Population Genetics: How Many Variable Genes Affect Variable Traits?

How many genes control a given trait? And are genes with defined knockout phenotypes affecting a given trait the same genes that also underlie population-wide variation in that trait? A new study in Drosophila melanogaster has some surprising answers.

Alternative evolutionary outcomes following endosymbiont-mediated selection on male mating preference alleles.

In many arthropods, intracellular bacteria, such as those of the genus Wolbachia, may spread through host populations as a result of cytoplasmic incompatibility (CI). Here, there is sterility or reduced fertility in crosses between infected males and uninfected females. As the bacterium is maternally inherited, the reduced fertility of uninfected females increases the frequency of the infection. If the transmission fidelity of the bacterium is less than 100%, the bacterium cannot invade from a low frequency, but if its frequency exceeds a threshold, it increases to a high, stable, equilibrium frequency. We explore the expected evolutionary dynamics of mutant alleles that cause their male bearers to avoid mating with uninfected females. For alleles which create this avoidance behaviour conditional upon the male being infected, there is a wide zone of parameter space that allows the preference allele to drive Wolbachia from the population when it would otherwise stably persist. There is also a wide zone of parameter space that allows a joint stable equilibrium for the Wolbachia and a polymorphism for the preference allele. When the male's avoidance of uninfected females is unconditional, the preference allele's effect on Wolbachia frequency is reduced, but there is a narrow range of values for the transmission rate and CI fertility that allow an unconditional preference allele to drive Wolbachia from the population, in a process driven by positive linkage disequilibrium between Wolbachia and the preference allele. The possibility of the evolution of preference could hamper attempts to manipulate wild populations through Wolbachia introductions.

Genetic Variation: Harmful Recessive Mutations Have Unexpected Effects on Variation.

New data are causing the standard model for the effect of selection on linked neutral variation in low recombination regions, combining the effects of background selection and selective sweeps, to be refined to include harmful recessive mutations creating associative overdominance.

Mutation Rates: Simpler Than We Thought?

Mutation rate variation is often explained by varying optimal rates, or through effective population sizes determining the effectiveness of selection. But a rate difference between humans and owl monkeys is now explained mechanistically as a consequence of differing reproductive longevities.

Biased image cropping and non-independent samples.

Any figure in a research article will typically represent only a small portion of the total data gained by a researcher for that experiment, and it is therefore key that the figure accurately reflects what was found overall. Furthermore, if individual observations form clusters with differing mean properties, those individual observations would not represent independent samples from the populations being compared. In this example, the question of how to fairly represent and treat image data is addressed.

Why are estimates of the strength and direction of natural selection from wild populations not congruent with observed rates of phenotypic change?

Observing adaptive evolution is difficult. In the fossil record, phenotypic evolution happens much more slowly than in artificial selection experiments or in experimental evolution. Yet measures of selection on phenotypic traits, with high heritabilities, suggest that phenotypic evolution should also be rapid in the wild, and this discrepancy often remains even after accounting for correlations between different traits (i.e. making predictions using the multivariate version of the breeder's equation). Are fitness correlations with quantitative traits adequate measures of selection in the wild? We should instead view fitnesses as average properties of genotypes, while acknowledging that they can be environment-dependent. Populations will tend to remain at fitness equilibria, once these are attained, and phenotypes will then be stable. Thus, studying the causes of adaptive change at a genotypic rather than phenotypic level may reveal that, typically, it is occurring too slowly to be easily observed.

Transposable element invasions.

Transposable elements have an ongoing, largely parasitic interaction with their hosts. We are interested in the timescale of this interaction. In a recent publication, we have examined the sequence divergence between class II DNA transposons from mammalian genomes. We asked whether these sequences undergo a continuing process of turnover, keeping a family as an integrated whole, as members of the family are continually created and lost. Alternatively, we envisaged that elements might have been involved in a burst of amplification, soon after they first occupied a mammalian genome, and the shared ancestry of present-day elements harks back to this initial amplification, a process that we termed a "life cycle." We resolved between these processes by estimating the time to common ancestry predicted from the genetic diversity of sequences found in a transposon family, and also estimating, from the mammalian orders that currently possess copies of the family, the time when the family first entered the mammalian genome. These times are approximately the same, supporting the "life cycle" model. This casts light on how far we can infer genetic changes in the past through the study of DNA sequences from the present.

Quantitative genetics: heritability is not always missing.

Quantitative trait loci (QTLs) underlying multifactorial disorders explain little of the heritability - most is 'missing'. A new yeast study has identified QTLs which explain most heritability in traits. Why is heritability missing in human diseases but not here?

