Multivariate heredity of melanin-based coloration,body mass and immunity

The genetic covariation among different traits may cause the appearance of correlated response to selection on multivariate phenotypes. Genes responsible for the expression of melanin-based color traits are also involved in other important physiological functions such as immunity and metabolism by pleiotropy, suggesting the possibility of multivariate evolution. However, little is known about the relationship between melanin coloration and these functions at the additive genetic level in wild vertebrates. From a multivariate perspective, we simultaneously explored inheritance and selection of melanin coloration, body mass and phytohemagglutinin (PHA)-mediated immune response by using long-term data over an 18-year period collected in a wild population of the common kestrel Falco tinnunculus. Pedigree-based quantitative genetic analyses showed negative genetic covariance between melanin-based coloration and body mass in male adults and positive genetic covariance between body mass and PHA-mediated immune response in fledglings as predicted by pleiotropic effects of melanocortin receptor activity. Multiple selection analyses showed an increased fitness in male adults with intermediate phenotypic values for melanin color and body mass. In male fledglings, there was evidence for a disruptive selection on rump gray color, but a stabilizing selection on PHA-mediated immune response. Our results provide an insight into the evolution of multivariate traits genetically related with melanin-based coloration. The differences in multivariate inheritance and selection between male and female kestrels might have resulted in sexual dimorphism in size and color. When pleiotropic effects are present, coloration can evolve through a complex pathway involving correlated response to selection on multivariate traits.     

EVOLVABILITY OF INDIVIDUAL TRAITS IN A MULTIVARIATE CONTEXT: PARTITIONING THE ADDITIVE GENETIC VARIANCE INTO COMMON AND SPECIFIC COMPONENTS

Genetic covariation among multiple traits will bias the direction of evolution. Although a trait's phenotypic context is crucial for understanding evolutionary constraints, the evolutionary potential of one (focal) trait, rather than the whole phenotype, is often of interest. The extent to which a focal trait can evolve independently depends on how much of the genetic variance in that trait is unique. Here, we present a hypothesis‐testing framework for estimating the genetic variance in a focal trait that is independent of variance in other traits. We illustrate our analytical approach using two Drosophila bunnanda trait sets: a contact pheromone system comprised of cuticular hydrocarbons (CHCs), and wing shape, characterized by relative warps of vein position coordinates. Only 9% of the additive genetic variation in CHCs was trait specific, suggesting individual traits are unlikely to evolve independently. In contrast, most (72%) of the additive genetic variance in wing shape was trait specific, suggesting relative warp representations of wing shape could evolve independently. The identification of genetic variance in focal traits that is independent of other traits provides a way of studying the evolvability of individual traits within the broader context of the multivariate phenotype.     

Effects on phenotypic variability of directional selection arising through genetic differences in residual variability

In standard models of quantitative traits, genotypes are assumed to differ in mean but not variance of the trait. Here we consider directional selection for a quantitative trait for which genotypes also confer differences in variability, viewed either as differences in residual phenotypic variance when individual loci are concerned or as differences in environmental variability when the whole genome is considered. At an individual locus with additive effects, the selective value of the increasing allele is given by ia/sigma + 1/2 ixb/sigma2, where i is the selection intensity, x is the standardized truncation point, sigma2 is the phenotypic variance, and a/sigma and b/sigma2 are the standardized differences in mean and variance respectively between genotypes at the locus. Assuming additive effects on mean and variance across loci, the response to selection on phenotype in mean is isigma2(Am)/sigma + 1/2 ixcov(Amv)/sigma2 and in variance is icov(Amv)/sigma + 1/2 ixsigma2(Av)/sigma2, where sigma2(Am) is the (usual) additive genetic variance of effects of genes on the mean, sigma2(Av) is the corresponding additive genetic variance of their effects on the variance, and cov(Amv) is the additive genetic covariance of their effects. Changes in variance also have to be corrected for any changes due to gene frequency change and for the Bulmer effect, and relevant formulae are given. It is shown that effects on variance are likely to be greatest when selection is intense and when selection is on individual phenotype or within family deviation rather than on family mean performance. The evidence for and implications of such variability in variance are discussed.     

