Increase In Brain Size Research Articles

Temporal lobe evolution in Hominidae and the origin of human lobe proportions.

Objectives Evolutionary changes in hominin social complexity have been associated with increases in absolute brain size. The temporal lobes are nestled in the middle cranial fossae (MCF) of the skull, the dimensions of which allow estimation of temporal lobe volume (TLV) in extant and fossil taxa. Materials and Methods The main aim of this study is to determine where along the hominid phylogeny, major temporal lobe size transitions occurred. We used computed tomography (CT) scans of crania, 3D photogrammetry data, and laser surface scans of endocranial casts to measure seven MCF metrics in 11 extant anthropoid taxa using multiple regressions to estimate TLV in 5 extant hominids and 10 fossil hominins. Phylogenetic comparative methods mapped temporal lobe size, brain size, and temporal lobe proportions onto phylogenetic trees broadly for Hominidae and specifically for Hominini. Results Extant Homo sapiens were not an outlier in relative brain size, temporal lobe size, or proportions of the temporal lobes, but some proportions within the lobe were uniquely altered. The most notable changes in relative temporal lobe size and proportions saw a decrease in relative temporal lobe size and proportions in the genus Pan compared to other extant great apes and fossil hominins while there was a relative increase in the temporal lobe width and length in Australopithecus-Paranthropus clade compared to the genus Homo and other extant great apes including modern humans. Discussion We do not find support for the social brain, environmental or functional craniology hypotheses alone but think it prudent to consider the implications of cerebral reorganization between the temporal lobes and other regions of the brain within the context of these hypotheses and with future investigation is warranted.

Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection.

New genes (or young genes) are genetic novelties pivotal in mammalian evolution. However, their phenotypic impacts and evolutionary patterns over time remain elusive in humans due to the technical and ethical complexities of functional studies. Integrating gene age dating with Mendelian disease phenotyping, our research shows a gradual rise in disease gene proportion as gene age increases. Logistic regression modeling indicates that this increase in older genes may be related to their longer sequence lengths and higher burdens of deleterious de novo germline variants (DNVs). We also find a steady integration of new genes with biomedical phenotypes into the human genome over macroevolutionary timescales (~0.07% per million years). Despite this stable pace, we observe distinct patterns in phenotypic enrichment, pleiotropy, and selective pressures across gene ages. Notably, young genes show significant enrichment in diseases related to the male reproductive system, indicating strong sexual selection. Young genes also exhibit disease-related functions in tissues and systems potentially linked to human phenotypic innovations, such as increased brain size, musculoskeletal phenotypes, and color vision. We further reveal a logistic growth pattern of pleiotropy over evolutionary time, indicating a diminishing marginal growth of new functions for older genes due to intensifying selective constraints over time. We propose a pleiotropy-barrier model that delineates higher potentials for phenotypic innovation in young genes compared to older genes, a process that is subject to natural selection. Our study demonstrates that evolutionarily new genes are critical in influencing human reproductive evolution and adaptive phenotypic innovations driven by sexual and natural selection, with low pleiotropy as a selective advantage.

How domestication, feralization and experience-dependent plasticity affect brain size variation in Sus scrofa

Among domestic species, pigs experienced the greatest brain size reduction, but the extent and factors of this reduction remain unclear. Here, we used the brain endocast volume collected from 92 adult skulls of wild, captive, feral and domestic Sus scrofa to explore the effects of domestication, feralization and captivity over the brain size variation of this species. We found a constant brain volume increase over 24 months, while body growth slowed down from month 20. We observed an 18% brain size reduction between wild boars and pigs, disagreeing with the 30%–40% reduction previously mentioned. We did not find significant sexual differences in brain volume, refuting the theory of the attenuation of male secondary sexual characteristics through the selection for reduced male aggression. Feralization in Australia led to brain size reduction—probably as an adaptation to food scarcity and drought, refuting the reversal to wild ancestral brain size. Finally, free-born wild boars raised in captivity showed a slight increase in brain size, potentially due to a constant and high-quality food supply as well as new allospecific interactions. These results support the need to further explore the influence of diet, environment and experience on brain size evolution during animal domestication.

