Genomic approaches for understanding the evolution of the human brain.

Yearbook of Physical Anthropology Preface.

Materials and methods. Scientific literature to review was collected from the PubMed database (https://pubmed.ncbi.nlm.nih.gov), some other publications were collected from the open internet sources. Results. Herein we represent a review of current data for genetics regarding the hybridization events of the human evolution. The paper reviews ancient human interactions that had place 30-1000 thousands of years ago and could be detected by the methods of genetics. Both, divergence of the Old World human population and consequent introgression and hybridization processes that had led to the formation of modern human are analyzed. Discussion. The current genetics allows to study and analyze genomes of human and other animals in the aim to discover their evolutionary relationships. The consequent reveal of the ancient and extinct animal genomes allowed to speak about palaeogenetics, while the genome comparisons have formed a new discipline, comparative genomics, an analogue of the comparative anatomy. Modern and ancient human genomes' analysis have discovered the ancient human subpopulations' interactions and relations, part of which gave rise to the modern humans. Conclusion. Modern humans are a result of i) evolution of the isolated ancient human populations which had formed 200–1000 thousands of years ago; and ii) of interaction between them. Indeed, a number of hybridization events we can see during the human evolution, most of them are reflected in the modern and ancient human genomes.

Pathogens and infectious diseases have imposed exceptionally strong selective pressure on ancient and modern human genomes and contributed to the current variation in many genes. There is evidence that modern humans acquired immune variants through interbreeding with ancient hominins, but the impact of such variants on human traits is not fully understood. The main objectives of this research were to infer the genetic signatures of positive selection that may be involved in adaptation to infectious diseases and to investigate the function of Neanderthal alleles identified within a set of 50 Lithuanian genomes. Introgressed regions were identified using the machine learning tool ArchIE. Recent positive selection signatures were analysed using iHS. We detected high-scoring signals of positive selection at innate immunity genes (EMB, PARP8, HLAC, and CDSN) and evaluated their interactions with the structural proteins of pathogens. Interactions with human immunodeficiency virus (HIV) 1 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were identified. Overall, genomic regions introgressed from Neanderthals were shown to be enriched in genes related to immunity, keratinocyte differentiation, and sensory perception.

Human Immunology through the Lens of Evolutionary Genetics

The role of natural selection in shaping biological diversity is an area of intense interest in modern biology. To date, studies of positive selection have primarily relied on genomic datasets from contemporary populations, which are susceptible to confounding factors associated with complex and often unknown aspects of population history. In particular, admixture between diverged populations can distort or hide prior selection events in modern genomes, though this process is not explicitly accounted for in most selection studies despite its apparent ubiquity in humans and other species. Through analyses of ancient and modern human genomes, we show that previously reported Holocene-era admixture has masked more than 50 historic hard sweeps in modern European genomes. Our results imply that this canonical mode of selection has probably been underappreciated in the evolutionary history of humans and suggest that our current understanding of the tempo and mode of selection in natural populations may be inaccurate.

Being human, we possess unique biological features, such as the big brain, upright walking and sophisticated language, which set us apart from our close relatives, the non-human primates since our divergence from the Pan lineage approximately 5 million years ago. Scientists have attempted to solve the mystery of our unique phenotypic traits with approaches from paleoanthropology, anatomy, psychology, behavior and social cognition etc. However, the answers are embedded in our genetic makeup. What are the genetic changes in our genome that make us human? By comparing the genomes of humans and nonhuman primates, scientists have identified a lot of genetic changes that might have contributed to the human-specific traits. These genetic changes work at different genetic levels, including sequence changes in protein-coding genes, gene expression changes, gene losses and gene duplications. Natural selection is the driving force pushing fixation of these genetic changes during human evolution, and they may have important contribution to human’s unique phenotypes. In this review, we mainly discuss the relationship between human-specific phenotypes and genetic changes. We summarize our current findings and understandings of genes with human-specific mutations and their possible functional effects. For example, a set of brain-size regulating genes have been identified and many of them showed strong signatures of Darwinian positive selection during primate evolution and human origin. These human-specific mutations likely work their ways through human brain development and eventually form a large brain. Another fascinating example is the language gene FOXP2 that has two human specific mutations, which may lead to a unique developmental pattern change of the human brain region responsible for human language ability. Furthermore, besides protein coding genes, there are other genetic changes, and many identified fast-evolving regions in the human genome are not located in the coding sequences. Instead they are distributed in regulatory sequences likely involved in gene expression regulation which affect the temporal and spatial pattern of human development. Finally, we introduce the recent advance of technologies that can be used to study the functional outcomes of the human specific mutations. These technologies provide useful tools that may reproduce the scenes of human evolution in the laboratory. The in vitro analysis of humanized iPSCs can to some extend mimic the in vivo development of the human brain. Notably, the newly developed gene editing tools including CRISPR-Cas9 and TALEN are promising in studying the human-specific traits using transgenic animal models, especially the transgenic monkey models which may provide much more mechanistic information than the traditional mouse model. The human-specific genetic changes accumulated during human evolution occurred at different levels, but they must work together to produce the human-specific traits. Future studies may establish the links by figuring out how changes at different genetic levels coordinate with each other to make us human.