Epistasis Is a Major Determinant of the Additive Genetic Variance in Mimulus guttatus

The influence of genetic interactions (epistasis) on the genetic variance of quantitative traits is a major unresolved problem relevant to medical, agricultural, and evolutionary genetics. The additive genetic component is typically a high proportion of the total genetic variance in quantitative traits, despite that underlying genes must interact to determine phenotype. This study estimates direct and interaction effects for 11 pairs of Quantitative Trait Loci (QTLs) affecting floral traits within a single population of Mimulus guttatus. With estimates of all 9 genotypes for each QTL pair, we are able to map from QTL effects to variance components as a function of population allele frequencies, and thus predict changes in variance components as allele frequencies change. This mapping requires an analytical framework that properly accounts for bias introduced by estimation errors. We find that even with abundant interactions between QTLs, most of the genetic variance is likely to be additive. However, the strong dependency of allelic average effects on genetic background implies that epistasis is a major determinant of the additive genetic variance, and thus, the population’s ability to respond to selection.     

Phenotypic variation and covariation indicate high evolvability of acoustic communication in crickets

Studying the genetic architecture of sexual traits provides insight into the rate and direction at which traits can respond to selection. Traits associated with few loci and limited genetic and phenotypic constraints tend to evolve at high rates typically observed for secondary sexual characters. Here, we examined the genetic architecture of song traits and female song preferences in the field crickets Gryllus rubens and Gryllus texensis. Song and preference data were collected from both species and interspecific F1 and F2 hybrids. We first analysed phenotypic variation to examine interspecific differentiation and trait distributions in parental and hybrid generations. Then, the relative contribution of additive and additive‐dominance variation was estimated. Finally, phenotypic variance–covariance ( P ) matrices were estimated to evaluate the multivariate phenotype available for selection. Song traits and preferences had unimodal trait distributions, and hybrid offspring were intermediate with respect to the parents. We uncovered additive and dominance variation in song traits and preferences. For two song traits, we found evidence for X‐linked inheritance. On the one hand, the observed genetic architecture does not suggest rapid divergence, although sex linkage may have allowed for somewhat higher evolutionary rates. On the other hand, P matrices revealed that multivariate variation in song traits aligned with major dimensions in song preferences, suggesting a strong selection response. We also found strong covariance between the main traits that are sexually selected and traits that are not directly selected by females, providing an explanation for the striking multivariate divergence in male calling songs despite limited divergence in female preferences.     

The role of founder effects on the evolution of reproductive isolation

Several theories argue that large changes in allele frequencies through genetic drift after a small founding population becomes allopatrically isolated can lead to significant changes in reproductive isolation and thus trigger the origin of new species. For this reason, founder speciation has been proposed as a potent force in the generation of new species. Nonetheless, the relative importance of such ‘founder effects’ remains largely untested. In this report, I used experimental evolution to create one thousand replicates that underwent an extreme bottleneck and to study whether founder effects can lead to an increase in reproductive isolation in Drosophila yakuba. Even though the most common outcome of inbreeding is extinction, founder effects can lead to increased premating reproductive isolation in a very small proportion of cases. Changes in reproductive isolation after a founding population bottleneck are similar to changes in other phenotypic traits, in which inbreeding might displace the mean phenotypic value and substantially increase the phenotypic variance. This increase in phenotypic variance does not confer an increase in the response to selection for reproductive isolation in artificial selection experiments, indicating that the increased phenotypic variance is not caused by increases in additive genetic variance. These results also demonstrate that, similar to morphological and life‐history traits, behavioural traits can be affected by inbreeding and genetic drift.     

The role of genetic constraints on the diversification of Iberian taxa of the genus Aquilegia (Ranunculaceae)

The microevolutionary process of adaptive phenotypic differentiation of quantitative traits between populations or closely‐related taxa depends on the response of populations to the action of natural selection. However, this response can be constrained by the structure of the matrix of additive genetic variance and covariance between traits in each population ( G matrix). In the present study, we obtained additive genetic variance and narrow sense heritability for 25 floral and vegetative traits of three subspecies of Aquilegia vulgaris, and one subspecies of Aquilegia pyrenaica through a common garden crossing experiment. For two vegetative and one floral trait, we also obtained the G matrix and genetic correlations between traits in each subspecies. The amount of genetic variation available in wild populations is not responsible for the larger differentiation of vegetative than floral traits found in this group of columbines. However, the low heritability of some traits constrained their evolution because phenotypic variability among taxa was larger for traits with larger heritability. We confirmed that the process of diversification of the studied taxa involved shifts in the G matrix, mainly determined by changes in the genetic covariance between floral and vegetative traits, probably caused by linkage disequilibrium in narrow endemic taxa. © 2013 The Linnean Society of London, Biological Journal of the Linnean Society, 2014, 111 , 252–261.     

