Genetics of primary cerebral gyrification: Heritability of length, depth and area of primary sulci in an extended pedigree of Papio baboons

Abstract

Genetic control over morphological variability of primary sulci and gyri is of great interest in the evolutionary, developmental and clinical neurosciences. Primary structures emerge early in development and their morphology is thought to be related to neuronal differentiation, development of functional connections and cortical lateralization. We measured the proportional contributions of genetics and environment to regional variability, testing two theories regarding regional modulation of genetic influences by ontogenic and phenotypic factors. Our measures were surface area, and average length and depth of eleven primary cortical sulci from high-resolution MR images in 180 pedigreed baboons. Average heritability values for sulcal area, depth and length (h²_Area = .38 ± .22; h²_Depth = .42 ± .23; h²_Length = .34 ± .22) indicated that regional cortical anatomy is under genetic control. The regional pattern of genetic contributions was complex and, contrary to previously proposed theories, did not depend upon sulcal depth, or upon the sequence in which structures appear during development. Our results imply that heritability of sulcal phenotypes may be regionally modulated by arcuate U-fiber systems. However, further research is necessary to unravel the complexity of genetic contributions to cortical morphology.

Introduction

Although the genetic control of primary gyrification is an area of active research, little is known about the genetic contribution to intersubject variability of cerebral landscape. The evolution of the primate brain provides, perhaps, the best evidence that cortical morphology is strongly influenced by genetic factors (Tamraz and Comair, 2006). During evolution, newly derived primate groups such as anthropoid and hominoid primates developed larger, more gyrified brains (Martin et al., 2007, Preuss, 2007, Welker, 1990). Yet, the gyrification pattern of the cerebral cortex across primates is recognizable by the pattern of morphological features, called primary cortical structures, that are conserved across different primate species (Tamraz and Comair, 2006). Primary gyrification begins in early stages of telencephalic development (Tamraz and Comair, 2006) as its onset coincides with completion of neuronal proliferation and migration and progression is accompanied by an explosive increase in cerebral growth (Armstrong et al., 1991, Armstrong et al., 1995, Pillay and Manger, 2007). The onset of primary gyrification also coincides with the onset of neuronal differentiation, a developmental process that partitions the cortical ply into an intricate mosaic of specialized functional areas (Neal et al., 2007). In Old World monkeys, apes and humans, cortical sulci and gyri appear during primary gyrogenesis in a tightly controlled ontogenic sequence (Armstrong et al., 1995, Pillay and Manger, 2007, Zilles et al., 1989). Primary gyrogenesis is completed before birth, and is followed by the myelination of cortical axons (Armstrong et al., 1991, Armstrong et al., 1995). In contrast, secondary and tertiary gyrification, more prominent in higher primates such as hominoid apes and humans, accompany postnatal cerebral growth and myelination, giving the brain its adult appearance (Tamraz and Comair, 2006).

The ontogenic order of appearance of primary cortical structures has been extensively studied and is found to be similar among humans and nonhuman primates (Armstrong et al., 1995, Pillay and Manger, 2007, Zilles et al., 1989). The order in which primary structures make their appearance is putatively related to such developmental processes as neuronal differentiation, development of functional associations and hemispheric lateralization (Galaburda and Pandya, 1982, Van Essen, 1997, Welker, 1990). Neurophysiological studies have long considered primary structures as the spatial landmarks and boundaries that form the intricate cortical mosaic of functional areas (Brodmann, 2005, Rademacher et al., 1993, Rademacher et al., 2001a,b). Functional and anatomical studies in humans also established a clear pattern of function–structure relationships among primary cortical structures and functional areas. However, the extensive secondary and tertiary gyrification of the human cortex make these associations more complex in humans than in nonhuman primates (Fischl et al., 2007, Van Essen, 2004).

Sources of individual morphological variability of the cortical landscape within a given primate species are not well understood. Detailed explanation of the causes and consequences of morphological variation in brain structure could have wide significance and numerous implications for neuroscience, psychology and psychiatry as well as for evolutionary biology. The first step in this direction is to study the proportion of individual variance that can be explained by genetic differences among related individuals. This measurement, called heritability (h²), is defined as the proportion of total phenotypic variance (σ²_p) that is explained by additive genetic factors (σ²_g) (Eq. 1).

$$h^2=\frac{{\sigma }_g^2}{{\sigma }_P^2}$$

High heritability has already been established for a number of neuroimaging-based phenotypes such as total brain size, gray matter volume, regional gray matter thickness, length of the corpus callosum and volume of cerebral ventricles (see Thompson et al., 2001 for a review). In our recent analyses in one nonhuman primate species (baboons, Papio hamadryas) we found high heritability for brain volume (h² = .86; p < 1e−4), gray matter volume (h² = .67; p = .01) and cortical surface area (h² = .73; p < 1e−3) (Rogers et al., 2007). The work presented here is an extension of our previous research with the goal of measuring the contribution of intersubject genetic differences to regional variation in the degree of cerebral gyrification.

