Genetics of human brain evolution

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Genetics of human brain evolution

1 Eric J. Vallender*

University of Mississippi Medical Center, Jackson, MS, United States Tulane National Primate Research Center, Covington, LA, United States *Corresponding author: Tel.: +1-601-984-5893; Fax: +1-601-984-5899, e-mail address: [email protected]

Abstract During the course of evolution the human brain has increased in size and complexity, ultimately these differences are the result of changes at the genetic level. Identifying and characterizing molecular evolution requires an understanding of both the genetic underpinning of the system as well as the comparative genetic tools to identify signatures of selection. This chapter aims to describe our current understanding of the genetics of human brain evolution. Primarily this is the story of the evolution of the human brain since our last common ape ancestor, but where relevant we will also discuss changes that are unique to the primate brain (compared to other mammals) or various other lineages in the evolution of humans more generally. It will focus on genetic changes that both directly affected the development and function of the brain as well as those that have indirectly influenced brain evolution through both prenatal and postnatal environment. This review is not meant to be exhaustive, but rather to begin to construct a general framework for understanding the full array of data being generated.

Keywords Comparative genomics, Molecular evolution, Selection, Adaptation, Gene expression, Gene regulation, Protein function, Specialization, Divergence

1 Introduction When we talk about the evolution of the human brain, we are simultaneously talking about three separate things. First, we are talking about the physical object, the pinkish-gray mass of neurons, glia, and other cells that sit in the skull. We are also talking about the function of the brain, the integration of sensory inputs and processing into physiological and behavioral outputs. But more abstractly, we are talking about the evolution of the mind. Of course, all of these concepts are interrelated and Progress in Brain Research, Volume 250, ISSN 0079-6123, https://doi.org/10.1016/bs.pbr.2019.01.003 © 2019 Elsevier B.V. All rights reserved.

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progress from one another. Understanding the emergence of the human mind is elusory and still perhaps better sought in the realm of philosophers than molecular biologists. We have, however, made admirable advancements in understanding both how the brain develops and how it performs its functions. Comparative studies at the organismal, anatomical, cellular, and molecular levels offer insight into the changes that have occurred during the evolution of humans. Although there is much that is still to be discovered, we have already begun to make inroads on the genetic changes that have occurred in the evolutionary past of Homo sapiens and their role in shaping the emergence of the human brain. Broadly speaking, we can focus on two categories of changes that are relevant in the evolution of the human brain. Direct changes exert their effects on the brain itself, altering development, structures, organization, activity, or function. Indirect changes influence the context in which the brain exists, often allowing for evolutionary freedoms that let more direct changes occur. Both of these categories of genes are important for understanding the emergence of the human brain. The causal relationship between these two categories is often confounding and rarely immediately obvious. This is generally true in many evolutionary stories, but is particularly relevant in the study of the brain because of the importance imbued, rightly or wrongly, to the role of adaptation and directionality in its origin. All too often, there is an anthropocentrism or survivorship bias in focusing on the human brain. Studies of evolution inherently begin with comparative work and it is through this lens that genetic studies of human brain evolution emerge as well. It is worth, however, thinking for a moment about these basic assumptions and their implications. To study “human” anything requires a separation between ourselves and whatever relatives that are being compared against. It can be easy to define human, and thus the human genome, as the population of H. sapiens walking around the planet today. Perhaps it can be slightly more broadly defined to include any individual of H. sapiens since the emergence of anatomically modern humans roughly 200,000 years ago (White et al., 2003), although subsequent introgression with other hominin species (Racimo et al., 2015) may further complicate this definition. More complicated is the choice of outgroup. A focus on non-primate mammals, notably rodents, may offer insights into evolution of the primate brain generally but perhaps not the human in particular. Using old world monkeys, rhesus macaques and baboons among others, similarly reflects the evolution of the ape brain. Among extant species, using chimpanzees or bonobos as outgroups allows for the closest comparisons, but it still reflects not only the evolution of H. sapiens, but also the various other extinct hominin genera (e.g., Australopithecines) and species (e.g., Homo erectus). Until recently, our knowledge of genetic evolution was limited to these extant species, but advances in both the technical aspects of isolating and sequencing ancient DNA and the development of tools to identify vestiges of ancient DNA in large modern human polymorphism surveys now even further refine the time frames that are possible for study (Fig. 1). Of course, all of these comparisons are valid and all are informative in an effort to identify the genetic changes associated with human brain evolution. After all, the human brain is an ape brain is a primate brain is a mammalian brain. In the context

1 Introduction

FIG. 1 Phylogeny of Homo sapiens and relevant outgroups.

of the research question, however, it is important to determine which of these is actually being considered. In the early years of the 21st century, when the genomic era was just beginning and few complete mammalian genomes were available with broad species representation of particular genes still rare as well, the vast majority of studies of human brain evolution better reflected the evolution of the primate brain. In the later years of that first decade, as additional primate species began to become available there was a move toward better understanding of the evolution of the ape brain. As more genomic data were amassed and the post-genomic era began, recent evolution, Homo-specific, began to take shape. There remains a gap, however, in identifying genetic changes associated with the emergence of the Australopithecine brain and the first several million years down the human lineage following the split from Pan.

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These evolutionary periods also affect the nature of the genetic changes that can be identified and characterized. Mutations that directly affect protein structure are more easily characterized and can be more easily identified solely from genomic sequence. Mutations that are regulatory in nature tend to be more difficult to functionally characterize or to identify from sequence data alone. Observed differences in expression patterns can indirectly reflect these regulatory mutations, and indeed are the functionally relevant changes themselves, but require extant tissues and species. This limits these studies existentially; it will forever be impossible to study gene expression in the brain of H. erectus, but also proves practically difficult even when technically possible, gene expression in the gorilla, chimpanzee, or bonobo brain, particularly during development, is not technically impossible, but is effectively impractical at best. These problems are only compounded further for the most abstract conception of the human brain, the mind. Together, these factors introduce a bias into our studies of genetic evolution of the human brain. The genes with the most evidence and rigorous support tend to be protein changes affecting the emergence of the primate or ape brain. Changes that have occurred since the human-Pan split tend to be more observational, but this is also where regulatory changes hold their own with protein changes. Almost all of the genetic changes studied rely heavily on correlational data for functional context. Protein changes can sometimes, though not always, be assayed in a test tube or cell culture plate, offering some validation even if rudimentary and incomplete. It is possible to identify the effect of regulatory changes on gene expression, but is difficult to identify the effect of gene expression changes on brain function more broadly, particularly in the context in which they arose. Nevertheless, with these caveats in mind, there has been tremendous advancement in understanding how the human brain came into existence in the past several decades.

2 Evolution through neurodevelopment The most obvious differences between the human brain and those of other mammals, including other primates, are the increases in size and gyrification. It requires no specialized training or vocabulary to easily point to differences. These obvious changes are the result of shifts in neurodevelopmental processes that lead to increased or prolonged growth. These gross changes only scratch the surface, however. Questions remain, however, whether the human brain reflects essentially a scaled-up version of the mammal (or primate) brain or if specific regions, notably the frontal cortex, demonstrate extraordinary elaboration. Similarly, does the increase in size reflect an increase in cell size or cell number, a change in ratio of neurons to glia, a change in synaptic number? Much of the early thought on these questions was inferred or based on intuition that was all-to-often clouded by anthropocentric biases, whether overt or implicit. In recent years, many of these assumptions have been challenged and, while some have held up, the extent of many has been scaled back.

