Encephalizations and Cerebral Developments in Genus Homo

Human Evolution (2006) 21:321–335 DOI 10.1007/s11598-006-9032-7 Encephalizations and Cerebral Developments in Genus Homo Giandonato Tartarelli Received: 30 October 2005 / Accepted: 24 November 2006 / Published online: 2 March 2007 # Springer Science + Business Media B.V. 2007 Abstract As Darwin observed in the second chapter of the The Descent of Man, brain size has the more obvious and direct anatomical correlation with the outstanding cognitive capabilities of our species in comparison with its closest relatives. If we extend the comparison to other mammals, we can observe that cognitive capabilities do not seem to strictly correlate with brain dimension in absolute and in relative terms, and the encephalization quotient (EQ) is not a universal advice of the cognitive capabilities of a particular species, too. Why and how the brain size in our lineage increased dramatically in absolute and in relative way during the last 3 million years? What is the relationship between our outstanding intellective capability and the brain size? The progressive encephalization of our ancestors was the origin or the effect for the development of the intellective capabilities of living humans. Recent advances in the knowledge of intrinsic organization of cerebral cortex and in the patterns of genetic expression are able to better outline the trajectories as the metabolic and structural constraints of the qualitative and quantitative encephalic development. The new scenario led to suggest more accurate explanations of the selective mechanism acting during the evolution of our species. Keywords Brain evolution . Human evolution Brain Size and Intelligence: an Elementary Deduction? No one, I presume, doubts that the large proportion which the size of man’s brain bears to his body, compared to the same proportion in the gorilla or orang, is closely connected with his higher mental powers. Darwin [23]. As Charles Darwin stated in 1879, the brain dimensions are a clear anatomic correlation of the outstanding cognitive capabilities of our species especially in comparison with its G. Tartarelli (*) Scuola Normale Superiore, Piazza dei Cavalieri 1, 56100 Pisa, Italy e-mail: [email protected] 322 Human Evolution (2006) 21:321–335 closest relatives. This consideration does not exhaust the several questions that rise when our brain inquires itself. For instance, we can ask if the differences in cognitive capabilities between Homo sapiens and its closest relatives are only a mere dimensional outcome or if the brain growth is itself the cause of this capabilities; finally, we can inquire the time and mode of the dimensional and cognitive developmental process as a whole. Perhaps the first logical question to ask is if the absolute dimensions of the brain are a good indicator of overall intelligence in an animal species, or if it is possible to find other more significant relationships between qualitative and quantitative features of the nervous system. To answer this question, we need a more formal definition of intelligence, also considering several meanings of this word in different scientific fields. As recently stated by Roth and Dicke [81], a definition of intelligence useful for comparative studies needs, in the meantime, the description of a method and system to measure it. The risk is just to judge the cognitive capabilities of other animals using an anthropocentric point of view unaware of different eco-ethological features typical of a species (or taxon). In the last decade, a definition of intelligence as the cognitive and ethological flexibility of a species (or in other words the capacity of a an individual to tackle with innovative strategy new or old problems during its lifespan) seems to be a compromise between the alternative definition used by neurobiologists, ethologists and comparative psychologists [15, 40, 81]. The principal consequence of this kind of definition is that intelligence is evolved repeatedly, at different levels, in different animal taxa, and so it is not a peculiarity of our lineage. Not only primates but also cetaceans, corvids and parrots show high intellective capabilities if analysed following the definition of intelligence described above. With this definition in mind, we are able to detect what kind of correlation exists between brain size and intelligence in living animal species. A direct correlation between absolute brain size and intelligence is not the better way in comparative studies because brain size is in allometric relationship with overall body size [33]. For this reason, the encephalization quotient (EQ) defined from Jerison [50] as EQ=BSr/BSe, where BSr is the brain size recorded for a given species and BSe is the expected brain size (using a simple regression model) for a species of a given weight, is sometimes more useful. Different allometric equations can be