James M. Cheverud

Evolutionary consequences of indirect genetic effects

Indirect genetic effects (IGEs) are environmental influences on the phenotype of one individual that are due to the expression of genes in a different, conspecific, individual. Historically, work has focused on the influence of parents on offspring but recent advances have extended this perspective to interactions among other relatives and even unrelated individuals. IGEs lead to complicated pathways of inheritance, where environmental sources of variation can be transmitted across generations and therefore contribute to evolutionary change. The existence of IGEs alters the genotype-phenotype relationship, changing the evolutionary process in some dramatic and non-intuitive ways.

A COMPARISON OF GENETIC AND PHENOTYPIC CORRELATIONS

Genetic variances and correlations lie at the center of quantitative evolutionary theory. They are often difficult to estimate, however, due to the large samples of related individuals that are required. I investigated the relationship of genetic‐ and phenotypic‐correlation magnitudes and patterns in 41 pairs of matrices drawn from the literature in order to determine their degree of similarity and whether phenotypic parameters could be used in place of their genetic counterparts in situations where genetic variances and correlations cannot be precisely estimated. The analysis indicates that squared genetic correlations were on average much higher than squared phenotypic correlations and that genetic and phenotypic correlations had only broadly similar patterns. These results could be due either to biological causes or to imprecision of genetic‐correlation estimates due to sampling error. When only those studies based on the largest sample sizes (effective sample size of 40 or more) were included, squared genetic‐correlation estimates were only slightly greater than their phenotypic counterparts and the patterns of correlation were strikingly similar. Thus, much of the dissimilarity between phenotypic‐ and genetic‐correlation estimates seems to be due to imprecise estimates of genetic correlations. Phenotypic correlations are likely to be fair estimates of their genetic counterparts in many situations. These further results also indicate that genetic and environmental causes of phenotypic variation tend to act on growth and development in a similar manner.

Quantitative genetics and developmental constraints on evolution by selection

It has often been argued that the principles of random mutation and selection are insufficient to account for macroevolutionary phenomena, such as the origin of morphological novelty and directionality in evolution. A third, epigenetic, principle is said to be required and this principle is thought not to be included in microevolutionary theory. The third principle has most recently been identified as internal selection and/or non-random phenotypic effects of mutation. It is shown that the genetic variance/covariance matrix of quantitative genetic theory measures developmental constraints due to internal selection and non-random mutation. The genetic variance/covariance matrix causes the response to selection to deviate from the optimal rate and direction as specified by the selection gradient, which measures direct selection on the phenotypes. Therefore, microevolutionary theory takes account of developmental constraints on evolution by natural selection through the genetic variance/covariance matrix. Theories for predicting the pattern of genetic variance and covariance from stabilizing selection and the phenotypic effects of mutation are discussed.

The road to modularity.

A network of interactions is called modular if it is subdivided into relatively autonomous, internally highly connected components. Modularity has emerged as a rallying point for research in developmental and evolutionary biology (and specifically evo–devo), as well as in molecular systems biology. Here we review the evidence for modularity and models about its origin. Although there is an emerging agreement that organisms have a modular organization, the main open problem is the question of whether modules arise through the action of natural selection or because of biased mutational mechanisms.

PERSPECTIVE:EVOLUTION AND DETECTION OF GENETIC ROBUSTNESS

Abstract Robustness is the invariance of phenotypes in the face of perturbation. The robustness of phenotypes appears at various levels of biological organization, including gene expression, protein folding, metabolic flux, physiological homeostasis, development, and even organismal fitness. The mechanisms underlying robustness are diverse, ranging from thermodynamic stability at the RNA and protein level to behavior at the organismal level. Phenotypes can be robust either against heritable perturbations (e.g., mutations) or nonheritable perturbations (e.g., the weather). Here we primarily focus on the first kind of robustness—genetic robustness—and survey three growing avenues of research: (1) measuring genetic robustness in nature and in the laboratory; (2) understanding the evolution of genetic robustness; and (3) exploring the implications of genetic robustness for future evolution.

The nature and identification of quantitative trait loci: a community’s view

This white paper by eighty members of the Complex Trait Consortium presents a communitys view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?

A simple correction for multiple comparisons in interval mapping genome scans.

Several approaches have been proposed to correct point-wise significance thresholds used in interval-mapping genome scans. A method for significance threshold correction based on the Bonferroni test is presented. This test involves calculating the effective number of independent comparisons performed in a genome scan from the variance of the eigenvalues of the observed marker correlation matrix. The more highly correlated the markers, the higher the variance of the eigenvalues and the lower the number of independent tests performed on a chromosome. This approach was evaluated by mapping 1000 normally distributed phenotypes along chromosomes of varying length and marker density in a population size of 500. Experiment-wise significance thresholds obtained from the simulation are compared to those calculated using the Bonferroni criterion and the newly developed measure of the effective number of independent tests in a genome scan. The Bonferroni calculation produced significance thresholds very similar to those obtained by simulation. The threshold levels for both Bonferroni and simulation analysis depended strongly on the marker density and size of chromosomes. There was a slight bias of about 1% in the thresholds obtained at the 5% and 10% point-wise significance levels. The method introduced here provides a relatively simple correction for multiple comparisons that can be easily calculated using standard statistics packages.