Assessing the role of meat consumption in human evolutionary changes. A review

The historical study of changes in food patterns is an integral part of the study of biological and social adaptations during the formation and further development of Homo sapiens species. For quite a long time, diets have been considered the driving force of human evolution. Changes in the type of food consumed and the way it was obtained have been associated with encephalization and the emergence of bipedalism, as well as ecological, social and cultural evolution of hominins1 . Archaeological and paleontological evidence indicates that at least about 3 million years ago, hominins increased their meat consumption and developed the necessary fabricated stone tools, while their brains and bodies evolved for a novel foraging niche and expanded hunting grounds. Animalsource foods have always been an integral part of the human diet. However, the way they are obtained and processed changed dramatically during human evolution. Meat became a common food source when systematic hunting began using technologies and tools focused on killing animals and meat cutting, which reduced the time and effort spent on chewing food, and later, on its cooking. At some point after this, humans began to hunt together, which made it possible to obtain meat from big game, and as a result, develop the social and altruistic skills to distribute the prey between sexes and ages. The eating habits of our ancestors have been studied using a variety of methods, including anthropometry, the use of archaeological data, and isotope analysis of bones and teeth to determine trophic status. The adaptive biological significance of meat-eating, which played an important role in human evolution, was analyzed, including the “expensive tissue hypothesis” draw attention to the evolutionary forces responsible for the increase in hominin brain size. Furthermore, data on changes in human anatomy, digestion and metabolism are systematized, indicating an evolutionary dependence on and compatibility with significant meat consumption. At the same time, a number of changes in the human body are associated with the skill of using fire in cooking. Heat processing of food stimulated our ancestors to overcome the food specialization intrinsic to animals. The question of what is the right diet for the human species and what are the potential consequences of limiting meat consumption is briefly addressed.

Brain enlargement with rostral bias in larvae from a spontaneously occurring female variant line of Xenopus; role of aberrant embryonic Wnt/β-catenin signaling

Increased brain size and its rostral bias are hallmarks of vertebrate evolution, but the underlying developmental and genetic basis remains poorly understood. To provide clues to understanding vertebrate brain evolution, we investigated the developmental mechanisms of brain enlargement observed in the offspring of a previously unrecognized, spontaneously occurring female variant line of Xenopus that appears to reflect a genetic variation. Brain enlargement in larvae from this line showed a pronounced rostral bias that could be traced back to the neural plate, the primordium of the brain. At the gastrula stage, the Spemann organizer, which is known to induce the neural plate from the adjacent dorsal ectoderm and give it the initial rostrocaudal patterning, was expanded from dorsal to ventral in a large proportion of the offspring of variant females. Consistently, siamois expression, which is required for Spemann organizer formation, was expanded laterally from dorsal to ventral at the blastula stage in variant offspring. This implies that the active region of the Wnt/β-catenin signaling pathway was similarly expanded in advance on the dorsal side, as siamois is a target gene of this pathway. Notably, the earliest detectable change in variant offspring was in fertilized eggs, in which maternal wnt11b mRNA, a candidate dorsalizing factor responsible for activating Wnt/β-catenin signaling in the dorsal embryonic region, had a wider distribution in the vegetal cortical cytoplasm. Since lateral spreading of wnt11b mRNA, and possibly that of other potential maternal dorsalizing factors in these eggs, is expected to facilitate lateral expansion of the active region of the Wnt/β-catenin pathway during subsequent embryonic stages, we concluded that aberrant Wnt/β-catenin signaling could cause rostral-biased brain enlargement via expansion of siamois expression and consequent expansion of the Spemann organizer in Xenopus. Our studies of spontaneously occurring variations in brain development in Xenopus would provide hints for uncovering genetic mutations that drive analogous morphogenetic variations during vertebrate brain evolution.

Complexity of avian evolution revealed by family-level genomes

Despite tremendous efforts in the past decades, relationships among main avian lineages remain heavily debated without a clear resolution. Discrepancies have been attributed to diversity of species sampled, phylogenetic method and the choice of genomic regions1–3. Here we address these issues by analysing the genomes of 363 bird species4 (218 taxonomic families, 92% of total). Using intergenic regions and coalescent methods, we present a well-supported tree but also a marked degree of discordance. The tree confirms that Neoaves experienced rapid radiation at or near the Cretaceous–Palaeogene boundary. Sufficient loci rather than extensive taxon sampling were more effective in resolving difficult nodes. Remaining recalcitrant nodes involve species that are a challenge to model due to either extreme DNA composition, variable substitution rates, incomplete lineage sorting or complex evolutionary events such as ancient hybridization. Assessment of the effects of different genomic partitions showed high heterogeneity across the genome. We discovered sharp increases in effective population size, substitution rates and relative brain size following the Cretaceous–Palaeogene extinction event, supporting the hypothesis that emerging ecological opportunities catalysed the diversification of modern birds. The resulting phylogenetic estimate offers fresh insights into the rapid radiation of modern birds and provides a taxon-rich backbone tree for future comparative studies.

