Skeletal diseases related to reduced bone strength, like osteoporosis, vary in frequency and severity among human populations due in part to underlying genetic differentiation. With >600 disease-associated mutations (DAMs), COL1a1, which encodes the primary subunit of type I collagen, the main structural protein in bone, is most commonly associated with this phenotypic variation. Although numerous studies have explored genotype-phenotype relationships with COL1a1, surprisingly, no study has undertaken an evolutionary approach to determine how changes in constraint over time can be modeled to help predict bone-related disease factors. Here, molecular population and comparative species genetic analyses were conducted to characterize the evolutionary history of COL1a1. First, nucleotide and protein sequences of COL1a1 in 14 taxa representing ~450 million years of vertebrate evolution were used to investigate constraint across gene regions. Protein residues of historically high conservation are significantly correlated with disease severity today, providing a highly accurate model for disease prediction, yet interestingly, intron composition also exhibits high conservation suggesting strong historical purifying selection. Second, a human population genetic analysis of 192 COL1a1 nucleotide sequences representing 10 ethnically and geographically diverse samples was conducted. This random sample of the population shows surprisingly high numbers of amino acid polymorphisms (albeit rare in frequency), suggesting that not all protein variants today are highly deleterious. Further, an unusual haplotype structure was identified across populations, but which is only associated with noncoding variation in the 5' region of COL1a1 where gene expression alteration is most likely. Finally, a population genetic analysis of 40 chimpanzee COL1a1 sequences shows no amino acid polymorphism, yet does reveal an unusual haplotype structure with significantly extended linkage disequilibrium >30 kilobases away, as well as a surprisingly common exon duplication that is generally highly deleterious in humans. Altogether, these analyses indicate a history of temporally and spatially varying purifying selection on not only coding, but noncoding COL1a1 regions that is also reflected in population differentiation. In contrast to clinical studies, this approach reveals potentially functional variation, which in future analyses could explain the observed bone strength variation not only seen within humans, but other closely related primates.

The bony pelvis is a pivotal component of the locomotor system, as it links the hindlimb with the trunk and serves as anchorage for the primary propulsive musculature. Its shape is therefore expected to be adapted to the biomechanical demands of habitual locomotor behavior. However, because the relationship between locomotor mechanics and pelvic morphology is not well understood, the adaptive significance of particular pelvic traits and overall pelvic shape remains unclear. This study used an integrative, dual approach to elucidate the relationship between form and function in the primate pelvis. A biomechanical cylinder model of pelvic stress resistance was tested using in vitro strain analysis of monkey and ape cadaver specimens. These results were used to refine adaptive hypotheses relating pelvic form to locomotor mechanics. Hypotheses of adaptation were then tested via univariate and geometric morphometric methods using a taxonomically broad, comparative sample of 67 primate taxa. These results suggest that the pelvis exhibits some iliac and ischial adaptations to stress resistance that are associated with the biomechanical demands of habitual locomotor loading and of body size. The ilium and ischium exhibit relatively low levels of strain during experimental loading as well as adaptations that increase strength. The pubis exhibits relatively high strains during loading and does not vary as predicted with locomotion. This integrated study clarifies the relationship between strain and adaptation; these results support the hypothesis that bones adapted to stress resistance exhibit low strains during typical loading. In general, the cylinder model of pelvic biomechanics is unsupported. While the predictions of loading regimes were generally rejected, the inability of these methods to test the possible occurrence of overlapping loading regimes precludes outright rejection of the cylinder model. However, the lack of support for predicted global responses to applied loading regimes suggests that pelvic stress resistance may be better explained by a model that accounts for local, functional subunits of pelvic structure. The coalescence of a localized model of pelvic biomechanics and comparative morphometrics has great potential to shed light on the evolution of the complex, multi-functional structure of the pelvis.