PARENTAL EFFECTS ON SEED DEVELOPMENT AND SEED YIELD IN RAPHANUS RAPHANISTRUM: IMPLICATIONS FOR NATURAL AND SEXUAL SELECTION

The possibility that sexual selection operates in angiosperms to effect evolutionary change in polygenic traits affecting male reproductive success requires that there is additive genetic variance for these traits. I applied a half-sib breeding design to individuals of the annual, hermaphroditic angiosperm, wild radish (Raphanus raphanistrum: Brassicaceae), to estimate paternal genetic effects on, or, when possible, the narrow-sense heritability of several quantitative traits influencing male reproductive success. In spite of significant differences among pollen donors with respect to in vitro pollen tube growth rates, I detected no significant additive genetic variance in male performance with respect to the proportion of ovules fertilized, early ovule growth, the number of seeds per fruit, or mean individual seed weight per fruit. In all cases, differences among maternal plants in these traits far exceeded differences among pollen donors. Abortion rates of pollinated flowers and fertilized ovules also differed more among individuals as maternal plants than as pollen donors, suggesting strong maternal control over these processes. Significant maternal phenotypic effects in the absence of paternal genetic or phenotypic effects on reproductive traits may be due to maternal environmental effects, to non-nuclear or non-additive maternal genetic effects, or to additive genetic variance in maternal control over offspring development, independent of offspring genotype. While I could not distinguish among these alternatives, it is clear that, in wild radish, the opportunity for natural or sexual selection to effect change in seed weight or seed number per fruit appears to be greater through differences in female performance than through differences in male performance.     

Rapid genome‐wide evolution in Brassica rapa populations following drought revealed by sequencing of ancestral and descendant gene pools

There is increasing evidence that evolution can occur rapidly in response to selection. Recent advances in sequencing suggest the possibility of documenting genetic changes as they occur in populations, thus uncovering the genetic basis of evolution, particularly if samples are available from both before and after selection. Here, we had a unique opportunity to directly assess genetic changes in natural populations following an evolutionary response to a fluctuation in climate. We analysed genome‐wide differences between ancestors and descendants of natural populations of Brassica rapa plants from two locations that rapidly evolved changes in multiple phenotypic traits, including flowering time, following a multiyear late‐season drought in California. These ancestor‐descendant comparisons revealed evolutionary shifts in allele frequencies in many genes. Some genes showing evolutionary shifts have functions related to drought stress and flowering time, consistent with an adaptive response to selection. Loci differentiated between ancestors and descendants (F_ST outliers) were generally different from those showing signatures of selection based on site frequency spectrum analysis (Tajima's D), indicating that the loci that evolved in response to the recent drought and those under historical selection were generally distinct. Very few genes showed similar evolutionary responses between two geographically distinct populations, suggesting independent genetic trajectories of evolution yielding parallel phenotypic changes. The results show that selection can result in rapid genome‐wide evolutionary shifts in allele frequencies in natural populations, and highlight the usefulness of combining resurrection experiments in natural populations with genomics for studying the genetic basis of adaptive evolution.     

Inheritance Beyond Plain Heritability: Variance-Controlling Genes in Arabidopsis thaliana

The phenotypic effect of a gene is normally described by the mean-difference between alternative genotypes. A gene may, however, also influence the phenotype by causing a difference in variance between genotypes. Here, we reanalyze a publicly available Arabidopsis thaliana dataset [1] and show that genetic variance heterogeneity appears to be as common as normal additive effects on a genomewide scale. The study also develops theory to estimate the contributions of variance differences between genotypes to the phenotypic variance, and this is used to show that individual loci can explain more than 20% of the phenotypic variance. Two well-studied systems, cellular control of molybdenum level by the ion-transporter MOT1 and flowering-time regulation by the FRI-FLC expression network, and a novel association for Leaf serration are used to illustrate the contribution of major individual loci, expression pathways, and gene-by-environment interactions to the genetic variance heterogeneity.     

Sexual selection in the cricket <Emphasis Type="Italic">Gryllus bimaculatus</Emphasis>: no good genes?

