The genotype-phenotype relationship and evolutionary genetics in the light of the Metabolic Control Analysis.

Metabolic control analysis has long been used as a systemic model of the genotype-phenotype (GP) relationship. By considering kinetic parameters and enzyme concentrations as reflecting the genotype level and metabolic fluxes or pools as phenotypes related to fitness, MCA has given a biological basis to the relationship between these two levels. The non-linear and concave relationship between enzymes and fluxes can account for common genetic effects that reductionist approaches have been powerless to explain, such as the dominance of active alleles over less active alleles, the various types of epistasis and heterosis, and reveals the structural links between these genetic effects. The summation property of the flux control coefficients accounts for the L-shaped distribution of Quantitative Trait Locus (QTL) effects, irrespective of other possible causes. Metabolic models of response to selection results in evolutionary scenarios that are markedly different from those derived from the classical infinitesimal model of quantitative genetics. In particular, evolution towards selective neutrality appears to be a consequence of the diminishing return of the flux-enzyme relationship. In this paper, we survey the historical and recent achievements of MCA in genetics, quantitative genetics and evolution, focusing on epistasis and the evolution of flux in relation to enzyme concentrations.

The decoupling between genetic structure and metabolic phenotypes in Escherichia coli leads to continuous phenotypic diversity.

To assess the extent of intra-species diversity and the links between phylogeny, lifestyle (habitat and pathogenicity) and phenotype, we assayed the growth yield on 95 carbon sources of 168 Escherichia strains. We also correlated the growth capacities of 14 E. coli strains with the presence/absence of enzyme-coding genes. Globally, we found that the genetic distance, based on multilocus sequence typing data, was a weak indicator of the metabolic phenotypic distance. Besides, lifestyle and phylogroup had almost no impact on the growth yield of non-Shigella E. coli strains. In these strains, the presence/absence of the metabolic pathways, which was linked to the phylogeny, explained most of the growth capacities. However, few discrepancies blurred the link between metabolic phenotypic distance and metabolic pathway distance. This study shows that a prokaryotic species structured into well-defined genetic and lifestyle groups can yet exhibit continuous phenotypic diversity, possibly caused by gene regulatory effects.

Evidence for autotetraploidy associated with reproductive isolation in Saccharomyces cerevisiae: towards a new domesticated species.

Partial or whole-genome duplications have played a major role in the evolution of new species. We have investigated the variation of ploidy level in a panel of domesticated strains of Saccharomyces cerevisiae coming from different geographical origins. Segregation studies and crosses with tester strains of different ploidy levels showed that part of the strains were well-balanced autotetraploids displaying tetrasomic inheritance. The presence of up to four different alleles for various loci is consistent with a polyploidization mechanism relying on the fusion of two nonreduced meiospores coming from two S. cerevisiae strains. Autotetraploidy was also in accordance with karyotype and flow cytometry analyses. Interestingly, most bakery strains were tetraploids, suggesting a link between ploidy level and human use. The null or drastically reduced fertility of the hybrids between tetraploid and diploid strains indicated that domesticated S. cerevisiae strains are composed of two groups isolated by post-zygotic reproductive barriers.

Fluxes and metabolic pools as model traits for quantitative genetics. I. The L-shaped distribution of gene effects.

The fluxes through metabolic pathways can be considered as model quantitative traits, whose QTL are the polymorphic loci controlling the activity or quantity of the enzymes. Relying on metabolic control theory, we investigated the relationships between the variations of enzyme activity along metabolic pathways and the variations of the flux in a population with biallelic QTL. Two kinds of variations were taken into account, the variation of the average enzyme activity across the loci, and the variation of the activity of each enzyme of the pathway among the individuals of the population. We proposed analytical approximations for the flux mean and variance in the population as well as for the additive and dominance variances of the individual QTL. Monte Carlo simulations based on these approximations showed that an L-shaped distribution of the contributions of individual QTL to the flux variance (R(2)) is consistently expected in an F(2) progeny. This result could partly account for the classically observed L-shaped distribution of QTL effects for quantitative traits. The high correlation we found between R(2) value and flux control coefficients variance suggests that such a distribution is an intrinsic property of metabolic pathways due to the summation property of control coefficients.

