Development and the evolvability of human limbs Nathan M. Younga,1, Günter P. Wagnerb, and Benedikt Hallgrímssonc aDepartment of Orthopaedic Surgery, University of California, San Francisco, CA 94110; bDepartment of Ecology and Evolutionary Biology, Yale University, New Haven, CT 06405; and cDepartment of Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada T2N4N1 Edited* by David Pilbeam, Harvard University, Cambridge, MA, and approved December 29, 2009 (received for review October 14, 2009) The long legs and short arms of humans are distinctive for a fore- and hindlimb modules was reduced, leading to a higher primate, the result of selection acting in opposite directions on degree of variational independence of limb size and shape. Our each limb at different points in our evolutionary history. This model predicts that selection for independent function of the mosaic pattern challenges our understanding of the relationship limbs should lead to alterations to limb covariational structure. of development and evolvability because limbs are serially homol- Specifically, humans and apes would be predicted to exhibit ogous and genetic correlations should act as a significant con- decreased phenotypic correlations between fore- and hindlimb straint on their independent evolution. Here we test a compared to quadrupeds. If decreases in integration between developmental model of limb covariation in anthropoid primates fore- and hindlimb are a product of selection for more inde- and demonstrate that both humans and apes exhibit significantly pendent function of limbs, then the timing of any change in reduced integration between limbs when compared to quadrupe- integration has implications for the reconstruction of ancestral dal monkeys. This result indicates that fossil hominins likely positional behaviors. Furthermore, because integration is linked escaped constraints on independent limb variation via reductions to the independent evolvability of limbs, our model predicts that to genetic pleiotropy in an ape-like last common ancestor (LCA). in lineages with weaker integration the evolutionary disparity in This critical change in integration among hominoids, which is limb proportions would be relatively higher, whereas in those reflected in macroevolutionary differences in the disparity lineages with stronger integration, disparity in limb proportions between limb lengths, facilitated selection for modern human would be relatively lower. limb proportions and demonstrates how development helps shape We tested these predictions by comparing humans to a sample evolutionary change. of apes (chimpanzees, gorillas, and gibbons) and quadrupedal Old and New World monkeys (macaques and leaf monkeys, and bipedalism | hominin | integration | macroevolution | serial homology squirrel and owl monkeys, respectively) (Methods and Table S1). For each species we computed the pairwise phenotypic correla- tions between individual limb element lengths of the stylopod imbs are serially repeated homologous structures (1, 2), like (humerus and femur), zeugopod (radius and tibia), and autopod Lteeth (3) and vertebrae (4). Importantly, the ancient duplica- (metacarpal III and metatarsal III). We also used a method to tion event that gave rise to the future hindlimb replicated both the account for artifacts in correlation estimates that have not been anatomical structure of the pectoral appendage and the genetic previously recognized in comparative studies. Specifically, we architecture responsible for its developmental induction, pat- corrected for differences in the magnitude of phenotypic corre- terning, and growth (1, 5, 6). This shared origin of the limbs has lations due to sampled population variation (SI Text, Figs, S1– important consequences for their evolution (7, 8). In particular, S3). This method enabled us to infer significant differences in quantitative genetics theory predicts that genetic correlations will integration with a degree of confidence not previously possible. cause limbs to evolve in parallel (9–11), especially between From these data we inferred patterns of modularity with partial homologous segments: i.e., the stylopod, zeugopod, and autopod correlations and estimated integration between and within limbs (Fig. 1A). This genetic integration, which is reflected in patterns of using analyses of correlation matrix eigenvalue structure phenotypic covariance (12), influences the variation that is avail- and dispersion. able to selection and thus the independent evolvability of limbs (11, 13). Whereas high correlations help ensure that similar limb proportions scale across body size, this same integration acts as a Results fi signi cant constraint on evolvability by limiting the phenotypes Our analyses indicate that