauritiana and D. simulans was investigated to gain insight into the evolutionary mechanisms of speciation. In this study, segments of the D. mauritiana third chromosome were introgressed into a D. simulans genetic background and tested as homozygotes for viability, male fertility, and female fertility. The entire third chromosome was covered with partially overlapping segments. Many segments were male sterile, while none were female sterile or lethal, confirming previous reports of the rapid evolution of hybrid male sterility (HMS). A statistical model was developed to quantify the HMS accumulation. In comparison with previous work on the X chromosome, we estimate that the X has approximately 2.5 times the density of HMS factors as the autosomes. We also estimate that the whole genome contains approximately 15 HMS "equivalents"-i.e., 15 times the minimum number of incompatibility factors necessary to cause complete sterility. Although some caveats for the quantitative estimate of a 2.5-fold density difference are described, this study supports the notion that the X chromosome plays a special role in the evolution of reproductive isolation. Possible mechanisms of a "large X" effect include selective fixation of new mutations that are recessive or partially recessive and the evolution of sex-ratio distortion systems.
Animals↗
Genetic dissection of hybrid incompatibilities between Drosophila simulans and D. mauritiana. II. Mapping hybrid male sterility loci on the third chromosome.
Hybrid male sterility (HMS) is a rapidly evolving mechanism of reproductive isolation in Drosophila. Here we report a genetic analysis of HMS in third-chromosome segments of Drosophila mauritiana that were introgressed into a D. simulans background. Qualitative genetic mapping was used to localize 10 loci on 3R and a quantitative trait locus (QTL) procedure (multiple-interval mapping) was used to identify 19 loci on the entire chromosome. These genetic incompatibilities often show dominance and complex patterns of epistasis. Most of the HMS loci have relatively small effects and generally at least two or three of them are required to produce complete sterility. Only one small region of the third chromosome of D. mauritiana by itself causes a high level of infertility when introgressed into D. simulans. By comparison with previous studies of the X chromosome, we infer that HMS loci are only approximately 40% as dense on this autosome as they are on the X chromosome. These results are consistent with the gradual evolution of hybrid incompatibilities as a by-product of genetic divergence in allopatric populations.
Alleles↗
Genetic dissection of hybrid incompatibilities between Drosophila simulans and D. mauritiana. III. Heterogeneous accumulation of hybrid incompatibilities, degree of dominance, and implications for Haldane's rule.
The genetic basis of Haldane's rule was investigated through estimating the accumulation of hybrid incompatibilities between Drosophila simulans and D. mauritiana by means of introgression. The accumulation of hybrid male sterility (HMS) is at least 10 times greater than that of hybrid female sterility (HFS) or hybrid lethality (HL). The degree of dominance for HMS and HL in a pure D. simulans background is estimated as 0.23-0.29 and 0.33-0.39, respectively; that for HL in an F1 background is unlikely to be very small. Evidence obtained here was used to test the Turelli-Orr model of Haldane's rule. Composite causes, especially, faster-male evolution and recessive hybrid incompatibilities, underlie Haldane's rule in heterogametic male taxa such as Drosophila (XY male and XX female). However, if faster-male evolution is driven by sexual selection, it contradicts Haldane's rule for sterility in heterogametic-female taxa such as Lepidoptera (ZW female and ZZ male). The hypothesis of a faster-heterogametic-sex evolution seems to fit the current data best. This hypothesis states that gametogenesis in the heterogametic sex, instead of in males per se, evolves much faster than in the homogametic sex, in part because of sex-ratio selection. This hypothesis not only explains Haldane's rule in a simple way, but also suggests that genomic conflicts play a major role in evolution and speciation.
Animals↗
Origin and evolution of a new gene expressed in the Drosophila sperm axoneme.