2 Evolution through neurodevelopment

The typical adult human brain weighs between 1250 and 1450 g, a three- to fourfold increase over chimpanzees, at 330–430 g, which in turn are substantially larger than non-ape anthropoids, ranging from 40 to 120 g (Jerison, 1973). Estimates of total neuron number are similar with humans estimated to have roughly 86 billion neurons and various Old World monkey species ranging from 3 to 10 billion with non-neuronal brain cells, mostly glia, being approximately the same (Azevedo et al., 2009; Gabi et al., 2010; Herculano-Houzel et al., 2007). So there is evidence that, within primates, there is a shared scaling factor that largely holds across species; this scaling factor, however, does reflect a change from other orders (HerculanoHouzel, 2009). The implications regarding cognition for these findings are not yet obvious. There is consistency within primate species, but other large brain and abundant neuron mammalian brains exist (e.g., the African elephant (Herculano-Houzel et al., 2014)), implicating heretofore unexplored mechanisms such as synapse number or circuit organization, or perhaps qualitative differences in neuronal identities. From a genetic standpoint, however, this consistency in primate brain scaling suggests a shift in existing programs, changes in developmental timing for instance, rather than a wholesale change in the way the brain is constructed. Such a fundamental change in development may underlie the Order effects observed, but within primates, whether New or Old World monkeys, apes, or humans it is expected that genetic changes will more subtly modify the existing developmental program. This does lead to two separate but related questions: When a brain gets bigger do all regions of the brain get bigger together or do they grow at different rates? Does the human brain deviate from this pattern? In studies of human brain evolution, here and elsewhere, the main focus is on the prefrontal cortex. Is the prefrontal cortex in humans the size we would expect for a brain the size we observe or is it disproportionately larger? The conception that all brain regions grow at a consistent rate relative to each other is sometimes referred to as “concerted” evolution (Finlay and Darlington, 1995), while the conception that different brain regions can grow independently of one another is “mosaic” evolution (Barton and Harvey, 2000). In answer to the first question, there now seems to be reasonable evidence that the answer lies somewhere in between the two extremes. One factor alone does not account for all changes in brain region size, but nor do each region (or even many regions) scale in size independently. Rather, it seems that there exist few, but nevertheless distinct, regions of developmentally linked modules (perhaps three main consisting of olfactory bulb, limbic structures, and the remainder of the brain (Charvet et al., 2013)). This also suggests that the forebrain of humans is not, by itself, extraordinarily large for a primate brain scaled to its size (Gabi et al., 2016). These theories of brain developmental evolution also have implications for underlying genetic programming (Montgomery et al., 2016; Vallender, 2013). Again, parsimony rules in evolution. Gene changes affecting brain development generally are more likely to exist, even if they are also less likely to be tolerated, than genetic changes altering only a specific region. The largely, though not wholly, correlated patterns of brain developmental evolution that are observed suggest that the genetic changes being sought likely have broad effects largely of degree.

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The molecular evolution of developmental changes is complex. Because development has such an outsized impact on the ultimate survival and phenotype of an organism, changes in these programs often have broad and potentially damaging pleiotropic effects. At the same time, however, they have the ability to create the kinds of large-scale change that is observed in the evolutionary record. The gross changes in the brain, notably changes in size, are certainly the result of mutations affecting development. Similarly, changes in more subtle aspects of neuroanatomy and circuitry are also likely to have developmental origins in patterning and organization, cellular migration, and synaptogenesis. Molecular changes in changes that influence these processes can offer insights into the origins of the human brain.

2.1 Cell number The most obvious and defining characteristic of the human brain is an increase in total neuronal number. Understanding how the developmental basis for this change in number has been a major effort in studies of human molecular evolution. Mature neurons are born from progenitor cells, primarily radial glial cells located in the ventricular zone (Kriegstein and Alvarez-Buylla, 2009). These neural precursor cells produce postmitotic neurons that migrate toward the cortical plate where they form columns. The radial unit hypothesis proposes that the size and organization of the brain are determined by the number of these progenitor cells and their position on a proto-map (Rakic, 1988). During neurodevelopment, these progenitor cells first divide symmetrically, producing the pool of neural stem cells that form the protomap, before shifting to an asymmetric division, producing a postmitotic daughter cell destined to become a neuron and another that maintains its proliferative capacity. The evolution of a larger brain, then, can be accomplished by changing the number of precursor cells or by extending the duration of asymmetric division during development (Rakic, 1995). The proteins of many genes in which mutations cause primary microcephaly in humans have been found to localize to the centrosome and appear to modulate mitotic events (Jayaraman et al., 2018). These genes were among the first to be explored for a role in human brain evolution. MCPH1 showed evidence for positive selection exclusively in the lineage separating apes from Old World monkeys (Evans et al., 2004a; Wang and Su, 2004), while ASPM was found to show evidence for positive selection both in this lineage as well as in the terminal lineage of humans since the divergence from chimpanzees (Evans et al., 2004b; Kouprina et al., 2004; Zhang, 2003). Other evidence for positive selection in primates was found for CDK5RAP2 and CENPJ (Evans et al., 2006), CEP152 (Guernsey et al., 2010), and WDR62 (Pervaiz and Abbasi, 2016). Subsequent studies found associations between microcephaly genes and evolution across primates (Ali and Meier, 2008; Montgomery and Mundy, 2012; Montgomery et al., 2011; Villanea et al., 2012) and mammals (Montgomery and Mundy, 2014; Xu et al., 2012, 2017) more generally. Mutations in these genes are hypothesized to effect some aspect of asymmetric division, altering the proliferative capacity of the neural progenitor cells.

2 Evolution through neurodevelopment

Another of the genes causing microcephaly, ZNF335, appears to act via regulation of REST itself a master regulator of neurogenesis (Yang et al., 2012). Recently, REST has been shown to have undergone positive selection in the human lineage after separating from the other African apes but before separation from Neandertals (Mozzi et al., 2017). As with many of these studies, the association of REST with neurogenesis provides an enticing suggestion of a putative functional relevance, but it is important to note that each of these genes has been implicated in cell division or proliferation more broadly and the evolutionary link to the brain in particular remains untested. Novel genes have also recently been associated with radial glia and proposed to play important roles during human brain development. TMEM14B is uniquely found in primate genomes and in expressed in a specific population of cortical progenitors. When this gene is expressed in mice, it produces cortical thickening and folding (Liu et al., 2017). Studies focusing on hominid specific gene duplications with expression in the fetal brain have identified 35 paralogs with expression during corticogenesis (Florio et al., 2018; Suzuki et al., 2018). Two of these genes, ARHGAP11B (Florio et al., 2015) and NOTCH2NL (Fiddes et al., 2018; Florio et al., 2018; Suzuki et al., 2018), have been demonstrated to promote progenitor cell maintenance and amplification. There have also been several studies focused not on protein-coding regions but rather on regulatory noncoding sequences during corticogenesis. The first of these studies determined active promoters and enhancers using epigenetic marks on histones in humans, rhesus macaques, and mice during development to identify regions that gained activity in humans (Reilly et al., 2015). A second study came to many of the same conclusions from an opposite direction. This study first identified highly conserved noncoding sequences that were unique in primates to hominoids and then determined that they were preferentially associated with epigenomic marks in fetal brain (Mahmoudi Saber and Saitou, 2017). This convergence of evidence offers additional validation and encourages further exploration moving forward. When focusing on human brain evolution it is easy to become fixated on the cerebrum, yet there is also evidence for an accelerated evolution of the cerebellum in humans and apes as well (Barton and Venditti, 2014). Early studies identified positive selection in AHI1, a gene implicated in cerebellar development (Doering et al., 2008; Ferland et al., 2004; Yu et al., 2009). Another survey of genes linked to cerebellar volume found positive selection in hominoids associated with ATRN and RGRIP1L (Harrison and Montgomery, 2017). In a parallel with the previous link to primary microcephaly, both AHI1 and RGRIP1L have been associated with Joubert syndrome, an underdevelopment of the cerebellar vermis.