calculated for all vertebrates or for groups of different taxonomic ranks (on this topic, see also Tartarelli and Bisconti, in this volume). Using EQ, it is simpler to detect if a species or a group shows a particular deviation from average brain/body ratio and also if this deviation correlates with particular cognitive capacities. With several cautions, the EQ can be estimated in the extinct species and can be used to detect the time and mode of encephalization processes in the different taxonomic lineages. Even if useful, EQ is all but a universal correlate of intelligence at any taxonomic ranks. It is not too difficult to understand why, on one hand, other variables expressing the brain size as a whole (e.g. weight, surface area) or of its inner structure at micro- and at macroscopic level (e.g. numbers of cortical neurons thickness of different layer) can be also correlated with intelligence, and, on the other, different constraints can affect in different ways the body weight and form.1 Generally, the comparative analysis of the variation in size of the different regions of the brain among species is more informative especially when integrated with taxonomic, phylogenetic and developmental data, but this kind of regional brain morphometry enriched 1 Furthermore, body weight can be very variable during the life of a species, and this can be a problem in the collection of reliable comparative data; in fact, Schoenemann [86] found lean body mass as a better correlate of brain size than total body weight. Human Evolution (2006) 21:321–335 323 in the last years by more refined technical skills (e.g. magnetic resonance imaging [MRI], positron-emission tomography [PET]) is, however, of limited utility in the study of fossil records. For living mammals, different reports show conflicting results in comparative analysis of regional brain size and a different role played by development and adaptation in establishing the relative size variations in the same taxon or among different taxa. For example, the conclusions of Barton and Harvey [6] seemed to show a mosaic brain evolution involving size changes concentrated in specific structures and functional systems that exclude an unyielding role of constraints acting towards a coordinated evolution among the majority of brain regions. On the contrary, Clark et al. [18] demonstrated how within each major mammal taxon brain regions are scalable, and fixed proportionality of size among the different brain regions is recognizable in front of variations in total brain volume. Finally, de Winter and Oxnard [24], using a great number of brain size variables and a refined multidimensional statistical analysis, were able to detect separate but eco-ethologically convergent evolutionary directions in mammal brain organization. In this model, selection acts as a major mechanism within orders, whereas a complex interaction between selection and constraints drives the evolution of brain proportions between orders. In any case, there is no clear evidence of a particular region of the brain that better correlates with intelligence; this is clearly true with absolute or relative size of the whole cortex and probably with the relative size of the prefrontal cortex too. This lack of clear univocal correlation, valid at any taxonomic level, between brain volume and intelligence is evident for many other brain size parameters, such as cortical surface area, number of cortical areas, average cortical thickness, cortical neuron density and number of cortical neurons, and for this reason, other anatomical features, such as the diameter of the myelinated fibers and the average distance between neurons, which are able to influence the “information processing capacity,” are probably better correlates of intelligence [80, 81]. For this and other considerations, the use of a single size parameter in comparative neurology is no more than a useful descriptive method, and better results are found when taxonomy and phylogeny are taken into account. Brain Size Evolution in Our Lineage Among the different terrestrial mammals, the order Primates shows the largest brain size relative to body size [65], and in anthropoids, the average brain size surpasses two times the size expected from allometric scaling (Passingham 1981). Beginning in Miocene, the tendency toward an increase in brain dimensions over time seems to be higher in primates than in other terrestrial mammals (e.g. carnivores). Dunbar [30] discerned the following groups of hypotheses to explain the encephalization in the order: (1) epiphenomenal, (2) developmental, (3) ecological and (4) social. The first two hypotheses postulate that brain evolution is the result of a complex interaction of developmental processes instead of an external selective pressure; on the contrary, the consideration that cerebral tissue is metabolically expensive suggests the existence of strong selective force