Summary. Each species has its own uniqueness, for which it is clear that species-specific genetic information forms the basis. The extent of genomic similarity among species can be evaluated by comparative studies of nucleotide substitutions in orthologous genes which are commonly present in all the species examined. Such studies using orthologous genes have shown that humans are most closely related to chimpanzees and that the nucleotide differences between them are merely a few percent. These studies are useful for construction of molecular phylogenetic trees and deduction of divergence dates, but are less useful for defining the genetic uniqueness of individual species. In order to elucidate the extent of dissimilarities among the genomes of humans and nonhuman primates and to clarify the genetic basis of human uniqueness, human-specific DNA sequences were sought as species-specific traits using the technique of genome subtraction. These sequences are present in the human genome alone but absent in the genomes of nonhuman primates.

Despite striking differences in cognition and behavior between humans and our closest primate relatives, several studies have found little evidence for adaptive change in protein-coding regions of genes expressed primarily in the brain. Instead, changes in gene expression may underlie many cognitive and behavioral differences. Here, we used digital gene expression: tag profiling (here called Tag-Seq, also called DGE:tag profiling) to assess changes in global transcript abundance in the frontal cortex of the brains of 3 humans, 3 chimpanzees, and 3 rhesus macaques. A substantial fraction of transcripts we identified as differentially transcribed among species were not assayed in previous studies based on microarrays. Differentially expressed tags within coding regions are enriched for gene functions involved in synaptic transmission, transport, oxidative phosphorylation, and lipid metabolism. Importantly, because Tag-Seq technology provides strand-specific information about all polyadenlyated transcripts, we were able to assay expression in noncoding intragenic regions, including both sense and antisense noncoding transcripts (relative to nearby genes). We find that many noncoding transcripts are conserved in both location and expression level between species, suggesting a possible functional role. Lastly, we examined the overlap between differential gene expression and signatures of positive selection within putative promoter regions, a sign that these differences represent adaptations during human evolution. Comparative approaches may provide important insights into genes responsible for differences in cognitive functions between humans and nonhuman primates, as well as highlighting new candidate genes for studies investigating neurological disorders.

Size isn't everything, comparatively speaking

The study of the evolution of brain structure and function, although fascinating, has been contentious, largely due to the correlative nature of neuroanatomical comparisons and the often ill-defined categorizations of habitat and behavior. We outline four conceptual approaches that will help the field of brain evolution emerge from a historical focus on descriptive comparative neuroanatomy. First, reliable, efficient and unbiased behavioral assays must be developed to characterize relevant cross-species differences in addition to focused studies of neuroanatomy. Second, developmental and physiological processes underlying neuroanatomical and behavioral differences can be analyzed using the comparative approach. Third, genome-wide comparisons including genome-wide linkage mapping, transcriptional profiling, and direct sequence comparisons, can be applied to identify the genetic basis for phenotypic differences. Finally, signatures of selection in DNA sequence can provide clues about adaptive genetic changes that affect the nervous system. These four approaches, which all depend on well-resolved phylogenies, will build on detailed neuroanatomical studies to provide a richer understanding of mechanistic and selective factors underlying brain evolution.