Recent studies have suggested that females of the field cricket Gryllus bimaculatus exercise post-copulatory choice over the paternity of their offspring. There is evidence that these choices are made in relation to the genetic compatibility of mates rather than their absolute quality, but the magnitude of heritable differences in males has not been thoroughly examined. Using a half-sib breeding design we measured additive genetic variance and dam effects in a suite of reproductive and non-reproductive traits. Both components explained relatively little of the phenotypic variance across traits. The dam component in our design contains variance caused by both maternal effects and dominance. If maternal effects are negligible as suggested by previous studies, our data suggest that dominance variance is an important source of variation in these traits. The lack of additive genetic variation, but possible existence of large amounts of non-additive genetic variation is consistent with the idea that female mate choice and multiple mating may be driven by differences in genetic compatibility between potential mates rather than by differences in genetic quality.     

Polymorphisms in a desaturase 2 ortholog associate with cuticular hydrocarbon and male mating success variation in a natural population of Drosophila serrata

Elucidating the nature of genetic variation underlying both sexually selected traits and the fitness components of sexual selection is essential to understanding the broader consequences of sexual selection as an evolutionary process. To date, there have been relatively few attempts to connect the genetic variance in sexually selected traits with segregating DNA sequence polymorphisms. We set out to address this in a well‐characterized sexual selection system – the cuticular hydrocarbons (CHCs) of Drosophila serrata – using an indirect association study design that allowed simultaneous estimation of the genetic variance in CHCs, sexual fitness and single nucleotide polymorphism (SNP) effects in an outbred population. We cloned and sequenced an ortholog of the D. melanogaster desaturase 2 gene, previously shown to affect CHC biosynthesis in D. melanogaster, and associated 36 SNPs with minor allele frequencies > 0.02 with variance in CHCs and sexual fitness. Three SNPs had significant multivariate associations with CHC phenotype (q‐value < 0.05). At these loci, minor alleles had multivariate effects on CHCs that were weakly associated with the multivariate direction of sexual selection operating on these traits. Two of these SNPs had pleiotropic associations with male mating success, suggesting these variants may underlie responses to sexual selection due to this locus. There were 15 significant male mating success associations (q‐value < 0.1), and interestingly, we detected a nonrandom pattern in the relationship between allele frequency and direction of effect on male mating success. The minor‐frequency allele usually reduced male mating success, suggesting a positive association between male mating success and total fitness at this locus.     

EPISTASIS AS A SOURCE OF INCREASED ADDITIVE GENETIC VARIANCE AT POPULATION BOTTLENECKS

The role of epistasis in evolution and speciation has remained controversial. We use a new parameterization of physiological epistasis to examine the effects of epistasis on levels of additive genetic variance during a population bottleneck. We found that all forms of epistasis increase average additive genetic variance in finite populations derived from initial populations with intermediate allele frequencies. Average additive variance continues to increase over many generations, especially at larger population sizes (N = 32 to 64). Additive-by-additive epistasis is the most potent source of additive genetic variance in this situation, whereas dominance-by-dominance epistasis contributes smaller amounts of additive genetic variance. With additive-by-dominance epistasis, additive genetic variance decreases at a relatively high rate immediately after a population bottleneck, rebounding to higher levels after several generations. Empirical examples of epistasis for murine adult body weight based on measured genotypes are provided illustrating the varying effects of epistasis on additive genetic variance during population bottlenecks.     

CONTRASTING PATTERNS OF HERITABLE GEOGRAPHIC VARIATION IN SHELL MORPHOLOGY AND GROWTH POTENTIAL IN THE MARINE GASTROPOD BEMBICIUM VITTATUM: EVIDENCE FROM FIELD EXPERIMENTS

