Colin D. Meiklejohn

A single mode of canalization

The evolution of mechanisms underlying the buffering of the phenotype against genetic and environmental influences has received much theoretical and experimental attention, yet many issues remain unresolved. Here, we consider the kinds of biological process that are likely to promote this buffering, or canalization, and the circumstances under which the evolution of these mechanisms will be favored. We conclude that evolution should produce a single mode of canalization that will buffer the phenotype against all kinds of perturbation, and that the major fitness benefit driving the fixation of canalizing alleles derives from a reduction in environmental influences on phenotypic variation.

RATES OF DIVERGENCE IN GENE EXPRESSION PROFILES OF PRIMATES, MICE, AND FLIES: STABILIZING SELECTION AND VARIABILITY AMONG FUNCTIONAL CATEGORIES

Abstract The extent to which natural selection shapes phenotypic variation has long been a matter of debate among those studying organic evolution. We studied the patterns of gene expression polymorphism and divergence in several datasets that ranged from comparisons between two very closely related laboratory strains of mice to comparisons across a considerably longer time scale, such as between humans and chimpanzees, two species of mice, and two species of Drosophila. The results were analyzed and interpreted in view of neutral models of phenotypic evolution. Our analyses used a number of metrics to show that most mRNA levels are evolutionary stable, changing little across the range of taxonomic distances compared. This implies that, overall, widespread stabilizing selection on transcription levels has prevented greater evolutionary changes in mRNA levels. Nevertheless, the range of rates of divergence is large with highly significant differences in the rate and patterns of transcription divergence across functional classes defined on the basis of the gene ontology annotation (primates and mice datasets) or on the basis of the pattern of sex‐biased gene expression (Drosophila). Moreover, rates of divergence of sex‐biased genes in the contrast between Drosophila species show a distinct pattern from that observed in the contrast between populations of D. melanogaster. Hence, we discuss the time scale of the changes observed and its consequences for the relationship between variation in gene expression within and between species. Finally, we argue that differences in mRNA levels of the magnitudes observed herein could be explained by a remarkably small number of generations of directional selection.

An Incompatibility between a Mitochondrial tRNA and Its Nuclear-Encoded tRNA Synthetase Compromises Development and Fitness in Drosophila

Mitochondrial transcription, translation, and respiration require interactions between genes encoded in two distinct genomes, generating the potential for mutations in nuclear and mitochondrial genomes to interact epistatically and cause incompatibilities that decrease fitness. Mitochondrial-nuclear epistasis for fitness has been documented within and between populations and species of diverse taxa, but rarely has the genetic or mechanistic basis of these mitochondrial–nuclear interactions been elucidated, limiting our understanding of which genes harbor variants causing mitochondrial–nuclear disruption and of the pathways and processes that are impacted by mitochondrial–nuclear coevolution. Here we identify an amino acid polymorphism in the Drosophila melanogaster nuclear-encoded mitochondrial tyrosyl–tRNA synthetase that interacts epistatically with a polymorphism in the D. simulans mitochondrial-encoded tRNATyr to significantly delay development, compromise bristle formation, and decrease fecundity. The incompatible genotype specifically decreases the activities of oxidative phosphorylation complexes I, III, and IV that contain mitochondrial-encoded subunits. Combined with the identity of the interacting alleles, this pattern indicates that mitochondrial protein translation is affected by this interaction. Our findings suggest that interactions between mitochondrial tRNAs and their nuclear-encoded tRNA synthetases may be targets of compensatory molecular evolution. Human mitochondrial diseases are often genetically complex and variable in penetrance, and the mitochondrial–nuclear interaction we document provides a plausible mechanism to explain this complexity.

Sex Chromosome-Specific Regulation in the Drosophila Male Germline But Little Evidence for Chromosomal Dosage Compensation or Meiotic Inactivation

Suppression of X-linked transgene reporters versus normal expression of endogenous X-linked genes suggest a novel form of X chromosome-specific regulation in Drosophila testes, instead of sex chromosome dosage compensation or meiotic inactivation.

Genetic conflict and sex chromosome evolution

Chromosomal sex determination systems create the opportunity for the evolution of selfish genetic elements that increase the transmission of one sex chromosome at the expense of its homolog. Because such selfish elements on sex chromosomes can reduce fertility and distort the sex ratio of progeny, unlinked suppressors are expected to evolve, bringing different regions of the genome into conflict over the meiotic transmission of the sex chromosomes. Here we argue that recurrent genetic conflict over sex chromosome transmission is an important evolutionary force that has shaped a wide range of seemingly disparate phenomena including the epigenetic regulation of genes expressed in the germline, the distribution of genes in the genome, and the evolution of hybrid sterility between species.

Mitochondrial-nuclear epistasis affects fitness within species but does not contribute to fixed incompatibilities between species of Drosophila

Efficient mitochondrial function requires physical interactions between the proteins encoded by the mitochondrial and nuclear genomes. Coevolution between these genomes may result in the accumulation of incompatibilities between divergent lineages. We test whether mitochondrial–nuclear incompatibilities have accumulated within the Drosophila melanogaster species subgroup by combining divergent mitochondrial and nuclear lineages and quantifying the effects on relative fitness. Precise placement of nine mtDNAs from D. melanogaster, D. simulans, and D. mauritiana into two D. melanogaster nuclear genetic backgrounds reveals significant mitochondrial–nuclear epistasis affecting fitness in females. Combining the mitochondrial genomes with three different D. melanogaster X chromosomes reveals significant epistasis for male fitness between X‐linked and mitochondrial variation. However, we find no evidence that the more than 500 fixed differences between the mitochondrial genomes of D. melanogaster and the D. simulans species complex are incompatible with the D. melanogaster nuclear genome. Rather, the interactions of largest effect occur between mitochondrial and nuclear polymorphisms that segregate within species of the D. melanogaster species subgroup. We propose that a low mitochondrial substitution rate, resulting from a low mutation rate and/or efficient purifying selection, precludes the accumulation of mitochondrial–nuclear incompatibilities among these Drosophila species.

