Most of the asymmetry literature has focused on the characterization of lateralized behavior. A much smaller number of investigations have been dedicated to the characterization of anatomic asymmetry and an even smaller fraction has attempted to study inter-individual variance for asymmetry traits. Non-human primate model systems are a potentially powerful resource for these studies, but to date, outside of great apes, have provided equivocal evidence regarding the extent and direction of anatomic asymmetry. In the current study, we leverage the power of a large sample of high-resolution brain MRIs acquired from an extended pedigree of vervet monkeys to make two general contributions to the study of anatomic asymmetry in primates. First, we provide significant evidence for pedigree-level directional bias in four of six measures of anatomic asymmetry in the VRC. Second, we estimated the environmental and genetic components of inter-individual variance for each phenotype, and show that about 30% of variance for anatomic asymmetry is due to genetic causes.
Of the six symmetry phenotypes, only hemisphere volume AQ and prefrontal width AQ did not demonstrate pedigree-level asymmetry. The fact that hemisphere volume, unlike most of the other measures, did not show any pedigree-level bias suggests that anatomic asymmetry arises from a differential distribution of cerebral volume within the two hemispheres. Taken together, the skews in the coronal and transverse plane indicate that the cerebral volume is distributed asymmetrically along both the anterior-posterior (AP) and dorsal-ventral (DV) axis. Compared to the left hemisphere, cerebral volume in the right hemisphere is shifted posteriorly along the AP axis and ventrally along the DV axis, whereas left hemisphere volume is shifted anteriorly and dorsally compared to the right. The transverse and coronal skews are moderately correlated with each other (r
0.25) indicating that the differential distribution of volume along the two orthogonal axes tends to occur together, but is not tightly coupled. Besides the skew measures, the other two asymmetry traits that showed pedigree-level bias support the general pattern of asymmetry described above. The posterior shift of volume in the right hemisphere is reflected in the pedigree-level tendency toward a wider right occipital lobe and in the finding that the ascending ramus of the right cingulate sulcus was shifted posteriorly on the AP axis in a majority (91.5%) of the animals with asymmetric cingulate sulci. The methods implemented in this study are relatively general, and do not provide much information regarding asymmetry that may be localized to specific regions. Methods have been developed to measure the asymmetry quotient from gray-matter maps at a voxel-sized scale along the AP and DV axis (e.g. Barrick et al. 
). These methods pose a multiple testing problem for genetic analysis, but allow for the possibility of ‘fine mapping’ asymmetry to specific anatomic structures with known behavioral correlates that may inform hypothesis about the functional significance of the asymmetry.
The pattern of asymmetry that we identified contrasts with the common pattern of anatomic asymmetry observed in humans, who have a population bias with volume shifted anteriorly in the right hemisphere and posteriorly in the left hemisphere. Most of the previous research on endocranial shapes has shown that chimpanzees and gorillas have a biased asymmetry similar to humans. However, a recent study using innovative three-dimensional methods to quantify asymmetry from endocasts found a majority of gorilla skulls in their sample demonstrated a rightward biased asymmetry in the occipital regions 
. This pattern is in the same direction as the current findings in vervets and support Balzeau et al.'s hypothesis that methodologies deigned to precisely measure asymmetry in three-dimensional space can identify subtle symmetries that previous, largely qualitative methods, were unable to detect. More generally, these findings underscore the importance of characterizing anatomic brain asymmetry without a priori
expectation of directional bias. Emerging evidence in comparative behavior suggest the possibility of a general trend across a broad range of species including fish, frogs, birds and mammals for right-hemisphere specialization for approach behaviors and left-hemisphere specialization for avoidance behaviors 
. The growing evidence for similarities in patterns of lateralized behavior has motivated a search for common patterns of anatomic asymmetry among species. However, an agnostic approach is preferable. A consistent trend in the directional bias of lateralized behavior across a wide range of species does not obligate a similar trend in the directional bias of brain asymmetry. Different species may employ alternate mechanisms to achieve lateralized behaviors that may manifest in different patterns of anatomic asymmetry, and may even account for the mixed findings for the directional bias of brain asymmetry among species of macaques. However, as noted in the Introduction
, previous studies of primate brain been characterized by substantial heterogeneity in sample size and protocols for measurement, and considerable additional investigation will be required to accurately compare patterns of asymmetry across species.
The functional significance of anatomic asymmetry in non-human primates is an important overarching question for the field. It is difficult to speculate about the functional significance of our findings. Even the cingulate sulcus trait, which is the most anatomically localized measure we employed, may represent a sensitive indicator of global volumetric shifts due to its central location at the midline. An additional limitation on functional hypotheses is the uncertainty regarding cytoarchitectonic similarities between vervets and macaques, for which detailed functional maps are available (see Woods et al. 
for discussion of comparative brain anatomy in Old World monkeys). In macaques, the cingulate sulcus is bordered by regions PE and PEci (rostral, dorsal), PEc (caudal, dorsal), and PGm (caudal, ventral). These regions integrate visual and limb movement information with motor regions of the frontal cortex suggesting they generate a representation of one's own body and integrate whole body interactions with the visual environment including hand-eye coordination 
. The hypothesis that cingulate sulcus asymmetry is correlated to lateralized behavior could be tested in the VRC using a hand-preference task.
Among the asymmetry measures, only transverse skew showed statistically significant evidence of heritability. The estimate of heritability for the dichotomous cingulate sulcus measure was similar in magnitude, but with a higher standard error compared to the estimate for transverse skew. In part this finding may be due to the better power of a continuous trait using the variance-component analysis method that we employed. It may also reflect an advantage of atlas-based methods, which use voxel data from the entire cerebral volume to linearly deform each image to match a symmetric atlas template and provide measures of global features that complement regional or localized measures like volume and width. Although the heritability estimate for transverse skew was significant, it was much lower than that observed for other neuroimaging phenotypes in the VRC 
. Although about 70% of the variance for this measure can be attributed to non-genetic sources, we have not yet identified the environmental factors that could account for this variance.
Although the genetic isolation and large complex pedigree structure of this sample adds power for genetic analysis, it must be emphasized that this dataset does not represent a population sample of independent individuals, and therefore the results cannot be generalized to other populations. The current work provides a rigorous investigation of anatomic asymmetry in a non-human primate genetic model system and demonstrates that it is possible for the primate brain to develop an asymmetry pattern quite different from that typically observed in humans. Although, the heritability estimates observed in this study cannot be extrapolated to study samples outside of the VRC pedigree, they provide the most conclusive evidence to date that genetic factors can contribute to inter-individual variance in anatomic asymmetry. Combined with growing evidence of anatomic asymmetry in other Old and New World monkeys 
, our findings strongly challenge the hypothesis that anatomic brain asymmetry is uniquely human. As an alternative, it suggests that anatomic asymmetry is a quantitative trait that lies on a continuum in primates, and its characterization across species may provide important insights into primate brain evolution.