acting in the direction of brain growth. These hypotheses are generally considered not mutually exclusive, but the relative importance of each one is an object of dispute. In comparison with other mammalian groups, Primates show a well-defined “cerebrotype” (sensu Clark et al. [18]) consisting in larger isocortex, striatum, cerebellum and diencephalon volumes relative to medulla [24]. Neocortical expansion is supposed to be 324 Human Evolution (2006) 21:321–335 driven by social challenges among the Primates and appears positively related to group size, cohesion, grooming [27–30], mating system [85] or to other complex social behaviours as the use of deceptive tactics for social manipulation [11, 13]. These results are the evidences adducted in favour of the so-called “social brain hypothesis” or “Machiavellian intelligence hypothesis [5, 6, 10]. It is important to remark that factors controlling primate neocortical expansion seem to be not uniform across the order and differ in their strength dealing with the nature of the animal’s environment (Sawaguchi [84]). Expansion of visual brain structures in Primates is probably correlated with the degree of orbital convergence and with associated stereoscopic vision, and seems to be specific to the parvocellular visual pathway [4]. The higher levels of relative brain size are reached independently in New World monkeys and in Old World monkeys and apes; the higher EQ in extant Primates species apart Man (EQ=7.4–7.8) can be found in White-fronted capuchin (EQ=4.8). The EQs calculated for our closest relative, chimpanzee and gorilla, range from 2.2 to 3 and from 1.2 to 1.8, respectively. For understanding the tempo and mode of human brain evolution in size and in faculty, we must refer to two sources of complementary data: neontological and paleontological ones. The anatomical or physiological comparisons with our extant relatives are useful to understand “what” and “where” are the differences that make humans so different from other primates; however, these comparisons fail to tell us “how” and “when” these differences evolved. For this last purpose, the only feasible way, with all its limits, is the study of brain endocasts (or virtual reproductions) [95] of our fossil ancestors that, as stigmatized by Holloway et al. [45], represent the only direct evidence from paleontology. This sort of study is the focus of “paleoneurology” [38, 45, 51]. The paleoneurological studies of the human fossil records are able to give us precious information not simply on brain size evolution but at least in part on the morphological changes that can be considered as evidence of the processes of reorganization at the origin of our outstanding cognitive capabilities. The most clear evidence of this kind of analysis is the circumstance that the process that led to the extreme increase in human brain size has happened in the last 5 million years and most of that has occurred in the last 2 million years. Changes in body mass have accompanied at different speeds this trend, and for this, the increase in brain size is the result of the profound interaction of allometric and non-allometric factors [82]. The older well-established paradigm in paleoanthropology associates the significant increase in brain size to the emergence of the genus Homo during Plio-Pleistocene and to the acquired capacity of manufacture and use of stone tools (Tobias [94]). More recently, the evidence for the possible presence of a trend toward brain enlargement in Paranthropus boisei s.l. and production and use of stone tools by non-Homo hominins seems to add more complexity to the background and challenges seriously the traditional view [32]. For Holloway et al. [45], it is possible to identify in the human brain evolution of the last 3 My five different phases: a minor allometric increase in Australopithecinae; a major, rapid increase both allometric and non-allometric in Homo habilis s.l.; a small allometric increase in H. erectus s.l.; a gradual and modest, mainly non-allometric increase in H. sapiens/H. neanderthalensis; and, finally, a small allometric reduction in brain size among modern H. sapiens. Different interpretations of the significance of the pattern of increase of brain size (absolute and/or relative) during the Plio-Pleistocene have been proposed: brain size evolution as a reflection of gradualism and continuity (Henneberg [41, 42]; Lee and Wolpoff [54], Wolpoff [102, 103]); brain size evolution as a reflection of stasis in certain portion of Human Evolution (2006) 21:321–335 325 human lineage (i.e. brain size evolved at a different rate and velocity in individual phases of hominid evolution; Rightmire [77]; D’amore et al. [22]); brain size evolution as a reflection of speciation event (Rightmire [78]); and, finally, brain size differences as a reflection of dissimilar evolutionary rates in different geographic regions (Beals et al. [7]; Leigh [55]). Sometimes different interpretations reflect differences in data sets or differences in the statistical methods used. It is important to draw attention to the fact that in this kind of analysis, as in every alternative to assess the allometric variation in brain size, the weak point can be the estimation of body mass in fossil species, which is surely more questionable than the calculation of the cranial capacity. In fact, the estimations of body size in fossil species are inferred by regression equations calculated from extant species, and consequently, the calculus of allometric variations retains a certain amount of inaccuracy. It is my personal opinion that the use in our lineage of absolute or relative brain sizes extrapolated by fossil data alone is unable to infer alfa taxonomy or to support punctuationism vs gradualism events or vice versa; this is valid at least from the actual available data set, even if refined and elegant statistical analyses are performed (e.g. D’Amore et al. [22]). The study of overall brain size evolution is not the only possible kind of work in paleoneurological studies. Especially with the aid of CT scan, laser scanner and computer graphics, it is possible to analyse and compare in fossil skulls the size of anatomically, ontologically and functionally discrete brain regions, such as the cerebellum [100, 101]. Concerning this important brain region, it is important to draw attention to the fact that its relative size (with respect to cerebral hemispheres) has not been constant during human evolution as a result of the differences in growth rates over time. Australopithecines and the early members of our genus show large cerebral hemispheres in proportion to the cerebellum in comparison with other hominoids. This difference grows up in the Middle and Late Pleistocene humans. Neanderthals, perhaps together with Early Upper Pleistocene “anatomically” modern humans, have the largest cerebral hemispheres relative to the volume of the cerebellum of any primates. In Holocene humans, the reciprocal relation between cerebral hemispheres changes with an increase of the cerebellum size. For an explanation of this evidence, Weaver [101] proposed a three-stage model where variations in the relative size of cerebellum are largely the outcome of different cerebellar complementary contributions to cognition over time as a consequence of increasingly cultural demands. In this view, the cerebellar expansion in Holocene humans reflects a way to increase cognitive efficiency when further enlargement in neocortex no longer represented a feasible way. Morphological Evolution The more controversial topic of paleoneurology is the inference of the reorganization processes of the brain over time by morphological evidence seen in fossil endocasts. It is clear that the resolution power of the study of fossil endocasts is quite different from a PET or CT scan on living subjects, but an accurate study can give important qualitative and quantitative information about variation in the brain in an evolutionary and comparative context. The individual variation in the grade of details imprinted in skull bones (consequence of the thickness of meninges in higher primates; [43]), unfortunately, restricts the study of the endocasts of fossil species to support only positive findings. One of the first convolutional details used as indicative of distinctive trajectory of hominine lineage is the position of the lunate sulcus (LS), the sulcus which bounds 326 Human Evolution (2006) 21:321–335 anteriorly the primary visual cortex (Brodmann’s area 17) and whose presence can be sporadically detected in brain endocasts. Considering the relatively reduced volume of the primary visual cortex in human brain compared to great apes, different scholars agree to use the position of the lunate sulcus as a guide to infer the relative reduction of the primary visual cortex and conversely the increase of the posterior parietal association cortex. Holloway et al. [45] found a clear evidence of a more posterior position of LS in the fossil specimen Stw 505 assigned to Australopithecus africanus and considered this piece of evidence symptomatic of reorganizational processes preceding the significant brain expansion that started with the first representatives of genus Homo. The real meanings of this evidence are now disputed considering the possible non-homology between human and ape lunate sulci, as new data from high-resolution MRI, functional image analysis and histological investigations seemed to show [2]. If confirmed, this datum advocates for a reappraisal of the extent and importance of occipital reorganizational processes that occurred in hominid evolution. Hominid endocasts, if obtained from well-preserved and undistorted fossil skulls, are able to show also traces of the noticeable hemispheric asymmetry that distinguishes our species from other Primates