2.2 Patterning and organization There is considerable interest in whether the human brain “simply” represents a scaled-up version of the primate brain or if there are specific regions that have been disproportionately expanded. In particular, much attention has been placed on the

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frontal cortex. There is evidence in the literature for a shift in the coordination of brain region growth at higher taxonomic levels (Herculano-Houzel et al., 2015), and a debate as to whether rodents harbor a prefrontal cortex continues (Dalley et al., 2004; Preuss, 1995; Rose and Woolsey, 1948; Uylings et al., 2003). While there is little dispute that the human prefrontal cortex is large, it is not obvious whether it is larger than expected for a primate with a human-sized brain. Beyond gross neuroanatomical regions, there is a further question as to whether more subtle regional patterning has changed. Particularly in the cerebrum, areas of functional specialization are known to have spatially shifted, grown, or contracted, during evolution. Whether this is the result of adaptive changes or nearly neutral differences, the genetic basis behind these shifts was laid down during development. Recent advances in large scale transcriptomics in the developing primate brain (Bakken et al., 2016) have allowed for a finer examination of these effects. Although not the only region of importance or interest, much of the focus on human brain evolution has revolved around the frontal, and prefrontal, cortex. The prefrontal cortex has long been recognized as a region associated with higher order functions and cognitive control (Miller and Cohen, 2001). Both these cognitive capabilities and enlarged prefrontal cortical areas are proposed to be derived traits in primates, perhaps with convergent evolution elsewhere in mammals (Smaers et al., 2018). As brain sizes increased in primates, apes, and humans the frontal cortex grew correspondingly, but whether this growth was disproportionate (Smaers et al., 2017) or expected (Barton and Venditti, 2013) has been unclear. Although recent studies have suggested that the total number of neurons in the human prefrontal cortex is not unexpected (Gabi et al., 2016), the presence of specific neuronal subtypes varies between apes and other anthropoid primates (Bianchi et al., 2013; Elston et al., 2001) and neuropil distribution differs in humans (Spocter et al., 2012). A molecular and genetic basis for these differences in brain region development can be achieved through alterations to patterning gradients. Comparing human and macaque fetal brain expression successfully identified gene network modules that differed between species in their patterns of spatial expression (Pletikos et al., 2014). Notably among these were CLMP and WNT7B, representing distinct modules that shifted in the frontal-occipital axis in humans relative to macaques. While these studies failed to identify any differences in inter-hemispheric variability, another study of human fetal tissues did detect left-right asymmetry mostly in large-scale subtle but consistent transcriptional profiles, as well as in several specific genes including KCTD12 and SNAI1 (De Kovel et al., 2018). Differentially expressed genes during fetal development have been demonstrated to be more likely to be associated with human-specific changes in regulatory regions suggesting a specific mechanism through which the broader patterning changes may occur. In particular, these genes under differential evolutionary selection seem to be associated with transcription factors and axon guidance molecules, classes of genes expected to play a major role in patterning during neurodevelopment occur (Johnson et al., 2009). Another study found human-specific changes, compared even to Neandertal and Denisovan genomes, in binding sites for SOX2 in the forebrain,

2 Evolution through neurodevelopment

FOS/JUND in the midbrain and forebrain, and RUNX1/3 in the hindbrain (Zehra and Abbasi, 2018). This work is both buoyed and constrained by the fact that it is focusing specifically on empirically determined brain-specific enhancers. While findings are more likely to be functionally relevant, there is also the high likelihood for false negatives in enhancer regions yet to be characterized. Another, more explicit, example can be found in the patterning of the temporal lobe. Previously mutations in GPR56 have been associated with polymicrogyria across the brain (Piao et al., 2004), but more recent studies have identified specific changes associated with targeted effects in regions near Broca’s area (Bae et al., 2014). Genomic analyses identified a proliferation of alternative promotors in humans relative to mouse resulting in a more specified pattern of gene expression during development and in turn allowing for genetic subfunctionalization. These findings represent an explicit case of molecular evolution affecting the specification of neural patterning during development and likely present a prototypical example by which other genes, where known changes are so far limited to gene expression only, may have evolved.

2.3 Synaptogenesis and pruning Changes in cell number and organization also facilitate differences in synapses and neural circuitry. Primates generally show an enlargement of supragranular layers that is thought to be reflective of changes in neuronal communication (Defelipe, 2011). Apes harbor a unique neuronal subtype, von Economo neurons, that likewise are believed to enhance cell-cell signaling (Nimchinsky et al., 1999). Synapse formation and elimination during development is one of the most obvious mechanisms through which complexity can arise. It allows for unique circuitry to emerge and for changes in the relationships and relatives strengths of existing circuitry. Molecular mechanisms underlying synaptogenesis and synaptic maintenance are a potential substrate underlying the evolution of the human brain. Synaptic development in both humans and chimpanzees has been found to be extended temporally during development relative to macaques. In humans, synaptic density reaches its zenith around 4–5 years of age, much later compared to rhesus macaques that reach a peak within the first months after birth (Rakic et al., 1986). This corresponds to a more general transcriptional neoteny in humans particularly in the gray matter (Somel et al., 2009). This shift in cortical synaptogenesis overlaps with pathways mediated by MEF2A (Liu et al., 2012) and includes genes such as ARC, SYNGAP1, and NR4A1 that have previously been associated with synapse development (Flavell et al., 2006, 2008). This extended period of synaptogenesis is believed to occur naturally and may be a consequence of earlier changes to developmental timing (Charvet et al., 2017). While this may reflect a consequence rather than a driver of evolutionary shifts in the human brain, it nevertheless has important implications for the overall phenotype change in adults. The migration of neurons or their processes to the appropriate locations are some of the first steps toward establishing synaptic connections and neural circuits that will