Non-traditional Alu evolution and primate genomic diversity

Interred with Their DNA

The evolution of human language has been discussed for centuries from different perspectives. Linguistic theory has proposed grammar as a core part of human language that has to be considered in this context. Recent advances in neurosciences have allowed us to take a new neurobiological look on the similarities and dissimilarities of cognitive capacities and their neural basis across both closely and distantly related species. A couple of decades ago, the comparisons were mainly drawn between human and non-human primates, investigating the cytoarchitecture of particular brain areas and their structural connectivity. Moreover, comparative studies were conducted with respect to their ability to process grammars of different complexity. So far the available data suggest that non-human primates are able to learn simple probabilistic grammars, but not hierarchically structured complex grammars. The human brain, which easily learns both grammars, differs from the non-human brain (among others) in how two language-relevant brain regions (Broca's area in the inferior frontal cortex and the superior temporal cortex) are connected structurally by fiber tracts which run dorsally and ventrally in the primate brain. Whether the more dominant dorsal pathway in humans compared to non-human primates is causally related to this behavioral difference is an issue of current debate. Ontogenetic findings suggest at least a correlation between the maturation of the dorsal pathway and the behavior to process syntactically complex structures, although the ultimate causal prove is still not available. Thus, the neural basis of complex grammar processing in humans remains to be defined. More recently it has been reported that songbirds are also able to distinguish between sound sequences reflecting complex grammar. Interestingly, songbirds learn to sing by imitating adult song in a process not unlike language development in children. Moreover, the neural circuits supporting this behavior in songbirds bear anatomical and functional similarities to those in humans. In adult humans the fiber tract connecting the auditory cortex and motor cortex dorsally is known to be involved in the repetition of spoken language. This pathway is present already at birth and is taken to play a major role during language acquisition. In songbirds, detailed information exist concerning the interaction of auditory, motor, and cortical-basal ganglia processing during song learning, and present a rich substrate for comparative studies. The scope of the Research Topic was to bring together contributions of researchers from different fields, who investigate grammar processing in humans, non-human primates, and songbirds with the aim to find answers to the question of what constitutes the neurobiological basis of language and language learning. A number of contributions discuss the ventral and dorsal pathways in human and non-human primates considering their functional roles in speech and language. Some of these take an evolutionary perspective comparing non-human and human primates (Rauschecker, 2012; Rilling et al., 2012), whereas other takes an ontogenetic perspective (Friederici, 2012). The functional roles of the ventral and dorsal pathways in language and other modalities in particular action including articulatory and hand gestures are discussed in further articles (Fitch, 2011; Aboitiz, 2012; Rijntjes et al., 2012). Two articles consider the language system at the interface of two other human specific abilities, namely number processing (Heim et al., 2012) and reading (Lachmann et al., 2012). A couple of contributions take the evolutionary perspective even further by including song birds into their comparative approach (Berwick et al., 2012; Kiggins et al., 2012; Petkov and Jarvis, 2012). The selection of the articles provides a picture of the current views on the evolutionary and neurobiological basis of the language and language learning.

Many of the most distinctive attributes of our species are a product of our brains. To understand the function, development, variability, and evolution of the human brain, we must engage with the field of neuroscience. Neuroscientific methods can be used to investigate research topics that are of special interest to anthropologists, such as the neural bases of primate behavioral diversity, human brain evolution, and human brain development. Traditional neuroscience methods had to rely on investigation of postmortem brains, as well as invasive studies in living nonhuman primates. However, recent neuroimaging methods have made it possible to compare living human and nonhuman primate brains using noninvasive techniques such as structural and functional magnetic resonance imaging, positron emission tomography, and diffusion tensor imaging. These methods are providing an integrated picture of brain structure and function that was not previously available. With a combination of these traditional and modern neuroscience methods, we are beginning to explore and understand the neural bases of some of the most distinctive cognitive and behavioral attributes of the human species, including language, tool use, altruism, and mental self-projection, and we can now begin to propose plausible scenarios by which the neural substrates supporting these human specializations evolved from pre-existing neural circuitry serving related functions in common ancestors we shared with the living nonhuman primates. Consideration of the process of neurodevelopment suggests plausible mechanisms by which the highly encephalized human brain might have evolved. Neurodevelopmental studies also demonstrate that experience can shape both brain structure and function, providing a mechanism by which people of different cultures learn to act and think differently. Finally, not only can anthropologists benefit from neuroscience, neuroscience can benefit from the more sophisticated concept of evolution that anthropology offers, including an appreciation of evolutionary diversity as well as consideration of the process by which the human brain was formed during evolution.

BackgroundMicroRNAs (miRNAs) are negative regulators of gene expression in multicellular eukaryotes. With the recently completed sequencing of three primate genomes, the study of miRNA evolution within the primate lineage has only begun and may be expected to provide the genetic and molecular explanations for many phenotypic differences between human and non-human primates.FindingsWe scanned all three genomes of non-human primates, including chimpanzee (Pan troglodytes), orangutan (Pongo pygmaeus), and rhesus monkey (Macaca mulatta), for homologs of human miRNA genes. Besides sequence homology analysis, our comparative method relies on various postprocessing filters to verify other features of miRNAs, including, in particular, their precursor structure or their occurrence (prediction) in other primate genomes. Our study allows direct comparisons between the different species in terms of their miRNA repertoire, their evolutionary distance to human, the effects of filters, as well as the identification of common and species-specific miRNAs in the primate lineage. More than 500 novel putative miRNA genes have been discovered in orangutan that show at least 85 percent identity in precursor sequence. Only about 40 percent are found to be 100 percent identical with their human ortholog.ConclusionHomologs of human precursor miRNAs with perfect or near-perfect sequence identity may be considered to be likely functional in other primates. The computational identification of homologs with less similar sequence, instead, requires further evidence to be provided.