Sdic is a new gene that evolved recently in the lineage of Drosophila melanogaster. It was formed from a duplication and fusion of the gene AnnX, which encodes annexin X, and Cdic, which encodes the intermediate polypeptide chain of the cytoplasmic dynein. The fusion joins AnnX exon 4 with Cdic intron 3, which brings together three putative promoter elements for testes-specific expression of Sdic: the distal conserved element (DCE) and testes-specific element (TSE) are derived from AnnX, and the proximal conserved element (PCE) from Cdic intron 3. Sdic transcription initiates within the PCE, and translation is initiated within the sequence derived from Cdic intron 3, continuing through a 10 base pair insertion that creates a new splice donor site that enables the new coding sequence derived from intron 3 to be joined with the coding sequence of Cdic exon 4. A novel protein is created lacking 100 residues at the amino end that contain sequence motifs essential for the function of cytoplasmic dynein intermediate chains. Instead, the amino end is a hydrophobic region of 16 residues that resembles the amino end of axonemal dynein intermediate chains from other organisms. The downstream portion of Sdic features large deletions eliminating Cdic exons v2 and v3, as well as multiple frameshift deletions or insertions. The new protein becomes incorporated into the tail of the mature sperm and may function as an axonemal dynein intermediate chain. The new Sdic gene is present in about 10 tandem repeats between the wildtype Cdic and AnnX genes located near the base of the X chromosome. The implications of these findings are discussed relative to the origin of new gene functions and the process of speciation.
Amino Acid Sequence↗
Bayesian analysis of gene expression levels: statistical quantification of relative mRNA level across multiple strains or treatments.
BACKGROUND: Methods of microarray analysis that suit experimentalists using the technology are vital. Many methodologies discard the quantitative results inherent in cDNA microarray comparisons or cannot be flexibly applied to multifactorial experimental design. Here we present a flexible, quantitative Bayesian framework. This framework can be used to analyze normalized microarray data acquired by any replicated experimental design in which any number of treatments, genotypes, or developmental states are studied using a continuous chain of comparisons. RESULTS: We apply this method to Saccharomyces cerevisiae microarray datasets on the transcriptional response to ethanol shock, to SNF2 and SWI1 deletion in rich and minimal media, and to wild-type and zap1 expression in media with high, medium, and low levels of zinc. The method is highly robust to missing data, and yields estimates of the magnitude of expression differences and experimental error variances on a per-gene basis. It reveals genes of interest that are differentially expressed at below the twofold level, genes with high 'fold-change' that are not statistically significantly different, and genes differentially regulated in quantitatively unanticipated ways. CONCLUSIONS: Anyone with replicated normalized cDNA microarray ratio datasets can use the freely available MacOS and Windows software, which yields increased biological insight by taking advantage of replication to discern important changes in expression level both above and below a twofold threshold. Not only does the method have utility at the moment, but also, within the Bayesian framework, there will be considerable opportunity for future development.
Bayes Theorem↗
Excess polymorphisms in genes for membrane proteins in Plasmodium falciparum.
The detection of single-nucleotide polymorphisms in pathogenic microorganisms has normally been carried out by trial and error. Here we show that DNA hybridization with high-density oligonucleotide arrays provides rapid and convenient detection of single-nucleotide polymorphisms in Plasmodium falciparum, despite its exceptionally high adenine-thymine (AT) content (82%). A disproportionate number of polymorphisms are found in genes encoding proteins associated with the cell membrane. These genes are targets for only 22% of the oligonucleotide probes but account for 69% of the polymorphisms. Genetic variation is also enriched in subtelomeric regions, which account for 22% of the chromosome but 76% of the polymorphisms.
Animals↗
Selection for short introns in highly expressed genes.
Transcription is a slow and expensive process: in eukaryotes, approximately 20 nucleotides can be transcribed per second at the expense of at least two ATP molecules per nucleotide. Thus, at least for highly expressed genes, transcription of long introns, which are particularly common in mammals, is costly. Using data on the expression of genes that encode proteins in Caenorhabditis elegans and Homo sapiens, we show that introns in highly expressed genes are substantially shorter than those in genes that are expressed at low levels. This difference is greater in humans, such that introns are, on average, 14 times shorter in highly expressed genes than in genes with low expression, whereas in C. elegans the difference in intron length is only twofold. In contrast, the density of introns in a gene does not strongly depend on the level of gene expression. Thus, natural selection appears to favor short introns in highly expressed genes to minimize the cost of transcription and other molecular processes, such as splicing.