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ultimately underlie behaviors. Human-specific accelerated evolution of cisregulatory regions has been found to be enhanced among genes implicated in axon guidance (Johnson et al., 2009). These findings have been characterized in the temporal lobe and associated with language centers (Lei et al., 2017) although this may represent an ascertainment bias rather than a functionally meaningful distinction. In particular, there is a convergence of evidence around the Slit-Robo signaling pathway, long associated with proliferation of neuroprogenitor cells, neuronal migration, axon patterning and dendritic outgrowth (Blockus and Chedotal, 2014; Cardenas et al., 2018). In addition to findings that regulatory regions of genes in the Slit-Robo pathway are under unique evolutionary patterns in humans (Lei et al., 2017; Mozzi et al., 2016), there is evidence for selective changes on the coding regions themselves. Changes in the protein sequence of both ROBO1 and ROBO2 show evidence for human-specific changes following the divergence between H. sapiens and Neandertals or Denisovans (Mozzi et al., 2016). Additionally, SRGAP2, a gene encoding a binding partner of ROBO, has not only been implicated in neuronal migration (Guerrier et al., 2009), but is part of a gene family that has undergone a duplication in humans after the divergence from chimpanzees (Dennis et al., 2012). This duplication event has created truncated paralogs that appear to antagonize the binding of the full-length protein to ROBO and modulate radial migration (Charrier et al., 2012). These findings are strongly suggestive of an adaptive change in humans driven by well-understood molecular and genomic events. Another transcriptional network that has been associated with both changes in neuronal migration and human-specific evolution is driven by CLOCK. Although primarily studied and understood as a regulator of circadian rhythms, the transcription factor was identified as a regulator of human-specific gene expression in the frontal pole (Konopka et al., 2012) and was determined to be arrhythmic in the neocortex (Chen et al., 2016; Li et al., 2013a). Subsequent studies have implicated genes transcriptionally regulated by CLOCK in neuronal migration both through ChIP-Seq (chromatin immunoprecipitation followed by next generation sequencing) analysis followed by bioinformatic enrichment studies as well as direct functional assays of migratory distance (Fontenot et al., 2017). As with the Slit-Robo signaling pathway, there may be an interaction between neuronal migration and cellular proliferation being mediated in part by CLOCK. This tension between the extension of the proliferative potential of neuronal progenitor cells and its necessary implication for cellular migration has been previously noted and remains unresolved (Geschwind and Rakic, 2013). Much as neuronal proliferation and synaptogenesis are extended in humans relative to other primates, so too is synaptic pruning. In humans, synaptic pruning begins during puberty but extends into an individual’s 20s (Petanjek et al., 2011), while in other primate species this also begins at puberty but is believed to reach its denouement more quickly (Woo et al., 1997). This is also consistent with findings suggesting an extended period of myelination in humans (Miller et al., 2012). Synaptic pruning has been associated with cortical thickness in the frontal cortex (Allswede et al., 2018) and also with schizophrenia (Selemon and Zecevic, 2015)

3 Evolution of brain function

and autism (Thomas et al., 2016). An appreciation of the role of synaptic pruning in human evolution and disease has only relatively recently come to the fore (Jernigan et al., 2016; Johnson and Stevens, 2018). The genetics underlying these processes are beginning to be explored and it is likely that the shifts observed at the phenotypic level between species will be recapitulated.

3 Evolution of brain function The differences between the human brain and those of other species are not limited simply to those that occur during development. Changes in brain function, from early childhood to adult, are also an important component in the emergence of the human phenotype. Of course, there is an inextricable link between the changes observed in development and the ultimate functional consequences. Changes in the size, volume and surface area, of the brain offer raw material for functional diversification as well. Changes in organization initially laid down during development manifest in the adult as differences in neuroanatomical structure. Drawing a line between development and function is, in many ways, arbitrary. It is not inaccurate (or original) to appropriate the architect Louis Sullivan’s aphorism “form ever follows function” when discussing the brain. Nevertheless, by creating this division, it is possible to more easily categorize and understand the ultimate effects of genetic changes on brain evolution. The most obvious areas of difference between the human brain and those of other species can be observed in the sensory cortices. These represent a fundamentally important function of the brain, but at the same time can vary wildly between species. Moreover, this variation between dependence upon, for instance, primarily visual, primarily olfactory, or primarily auditory sensation to gather information from the environment is readily apparent and has long been a core defining feature of species. These differences are equally as apparent within the brain and are among the most easily identified in the genome as well. Many core brain functions, particularly those located in the limbic system or colloquially referred to as the “lizard brain,” remain remarkably similar in humans compared to other species. That is not, of course, to say that they are identical. Temperature regulation, for instance, has unique features in humans. While important, however, these tend not to be the salient features of human brain evolution that broadly captures the imagination of the public or of natural philosophers. Rather, there tends to be more interest in changes associated with cognition or executive function, processes that are located in the prefrontal cortex, the most elaborated of human brain structures. In no small part because these factors do not easily lend themselves to study, it has been difficult to definitively characterize the changes relevant to human evolution. This variation can result from different types of neurons, or changes in the molecular milieu within neurons, or it can result from changes in connections between neurons; in all likelihood, it will be both. Connectomics, particularly within the prefrontal cortex, is still in its infancy, and our understanding

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of the genetic and molecular factors that ultimately drive connectivity differences lags even further. What is more possible, though, is to understand patterns of gene expression in the brain, how it changes spatially and temporally, and what differences exist between species. One area of complex function that does seem to be amenable to study is language. It is perhaps surprising that a facility for language should be so specifically located in the brain or so tractable to genetic manipulation; it is not immediately obvious that it should be. Yet not only are regions of the brain well defined, Wernicke’s area and Broca’s area have been generally understood since the mid-19th century. The evolution of language, naturally, is significantly more complicated and something that continues to elude the scientific community, but because it does seem to have some more discreet characteristics than other complex functions normally associated with the human brain, there have been many attempts, and some successes, in understanding its emergence (see, e.g., chapter “Genetics of human brain evolution” by Vallender, this volume). Consider then, the molecular and genetic changes that have been and continue to be identified associated with function of the human brain. While not as numerous or superficially impressive as those associated with neurodevelopment, these changes are likely to be as important.

3.1 Sensory cortex One of the most obvious changes to the adult function of the human brain is observed in shifts in regions associated with sensory information. Given that making sense of the world around the organism is perhaps the single most important ancestral function of the brain, it makes sense that there should be meaningful shifts during evolutionary adaptation. In primates, the adaptation toward primarily visual sensation is readily apparent. Much has been written about this shift in the past and it is readily observed in anatomical and behavioral changes. These changes in the relative importance of the visual system are also reflected in shifts in brain regions responsible for integrating the information. At the same time, an increased cognitive capacity in primates has caused a decrease in the relative proportion of the brain devoted to sensory information generally. When compared to other mammals these patterns are broadly observed in primates (Krubitzer and Seelke, 2012). At the genetic level, the emerging importance of the visual system in primates, and particularly in catarrhines, gives some of the best and most clear evidence of molecular evolution. The first main line of evidence for evolutionary change is seen in the loss of importance of the olfactory system in primates. The olfactory system is unique in that each olfactory neuron expresses a specific olfactory receptor (Chess et al., 1994). Because of this the complexity and intricacy of the olfactory system are dependent upon a rather disproportionately large number of olfactory receptors (Malnic et al., 1999). The ancestral mammalian genome is believed to have roughly 1250 distinct olfactory receptors (Hayden et al., 2010) similar to numbers observed in Rodentia, the sister order to Primates (Quignon et al., 2005; Zhang and Firestein, 2002). Many of these genes have undergone pseudogenization, a loss of function

3 Evolution of brain function

followed by gene decay, in primates with humans losing approximately 60% of these ancestral olfactory receptors (Gilad et al., 2003). This loss of sensitivity and de-emphasis of the olfactory system appears to occur concurrently with the rise in importance of the visual system and trichromatic vision (Gilad et al., 2004). The emergence of trichromatic vision itself is an archetypal example of evolution at the molecular level (Shyue et al., 1995). Ancestral primates, and basal strepsirrhines, have two opsin genes: a blue, short-wave, opsin located autosomally and a green, middle-wave, opsin located on the X chromosome. Mutations in opsins can change the wavelength of light that they detect and indeed variation at the green opsin in New World monkeys has given rise to alternative alleles of a red, long-wave, opsin (Boissinot et al., 1998). In catarrhines, a duplication event occurred on the X chromosome allowing for a fixation of both these alleles and true trichromatic vision within individuals (Dulai et al., 1999; Ibbotson et al., 1992). This is perhaps one of the most straightforward examples of gene duplication followed by neofunctionalization in mammals. This is attributable, in part, to the fact that the changes observed occur in the amino acid sequence and that the functional variation is so readily assayable. That it should coincide with such a fundamentally interesting and important phenotypic characteristic of primate and human evolution is a lucky coincidence (although perhaps a statistician would argue here about multiple comparison fallacies). These examples are included here because of their fundamental importance and the unequivocality of the evidence. Certainly, they represent excellent case studies in the genetic changes underlying primate evolution, but it should be clear that they are not unique to humans. These changes in sensory modalities perhaps best represent a major adaptive event in the evolution of the catarrhine brain, itself no small feat, but they do not, by-and-large, represent changes unique to humans and separate from Old World monkeys or other apes.