Aedes aegypti mosquitoes exhibit decreased repellency by DEET following previous exposure.

DEET (N,N-Diethyl-m-toluamide) is one of the most widely used mosquito repellents. Although DEET has been shown to be extremely effective, recent studies have revealed that certain individual insects are unaffected by its presence. A genetic basis for this has been shown in Aedes aegypti mosquitoes and the fruit fly Drosophila melanogaster, but, for the triatomine bug, Rhodnius prolixus, a decrease in response to DEET occurred shortly after previous exposure, indicating that non-genetic factors may also be involved in DEET "insensitivity". In this study, we examined host-seeking behaviour and electrophysiological responses of A. aegypti after pre-exposure to DEET. We found that three hours after pre-exposure the mosquitoes showed behavioural insensitivity, and electroantennography revealed this correlated with the olfactory receptor neurons responding less to DEET. The change in behaviour as a result of pre-exposure to DEET has implications for the use of repellents and the ability of mosquitoes to overcome them.

The diversity of class II transposable elements in mammalian genomes has arisen from ancestral phylogenetic splits during ancient waves of proliferation through the genome.

DNA transposons make up 3% of the human genome, approximately the same percentage as genes. However, because of their inactivity, they are often ignored in favor of the more abundant, active, retroelements. Despite this relative ignominy, there are a number of interesting questions to be asked of these transposon families. One particular question relates to the timing of proliferation and inactivation of elements in a family. Does an ongoing process of turnover occur, or is the process more akin to a life cycle for the family, with elements proliferating rapidly before deactivation at a later date? We answer this question by tracing back to the most recent common ancestor (MRCA) of each modern transposon family, using two different methods. The first method identifies the MRCA of the species in which a family of transposon fossils can still be found, which we assume will have existed soon after the true origin date of the transposon family. The second method uses molecular dating techniques to predict the age of the MRCA element from which all elements found in a modern genome are descended. Independent data from five pairs of species are used in the molecular dating analysis: human-chimpanzee, human-orangutan, dog-panda, dog-cat, and cow-pig. Orthologous pairs of elements from host species pairs are included, and the divergence dates of these species are used to constrain the analysis. We discover that, in general, the times to element common ancestry for a given family are the same for the different species pairs, suggesting that there has been no order-specific process of turnover. Furthermore, for most families, the ages of the common ancestor of the host species and of that of the elements are similar, suggesting a life cycle model for the proliferation of transposons. Where these two ages differ, in families found only in Primates and Rodentia, for example, we find that the host species date is later than that of the common ancestor of the elements, implying that there may be large deletions of elements from host species, examples of which were found in their ancestors.

Host-parasite relationships in the genome.

Transposable elements are best interpreted as genomic parasites, proliferating in genomes through their over-replication relative to the rest of the genome. A new study examining correlations across Drosophila species between transposable element numbers and rates of host evolution has brought into focus one of the most complex questions in transposable element biology-what it is that determines the proportion of the genome that is transposable elements.

Investigation of the origin and spread of a Mammalian transposable element based on current sequence diversity.

Almost half the human genome consists of mobile DNA elements, and their analysis is a vital part of understanding the human genome as a whole. Many of these elements are ancient and have persisted in the genome for tens or hundreds of millions of years, providing a window into the evolution of modern mammals. The Golem family have been used as model transposons to highlight computational analyses which can be used to investigate these elements, particularly the use of molecular dating with large transposon families. Whole-genome searches found Golem sequences in 20 mammalian species. Golem A and B subsequences were only found in primates and squirrel. Interestingly, the full-length Golem, found as a few copies in many mammalian genomes, was found abundantly in horse. A phylogenetic profile suggested that Golem originated after the eutherian-metatherian divergence and that the A and B subfamilies originated at a much later date. Molecular dating based on sequence diversity suggests an early age, of 175 Mya, for the origin of the family and that the A and B lineages originated much earlier than expected from their current taxonomic distribution and have subsequently been lost in some lineages. Using publically available data, it is possible to investigate the evolutionary history of transposon families. Determining in which organisms a transposon can be found is often used to date the origin and expansion of the families. However, in this analysis, molecular dating, commonly used for determining the age of gene sequences, has been used, reducing the likelihood of errors from deleted lineages.

Behavioral insensitivity to DEET in Aedes aegypti is a genetically determined trait residing in changes in sensillum function.