for its extent. Brain directional asymmetries, at cortical and subcortical levels, are not rare in vertebrate brains, but in humans, it is generally referred to the handness, hemispheric specialization for processing different kinds of information and especially to language capabilities [83]. The marked functional lateralisation of our brain is supported by more than one century of impressive electrophysiological and clinical research and is generally interpreted as a way to prevent overload of competitive interferences between equivalent functions on opposite sides [16]. Different forms (e.g. anatomical, physiological, functional) and levels (e.g. cortical, subcortical, macroscopic, microscopic) of asymmetry can be described in the human brain, but the more visible in endocasts are petalias [46, 56], as to say, the asymmetrical projection (into the internal table of cranial bone) of occipital and frontal cortex anteriorly, posteriorly as well as laterally [44, 45]. Contrary to Pongids, the modern human brain seems to show both occipital and frontal petalias (the most frequent is a left occipital–right frontal bias) in a rather distinctive pattern ([44, 46]; but see [56, 57] and [58]). The application of MRI to comparative neuroanatomical analysis was able to confirm width asymmetry at frontal, parietal and temporal levels in great apes. Generally, in Pongids, the right frontal lobe is wider than the left one, and the left occipital lobe is wider than the right one [47], and a noticeable directional asymmetry in the planum temporale is also present [48]. Besides petalia, which represents the overall brain directional asymmetry, it is possible to find several side differences in the peri-sylvian area of hominin fossil records. This asymmetry is often interpreted as a very indirect evidence of some behavioural capabilities (especially language and tool use), and if this assertion can be only speculative, it is important to remark how petalia and marked asymmetry in Broca’s, orbital or frontal cap region (third inferior frontal convolution in lateral prefrontal cortex, Brodmann’s areas 44, 45 and 47) can be already detected in a fossil, KMN ER 1470, dating back to about 2.0 My. Comparative analysis of brain shape variations in fossil endocasts by means of morphometry can be a valuable source of information to recognize the evolutionary trajectories in brain evolution. The comparison of this information with neuroanatomical and neurophysiological evidence in living primates permits to speculate about the time and mode of development of the modern human’s cognitive capabilities. Bruner et al. [12] found two major patterns of variation: an archaic structural trajectory shared by non-modern taxa (H. erectus s.l.) and characterised by an allometric vertical development, frontal Human Evolution (2006) 21:321–335 327 enlargement and parietal relative shortening opposed to a modern human pattern consisting in “neomorphic hypertrophy of the parietal volumes leading to a dorsal growth and ventral flexion (convolution) and consequent globularity of the whole structure” [31]. It is difficult to interpret univocally these variations in a functional way, but this parietal enlargement can reflect improvements in spatial discrimination and visuospatial analysis and consequently in toolmaking. However, the complex reciprocal interactions acting among different brain regions during morphogenesis put some uncertainties to this interpretation. The high frontal angle and the distinctive vault profiles (in lateral and in frontal view) of H. sapiens skull seem to indicate that frontal lobes developed more than other brain areas [62]. However, recent findings [87, 88, 90, 91] using three-dimensional reconstructions of MR scans of the brain showed that the relative size of the frontal lobe is similar across hominoids, and that our species does not have a larger frontal lobe than expected from a primate brain of the human size. Analogous results are found in the analysis of the prefrontal lobe [89], but not in temporal lobe in which the relative size in humans is about 20–30% larger than expected [79]. A possible interpretation for the relatively constant relative dimension of the frontal lobe during hominin evolution can be interpreted in light of a more consistent qualitative, rather than quantitative, reorganization of the cortex through differences in individual cortical areas (some enlarged and some shrink) and to a richer interconnectivity [76]. Considering the importance of the frontal area in several cognitive abilities very complex in our species, these results are anything but waited and alert to the real efficacy of inference from the shape analysis of the functional reorganization processes of the brain during hominid evolution, putting forward the strong influence of intricate ontogenetic factors in the development of relative dimensions among different brain regions