3.2 Gene expression patterns Some of the most common modern comparative studies of the brain are based not on function but solely on gene expression. These approaches eschew previous attempts at defining functional or neuroanatomical differences between species and focus instead on identifying molecular differences agnostic to functional relevance. This approach is akin to the “reverse genetics” approach to gene function. While there remains the difficulty of determining homology across regions between species, knowing what comparisons are meaningful, these approaches have the advantage of not requiring definitive a priori understandings of the brain. Changes in gene expression patterns can result from changes in cellular composition or molecular differences to the cells themselves, or it can result from shifts in neuroanatomical boundaries or regional homology. These studies are ambivalent to the origin of the changes in gene expression and often cannot attribute function to the differences that are observed. Nevertheless, because they unambiguously and clearly define

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differences between species, these studies represent one of the strongest approaches going forward to determining evolutionary changes in the brain. These approaches have only recently become possible, first with the widespread adoption of microarray technologies and more recently with next generation sequencing. These techniques allowed researchers to interrogate large numbers of genes, increasingly the entirety of the transcriptome, rather than focus on specific targets. Moreover, these approaches made this high throughput approach to gene expression screening cost-effective and practical in available tissue samples (Bakken et al., 2016; Hawrylycz et al., 2012; Miller et al., 2014). Early difficulties resulted from a lack of genomic information on species other than humans or rodents, but with the emergence of the post-genomic era these issues have largely been rendered irrelevant as more non-model organism genomes are available and modern approaches do not require knowledge of sequences beforehand. Moreover, tools such as laser capture microdissection (Corgiat and Mueller, 2017; Tagliafierro et al., 2016), fluorescence associated cell or nuclei sorting (Lobo et al., 2006; Okada et al., 2011), and single cell RNAseq (Grindberg et al., 2013; Lake et al., 2016, 2018) are allowing exploration at anatomical divisions previously unimaginable. The earliest studies of comparative transcriptomic profiles focused on bulk tissues from broadly defined regions in humans, chimpanzees, and outgroup primate species (Ca´ceres et al., 2003; Enard et al., 2002a; Khaitovich et al., 2004). Despite these limitations and small sample size consideration, even at these gross levels differences were observed between the human and chimpanzee brain. As technologies made it possible to focus on larger numbers of individuals these patterns originally observed were held up and were refined in specificity (Konopka et al., 2012; Somel et al., 2009). The importance of regional specificity in transcriptional analysis, especially given the difficulties associated with neuroanatomical homology, was recognized and, as technologies became more widely available and large-scale projects more feasible, studies that were able to integrate multiple brain regions improved the earlier understandings (He et al., 2017; Sousa et al., 2017; Xu et al., 2018a; Zhu et al., 2018). The field has also developed to focus on transcriptional differences between induced pluripotent stem cell (iPSC) derived neuronal cultures (Mora-Bermudez et al., 2016; Sousa et al., 2017). In addition to finding increases in rates of change in humans relative to chimpanzees or outgroup species, each of these studies has also produced lists of differentially expressed genes. Across studies, different genes have been identified, but there remains a remarkable overlap in functionally enriched categories, such as cell proliferation, transcriptional regulation, and axon guidance. Regulation of gene expression is mediated in part epigenetically and this too can be explored from a comparative framework. Again, humans and chimpanzees can be meaningfully compared with a rhesus macaque outgroup and distinct speciesspecific patterns observed (Mendizabal et al., 2016; Zeng et al., 2012). While these differences in methylation are present in neurons as well, recent studies have shown that the vast majority of differences in methylation between human and chimpanzee are in non-neuronal brain cells (Bock et al., 2018). These changes can be also considered in the context of an apparent increase in regulation of gene expression by

3 Evolution of brain function

transcription factors in humans compared to other apes and African apes (Homo, Pan, Gorilla) compared to orangutans (Gunbin et al., 2018). Transcription factor control of gene expression seems to have stronger effects on humans than other species (Berto and Nowick, 2018; Nowick et al., 2009). Our understanding of genetic substrates has also greatly progressed in the decades immediately following the publication of the human genome. This has allowed for studies of gene expression differences that move beyond proteincoding genes. Expression differences have now been extended to include miRNAs (Chakraborty et al., 2018; Somel et al., 2011), with findings that parallel those of protein-coding genes. Similarly differences in alternative splicing have been identified between humans, chimpanzees, and rhesus macaques that suggest a greater diversity of isoforms in the prefrontal cortex of humans (Mazin et al., 2013, 2018). These studies reflect additional substrates capable of driving phenotypic divergence in the brain. Necessarily, gene expression studies have focused on differences between extant species; even the inclusion of post-mortem chimpanzee and prenatal macaque tissue is extremely laudable given the associated difficulties. Yet this restricts the time frame of human evolution that is possible to study. Using allele-specific expression of sequences identified in the Neandertal genome that have introgressed into living humans, it has been possible to identify cis-regulatory differences from these species as well (McCoy et al., 2017). In particular, gene expression in the brain showed significant downregulation of Neandertal alleles compared to human alleles offering tantalizing, if suggestive, possibilities for our understanding of recent human genomic evolution of the brain.

3.3 Language It is not obvious when language first developed in humans. Communication between individuals has long been an important social component for animals, but spoken language is uniquely human and not simply because of unique anatomical adaptations, although the importance of these changes is not to be minimized either. The emergence of language is thought to coincide with advances in symbolic thought and complex tool use and is likely closely tied to concepts of the mind. It is also a remarkably discrete entity. Broca’s area is located in the dominant, usually left, hemisphere in the ventrolateral prefrontal cortex and has been associated primarily with language production. Wernicke’s area is located in the same hemisphere as Broca’s area but in the posterior superior temporal cortex, and has been associated more with language processing. While these regions are not rigorously defined neuroanatomically, they do support a functional consistency that underlies a more general relationship between brain function and language (Tremblay and Dick, 2016). The gene that has received the most attention in the evolution of language, and perhaps in all of human evolution, is FOXP2. This gene first aroused interest after a familial mutation was identified which resulted in a severe speech and language pathology (Lai et al., 2001). Quickly following this initial study, it was recognized