Regulatory evolution across the protein interaction network

Protein-protein interactions may impose constraints on both structural and regulatory evolution. Here we show that protein-protein interactions are negatively associated with evolutionary variation in gene expression. Moreover, interacting proteins have similar levels of variation in expression, and their expression levels are positively correlated across strains. Our results suggest that interacting proteins undergo similar evolutionary dynamics, and that their expression levels are evolutionarily coupled. These patterns hold for organisms as diverse as budding yeast and fruit flies.

Little evidence for demasculinization of the Drosophila X chromosome among genes expressed in the male germline.

Male-biased genes—those expressed at higher levels in males than in females—are underrepresented on the X chromosome of Drosophila melanogaster. Several evolutionary models have been posited to explain this so-called demasculinization of the X. Here, we show that the apparent paucity of male-biased genes on the X chromosome is attributable to global X-autosome differences in expression in Drosophila testes, owing to a lack of sex chromosome dosage compensation in the male germline, but not to any difference in the density of testis-specific or testis-biased genes on the X chromosome. First, using genome-wide gene expression data from 20 tissues, we find no evidence that genes with testis-specific expression are underrepresented on the X chromosome. Second, using contrasts in gene expression profiles among pairs of tissues, we recover a statistical underrepresentation of testis-biased genes on the X but find that the pattern largely disappears once we account for the lack of dosage compensation in the Drosophila male germline. Third, we find that computationally “demasculinizing” the autosomes is not sufficient to produce an expression profile similar to that of the X chromosome in the testes. Our findings thus show that the lack of sex chromosome dosage compensation in Drosophila testes can explain the apparent signal of demasculinization on the X, whereas evolutionary demasculinization of the X cannot explain its overall reduced expression in the testes.

The roles of cis- and trans-regulation in the evolution of regulatory incompatibilities and sexually dimorphic gene expression

Evolutionary changes in gene expression underlie many aspects of phenotypic diversity within and among species. Understanding the genetic basis for evolved changes in gene expression is therefore an important component of a comprehensive understanding of the genetic basis of phenotypic evolution. Using interspecific introgression hybrids, we examined the genetic basis for divergence in genome-wide patterns of gene expression between Drosophila simulans and Drosophila mauritiana. We find that cis-regulatory and trans-regulatory divergences differ significantly in patterns of genetic architecture and evolution. The effects of cis-regulatory divergence are approximately additive in heterozygotes, quantitatively different between males and females, and well predicted by expression differences between the two parental species. In contrast, the effects of trans-regulatory divergence are associated with largely dominant introgressed alleles, have similar effects in the two sexes, and generate expression levels in hybrids outside the range of expression in both parental species. Although the effects of introgressed trans-regulatory alleles are similar in males and females, expression levels of the genes they regulate are sexually dimorphic between the parental D. simulans and D. mauritiana strains, suggesting that pure-species genotypes carry unlinked modifier alleles that increase sexual dimorphism in expression. Our results suggest that independent effects of cis-regulatory substitutions in males and females may favor their role in the evolution of sexually dimorphic phenotypes, and that trans-regulatory divergence is an important source of regulatory incompatibilities.

Sex Chromosome-wide Transcriptional Suppression and Compensatory Cis-Regulatory Evolution Mediate Gene Expression in the Drosophila Male Germline

The evolution of heteromorphic sex chromosomes has repeatedly resulted in the evolution of sex chromosome-specific forms of regulation, including sex chromosome dosage compensation in the soma and meiotic sex chromosome inactivation in the germline. In the male germline of Drosophila melanogaster, a novel but poorly understood form of sex chromosome-specific transcriptional regulation occurs that is distinct from canonical sex chromosome dosage compensation or meiotic inactivation. Previous work shows that expression of reporter genes driven by testis-specific promoters is considerably lower—approximately 3-fold or more—for transgenes inserted into X chromosome versus autosome locations. Here we characterize this transcriptional suppression of X-linked genes in the male germline and its evolutionary consequences. Using transgenes and transpositions, we show that most endogenous X-linked genes, not just testis-specific ones, are transcriptionally suppressed several-fold specifically in the Drosophila male germline. In wild-type testes, this sex chromosome-wide transcriptional suppression is generally undetectable, being effectively compensated by the gene-by-gene evolutionary recruitment of strong promoters on the X chromosome. We identify and experimentally validate a promoter element sequence motif that is enriched upstream of the transcription start sites of hundreds of testis-expressed genes; evolutionarily conserved across species; associated with strong gene expression levels in testes; and overrepresented on the X chromosome. These findings show that the expression of X-linked genes in the Drosophila testes reflects a balance between chromosome-wide epigenetic transcriptional suppression and long-term compensatory adaptation by sex-linked genes. Our results have broad implications for the evolution of gene expression in the Drosophila male germline and for genome evolution.