Genetic Mechanisms Underlying the Evolution of Connectivity in the Human Cortex

One of the most salient features defining modern humans is our remarkable cognitive capacity, which is unrivaled by any other species. Although we still lack a complete understanding of how the human brain gives rise to these unique abilities, the past several decades have witnessed significant progress in uncovering some of the genetic, cellular, and molecular mechanisms shaping the development and function of the human brain. These features include an expansion of brain size and in particular cortical expansion, distinct physiological properties of human neurons, and modified synaptic development. Together they specify the human brain as a large primate brain with a unique underlying neuronal circuit architecture. Here, we review some of the known human-specific features of neuronal connectivity, and we outline how novel insights into the human genome led to the identification of human-specific genetic modifiers that played a role in the evolution of human brain development and function. Novel experimental paradigms are starting to provide a framework for understanding how the emergence of these human-specific genomic innovations shaped the structure and function of neuronal circuits in the human brain.

Limb Preference in Animals: New Insights into the Evolution of Manual Laterality in Hominids

Until the 1990s, the notion of brain lateralization—the division of labor between the two hemispheres—and its more visible behavioral manifestation, handedness, remained fiercely defined as a human specific trait. Since then, many studies have evidenced lateralized functions in a wide range of species, including both vertebrates and invertebrates. In this review, we highlight the great contribution of comparative research to the understanding of human handedness’ evolutionary and developmental pathways, by distinguishing animal forelimb asymmetries for functionally different actions—i.e., potentially depending on different hemispheric specializations. Firstly, lateralization for the manipulation of inanimate objects has been associated with genetic and ontogenetic factors, with specific brain regions’ activity, and with morphological limb specializations. These could have emerged under selective pressures notably related to the animal locomotion and social styles. Secondly, lateralization for actions directed to living targets (to self or conspecifics) seems to be in relationship with the brain lateralization for emotion processing. Thirdly, findings on primates’ hand preferences for communicative gestures accounts for a link between gestural laterality and a left-hemispheric specialization for intentional communication and language. Throughout this review, we highlight the value of functional neuroimaging and developmental approaches to shed light on the mechanisms underlying human handedness.

Single-nuclei isoform RNA sequencing reveals combination patterns of transcript elements across human brain cell types

Single-nuclei RNA-Seq is being widely employed to investigate cell types, especially of human brain and other frozen samples. In contrast to single-cell approaches, however, the majority of single-nuclei RNA counts originate from partially processed RNA leading to intronic cDNAs, thus hindering the investigation of complete isoforms. Here, using microfluidics, PCR-based artifact removal, target enrichment, and long-read sequencing, we developed single-nuclei isoform RNA-sequencing ('SnISOr-Seq'), and applied it to the analysis of human adult frontal cortex samples. We found that exons associated with autism exhibit coordinated and more cell-type specific inclusion than exons associated with schizophrenia or ALS. We discovered two distinct modes of combination patterns: first, those distinguishing cell types in the human brain. These are enriched in combinations of TSS-exon, exon-polyA site, and distant (non-adjacent) exon pairs. Second, those with all isoform combinations found within one neural cell type, which are enriched in adjacent exon pairs. Furthermore, adjacent exon pairs are predominantly mutually associated, while distant pairs are frequently mutually exclusive. Finally, we observed that human-specific exons are as tightly coordinated as conserved exons, pointing to an efficient evolutionary mechanism underpinning coordination. SnISOr-Seq opens the door to single-nuclei long-read isoform analysis in the human brain, and in any frozen, archived or hard-to-dissociate sample.

Species-specific mitochondria dynamics and metabolism regulate the timing of neuronal development.

The evolution of species involves changes in the timeline of key developmental programs. Among these, neuronal development is considerably prolonged in the human cerebral cortex compared with other mammals, leading to brain neoteny. Here we explore whether mitochondria influence the species-specific properties of cortical neuron maturation. By comparing human and mouse cortical neuronal maturation at high temporal and cell resolution, we found a slower pattern of mitochondria development in human cortical neurons compared with the mouse, together with lower mitochondria metabolic activity, particularly oxidative phosphorylation. Stimulation of mitochondria metabolism in human neurons resulted in accelerated maturation, leading to excitable and complex cells weeks ahead of time. Our data identify mitochondria as important regulators of the pace of neuronal development underlying human-specific features of brain evolution.

Morphological and genomic characterisation of the Schistosoma hybrid infecting humans in Europe reveals admixture between Schistosoma haematobium and Schistosoma bovis

Schistosomes cause schistosomiasis, the world’s second most important parasitic disease after malaria in terms of public health and social-economic impacts. A peculiar feature of these dioecious parasites is their ability to produce viable and fertile hybrid offspring. Originally only present in the tropics, schistosomiasis is now also endemic in southern Europe. Based on the analysis of two genetic markers the European schistosomes had previously been identified as hybrids between the livestock- and the human-infective species Schistosoma bovis and Schistosoma haematobium, respectively. Here, using PacBio long-read sequencing technology we performed genome assembly improvement and annotation of S. bovis, one of the parental species for which no satisfactory genome assembly was available. We then describe the whole genome introgression levels of the hybrid schistosomes, their morphometric parameters (eggs and adult worms) and their compatibility with two European snail strains used as vectors (Bulinus truncatus and Planorbarius metidjensis). Schistosome-snail compatibility is a key parameter for the parasites life cycle progression, and thus the capability of the parasite to establish in a given area. Our results show that this Schistosoma hybrid is strongly introgressed genetically, composed of 77% S. haematobium and 23% S. bovis origin. This genomic admixture suggests an ancient hybridization event and subsequent backcrosses with the human-specific species, S. haematobium, before its introduction in Corsica. We also show that egg morphology (commonly used as a species diagnostic) does not allow for accurate hybrid identification while genetic tests do.