Animals↗
The cost of inbreeding in Arabidopsis.
Population geneticists have long sought to estimate the distribution of selection intensities among genes of diverse function across the genome. Only recently have DNA sequencing and analytical techniques converged to make this possible. Important advances have come from comparing genetic variation within species (polymorphism) with fixed differences between species (divergence). These approaches have been used to examine individual genes for evidence of selection. Here we use the fact that the time since species divergence allows combination of data across genes. In a comparison of amino-acid replacements among species of the mustard weed Arabidopsis with those among species of the fruitfly Drosophila, we find evidence for predominantly beneficial gene substitutions in Drosophila but predominantly detrimental substitutions in Arabidopsis. We attribute this difference to the Arabidopsis mating system of partial self-fertilization, which corroborates a prediction of population genetics theory that species with a high frequency of inbreeding are less efficient in eliminating deleterious mutations owing to their reduced effective population size.
Amino Acid Substitution↗
The paradoxical population genetics of Plasmodium falciparum.
Among the leading causes of death in African children is cerebral malaria caused by the parasitic protozoan Plasmodium falciparum. Endemic forms of this disease are thought to have originated in central Africa 5000-10000 years ago, coincident with the innovation of slash-and-burn agriculture and the diversification of the Anopheles gambiae complex of mosquito vectors. Population genetic studies of P. falciparum have yielded conflicting results. Some evidence suggests that today's population includes multiple ancient lineages pre-dating human speciation. Other evidence suggests that today's population derives from only one, or a small number, of these ancient lineages. Resolution of this issue is important for the evaluation of the long-term efficacy of drug and immunological control strategies.
Animals↗
Efficient mobilization of mariner in vivo requires multiple internal sequences.
Aberrant products of mariner excision that have an impaired ability to be mobilized often include internal deletions that do not encroach on either of the inverted repeats. Analysis of 13 such deletions, as well as 7 additional internal deletions obtained by various methods, has revealed at least three internal regions whose integrity is necessary for efficient mariner mobilization. Within the 1286-bp element, the essential regions are contained in the intervals bounded by coordinates 229-586, 735-765, and 939-1066, numbering in base pairs from the extreme 5' end of the element. These regions may contain sequences that are necessary for transposase binding or that are needed to maintain proper spacing between binding sites. The isolation of excision-defective elements with point mutations at nucleotide positions 993 and 161/179 supports the hypothesis of sequence requirements, but the reduced mobility of transformation vectors with insertions into the SacI site at position 790 supports the hypothesis of spacing requirements. The finding of multiple internal regions that are essential for efficient mariner mobilization in vivo contrasts with reports that mini-elements with as little as 43 bp of DNA between the inverted repeats can transpose efficiently in vitro.
Animals↗
Unexpected stability of mariner transgenes in Drosophila.
A number of mariner transformation vectors based on the mauritiana subfamily of transposable elements were introduced into the genome of Drosophila melanogaster and examined for their ability to be mobilized by the mariner transposase. Simple insertion vectors were constructed from single mariner elements into which exogenous DNA ranging in size from 1.3 to 4.5 kb had been inserted; composite vectors were constructed with partial or complete duplications of mariner flanking the exogenous DNA. All of the simple insertion vectors showed levels of somatic and germline excision that were at least 100-fold lower than the baseline level of uninterrupted mariner elements. Although composite vectors with inverted duplications were unable to be mobilized at detectable frequencies, vectors with large direct duplications of mariner could be mobilized. A vector consisting of two virtually complete elements flanking exogenous DNA yielded a frequency of somatic eye-color mosaicism of approximately 10% and a frequency of germline excision of 0.04%. These values are far smaller than those observed for uninterrupted elements. The results imply that efficient mobilization of mariner in vivo requires the presence and proper spacing of sequences internal to the element as well as the inverted repeats.
Animals↗