Genetic and nongenetic bases for the L-shaped distribution of quantitative trait loci effects.

The L-shaped distribution of estimated QTL effects (R(2)) has long been reported. We recently showed that a metabolic mechanism could account for this phenomenon. But other nonexclusive genetic or nongenetic causes may contribute to generate such a distribution. Using analysis and simulations of an additive genetic model, we show that linkage disequilibrium between QTL, low heritability, and small population size may also be involved, regardless of the gene effect distribution. In addition, a comparison of the additive and metabolic genetic models revealed that estimates of the QTL effects for traits proportional to metabolic flux are far less robust than for additive traits. However, in both models the highest R(2)'s repeatedly correspond to the same set of QTL.

Individual multilocus genotypes using microsatellite polymorphisms to permit the analysis of the genetic variability within and between Italian beef cattle breeds.

We investigated the genetic variability within and between cattle breeds. The polymorphisms of 17 microsatellites were studied in 220 unrelated animals belonging to four Italian beef cattle breeds (Chianina, Marchigiana, Romagnola, and Piemontese). Variations of allelic frequencies were examined to characterize the breeds and their relationships. Wahlund coefficients, Polymorphism Information Content values, and Haldane exact test for Hardy-Weinberg proportions were calculated. The results show that the Hardy-Weinberg equilibrium is not always maintained. Moreover, in addition to the classical genetic distances, a new method, based on the consideration of a multilocus genotype of each animal, was set up to measure the genetic similarity between animals or within groups of animals. All the results showed that, whereas Chianina occupies an intermediate position and Piemontese is the most distinct of all four breeds, Marchigiana and Romagnola display the strongest similarity. The new method also provides evidence that average similarities are always higher within breeds than between breeds. By comparing pairwise the multilocus genotypes, it was also possible to discriminate the individuals with higher or lower genetic similarities so that each breed could be subdivided into two groups of animals in relation to their similarity to the average breed multilocus genotype. High similarities between breeds were detected, somewhat surprisingly, when the most homogeneous groups of each breed were compared. The microsatellite multilocus genotype is particularly efficient in evaluating the between- and within-breeds genetic similarities and for subgrouping genetically more homogeneous animals.

A general algorithm to compute multilocus genotype frequencies under various mating systems.

This paper provides a general method to derive algebraic expressions of genotype frequencies for multiple loci under various mating systems, including random mating, back-crossing, selfing, and full-sib mating. For each mating system, general equations are presented. In the case of three loci, comprehensive tables provide recurrence equations for genotype frequencies under random or self mating, and expected genotype frequencies after two generations of full-sib mating. Our results should prove useful in genetic linkage analysis.

Optimisation of enzyme concentrations for unbranched reaction chains: the concept of combined response coefficient.

In the metabolic control theory, the control coefficient is a key parameter in quantifying the sensitivity of the flux towards an infinitesimal variation of enzyme activity. This concept does not apply just as it is for variations of enzyme concentrations whenever there is spatial, energy or resources limitations in the cell. Due to constraint on total enzyme concentration, the variation of concentration of any given enzyme may affect the concentrations of other enzymes. To take into account these correlations between enzyme concentrations, we propose the concept of "combined response coefficient". Its definition is similar to that of the control coefficient, but its mathematical expression is different. Its range of variation is from -infinity to +1, the null value corresponding to optimum enzyme concentration, i.e. to concentrations that maximise the flux, and the negative values to concentrations beyond the optimum value. A summation property could be derived using a simple weighting of the combined response coefficients, the sum of the weighed coefficient being 0.