Exposure to Bisphenol F and Bisphenol S during development induces autism-like endophenotypes in adult Drosophila melanogaster

Bisphenol F (BPF) and Bisphenol S (BPS) are being widely used by the industry with the claim of “safer substances”, even with the scarcity of toxicological studies. Given the etiological gap of autism spectrum disorder (ASD), the environment may be a causal factor, so we investigated whether exposure to BPF and BPS during the developmental period can induce ASD-like modeling in adult flies. Drosophila melanogaster flies were exposed during development (embryonic and larval period) to concentrations of 0.25, 0.5, and 1 mM of BPF and BPS, separately inserted into the food. When they transformed into pupae were transferred to a standard diet, ensuring that the flies (adult stage) did not have contact with bisphenols. Thus, after hatching, consolidated behavioral tests were carried out for studies with ASD-type models in flies. It was observed that 1 mM BPF and BPS caused hyperactivity (evidenced by open-field test, negative geotaxis, increased aggressiveness and reproduction of repetitive behaviors). The flies belonging to the 1 mM groups of BPF and BPS also showed reduced cognitive capacity, elucidated by the learning behavior through aversive stimulus. Within the population dynamics that flies exposed to 1 mM BPF and 0.5 and 1 mM BPS showed a change in social interaction, remaining more distant from each other. Exposure to 1 mM BPF, 0.5 and 1 mM BPS increased brain size and reduced Shank immunoreactivity of adult flies. These findings complement each other and show that exposure to BPF and BPS during the development period can elucidate a model with endophenotypes similar to ASD in adult flies. Furthermore, when analyzing comparatively, BPS demonstrated a greater potential for damage when compared to BPF. Therefore, in general these data sets contradict the idea that these substances can be used freely.

Problem-solving skills are predicted by technical innovations in the wild and brain size in passerines

Behavioural innovations can provide key advantages for animals in the wild, especially when ecological conditions change rapidly and unexpectedly. Innovation rates can be compared across taxa by compiling field reports of novel behaviours. Large-scale analyses have shown that innovativeness reduces extinction risk, increases colonization success and is associated with increased brain size and pallial neuron numbers. However, appropriate laboratory measurements of innovativeness, necessary to conduct targeted experimental studies, have not been clearly established, despite decades of speculation on the most suitable assay. Here we implemented a battery of cognitive tasks on 203 birds of 15 passerine species and tested for relationships at the interspecific and intraspecific levels with ecological metrics of innovation and brain size. We found that species better at solving extractive foraging problems had higher technical innovation rates in the wild and larger brains. By contrast, performance on other cognitive tasks often subsumed under the term behavioural flexibility, namely, associative and reversal learning, as well as self-control, were not related to problem-solving, innovation in the wild or brain size. Our study yields robust support for problem-solving as an accurate experimental proxy of innovation and suggests that novel motor solutions are more important than self-control or learning of modified cues in generating technical innovations in the wild.

The uniqueness of the human brain: a review.

The purpose of this review is to highlight the most important aspects of the anatomical and functional uniqueness of the human brain. For this, a comparison is made between our brains and those of our closest ancestors (chimpanzees and bonobos) and human ancestors. During human evolution, several changes occurred in the brain, such as an absolute increase in brain size and number of cortical neurons, in addition to a greater degree of functional lateralization and anatomical asymmetry. Also, the cortical cytoarchitecture became more diversified and there was an increase in the number of intracortical networks and networks extending from the cerebral cortex to subcortical structures, with more neural networks being invested in multisensory and sensory-motor-affective-cognitive integration. These changes permitted more complex, flexible and versatile cognitive abilities and social behavior, such as shared intentionality and symbolic articulated language, which, in turn, made possible the formation of larger social groups and cumulative cultural evolution that are characteristic of our species.