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that the FOXP2 gene, while evolutionarily extraordinarily conserved across mammals, had undergone a multiple amino acid changing mutations in humans following the divergence from chimpanzees (Enard et al., 2002b). Numerous subsequent studies have followed including differential regulation of downstream targets by human and chimpanzee FOXP2 (Konopka et al., 2009), differences in gene expression in putative Broca’s and Wernicke’s areas in human and chimpanzee regulated by FOXP2 (Lambert et al., 2011), evidence for positive selection in genes regulated by FOXP2 (Ayub et al., 2013), and variation in FOXP2 across ape species (Staes et al., 2017). More recent studies, however, have invalidated a second line of evidence offered for a recent evolutionary sweep at FOXP2 in modern humans (Atkinson et al., 2018). Interest in FOXP2 and confidence in its role in human evolution, which swung so strongly in its favor early on, seems to be rapidly returning to more measured expectations. That is not to say, however, that interest in the evolution of language has been assuaged. The relationship between language and lateralization of the brain is robust and the two are believed to have evolved in humans together (Corballis, 2009). Recent studies have begun to characterize the emergence of this asymmetry in primates through interhemispheric gene expression comparisons between humans and rhesus macaques. These studies identified asymmetrically defined gene co-expression modules unique to humans in a region broadly equivalent to Wernicke’s area (Muntane et al., 2017). Gene expression remains a crude tool and may obscure more meaningful differences in circuitry or shifts in organization. Attributing homology to neuroanatomical regions, particularly ones defined primarily by function (and where a homologous function may not exist in a comparator species), further causes difficulty. That said, this work demonstrates some early evidence for meaningful genetic changes associated with language and brain function. Genetic factors have previously been identified that associated with lateralization. Notably among these is LMO4, a transcription factor with asymmetric expression patterns in the fetal human brain (Sun et al., 2005), and that has been manipulated in mouse transgenic studies to induce laterality (Li et al., 2013b). LMO4 demonstrates the potentiality for a genetic basis to the lateralization seen in humans, but there is no evidence to suggest that changes in this gene or its regulation specifically have played a role in human evolution. Conversely, there is a great deal of information about the molecular evolution of PCDH11X/Y, a cell adhesion molecule expressed in developing neurons of the ventricular zone (Priddle and Crow, 2013b). This gene resides in the pseudoautosomal region of the sex chromosome in ancestral primates, but a duplicative translocation and subsequent accelerated evolution occurred in humans following the chimpanzee split (Williams et al., 2006). While the evidence for a direct role in developmental asymmetry is more speculative, plausible hypotheses exist that can be tested (Matsunaga et al., 2013; Priddle and Crow, 2013a). One prominent theory on the evolution of language associates its emergence with a species susceptibility to schizophrenia, hypothesizing that the same genetic mutations that gave rise to language and symbolic thought also cause the human brain to

4 Evolution through secondary effects

be vulnerable to unique disruption (Crow, 1995). This has also been expanded to include other neurodevelopmental disorders such as autism (Crespi et al., 2009). Copy number deletions associated with schizophrenia have also been associated with microcephaly while duplications associated with autism have been associated with macrocephaly (Brunetti-Pierri et al., 2008; Deshpande and Weiss, 2018). Brain studies of individuals with schizophrenia have also demonstrated reduced asymmetries (Oertel-Knochel and Linden, 2011). This has led to the search for signatures of molecular evolution in genes associated with these diseases and evidence for positive selection has been found in the protein sequence of genes associated with schizophrenia (Crespi et al., 2007; Ogawa and Vallender, 2014), as well as in regulatory elements (Short et al., 2018). Similarly, regions associated with schizophrenia (Srinivasan et al., 2016) and various cognitive traits (Srinivasan et al., 2018) have been demonstrated to show signs of recent selective sweeps following the divergence of humans and Neandertals. Some of the strongest evidence for specific genes associated with both cognitive capability and schizophrenia is for ARHGAP11B and those containing the DUF1220 domain (Sikela and Searles Quick, 2018). ARHGAP11B is expressed in radial glia and arouse from a gene duplication after the human-chimpanzee split (Florio et al., 2015). Its transgenic results in increased neuronal progenitor cell production in both the mouse (Florio et al., 2015) and the ferret (Kalebic et al., 2018). DUF1220domain containing genes show significant increases in number associated with anthropoid and human evolution (O’Bleness et al., 2012; Popesco et al., 2006) and have also been associated with neuronal stem cell proliferation (Keeney et al., 2015; Zhu et al., 2017). These genes are not likely to represent the only examples to be derived from this approach; there is certainly value to be found in further studies aiming at the intersection of these areas of interest.

4 Evolution through secondary effects To this point, the focus has been primarily on the brain itself. But the evolution of the human brain did not occur in a vacuum and it is important to consider the context that both allowed and facilitated this evolution. In some instances, the order of cause and effect is clear, certain changes in the brain could not occur without other circumstances first having been met. In other cases this is less obvious, with the changes occurring in the brain and the changes occurring elsewhere likely creating a positive feedback cycle that drove both. It is clear, however, that there are also important evolutionary changes that have occurred that have indirectly affected the emergence of the human brain. It can sometimes be difficult to remember when abstracted, but the brain is foremost a physical object. For the brain to change its size and shape also requires other changes in the human body plan and physical structures. Some of these, such as the general shift from a quadrupedal to a bipedal body posture and the associated changes in positioning of the foramen magnum and brain stem (Russo and Kirk, 2013),

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may have changed the brain as a physical object but had little to do with the more metaphysical changes that generally are of interest. Other times, however, the relationship is more complicated. For the brain to grow in size, the skull needed to be able to expand as well. This may have required structural changes. Also, as the brain grew its energy requirements changed as well. Novel adaptations may have been necessary to support the newly enlarged structure. These changes needed to occur within the organism then for the brain to become elaborated as it has. The context in which the modern human brain evolved is not simply within the individual itself either. Some of the changes observed in brain development necessitate changes in pregnancy and gestation. Both these changes, as well as those in parental behavior necessitated from secondary altriciality, itself a complicated cause and effect of brain development, must occur in adults to create an environment in which changes to the brain are tolerated or viable. While not directly altering the brain, nor, in theory, necessarily causative to brain evolution, these evolutionary changes created a context in which the more direct changes in brain structure and function could take hold. Indirect changes, also attributable to genetic differences between humans and the species of our other close relatives, were instrumental in the emergence of the human brain. These changes in physical structures, physiological programs, and behavioral organizations were necessary for the direct changes to take root.

4.1 Physical constraints During the evolution of the brain, certain structural changes necessarily needed to occur. Of course, this means an enlargement of the skull, but it also includes structural changes to the pelvis to support childbirth and changes to the throat and respiratory system to facilitate language. For the brain to expand in size or to develop new communicative functions, it was also necessary to change the context in which that brain operated. These changes are certainly genetically controlled as well, but by themselves do not necessitate or require changes in the brain. Nevertheless, without these adaptations the human brain would not have taken the form or function that it has. Just as the size and gyrification of the human brain is immediately obvious to the untrained eye when compared to other primate species, so too is the human skull. When compared to other apes or fossilized hominins, the human skull shows striking changes including a reduced prognathism and facial projection (Lieberman, 1998). Various factors have been put forth to explain these changes including masticatory adaptations (Katz et al., 2017), respiratory adaptations (Zwicker et al., 2018), and shifts in craniobasal topography (Bastir and Rosas, 2016). Regardless of the cause, these patterns of covariation are shared across hominoids (Neaux, 2017) suggesting adaptation by modification of a single existing program. Several genes have been implicated in extant human facial variation through genome-wide association studies including DCHS2, RUNX2, GLI3, PAX1 and EDAR (Adhikari et al., 2016). RUNX2 in particular has been associated with prognathism in dog breeds (Sears et al., 2007)