Several studies report high heritability estimates for phenotypes describing regional cortical morphology (Cheverud et al., 1990, Hulshoff Pol et al., 2006, Le Goualher et al., 2000, Lohmann et al., 1999, Lohmann et al., 2007, Thompson et al., 2002). The degree of genetic contribution to cortical morphology varies across the brain. To explain these findings, two theoretical models have been proposed, but not formally tested. The first model, suggested by a study by Cheverud and colleagues (1990), draws a connection between developmental factors such as prenatal neurohormonal environment and the genetic versus environmental contributions to variability in the length of cortical sulci. Using an innovative approach and measuring endocranial casts from free-ranging rhesus macaques, Cheverud and colleagues (1990) found progressively lower heritabilities for the length of the primary sulci that appear later in cerebral development. This implied that lower heritability for later-appearing sulci may be due to higher contributions of environmental factors to the overall phenotypic variance across animals. They suggested that higher environmental contribution to sulcal morphology could be due to changes in prenatal hormone-mediated neurohumoral environment and tissue receptivity, which become progressively more variable during development (Cheverud et al., 1990). A trend toward higher heritability values for primary cortical structures appearing earlier in development was also reported in humans (Brun et al., 2008, Chiang et al., 2008, Le Goualher et al., 2000, Lohmann et al., 2007, Lohmann et al., 1999).

The second theoretical model, proposed by Lohmann and colleagues (1999), suggests that the genetic versus environmental contributions to morphological variability are modulated by sulcal depth, with deeper primary sulci under more genetic control than shallower structures. In their study of cortical variability in human twin-pairs, Lohmann and colleagues observed that the deepest of the cortical structures appeared to be the least affected by the environmental component of the “macromechanical forces” directing the postnatal brain growth and development. This conclusion was based in part on theories of cerebral gyrification, which postulate that the depth of individual sulci is influenced by mechanical tensions in the underlying white matter tracts (Van Essen, 1997, Welker, 1990). Under this model, deeper cortical sulci are postulated to be formed earlier during development due to greater tension between a specific sulcal fundus and the other cortical structures to which it is “anchored” by underlying white matter tracts. Greater mechanical tension responsible for the formation of deeper sulci was thus suggested to be the reason for higher inter-twin similarity observed in these structures (Lohmann et al., 1999, Lohmann et al., 2008).

The goal of this study is to formally test the two proposed theoretical models of genetic contribution to variation in cerebral gyrification. Neither of these proposed models was fully tested by the original authors due to methodological limitations in each analysis. The innovative study by Cheverud et al. (1990) measured sulcal length indirectly from the endocranial casts, based on the bony impressions on the inner surface of the cranial cavity. This limited their analysis to cortical sulci with corresponding endocranial impressions, excluding many sulci from the limbic, parietal and occipital lobes. Another limitation was that heritability estimates were calculated based on incomplete pedigree information, since the dam but not the sire was known for each study individual (Cheverud et al., 1990). The study by Lohmann et al. (1999) had limited numbers of subjects (only 19 twin-pairs), preventing them from directly calculating the genetic contribution to sulcal variability. Instead, genetic contribution was indirectly estimated as the ratios of the within versus across twin-pairs variance. Despite not being formally tested, the proposed hypotheses have been used to explain findings in normal cortical variability and disease-specific differences observed in disorders such as bipolar depression and schizophrenia (Cykowski et al., 2008a, Cykowski et al., 2008b, Fornito et al., 2007, Harris et al., 2004, Narr et al., 2004). This study was designed to overcome these limitations, while analyzing a comparable set of phenotypes.

In the current study, we measure sulcal area, length and depth from high-resolution MR imaging from 180 pedigreed Papio baboons (Papio hamadryas). Papio baboons are uniquely suited among nonhuman primates for translational neuroimaging genetic research. Phylogenetically, Papio baboons and other cercopithecoids (Old World monkeys), are more closely related to humans than all other primates, with the exception of ape (hominoid) species (Stewart and Disotell, 1998). Papio baboons express all primary cortical structures, but do not develop prominent secondary/tertiary anastomotic sulci. In apes and humans, anastomotic sulci often interfere with and/or interrupt the spatial course of the primary sulci, thus artificially increasing morphological variability and complicating phenotypic analysis. From a neuroimaging prospective, Papio baboons have the largest brains of any commonly studied laboratory primate except chimpanzees, which are apes and have more prominent secondary cortical sulci. The average cerebral volume in adult baboons (∼180 cm³) is more than twice that of adult rhesus macaques or cynomolgus macaques (Leigh, 2004, Leigh et al., 2003, Martin, 1990, Rogers et al., 2007).