An energy costly architecture of neuromodulators for human brain evolution and cognition

In comparison to other species, the human brain exhibits one of the highest energy demands relative to body metabolism. It remains unclear whether this heightened energy demand uniformly supports an enlarged brain or if specific signaling mechanisms necessitate greater energy. We hypothesized that the regional distribution of energy demands will reveal signaling strategies that have contributed to human cognitive development. We measured the energy distribution within the brain functional connectome using multimodal brain imaging and found that signaling pathways in evolutionarily expanded regions have up to 67% higher energetic costs than those in sensory-motor regions. Additionally, histology, transcriptomic data, and molecular imaging independently reveal an up-regulation of signaling at G-protein-coupled receptors in energy-demanding regions. Our findings indicate that neuromodulator activity is predominantly involved in cognitive functions, such as reading or memory processing. This study suggests that an up-regulation of neuromodulator activity, alongside increased brain size, is a crucial aspect of human brain evolution.

Transcription factors in microcephaly.

Higher cognition in humans, compared to other primates, is often attributed to an increased brain size, especially forebrain cortical surface area. Brain size is determined through highly orchestrated developmental processes, including neural stem cell proliferation, differentiation, migration, lamination, arborization, and apoptosis. Disruption in these processes often results in either a small (microcephaly) or large (megalencephaly) brain. One of the key mechanisms controlling these developmental processes is the spatial and temporal transcriptional regulation of critical genes. In humans, microcephaly is defined as a condition with a significantly smaller head circumference compared to the average head size of a given age and sex group. A growing number of genes are identified as associated with microcephaly, and among them are those involved in transcriptional regulation. In this review, a subset of genes encoding transcription factors (e.g., homeobox-, basic helix-loop-helix-, forkhead box-, high mobility group box-, and zinc finger domain-containing transcription factors), whose functions are important for cortical development and implicated in microcephaly, are discussed.

Phylogenetic comparative analysis of the cerebello-cerebral system in 34 species highlights primate-general expansion of cerebellar crura I-II

The reciprocal connections between the cerebellum and the cerebrum have been suggested to simultaneously play a role in brain size increase and to support a broad array of brain functions in primates. The cerebello-cerebral system has undergone marked functionally relevant reorganization. In particular, the lateral cerebellar lobules crura I-II (the ansiform) have been suggested to be expanded in hominoids. Here, we manually segmented 63 cerebella (34 primate species; 9 infraorders) and 30 ansiforms (13 species; 8 infraorders) to understand how their volumes have evolved over the primate lineage. Together, our analyses support proportional cerebellar-cerebral scaling, whereas ansiforms have expanded faster than the cerebellum and cerebrum. We did not find different scaling between strepsirrhines and haplorhines, nor between apes and non-apes. In sum, our study shows primate-general structural reorganization of the ansiform, relative to the cerebello-cerebral system, which is relevant for specialized brain functions in an evolutionary context.

An economic model and evidence of the evolution of human intelligence in the Middle Pleistocene: Climate change and assortative mating.

A main objective of this paper is to provide the first model of how climate change, working through sexual selection, could have led to dramatic increases in hominin brain size, and presumably intelligence, in the Middle Pleistocene. The model is built using core elements from the field of family economics, including assortative mating and specialization and complementarities between mates. The main assumptions are that family public goods (e.g., conversation, shelter, fire) were particularly cognitively intensive to produce and became increasingly important for child survival during glacial phases. Intermediate climates (e.g., not the depths of severe glacial phases) create the largest gains from specialization, encouraging negative assortative mating. In contrast, severe glacial phases encourage positive assortative mating because of the rising importance of family public goods. One testable hypothesis is that absence of severe glacial phases should have led to stasis in brain size. Two other testable hypotheses are that severe glacial phases should have led to speciation events, as well as increases in brain size. The evidence shows that there was a million-year stasis in cranial size prior to the start of the severe glacial phases. This stasis is broken by a speciation event (Homo heidelbergensis), with the oldest fossil evidence dated near the close of the first severe glacial phase. In the next 300 kyr, there are two additional severe glacial phases, accompanied by considerable increases in cranial capacity. The last speciation event is Homo sapiens, with the earliest fossils dated near the end of the last of these two glacial phases.