Human neural networks with sparse TDP-43 pathology reveal NPTX2 misregulation in ALS/FTLD

Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating these age-dependent diseases. Such systems are particularly needed for TDP-43 proteinopathies, which involve human-specific mechanisms that cannot be directly studied in animal models. To explore the emergence and consequences of TDP-43 pathologies, we generated iPSC-derived, colony morphology neural stem cells (iCoMoNSCs) via manual selection of neural precursors. Single-cell transcriptomics (scRNA-seq) and comparison to independent NSCs, showed that iCoMoNSCs are uniquely homogenous and self-renewing. Differentiated iCoMoNSCs formed a self-organized multicellular system consisting of synaptically connected and electrophysiologically active neurons, which matured into long-lived functional networks. Neuronal and glial maturation in iCoMoNSC-derived cultures was similar to that of cortical organoids. Overexpression of wild-type TDP-43 in a minority of iCoMoNSC-derived neurons led to progressive fragmentation and aggregation, resulting in loss of function and neurotoxicity. scRNA-seq revealed a novel set of misregulated RNA targets coinciding in both TDP-43 overexpressing neurons and patient brains exhibiting loss of nuclear TDP-43. The strongest misregulated target encoded for the synaptic protein NPTX2, which was consistently misaccumulated in ALS and FTLD patient neurons with TDP-43 pathology. Our work directly links TDP-43 misregulation and NPTX2 accumulation, thereby highlighting a new pathway of neurotoxicity.

Evolution of Human-specific Alleles Protecting Cognitive Function of Grandmothers

Late-onset Alzheimers Disease (LOAD) pathology is rare in our closest living evolutionary relatives (chimpanzees), which also express much lower microglial levels of CD33(Siglec-3), a myelomonocytic receptor inhibiting innate immune reactivity by extracellular V-set domain recognition of sialic acid(Sia)-containing self-associated molecular patterns (SAMPs). We earlier showed that V-set domain-deficient CD33-variant allele, protective against LOAD, is derived and specific to hominin-lineage. We now report that CD33 also harbors multiple hominin-specific V-set domain mutations and explore selection forces that may have favored such genomic changes. N-glycolylneuraminic acid (Neu5Gc), the preferred Sia-ligand of ancestral CD33 is absent in humans, due to hominin-specific, fixed loss-of-function mutation in CMAH, which generates CMP-Neu5Gc from its precursor, CMP-N-acetylneuraminic acid (Neu5Ac). Extensive mutational analysis and MD-simulations indicate that fixed change in amino acid 21 of hominin V-set domain and conformational changes related to His45 corrected for Neu5Gc-loss by switching to Neu5Ac-recognition. Considering immune-evasive molecular mimicry of SAMPs by pathogens, we found that human-specific pathogens Neisseria gonorrhoeae and Group B Streptococcus (affecting fertility and fetuses/neonates respectively) selectively bind huCD33 and this binding is significantly impacted by amino acid 21 modification. Alongside LOAD-protective CD33 alleles, humans harbor additional, derived, population-universal, cognition-protective variants absent in great ape genomes. Interestingly, 11 of 13 SNPs in these human genes (including CD33), that protect the cognitive health of elderly populations, are not shared by genomes of archaic hominins: Neanderthals and Denisovans. Finally, we present a plausible evolutionary scenario to compile, correlate and comprehend existing knowledge about huCD33 evolution and suggest that grandmothering emerged in humans.

Whole Genome Sequencing Illuminates the Developmental Signatures of Human Language Ability

Language is the foundation of human social interaction, education, commerce, and mental health. The heritability underlying language is well-established, but our understanding of its genetic basis - and how it compares to that of more general cognitive functioning - remains unclear. To illuminate the language-specific contributions of rare and common variation, we performed whole genome sequencing in N=350 individuals, who were characterized with seven latent language phenotypes. We conducted region, gene, and gene set-based analyses to identify patterns of genetic burden that disproportionately explained these language factors compared to nonverbal IQ. These analyses identified language-specific associations with NDST4 and GRIN2A, with common variant replication of NDST4 in an independent sample. Rare variant burden analyses revealed three distinct functional profiles of genes that make contributions to language: a prenatally-expressed profile with enrichment for chromatin modifiers and broad neuropsychiatric risk, a postnatal cortex-expressed profile with enrichment for ion channels and cognitive/neuropsychiatric associations, and a postnatal, subcortically-expressed profile with enrichment of cilium-related proteins. Compared to a profile strongly associated with nonverbal IQ, these language-related profiles showed less intolerance to damaging variation, suggesting that the selection patterns acting on language differ from patterns linked to intellectual disability. Furthermore, we found evidence that rare potential reversions to an ancestral state are associated with poorer overall specific language ability. The breadth of these variant, gene, and profile associations suggest that while human-specific selection patterns do contribute to language, these are distributed broadly across numerous key mechanisms and developmental periods, and not in one or a few "language genes".