N,N-Diethyl-m-toluamide (DEET) is one of the most effective and commonly used mosquito repellents. However, during laboratory trials a small proportion of mosquitoes are still attracted by human odors despite the presence of DEET. In this study behavioral assays identified Aedes aegypti females that were insensitive to DEET, and the selection of either sensitive or insensitive groups of females with males of unknown sensitivity over several generations resulted in two populations with different proportions of insensitive females. Crossing experiments showed the "insensitivity" trait to be dominant. Electroantennography showed a reduced response to DEET in the selected insensitive line compared with the selected sensitive line, and single sensillum recordings identified DEET-sensitive sensilla that were nonresponders in the insensitive line. This study suggests that behavioral insensitivity to DEET in A. aegypti is a genetically determined dominant trait and resides in changes in sensillum function.

Experimental evolution: the rate of adaptive evolution.

Next-generation sequencing technology allows the identification of molecular changes that have arisen in the genomes of microorganisms undergoing experimental evolution. This permits the elucidation of the molecular evolutionary dynamics in these populations.

Source gene composition and gene conversion of the AluYh and AluYi lineages of retrotransposons.

BACKGROUND: Alu elements are a family of SINE retrotransposons in primates. They are classified into subfamilies according to specific diagnostic mutations from the general Alu consensus. It is now believed that there may be several retrotranspositionally-competent source genes within an Alu subfamily. In this study, subfamilies falling on the AluYi and AluYh lineages, and the AluYg6 subfamily, are assessed for the presence of secondary source genes, and the influence of gene conversion on the AluYh and AluYi lineages is also described. RESULTS: The AluYh7 and AluYi6 subfamilies appear to contain multiple source genes. The novel subfamilies AluYh3a1 and AluYh3a3 are described, for which there is no convincing evidence to suggest the presence of secondary sources. The mutational substructure of AluYh3a3 can be explained completely by inference of single master gene. A complete backwards gene conversion event appears to have inactivated the AluYh3a3 master gene in humans. Polymorphism data suggest a larger number of secondary source elements may be active in the AluYg6 family than previously thought. CONCLUSION: It is clear that there is considerable variation in the number of source genes present in each of the young Alu subfamilies. This can range from a single master source gene, as for AluYh3a3, to as many as 14 source elements in AluYi6.

The evolutionary influence of binding site organisation on gene regulatory networks.

Gene regulatory networks are shaped by selection for advantageous gene expression patterns. Can we use this fact to predict and explain the structure and properties of gene regulatory networks? Here we address this question with evolutionary simulations of small (two to four genes) transcriptional regulatory networks. Each modeled network is tested for the frequency with which it evolves to produce a bimodal spatial expression pattern of a target gene (the output), in response to a linear trigger gradient (the input). By including network features such as the organisation of binding sites that do not evolve in the model, we can compare the relative chances of evolutionary success between networks differing only in these features. Specifically, we show that networks with competitive binding sites (where binding of one transcription factor excludes another) are more likely to evolve bimodal patterns of gene repression than are networks with independent binding sites (where binding of multiple transcription factors can occur simultaneously). These predictions have implications for the likely structure of gene regulatory networks carrying out bimodal (including bistable) gene expression functions in vivo. The capacity to predict the evolution of structure-function relationships in gene regulatory networks is constrained by gaps in current understanding such as the unknown prior probabilities of the network features, and the quantitative nature of the molecular interactions involved in gene expression. Methods for the circumvention of these constraints, and the potential of the evolutionary modeling approach, are discussed.

Evolution and evolvability: celebrating Darwin 200.

The concept of 'evolvability' is increasingly coming to dominate considerations of evolutionary change. There are, however, a number of different interpretations that have been put on the idea of evolvability, differing in the time scales over which the concept is applied. For some, evolvability characterizes the potential for future adaptive mutation and evolution. Others use evolvability to capture the nature of genetic variation as it exists in populations, particularly in terms of the genetic covariances between traits. In the latter use of the term, the applicability of the idea of evolvability as a measure of population's capacity to respond to natural selection rests on one, but not the only, view of the way in which we should envisage the process of natural selection. Perhaps the most potentially confusing aspects of the concept of evolvability are seen in the relationship between evolvability and robustness.

Evolutionary modelling of feed forward loops in gene regulatory networks.

Feed forward loops (FFLs) are gene regulatory network motifs. They exist in different types, defined by the signs of the effects of genes in the motif on one another. We examine 36 feed forward loops in Escherichia coli, using evolutionary simulations to predict the forms of FFL expected to evolve to generate the pattern of expression of the output gene. These predictions are tested using likelihood ratios, comparing likelihoods of the observed FFL structures with their likelihoods under null models. The very high likelihood ratios generated, of over 10(11), suggest that evolutionary simulation is a valuable component in the explanation of FFL structure.