Systematic cortical thickness and curvature patterns in primates

Humans are known to have significant and consistent differences in thickness throughout the cortex, with thick outer gyral folds and thin inner sulcal folds. Our previous work has suggested a mechanical basis for this thickness pattern, with the forces generated during cortical folding leading to thick gyri and thin sulci, and shown that cortical thickness varies along a gyral–sulcal spectrum in humans. While other primate species are expected to exhibit similar patterns of cortical thickness, it is currently unknown how these patterns scale across different sizes, forms, and foldedness. Among primates, brains vary enormously from roughly the size of a grape to the size of a grapefruit, and from nearly smooth to dramatically folded; of these, human brains are the largest and most folded. These variations in size and form make comparative neuroanatomy a rich resource for investigating common trends that transcend differences between species. In this study, we examine 12 primate species in order to cover a wide range of sizes and forms, and investigate the scaling of their cortical thickness relative to the surface geometry. The 12 species were selected due to the public availability of either reconstructed surfaces and/or population templates. After obtaining or reconstructing 3D surfaces from publicly available neuroimaging data, we used our surface-based computational pipeline (https://github.com/mholla/curveball) to analyze patterns of cortical thickness and folding with respect to size (total surface area), geometry (i.e. curvature, shape, and sulcal depth), and foldedness (gyrification). In all 12 species, we found consistent cortical thickness variations along a gyral–sulcal spectrum, with convex shapes thicker than concave shapes and saddle shapes in between. Furthermore, we saw an increasing thickness difference between gyri and sulci as brain size increases. Our results suggest a systematic folding mechanism relating local cortical thickness to geometry. Finally, all of our reconstructed surfaces and morphometry data are available for future research in comparative neuroanatomy.

Regulatory and coding sequences of TRNP1 co-evolve with brain size and cortical folding in mammals.

Brain size and cortical folding have increased and decreased recurrently during mammalian evolution. Identifying genetic elements whose sequence or functional properties co-evolve with these traits can provide unique information on evolutionary and developmental mechanisms. A good candidate for such a comparative approach is TRNP1, as it controls proliferation of neural progenitors in mice and ferrets. Here, we investigate the contribution of both regulatory and coding sequences of TRNP1 to brain size and cortical folding in over 30 mammals. We find that the rate of TRNP1 protein evolution (ω) significantly correlates with brain size, slightly less with cortical folding and much less with body size. This brain correlation is stronger than for >95% of random control proteins. This co-evolution is likely affecting TRNP1 activity, as we find that TRNP1 from species with larger brains and more cortical folding induce higher proliferation rates in neural stem cells. Furthermore, we compare the activity of putative cis-regulatory elements (CREs) of TRNP1 in a massively parallel reporter assay and identify one CRE that likely co-evolves with cortical folding in Old World monkeys and apes. Our analyses indicate that coding and regulatory changes that increased TRNP1 activity were positively selected either as a cause or a consequence of increases in brain size and cortical folding. They also provide an example how phylogenetic approaches can inform biological mechanisms, especially when combined with molecular phenotypes across several species.

Early-Life Dietary Restriction and Diet Type Affect Juvenile Brain Morphology in Spadefoot Toads (Spea bombifrons)

Across a breadth of animal taxa, early-life environmental variation has been demonstrated to have lasting effects on later-life traits, including brain morphology. Here, we use Plains Spadefoot Toads (Spea bombifrons) to evaluate how larval diet type and amount influence later-stage, juvenile brain size and the relative sizes of brain regions. We specifically investigate whether developmental plasticity in brain morphology mirrors previously documented interspecific variation with relation to nutritional restriction and carnivory. Our findings demonstrate, contrary to expectation, that exposure to dietary restriction during the larval stage causes an increase in relative juvenile brain size. However, consistent with our predictions, consuming a prey-based shrimp diet during the larval stage results in relatively larger juvenile telencephalons, an intraspecific response that parallels an interspecific pattern in frogs where more-carnivorous species possess relatively larger telencephalons. Our results demonstrate that early-life dietary restriction and early-life diet type can generate changes in juvenile brain size and morphology in ways that may influence later-life behaviors and fitness. Further, our study suggests that intraspecific and environmentally induced changes in brain morphology can mirror interspecific divergence in brain morphology, supporting a role for developmental plasticity in promoting evolutionary change.

Why only a man turned out to be the owner of mind?