Similar phenotypes do not always imply similar genotypes. In species distributed over a broad latitudinal range, geographical variation in morphological and life-history traits may reflect very different relations between genotypic and environmental effects on these traits. Patterns of selection among latitudinally separated sites may minimize phenotypic differences in life-history traits but promote phenotypic differences in form. Thus, for example, latitudinal variation in temperature often leads to genetically based metabolic differences that minimize differences in growth rate among populations at different latitudes (countergradient variation). However, variation in habitat experienced by the same populations may promote genetically based differences in shell form (cogradient variation). Few attempts have been made to assess simultaneously such mosaic effects of natural selection on the genetic basis of variation in both morphological and life-history traits among geographically separated populations. I quantified the extent to which widely separated populations of the rocky shore marine gastropod Bembicium vittatum exhibited genetic differences in shell shape, shell pattern, and growth rate. Bembicium vittatum occurs naturally at only three widely separated locations on the Western Australian coast. Individuals were transplanted from all three locations to a latitudinally intermediate site, where they were released in different pairwise combinations and allowed to reproduce. F₁ offspring from crosses between same- or different-source parents were identified using allozyme markers. When grown in a common environment, offspring from same-source parents exhibited similar differences in shell shape and pattern, but dramatic differences in growth rates, compared to native populations. Genetic variation therefore exists for all three traits. Growth rates in the common environment were positively correlated with latitude of the source population, confirming the existence of countergradient variation for growth associated with metabolic compensation. In addition, for both shell shape and growth rate, hybrids exhibited phenotypes roughly midway between the same-source parents, suggesting that genetic differences have a large additive component. In contrast, when one parent had pigmented spots, the offspring also had spots, suggesting a strong dominance component to the genetic basis of shell pattern. Genetic differences therefore yield different morphological phenotypes but similar life-history phenotypes, among latitudinally distant populations, and confirm a pattern of mosaic evolution in B. vittatum.     

The convergent evolution of blue iris pigmentation in primates took distinct molecular paths

How many distinct molecular paths lead to the same phenotype? One approach to this question has been to examine the genetic basis of convergent traits, which likely evolved repeatedly under a shared selective pressure. We investigated the convergent phenotype of blue iris pigmentation, which has arisen independently in four primate lineages: humans, blue‐eyed black lemurs, Japanese macaques, and spider monkeys. Characterizing the phenotype across these species, we found that the variation within the blue‐eyed subsets of each species occupies strongly overlapping regions of CIE L*a*b* color space. Yet whereas Japanese macaques and humans display continuous variation, the phenotypes of blue‐eyed black lemurs and their sister species (whose irises are brown) occupy more clustered subspaces. Variation in an enhancer of OCA2 is primarily responsible for the phenotypic difference between humans with blue and brown irises. In the orthologous region, we found no variant that distinguishes the two lemur species or associates with quantitative phenotypic variation in Japanese macaques. Given the high similarity between the blue iris phenotypes in these species and that in humans, this finding implies that evolution has used different molecular paths to reach the same end. Am J Phys Anthropol 151:398–407, 2013.© 2013 Wiley Periodicals, Inc.     

Dominance Genetic Variance for Traits Under Directional Selection in Drosophila serrata

In contrast to our growing understanding of patterns of additive genetic variance in single- and multi-trait combinations, the relative contribution of nonadditive genetic variance, particularly dominance variance, to multivariate phenotypes is largely unknown. While mechanisms for the evolution of dominance genetic variance have been, and to some degree remain, subject to debate, the pervasiveness of dominance is widely recognized and may play a key role in several evolutionary processes. Theoretical and empirical evidence suggests that the contribution of dominance variance to phenotypic variance may increase with the correlation between a trait and fitness; however, direct tests of this hypothesis are few. Using a multigenerational breeding design in an unmanipulated population of Drosophila serrata, we estimated additive and dominance genetic covariance matrices for multivariate wing-shape phenotypes, together with a comprehensive measure of fitness, to determine whether there is an association between directional selection and dominance variance. Fitness, a trait unequivocally under directional selection, had no detectable additive genetic variance, but significant dominance genetic variance contributing 32% of the phenotypic variance. For single and multivariate morphological traits, however, no relationship was observed between trait–fitness correlations and dominance variance. A similar proportion of additive and dominance variance was found to contribute to phenotypic variance for single traits, and double the amount of additive compared to dominance variance was found for the multivariate trait combination under directional selection. These data suggest that for many fitness components a positive association between directional selection and dominance genetic variance may not be expected.     