A COMPARISON OF PHENOTYPIC VARIATION AND COVARIATION PATTERNS AND THE ROLE OF PHYLOGENY, ECOLOGY, AND ONTOGENY DURING CRANIAL EVOLUTION OF NEW WORLD MONKEYS

Abstract Similarity of genetic and phenotypic variation patterns among populations is important for making quantitative inferences about past evolutionary forces acting to differentiate populations and for evaluating the evolution of relationships among traits in response to new functional and developmental relationships. Here, phenotypic covariance and correlation structure is compared among Platyrrhine Neotropical primates. Comparisons range from among species within a genus to the superfamily level. Matrix correlation followed by Mantels test and vector correlation among responses to random natural selection vectors (random skewers) were used to compare correlation and variance/covariance matrices of 39 skull traits. Sampling errors involved in matrix estimates were taken into account in comparisons using matrix repeatability to set upper limits for each pairwise comparison. Results indicate that covariance structure is not strictly constant but that the amount of variance pattern divergence observed among taxa is generally low and not associated with taxonomic distance. Specific instances of divergence are identified. There is no correlation between the amount of divergence in covariance patterns among the 16 genera and their phylogenetic distance derived from a conjoint analysis of four already published nuclear gene datasets. In contrast, there is a significant correlation between phylogenetic distance and morphological distance (Mahalanobis distance among genus centroids). This result indicates that while the phenotypic means were evolving during the last 30 millions years of New World monkey evolution, phenotypic covariance structures of Neotropical primate skulls have remained relatively consistent. Neotropical primates can be divided into four major groups based on their feeding habits (fruit-leaves, seed-fruits, insect-fruits, and gum-insect-fruits). Differences in phenotypic covariance structure are correlated with differences in feeding habits, indicating that to some extent changes in interrelationships among skull traits are associated with changes in feeding habits. Finally, common patterns and levels of morphological integration are found among Platyrrhine primates, suggesting that functional/developmental integration could be one major factor keeping covariance structure relatively stable during evolutionary diversification of South American monkeys. Corresponding Editor: T. Mousseau

Methods for the Comparative Analysis of Variation Patterns

-Although comparisons of variation patterns with theoretical expectations and across species are playing an increasingly important role in systematics, there has been a lack of appropriate procedures for statistically testing the proposed hypotheses. We present a series of statistical tests for hypotheses of morphological integration and for interspecific comparison, along with examples of their application. These tests are based on various randomization and resampling procedures, such as Mantels test with its recent extensions and bootstrapping. They have the advantage of avoiding the specific and strict distributional assumptions invoked by analytically-based statistics. The statistical procedures described include one for testing the fit of observed correlation matrices to hypotheses of morphological integration and a related test for significant differences in the fit of two alternative hypotheses of morphological integration to the observed correlation structure. Tests for significant similarity in the patterns and magnitudes of variance and correlation among species are also provided. [Morphometrics; comparative analysis; morphological integration; quadratic assignment procedures; Mantels test; bootstrap.] Comparing observed patterns of morphometric variation to theories of morphological integration (Olson and Miller, 1958; Cheverud, 1982) and among species, or subspecific populations (Arnold, 1981; Riska, 1985), has been a largely ad hoc procedure. Previously, a large body of methods has been used to analyze variation patterns, including various forms of cluster analysis, factor analysis, principal components, multi-dimensional scaling, matrix correlations, and visual inspection. The results of such analyses were then discussed relative to some theory of variation patterns or compared between species or populations. These comparisons might either be verbal or quantitative, but tests of statistical significance were rarely employed. More recently, there has been an increase in statistical rigor in the field, particularly involving the use of quadratic assignment procedures (QAP; sometimes referred to as Mantels test) (Mantel, 1967; Deitz, 1983; Dow and Cheverud, 1985; Smouse et al., 1986; Dow et al., 1987a, b; Hubert, 1987) for testing the statistical significance of matrix comparisons (Cheverud and Leamy, 1985; Lofsvold, 1986; Kohn and Atchley, 1988; Cheverud, 1989a; Wagner, 1989) and the use of confirmatory factor analysis (Zelditch, 1987, 1988) for testing hypotheses concerning levels and patterns of variation. These new methods allow statistical inference for hypotheses of morphological integration and for comparisons across species. We will describe the use of several of these newer methods, especially those using randomization, for testing hypotheses of morphological integration and interspecific comparison and provide brief examples of their use. The procedures described below can be used to rigorously test hypotheses concerning the causes of morphological variation and covariation patterns. A closely related set of procedures can be directed towards comparative, cross-taxon, analyses of variation and correlation patterns. The systematic study of distinction among group means is well known and extensively represented in the literature. However, systematic studies of variation patterns (as measured by a multivariate variance/covariance or correlation matrix) have been relatively rare. This has been due, in part, to a lack of relevant theory and appropriate systematic methodology. Important theoretical advances over the

A High-Resolution Map of Segmental DNA Copy Number Variation in the Mouse Genome

Submicroscopic (less than 2 Mb) segmental DNA copy number changes are a recently recognized source of genetic variability between individuals. The biological consequences of copy number variants (CNVs) are largely undefined. In some cases, CNVs that cause gene dosage effects have been implicated in phenotypic variation. CNVs have been detected in diverse species, including mice and humans. Published studies in mice have been limited by resolution and strain selection. We chose to study 21 well-characterized inbred mouse strains that are the focus of an international effort to measure, catalog, and disseminate phenotype data. We performed comparative genomic hybridization using long oligomer arrays to characterize CNVs in these strains. This technique increased the resolution of CNV detection by more than an order of magnitude over previous methodologies. The CNVs range in size from 21 to 2,002 kb. Clustering strains by CNV profile recapitulates aspects of the known ancestry of these strains. Most of the CNVs (77.5%) contain annotated genes, and many (47.5%) colocalize with previously mapped segmental duplications in the mouse genome. We demonstrate that this technique can identify copy number differences associated with known polymorphic traits. The phenotype of previously uncharacterized strains can be predicted based on their copy number at these loci. Annotation of CNVs in the mouse genome combined with sequence-based analysis provides an important resource that will help define the genetic basis of complex traits.