and, consequently, brain shape. The phenomenon of arealization, as to say, the appearance of new functionally cortical fields instead of mere enlargement of existing area, must be also taken into account. Nevertheless, it is important to point out as morphometrical analyses can reveal the existence of morphological integrations as far as modularity among different skull districts in extant and fossil taxa [74]. The existence of modularity and integration adds new levels of analysis and must be taken into account in interpreting functionally the evolution of brain form. The indirect line of evidence of comparative neuroanatomy integrated by modern medical imaging techniques can also supply interesting suggestions on the different brain trajectories followed by great apes and humans. Using MRI images and morphing techniques, Karl Zilles and his team [8] were able to recognize in ventro-orbital prefrontal cortex, in ventral stream of the visual cortex and in the hypothalamic neuroendocrine regions the brain zones that account for major morphological differences between H. sapiens and Pan paniscus. Growth Affair Alterations in developmental timing and heterochronic processes were supposed to play an important role in the increase of brain size in human lineage for a long time, and certainly these processes acted together with the other selective forces in the evolution of human brain. Particularly significant is the compulsory coevolution between brain size at birth and pelvis anatomy (towards wider pelvic inlet and outlet of H. sapiens) because early hominid pelvis was adapted to bipedality but not to the parturition of large-brained infants [63]. 328 Human Evolution (2006) 21:321–335 The so-called brain allometry extension theory (Count [20]) recognizes that the progressive extension of conserved primate brain allometry into postnatal life was a key role for brain size evolution in the human lineage. According to this theory, primates show a higher grade of ontogenetic brain allometry (that remains constant during the development) than other altricial mammals; humans preserve longer after birth the fetal brain allometry (relatively rapid brain growth in relation to body size), and as a consequence, humans show a much lower ratio of neonatal-to-adult brain size (about 25%) than other Primates, but the size continues to grow at a pace of fetal development for at least 12 months after birth (secondary altriciality). The corollary of this theory is the necessity for our species to develop new ethological or physiological strategies for sustaining the energetic cost (especially in the first year after birth) of the fast growth of the brain [72]. Recently, Vinicius [98] challenged systematically the postulates of this theory and showed that probably human brain size is instead the result of a peculiar mix of changes in brain growth and body growth. In this alternative view, the major role of postnatal growth is reappraised and its duration questioned. In the proposed scenario, our species evolved its own brain allometry and turned towards important reduction in postnatal body growth rates. At present, few are unfortunately the lines of direct evidence to test these topics and to understand when and how the secondary altriciality evolved. The only preserved Asian specimen of H. erectus infant (Perning 1, a.k.a. Mojokerto child), with age about 1.8 million years old (but see [49]), was indicated as a possible evidence in this species of the retention of an ape pattern of brain developmental rate and a shorter time of brain maturation in extrauterine life [14]. However, the comparative data set used can be questionable (Vinicius [98]), and the interpretations of age at death of the specimen controversial [3, 14]. A more indirect and perhaps much questionable estimate based on the African subadult Nariokotome skeleton (KNM-WT-15000, circa 1.8 My ago) [99] does not support chimpanzee-like prenatal brain-growth pattern in this old representative of our genus [25]. If the flaws of the brain allometry extension theory will be confirmed, different evolutionary contexts for the evolution of human brain should be taken into consideration. Assessment of the change in developmental pattern in our ancestor is of utmost importance because of the influences, direct or indirect, of brain maturation in shaping cognitive skills or group social interactions. Building hardware when software is just running may have been a real vantage for our ancestors. Metabolic and Dietary Constraints Proximal and distal causes used to explain brain enlargement in our lineage must accommodate for the costs to sustain a metabolically very expensive organ. Bearing in mind how the large brain of our species (about 2% of body mass) account for 20% of total metabolic (about 40% in newborn) energy and how brain tissue is unable to downregulate the metabolism in case of negative energy balance (i.e. under starvation), the existence of some kind of metabolic constraint is a particularly compelling argument. This evidence, together with the consideration that human brain at birth is only about 25–30% of the adult size and this percentage rises at about 60% after only 1 year of extrauterine life, is the basis of the so-called maternal energy hypothesis [65–69]. According to this theory, the energy indispensable to the growth of large brains is mostly supported by a mother investment during pregnancy and lactation, and for this reason, Human Evolution (2006) 21:321–335 329 “mother’s metabolic turnover constrains energy availability for brain development in the embryo/foetus during intrauterine development and in the offspring during postnatal life up to the time of weaning” [64]. More generally, the relationship existing between brain size and gestation/lactation period can be evidenced to explain the variations in the linkage between basal metabolic rate and brain size in placental mammals [64, 65]. Nutritional habits and body composition are other factors supposed to be changed during human evolution as a consequence of the high energy demands of the human brain size. It is probable that these factors were critical especially when the major, rapid increase (both allometric and non-allometric) of brain size started. Different variations in body composition have been proposed. In the “expensive tissue hypothesis,” Aiello and Wheeler [1] proposed a negative relationship existing between relative gut size and brain size to explain how the metabolic price of relatively large brains can be paid without increasing the basal metabolic rate. The relative reduction of gut size with respect to brain dimension and the consequent improvement in dietary quality (high quality and more digestible foods) could be a common trend in primates [39] as shown by the positive correlation of diet quality and brain size. For Leonard et al. [59], dietary quality to sustain the increasing brain size was improved in our lineage (in H. erectus s.l.) at first by the incorporation of more animal food into the diet, enhanced tool technology, development of food sharing together with a hunting and gathering lifestyle, and later by use of fire and cooking. Other developmental aspect of body size composition can be claimed as an outcome of brain enlargement, e.g. the reduction of sexual dimorphism and the trade-off between muscle and fat [92]. Our species looks relatively less muscular and fatter than other primate species (Leonard et al. [59]). Human infants are born fat and continue to gain fat especially during the first years of life perhaps to have a good amount of energy stored to use in case of a need to support brain growth and contemporaneously to replace metabolically more expensive muscle with adipose tissue. These considerations and the fact that the human female sustains a great part of this energetic requirement during lactation and weaning indicate as the progressive diminution in sexual dimorphism (started with H. erectus s.l.) and the trade-off between muscle and fat evolved in response to a common underlying process. Not only the energetic value of food but also its biochemical profile could have acted as a constrain during brain evolution in our lineage. Mammalian brain is composed principally of two long-chain polyunsaturated fatty acids (LC PUFA), docosahexaenoic acid (DHA) and arachidonic acid (AA), belonging respectively to omega-3 and omega-6 fatty acids series. LC PUFA was synthesized (primarily in the liver by a process of elongation and desaturation) from essential (i.e. must be taken in diet) shorter chain precursor (linoleic acid to AA and alpha-linoleic acid to DHA). However, in humans, this synthesis is rather inefficient especially when the extremely high encephalization and the peculiarity in developmental timing are considered. The nutritional shift towards a dietetic habit more abundant in animal food (meat, marrow, other brains, fish, shellfish) rich in DHA and AA could represent the necessary substrate to assure brain enlargement during the human evolution [9, 19, 73]. Molecular Suggestions The molecular bias of brain evolution is a matter of controversy, and at present, there is no clear evidence showing the involvement of a few or many genes in coding or in regulatory sequences. 