Adcyap1 polymorphism covaries with breeding latitude in a Nearctic migratory songbird,the Wilson's warbler (Cardellina pusilla)

Understanding the genetic background of complex behavioral traits, showing multigenic control and extensive environmental effects, is a challenging task. Among such traits, migration is known to show a large additive genetic component. Yet, the identification of specific genes or gene regions explaining phenotypic variance in migratory behavior has received less attention. Migration ultimately depends on seasonal cycles, and polymorphism at phenological candidate genes may underlie variation in timing of migration or other aspects of migratory behavior. In this study of a Nearctic–Neotropical migratory songbird, the Wilson's warbler (Cardellina pusilla), we investigated the association between polymorphism at two phenological candidate genes, Clock and Adcyap1, and two aspects of the migratory phenotype, timing of spring migration through a stopover site and inferred latitude of the breeding destination. The breeding destination of migrating individuals was identified using feather deuterium ratio (δ²H), which reliably reflects breeding latitude throughout the species' western breeding range. Ninety‐eight percent of the individuals were homozygous at Clock, and the rare heterozygotes did not deviate from homozygous migration phenology. Adcyap1 was highly polymorphic, and allele size was not significantly associated with migration date. However, Adcyap1 allele size significantly positively predicted the inferred breeding latitude of males but not of females. Moreover, we found a strong positive association between inferred breeding latitude and Adcyap1 allele size in long‐distance migrating birds from the northern sector of the breeding range (western Canada), while this was not the case in short‐distance migrating birds from the southern sector of the breeding range (coastal California). Our findings support previous evidence for a role of Adcyap1 in shaping the avian migratory phenotype, while highlighting that patterns of phenological candidate gene–phenotype associations may be complex, significantly varying between geographically distinct populations and even between the sexes.     

QUANTITATIVE GENETICS OF BRYOZOAN PHENOTYPIC EVOLUTION. III. PHENOTYPIC PLASTICITY AND THE MAINTENANCE OF GENETIC VARIATION

Cheilostome bryozoan species show long-term morphologic stasis, implying stabilizing selection sustained for millions of years, but nevertheless retain significant heritable variation in traits of skeletal morphology. The possible role of within-genotype (within-colony) phenotypic variability in preserving genetic diversity was analyzed using breeding data for two species of Stylopoma from sites along 110 km of the Caribbean coast of Panama. Variation among zooids within colonies accounts for nearly two-thirds of the phenotypic variance on average, increases with environmental heterogeneity, and includes significant genotype-environment interaction. Thus, within-colony variability apparently represents phenotypic plasticity, at least some of which is heritable, rather than random “developmental noise.” Almost all of the among-colonies component of phenotypic variance is accounted for by additive genetic differences in trait means, suggesting that within-colony plasticity includes virtually all of the environmental component of phenotypic variance in these populations of Stylopoma. Thus, heritable within-colony plasticity could play a significant part in maintaining genetic diversity in cheilostomes, but it is also possible that rates of polygenic mutation alone are sufficient to balance the effects of selection.     

Genetic architecture and maternal contributions of early‐life survival in lake trout Salvelinus namaycush

The influences of additive, non‐additive and maternal effects on early survival (uneyed embryo survival, eyed embryo survival, alevin survival and overall survival to first feeding) were quantified in lake trout Salvelinus namaycush using a 7 × 7 full‐factorial breeding design. Maternal effects followed by non‐additive genetic effects explained around one third of the phenotypic variance of the survival traits. Although the amount of additive genetic effects were low (<1%), suggesting a limited potential of the traits to respond to new selection pressures, how maternal and non‐additive genetic effects may respond to selection under certain circumstances are discussed.     

Effects of Interaction between Angiotensin I‐Converting Enzyme Polymorphisms and Lifestyle on Adiposity in Adolescent Greeks

Genetic variation in the human angiotensin I‐converting enzyme (ACE) gene has been associated with many heritable traits, including obesity. Herein, we report the results of a study of obesity‐related phenotypes and lifestyle in 1016 teen‐aged Greeks. We show that there is a strong association (p = 0.001) between subcutaneous fat and the ACE insertion/deletion (I/D) polymorphism in females, possession of genotypes containing the D allele being associated with increased fat thickness. This association is strongest in females who participate in no extra exercise and accounts for 6.5% of the phenotypic variance in fat thickness by ANOVA. The association is additive, with the mean phenotypic values in heterozygotes intermediate between the means of the two homozygotes, and the association acts at both extremes of the fat thickness distribution in a classical polygenic manner. Other ACE polymorphisms (rs4424958, rs4311) that define major haplotypes in European populations fail to provide stronger associations with the subcutaneous fat phenotype. Because ACE I/D is the polymorphism most strongly associated with circulating ACE levels in European populations, we propose that the functional allelic differences that influence circulating ACE levels also mediate the associations with the obesity‐related phenotypes studied here.