It is considered that the main distinguishing feature of Homo sapiens from other living beings is the presence of his mind. There are many hypotheses regarding the origin of the human mind. The complexity of the problem lies in the fact that it is impossible to experimentally test any of the existing hypotheses. Perhaps we will never fully know how the human mind arose, but it is necessary to strive for this. Here we discuss the possible causes of the origin of a large brain in modern man, implying that the mind is ultimately a product of the human brain. We believe that in order for such a large brain to arise, profound and possibly unique changes in the genome and in the human body had to occur, which did not take place in other higher primates. The role of the evolution of the karyotype and heterochromatin part of the genome in the immediate ancestors of Homo s. sapiens, which led to an increase in the level of heat conductivity of their bodies changed the existing mechanisms of thermoregulation and led to the appearance of hairless skin, which, together, led to a sharp increase in the size of the brain, with the ensuing consequences, is discussed. We believe that the increase of the human brain size was not the result of drastically changes of the structural genes. Most likely it was the consequence of more ordinary events, such as evolution of karyotype, constitutive heterochromatin in chromosomes, human body heat conductivity, skin and thermoregulation. An experimental test is proposed to test the hypothesis put forward.

Both Diet and Sociality Affect Primate Brain-Size Evolution.

Increased brain size in humans and other primates is hypothesized to confer cognitive benefits but brings costs associated with growing and maintaining energetically expensive neural tissue. Previous studies have argued that changes in either diet or levels of sociality led to shifts in brain size, but results were equivocal. Here we test these hypotheses using phylogenetic comparative methods designed to jointly account for and estimate the effects of adaptation and phylogeny. Using the largest current sample of primate brain and body sizes with observation error, complemented by newly compiled diet and sociality data, we show that both diet and sociality have influenced the evolution of brain size. Shifting from simple to more complex levels of sociality resulted in relatively larger brains, while shifting to a more folivorous diet led to relatively smaller brains. While our results support the role of sociality, they modify a range of ecological hypotheses centered on the importance of frugivory, and instead indicate that digestive costs associated with increased folivory may have resulted in relatively smaller brains. [adaptation; allometry; bayou; evolutionary trend; energetic constraints; phylogenetic comparative methods; primate brain size; Slouch; social-brain hypothesis.].

Sociality, ecology and developmental constraints predict variation in brain size across birds.

Conflicting theories have been proposed to explain variation in relative brain size across the animal kingdom. Ecological theories argue that the cognitive demands of seasonal or unpredictable environments have selected for increases in relative brain size, whereas the 'social brain hypothesis' argues that social complexity is the primary driver of brain size evolution. Here, we use a comparative approach to test the relative importance of ecology (diet, foraging niche and migration), sociality (social bond, cooperative breeding and territoriality) and developmental mode in shaping brain size across 1886 bird species. Across all birds, we find a highly significant effect of developmental mode and foraging niche on brain size, suggesting that developmental constraints and selection for complex motor skills whilst foraging generally imposes important selection on brain size in birds. We also find effects of social bonding and territoriality on brain size, but the direction of these effects do not support the social brain hypothesis. At the same time, we find extensive heterogeneity among major avian clades in the relative importance of different variables, implying that the significance of particular ecological and social factors for driving brain size evolution is often clade- and context-specific. Overall, our results reveal the important and complex ways in which ecological and social selection pressures and developmental constraints shape brain size evolution across birds.

The HUSH complex controls brain architecture and protocadherin fidelity

The HUSH (human silencing hub) complex contains the H3K9me3 binding protein M-phase phosphoprotein 8 (MPP8) and recruits the histone methyltransferase SETDB1 as well as Microrchidia CW-type zinc finger protein 2 (MORC2). Functional and mechanistic studies of the HUSH complex have hitherto been centered around SETDB1 while the in vivo functions of MPP8 and MORC2 remain elusive. Here, we show that genetic inactivation of Mphosph8 or Morc2a in the nervous system of mice leads to increased brain size, altered brain architecture, and behavioral changes. Mechanistically, in both mouse brains and human cerebral organoids, MPP8 and MORC2 suppress the repetitive-like protocadherin gene cluster in an H3K9me3-dependent manner. Our data identify MPP8 and MORC2, previously linked to silencing of repetitive elements via the HUSH complex, as key epigenetic regulators of protocadherin expression in the nervous system and thereby brain development and neuronal individuality in mice and humans.