humans, apes, and monkeys share a available to selection (7, 8, 13). Thus, the inferred primitive pat- common modular structure in which developmentally homolo- tern of strong integration between homologous developmental gous fore- and hindlimb elements exhibit elevated partial cor- fi modules can be a signi cant bias on limb variation and evolution relations compared to nonhomologous elements, despite B toward size-scaled variants (Fig. 1 ). millions of years of evolution, dramatic alterations of limb pro- Humans are a challenge to this model because the relative portions, and highly specialized adaptations (Fig. 2A and Tables proportions of our limbs, which are thought to reflect inde- S2–S10). In contrast, within-limb correlations between functional pendent adaptations for bipedalism (14–16), endurance, running modules are more variable, likely because they share fewer (17), manual dexterity, and tool use (15, 18), distinguish us from pleiotropic interactions and so are freer to respond to selection all other primates (14–16, 19) (Fig. 1C). Importantly, the hom- for coordinated variation (e.g., for locomotion). Humans exhibit inin fossil record indicates that these selective factors likely strong partial correlations of adjacent hindlimb elements, con- varied in terms of timing, functional targeting, and directional sistent with selection for bipedal locomotion, whereas suspensory effect on the individual elements of each limb (18, 20) (Fig. 1D). Thus our distinctive limb proportions and associated adaptations evolved via a history of selection that both is divergent in Author contributions: N.M.Y. designed research; N.M.Y. performed research; N.M.Y. and direction and, more to the point, is at odds with the ancestral B.H. contributed new reagents/analytic tools; N.M.Y., G.W., and B.H. analyzed data; and genetic correlations due to serial homology. Given the devel- N.M.Y., G.W., and B.H. wrote the paper. opmental constraints on independent limb variation, how can we The authors declare no conflict of interest. reconcile predictions derived from the common genetic archi- *This Direct Submission article had a prearranged editor. tecture of limbs with the evolutionary history of hominins? 1To whom correspondence should be addressed. E-mail: [email protected]. A possible solution to this problem is to assume that at some This article contains supporting information online at www.pnas.org/cgi/content/full/ point in primate evolution the integration between homologous 0911856107/DCSupplemental. 3400–3405 | PNAS | February 23, 2010 | vol. 107 | no. 8 www.pnas.org/cgi/doi/10.1073/pnas.0911856107 Downloaded by guest on September 28, 2021 A B Forelimb Hindlimb Forelimb Hindlimb Stylopod Stylopod r = 0.00 r = 0.50 Stylopod Zeugopod Zeugopod Zeugopod Autopod Developmental Modules Developmental Autopod 9 10 11 12 13 9 10 11 12 13 Autopod Hox Functional Modules r = 0.70 r = 0.95 C D Human 2 BOU-12/1 H.ergaster Human N et S Gibbon election Au.afarensis 1 Siamang ANTHROPOLOGY Chimpanzee s key on LCA Orangutan Relative Hindlimb Length Hindlimb Length Relative Relative Hindlimb Length Hindlimb Length Relative l M eda up Gorilla adr Qu LCA Relative Forelimb Length Relative Forelimb Length Fig. 1. (A) The common genetic architecture of limbs, as demonstrated by their similar Hox patterning (gray, low expression; black, primary expression) (6), reflects their serial homology and suggests a hierarchical limb covariation structure apportioned between and within limbs (7, 8). Theoretical developmental and functional modules of the human limb are shown: stylopod (humerus and femur), zeugopod (radius/ulna, tibia/fibula), and autopod (hands, feet, and digits). (B) Covariation between developmental modules of the limbs in response to selection determines the phenotypic space (gray ellipses) and the inde- pendent evolvability of limbs. When correlations are low, phenotypic space is more evenly distributed (Upper Left). When correlations are high this space will tend toward individuals differing in size but with similar proportions (Bottom Right). The model predicts that the mosaic evolution of modern human limb proportions required reductions in integration. (C) Humans (black circle) have relative limb proportions that are distinct from apes (gray circles) and quad- rupedal monkeys (white circles). The net direction of evolutionary change was an increase to relative leg length and a smaller decrease in relative arm length and is approximately orthogonal to interspecific allometry of quadrupedal relative limb proportions (dashed line). Data are based on ref. 19. (D) Selection in hominins occurred in at least two phases: (i) in early hominins such as the australopithecines [Au. afarensis (AL-288-1) and BOU-12/1, gray, reconstructed] relative