4 Evolution through secondary effects

and a selective sweep in the Neandertal genome (Green et al., 2010). The loss of another gene, MYH16, in humans was proposed to reflect a shift in craniofacial muscle development (Stedman et al., 2004), although the timing on this gene loss is unclear (Perry et al., 2005). Conceptually, the suggestion is that the masticatory apparatus required by early hominids precluded skull growth, but that as diets changed to more nutrient rich foods, these muscles were unnecessary and their loss added freedom to craniofacial evolution. More recently, even studies of FOXP2 knockouts in mice have suggested a role in craniofacial morphogenesis that has been attributed to salient human evolutionary features (Xu et al., 2018b). Another important anatomical change during human evolution was the descent of the larynx (Ghazanfar and Rendall, 2008). This shift produces a distinctly human enlarged pharyngeal cavity that is believed to allow for greater variability in the production of sounds, a necessary adaptation for the emergence of spoken language. The development of the laryngopharynx is only modestly understood from a genetic perspective (Lungova et al., 2015) and the relevant transcriptional factors, FOXA2, SOX2, and NKX2-1, are also reflected in numerous other patterning events. This suggests that the important genetic changes are likely to be found in regulatory regions that result in shifts in gene expression rather than dramatic protein change. While the genetic evolution of these morphological changes is still unknown, our understanding of the developmental programming of the structures offers fertile ground for future studies. Perhaps no skeletal change has received greater attention in human evolution than the rearrangement of the pelvis. Two factors unique to humans have influenced pelvic evolution, a shift to bipedalism and the obstetric constraints associated with developmental impacts of the enlarged brain. These two factors not only both impact pelvic structure, but are often considered antagonistic toward each other, the “obstetrical dilemma” (Grabowski, 2013). The degree to which these two facets are truly at odds, or whether either or both are incontrovertibly defined by pelvic morphology, is a matter of continued debate (e.g., Dunsworth, 2018 or Ruff, 2017), but it is certainly true that the human pelvis has changed in structure and orientation compared to other apes (Gruss and Schmitt, 2015). In humans, genome-wide association studies have identified associations with hip shape (Baird et al., 2018) and dysplasia (Hatzikotoulas et al., 2018; Yan et al., 2018). As with the larynx, it seems likely that many of the genetic effects responsible for these changes are regulatory. Indeed, one unique regulatory element identified in humans is found in an intron of FBN1 and has been associated with hip dysplasia and stature abnormalities (Marcovitz et al., 2016). Changes in the brain during the evolution of humans also occurred within a larger context. Some of these other adaptations were truly independent or otherwise did not affect, or were not affected by, the evolution of the brain. Others, however, were more closely linked. Anatomical changes in craniofacial structure, in positioning of the larynx, and in shape and orientation of the pelvis all have important implications for the evolution of the brain. Considering these indirect effects is necessary for a complete understanding of the emergence of human unique cognitive capacity.

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4.2 Energetics The brain is one of the most energetically expensive organs in the body, when it grew in size these energy requirements scaled up as well. In fact, a major hypothesis on human evolution postulates that it was this energy need that formed the critical barrier to evolutionary brain growth and that it was only when humans mastered fire and were able to unlock energy rich foods that the full elaboration of the human brain was possible (Carmody and Wrangham, 2009; Fonseca-Azevedo and Herculano-Houzel, 2012). Certainly, adaptations were needed to supply the meet the energetic needs of the newly expanded human brain, but these energetic demands had other impacts as well. Extended brain growth and gestational timing made increasing demands on maternal energy requirements as well. The adaptations necessary to accommodate these increased energetic demands, whether at the behavioral level or at the physiological level, are also reflected in molecular and genetic evolution. Across mammalian species, particularly those with fewer offspring and greater parental investment, pregnancy places an enormous metabolic burden on the mother. Constraints on the ability of the mother to meet this requirement have been proposed to be a primary determinant of gestational length, the “energetics of gestation and growth” hypothesis (Dunsworth et al., 2012). Adaptation by mothers to support the energy demands of the offspring, while still maintaining her own needs for survival, is thought to be reflected in the genome and in the physiology of the placenta (Wildman et al., 2006). Genes expressed in the placenta serve several roles, but one is a role in mediating metabolic demands (Sood et al., 2006). One study focusing on the prenatal environment identified genes with signatures of adaptation in the lineage leading to apes (Uddin et al., 2008). Several hormone-associated genes were identified, among them MUC1, GH2, and CGA, but one gene in particular, CCK, shows evidence of positive selection and is known to regulate leptin levels and be associated with intrauterine growth (Mise et al., 2007). Humans show greater total energy expenditure than other apes, largely due to an increased basal metabolic rate, a proxy for organ metabolic requirements (Pontzer et al., 2016), although this may have been a reversion to a primate mean following a depression in ape species (Simmen et al., 2017). The human brain demand for energy is particularly high during development (Kuzawa et al., 2014). These changes have been variously interpreted as supportive of human brain evolution as directly providing for greater energy needs or simply providing for standard energy needs but with greater density and therefore increased efficiency. Dietary shifts toward more energy dense foods also may have had other indirect effects on the human genome. Unique metabolic biomarkers associated with diet differ between humans and other apes and have been suggested to result in part from a downregulation of UGT1A1, an enzyme responsible for processing plant compounds (Ronke et al., 2015). Positive selection on salivary amylase (AMY1), a gene associated with starch processing, has also been identified in humans (Perry et al., 2007) and recently dated to after the divergence from Neandertals (Inchley et al., 2016). There have also been a large number of genes associated with lipid metabolism for which signature of selection has been detected. An anthropoid specific change in the regulation of the low

4 Evolution through secondary effects

density lipoprotein receptor (LDLR) was identified (Wang et al., 2006) and PCSK9, a regulator of LDLR activity, was found to have undergone recent positive selection in humans (Ding and Kullo, 2008). A similar signal of recent selection was found in ANGPTL4, a regulator of HDL levels (Romeo et al., 2007). More direct changes in energy metabolism also may have occurred during evolution. Synaptosomal lactate dehydrogenase (LDH) expression appears to have shifted multiple times in primate evolution, during the divergence of haplorrhines and strepsirrhines (Duka et al., 2014) and in apes after divergence from Old World monkeys (Duka et al., 2017). A duplication of glutamate dehydrogenase in apes led to a paralog expressed uniquely in the brain and testes and optimized to function in environments of high GTP concentrations (Burki and Kaessmann, 2004). Positive selection in the regulatory regions of the glucose transporters SLC2A1 and SLC2A4 resulted in compensatory shifts in expression in brain and skeletal muscle (Fedrigo et al., 2011). Finally, three genes involved in human cortical glucose utilization, BCAN, GRIN3A, and ANKRD57, also show evidence of adaptive evolution in cis-regulatory regions (Sterner et al., 2013). As evidenced by these studies, there is a great deal of suggestive findings surrounding changes associated with energetics in humans, but additional work is necessary to better integrate these diverse strands into a coherent whole.

4.3 Gestation Previously we touched upon the effect of changes in developmental timing had specifically on the developing brain. These direct effects on the offspring are important, but it would be imprudent to overlook the changes necessary in the mother during gestation that are necessary to support these shifts in the offspring. The physical constraints associated with childbirth and the structural changes in the pelvis necessary to accommodate birthing are one obstacle that needed to be overcome, another are the energetic demands placed upon the mother to support a developing fetus. The physiological changes in the mother required to create a gestationally appropriate environment to accommodate changes in brain growth is an important component of the changes necessary for human evolution. Allometric shift exists in rates of brain growth across mammalian species including primates and humans. These shifts are of interest in understanding evolution. As brains grew larger in primate species the duration of fetal growth rates was extended; while in rhesus fetal brain growth is largely completed at birth, this growth rate extends approximately 1 year in chimpanzees and 2 years in humans. Adult brain volumes are reached at roughly 1 year of age in rhesus, 3 years in chimpanzees, and 5 years in humans (Sakai et al., 2013). The scaled rate of brain growth is consistent across species, but the timing of birth is shifted (Hawkes and Finlay, 2018). Theories on the proximate evolutionary cause for this change include the aforementioned “obstetrical dilemma” (Grabowski, 2013) and “energetics of gestation and growth” (Dunsworth et al., 2012). Regardless of why birth timing shifted, genetic changes associated with pregnancy and birthing were necessary for the evolutionary shifts associated with a larger brain.