330 Human Evolution (2006) 21:321–335 In the last few years, specific genes are proposed as linked more or less directly to the brain evolution of our ancestors. Recently, Dorus et al. [26], comparing an extensive set of nervous-system-related genes (divided in three subgroups: developmentally biased, physiologically biased and unclassified) between and within primates and rodents taxa, found a marked increase in the rates of protein evolution as scaled to neutral divergence (expressed by higher value in ratio between non-synonymous, Ka, and synonymous, Ks, substitution rates) [60, 61] in primates than in rodents. Moreover, the rates of protein evolution, which, in comparison with housekeeping genes, is not widespread in all the genome, are marked in the subgroup of nervous system genes with developmentally biased functions. Within primates, these same genes evolved more quickly in lineage leading to humans. For this and other considerations, this study seems to show a molecular evidence of strong adaptive evolution. Greatly investigated but also questioned is the possible role of two genes MCPH1 (microcephalin) and MCPH5, also called ASPM (abnormal spindle-like microcephaly associated), two of the six known loci for which recessive mutations cause primary microcephaly disease. This disease causes reductions in brain size, mental retardation but retention of normal brain structure and no other clinically evident abnormalities outside the nervous system. The patients recessive for MCPH1 show a cranial capacity of about 400 ml and a cerebral cortex thinner than normal. Microcephalin acts probably by controlling the proliferation and/or differentiation of neuroblasts during neurogenesis, while for ASPM, a role in regulation of neural stem cell proliferation and/or differentiation during brain development is suggested. For both MCPH1 and ASPM, phylogenetic molecular analyses had revealed strong positive selection in human lineage, and a possible role in human brain evolution has been proposed [35, 53, 71]. Intriguingly adaptive evolutionary trend of MCPH1 and ASPM seemed to postdate the emergence of anatomically modern humans and coincided approximately with the two important events in human evolution: the introduction of the modern human in Europe and the diffusion of domestication. In fact, the haplogroup D of MCPH1 (the more common genetic variance today, ≈70%) has been supposed to originate from a lineage separate from modern humans around 1.1 My ago and after being introgressed into humans (≈37,000 years ago) from the admixture between modern humans and archaic Homo populations (e.g. Neanderthals), whereas for ASPM, a haplogroup that emerged more recently (just 5,800 years) has been found. Two other genes of the six known loci implicated in microcephaly, CDK5RAP2 (MCPH3) and CENPJ (MCPH6) show, to a less extent, suggestions for the existence of positive selection mechanisms in primate lineage [36, 37]. It is important to point out how these findings are questioned from different viewpoints. First of all, the importance of the microcephalin and ASPM as brain size determinant in modern humans seems very subtle [104]. Moreover, both MCPH1 and ASPM are expressed also outside the brain, and for this reason, selective forces acting at a level other than the brain can be supposed [53, 96]. Finally, the haplotype frequency data for ASPM and MCPH1 can be explained by demographic models without invoking necessarily selective mechanism [21]. A possible role in phenotypic evolution of the human brain has also been proposed for other genes especially after the comparison between human and chimpanzee genomes. Particularly intriguing are the role of the gene FOXP2 in acquiring language ability in human lineage, the role of ADCYAP1, the gene encoding the precursor of pituitary adenylate cyclase-activating polypeptide (a polypeptide involved in neurogenesis), and finally in Sia-binding receptors (Siglecs) involved in the biology of sialic acid in brain cortex microglia. Human Evolution (2006) 21:321–335 331 A potential role in the regulation of the organization of the cortex during early neural development has been proposed also for HAR1F, a gene coding for a particular RNA, which is particularly active in human embryo probably as a controller of gene expression [75]. This recent evidence seems to assign a pivotal role to altered gene activity as an origin of brain diversity between humans and chimpanzees as stated by Enard et al. [34], which compared the overall amount of mRNA in different tissues and in different primate species including humans and chimpanzees, and which was confirmed later in several works (e.g. [17, 52, 97]). The possible indirect role on brain evolution of a mutation in MYH16 (the sarcomeric myosin heavy chain) has also been proposed. In a different way to other anthropoids in humans, this gene is not active probably because of an incorporated stop codon in the sequence. For Stedman et al. [93], this inactivation in our ancestor, by the resulting reduction in masticatory muscle mass and corresponding loss in contractile force, is the origin of the dramatic gracilization of the skull that permits the braincase expansion in the first representative of our genus. More recently, McCollum et al. [70] have shown some weak points in the scenario proposed by Stedman et al. that appear to assign no role to MYH16 in the evolution of brain in human lineage. 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