Canalization and developmental stability refer to the tendency of developmental processes to follow particular trajectories, despite external or internal perturbation. Canalization is the tendency for development of a specific genotype to follow the same trajectory under different conditions (different environments or different genetic backgrounds), while developmental stability is the tendency for the development of a specific genotype to follow the same trajectory under the same conditions. Morphological integration refers to the tendency for structures to show correlated variation because they develop in response to shared developmental processes or function in concert with other structures. All three phenomena are emergent properties of developmental systems that can affect the interaction of development and evolution. In this paper, we review the topics of canalization, developmental stability, and morphological integration and their relevance to primate and human evolution. We then test three developmentally motivated hypotheses about the patterning of variability components in the mammalian limb. We find that environmental variances and fluctuating asymmetries (FA) increase distally along the limb in adult macaques but not in fetal mice. We infer that the greater variability of more distal segments in macaques is due to postnatal mechanical effects. We also find that heritability and FA are significantly correlated when different limb measurements are compared in fetal mice. This supports the idea that the mechanisms underlying canalization and developmental stability are related. Finally, we report that the covariation structure of fore‐ and hindlimb skeletal elements shows evidence for morphological integration between serially homologous structures between the limbs. This is evidence for the existence of developmental modules that link structures between the limbs. Such modules would produce covariation that would need to be overcome by selection for divergence in hind‐ and forelimb morphology. Yrbk Phys Anthropol 45:131–158, 2002.

The tetrapod forelimb and hindlimb are serially homologous structures that share a broad range of developmental pathways responsible for their patterning and outgrowth. Covariation between limbs, which can introduce constraints on the production of variation, is related to the duplication of these developmental factors. Despite this constraint, there is remarkable diversity in limb morphology, with a variety of functional relationships between and within forelimb and hindlimb elements. Here we assess a hierarchical model of limb covariation structure based on shared developmental factors. We also test whether selection for morphologically divergent forelimbs or hindlimbs is associated with reduced covariation between limbs. Our sample includes primates, murines, a carnivoran, and a chiropteran that exhibit varying degrees of forelimb and hindlimb specialization, limb size divergence, and/or phylogenetic relatedness. We analyze the pattern and significance of between-limb morphological covariation with linear distance data collected using standard morphometric techniques and analyzed by matrix correlations, eigenanalysis, and partial correlations. Results support a common limb covariation structure across these taxa and reduced covariation between limbs in nonquadruped species. This result indicates that diversity in limb morphology has evolved without signficant modifications to a common covariation structure but that the higher degree of functional limb divergence in bats and, to some extent, gibbons is associated with weaker integration between limbs. This result supports the hypothesis that limb divergence, particularly selection for increased functional specialization, involves the reduction of developmental factors common to both limbs, thereby reducing covariation.

Cornelia de Lange Syndrome (CdLS) is a multi-organ system birth defects disorder linked, in at least half of cases, to heterozygous mutations in the NIPBL gene. In animals and fungi, orthologs of NIPBL regulate cohesin, a complex of proteins that is essential for chromosome cohesion and is also implicated in DNA repair and transcriptional regulation. Mice heterozygous for a gene-trap mutation in Nipbl were produced and exhibited defects characteristic of CdLS, including small size, craniofacial anomalies, microbrachycephaly, heart defects, hearing abnormalities, delayed bone maturation, reduced body fat, behavioral disturbances, and high mortality (75–80%) during the first weeks of life. These phenotypes arose despite a decrease in Nipbl transcript levels of only ∼30%, implying extreme sensitivity of development to small changes in Nipbl activity. Gene expression profiling demonstrated that Nipbl deficiency leads to modest but significant transcriptional dysregulation of many genes. Expression changes at the protocadherin beta (Pcdhb) locus, as well as at other loci, support the view that NIPBL influences long-range chromosomal regulatory interactions. In addition, evidence is presented that reduced expression of genes involved in adipogenic differentiation may underlie the low amounts of body fat observed both in Nipbl+/− mice and in individuals with CdLS. Cornelia de Lange Syndrome (CdLS) is a genetic disease marked by growth retardation, cognitive and neurological problems, and structural defects in many organ systems. The majority of CdLS cases are due to mutation of one copy of the Nipped B-like (NIPBL) gene, the product of which regulates a complex of chromosomal proteins called cohesin. How reduction of NIPBL function gives rise to pervasive developmental defects in CdLS is not understood, so a model of CdLS was developed by generating mice that carry one null allele of Nipbl. Developmental defects in these mice show remarkable similarity to those observed in individuals with CdLS, including small stature, craniofacial abnormalities, reduced body fat, behavioral disturbances, and high perinatal mortality. Molecular analysis of tissues and cells from Nipbl mutant mice provide the first evidence that the major role of Nipbl in the etiology of CdLS is to exert modest, but significant, effects on the expression of diverse sets of genes, some of which are located in characteristic arrangements along the DNA. Among affected genes is a set involved in the development of adipocytes, the cells that make and accumulate body fat, potentially explaining reductions in body fat accumulation commonly observed in individuals with CdLS.

The long legs and short arms of humans are distinctive for a primate, the result of selection acting in opposite directions on each limb at different points in our evolutionary history. This mosaic pattern challenges our understanding of the relationship of development and evolvability because limbs are serially homologous and genetic correlations should act as a significant constraint on their independent evolution. Here we test a developmental model of limb covariation in anthropoid primates and demonstrate that both humans and apes exhibit significantly reduced integration between limbs when compared to quadrupedal monkeys. This result indicates that fossil hominins likely escaped constraints on independent limb variation via reductions to genetic pleiotropy in an ape-like last common ancestor (LCA). This critical change in integration among hominoids, which is reflected in macroevolutionary differences in the disparity between limb lengths, facilitated selection for modern human limb proportions and demonstrates how development helps shape evolutionary change.