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Much of our understanding of the genetic underpinnings of gestational length has been derived from studies of preterm birth in humans. Much of the focus to date has been on five categories of genes: endocrine, tissue remodeling, vascular and angiogenesis, metabolism, and immunity and inflammation (Sheikh et al., 2016). These broad categories, if not necessarily specific genes, have also been largely recapitulated by genome-wide association studies (Zhang et al., 2017). The overlap of these genes with studies of human molecular evolution can be difficult to characterize. Many genes implicated in immunity and inflammation associated with pregnancy are likely to have other roles related to infectious disease that are likely significant evolutionary pressures. Similarly, many of the changes in endocrine genes have been associated with behavioral adaptations that need not be pregnancy focused. Nevertheless, this standard confound of evolutionary studies aside, there are several examples of possible genetic changes associated with gestation and birth timing. One study of genes associated with embryonic implantation in humans, chimpanzees, and gorillas identified genes with signatures of positive selection (Civetta, 2015). For two of these genes, FOXA2 and APOL2, the timing of positive selection could not be formally assigned, but for the remaining two, HLA-E and KIR2DL4, evidence suggested an African ape specific bout of selection. These latter two genes are suggested to be involved in the emergence of uterine tolerance of embryonic implantation. These findings are also consistent with more general studies of gene evolution associated with implantation among mammals (Kin et al., 2016) and studies of genes associated with pregnancy phenotypes near human accelerated non-coding regions (Hirbo et al., 2015). Whether these molecular changes represent adaptive changes specific to the phenotypic change or, perhaps more likely, a prezygotic isolation speciation effect is not obvious. Among endocrine factors associated with gestational length, the most interesting from the evolutionary perspective is progesterone and its receptor. Progesterone signaling is an important component of the maintenance of pregnancy and shifts in progesterone levels are associated with the timing of birth (Swaggart et al., 2015). Positive selection has been detected in the progesterone receptor (PGR) in both human and chimpanzee lineages when compared to other primates and mammals (Chen et al., 2008). The location of the positive selection, on the N-terminal extracellular domain, has been used to infer a shift in transcriptional regulatory effects. Interestingly, recent studies comparing the progesterone receptor in living human populations and the Neandertal genome have also identified signatures of selection in a more recent time frame (Li et al., 2018). An explicitly evolutionary approach to identifying selection in genes involved human birth timing also identified the progesterone receptor along with a number of additional endocrine genes: OXT, OXTR, PTGER4, ESR1, and FSHR (Plunkett et al., 2011). Follicle-stimulating hormone receptor (FSHR), in particular, regulates relative abundance of the progesterone receptor isoforms associated with parturition. These endocrine changes offer specific testable hypotheses for their role in evolutionary changes associated with gestation and their association with preterm birth in modern populations supports a functional validity.

5 Conclusions

4.4 Parental care Human babies are born altricial and continue to experience fetal rates of brain growth for their first year of life, necessitating increased parental care. Many other primate species have similar parental investment and life history patterns, so-called K-selection with a focus on increased efficiency at the expense of offspring quantity, but humans represent one of the most extreme examples (Crews and Gerber, 2003). This is supported, in part, by high levels of sociality and affiliative behavior in primate groups. Social and behavioral adaptations that support a slower developmental trajectory and delays in reaching sexual maturity are both culturally and biologically defined. Genetic variation associated with these behaviors has previously been identified, and selection of these genes may have played a role in creating a social environment favorable to the emergence of the primate, and modern human, brain. One conception of brain evolution posits that altricial offspring requires parents with advanced cognitive abilities which requires larger brains which necessitates altriciality, all of which create a positive feedback loop (Piantadosi and Kidd, 2016). Certainly humans show a unique social structure with regard to raising offspring. Alloparenting, child care by individuals other than biological parents, is common in human societies and has been suggested to alleviate energetic demands associated with larger brains and to have facilitated the development of language (Kenkel et al., 2017). Interestingly, despite being a relatively complex behavior, specific genetic changes have been identified that appear to have relevant functional behavior effects. One of the most well-tested of these behavioral genetic effects is associated with oxytocin. Oxytocin is associated with affiliative and maternal behaviors across species including humans and has been shown to be modulated in part by genetic polymorphism at the oxytocin receptor (Marsh et al., 2012). As described previously, both the gene encoding oxytocin (OXT) and the gene encoding its receptor (OXTR) have been shown to have undergone positive selection in humans (Plunkett et al., 2011). This work has been replicated and extended to include the arginine vasopressin receptor gene (AVPR1A) with which it operates in tandem (Schaschl et al., 2015). These evolutionary changes are associated with regulatory elements are result in differences in expression and pro-social behaviors. Another hormone associated with parental behaviors, prolactin, shows both a major shift in protein sequence between haplorrhines and strepsirrhines as well as changes in regulatory regions within primate species (Wallis et al., 2005).

5 Conclusions The study of human brain evolution goes back as far as the study of evolution itself; the question of what separates the mind of a man from that of an animal goes back even further. Many fields, from philosophy to comparative neurobiology, have

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focused their expertise on answering these questions. From the earliest days of genetics it was recognized that there must have been some changes in the sequence of DNA that was ultimately responsible. Even with this knowledge, however, researchers struggled with candidate genes and limited species comparators. As in so many fields, the post-genomic era has rapidly and explosively changed the domain. Contemporary studies of molecular evolution of the brain are not limited by a priori knowledge to candidate genes, and they explore the entirety of the genome for meaning. Similarly, the field has finally moved beyond an exclusive focus on changes in proteins to include extensive studies of regulatory regions presaged by King and Wilson (1975). It also has moved past the early days of focusing only on humans and laboratory rodents to include the genomes of numerous additional mammal and primate species, even extinct hominins such as Neandertals and Denisovans. Studies of molecular evolution also now encompass, in addition to DNA sequences, transcriptomics from increasingly specific neuroanatomical and developmental time points even extending to individual cells. It would be a simple clich
e to say that these advances were unimaginable, but it would not be true. Even before the technologies were available to make these approaches feasible, researchers were thinking about how the studies would be done and what they could be hoped to demonstrate. As these methodologies became possible and practical, they have been rapidly put into use and there has been a deluge of information that shows no sign of abating. Nearly every line of inquiry associated with human brain evolution has been subjected to, and advanced by, molecular evolution studies in the past decade. That is not to say, however, that some of the issues that have plagued the field are entirely resolved. It is still difficult to link specific genetic changes to specific functional outcomes and more difficult to demonstrate that these changes are the substrates of evolution and selection. Moreover, the field has gone from too few examples, resulting in overinterpretation, to too much data and a difficulty in synthesis. This will be the primary challenge in the coming years. The brain is a complex organ, the human brain perhaps infinitely more so. Likewise, evolutionary change is complicated and understanding the specific genetic mechanisms through which it was effected retrospectively and with limited information is a daunting task. Great strides have nevertheless been taken in identifying the genetic mutations responsible for the direct and indirect factors that have led to the human brain. These studies represent some of the first fruits of seeds planted long ago and portent future bountiful harvests. The genetic evolution of the human brain has become a tractable problem; it is now possible to actualize what has for so long been only theoretical.

Acknowledgments This work was supported by grants from the National Institutes of Health: GM103328 and OD011104.

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