scholarly journals Genetic Mechanisms Underlying the Evolution of Connectivity in the Human Cortex

2022 ◽  
Vol 15 ◽  
Author(s):  
Ewoud R. E. Schmidt ◽  
Franck Polleux
Keyword(s):  
Human Brain ◽  
Molecular Mechanisms ◽  
Brain Size ◽  
Cognitive Capacity ◽  
Genetic Modifiers ◽  
Physiological Properties ◽  
Human Neurons ◽  
Genetic Mechanisms ◽  
And Function ◽  
Human Specific

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.

scholarly journals New gene discoveries in skeletal diseases with short stature

2021 ◽  
Author(s):  
Alice Costantini ◽  
Mari H Muurinen ◽  
Outi Mäkitie
Keyword(s):  
Short Stature ◽  
Molecular Mechanisms ◽  
Bone Growth ◽  
Massively Parallel Sequencing ◽  
Matrix Composition ◽  
Biological Processes ◽  
Novel Gene ◽  
Genetic Mechanisms ◽  
New Gene ◽  
And Function

In the last decade, the widespread use of massively-parallel sequencing has considerably boosted the number of novel gene discoveries in monogenic skeletal diseases with short stature. Defects in genes playing a role in the maintenance and function of the growth plate, the site of longitudinal bone growth, are a well-known cause of skeletal diseases with short stature. However, several genes involved in extracellular matrix composition or maintenance as well as genes partaking in various biological processes have also been characterized. This review aims to describe the latest genetic findings in spondyloepiphyseal and spondyloepimetaphyseal dysplasias and in some monogenic forms of isolated short stature. Strategies on how to successfully characterize novel skeletal phenotypes with short stature and genetic approaches to detect and validate novel gene-disease correlations will be discussed in detail. Finally, novel genetic mechanisms in the field of skeletal diseases, including variants affecting miRNAs and disrupting the chromatin structure, will be described. In summary, we discuss the latest gene discoveries underlying skeletal diseases with short stature and emphasize the importance of characterizing novel molecular mechanisms for genetic counseling, optimal management of the disease and for therapeutic innovations.

scholarly journals Evolution of Human Brain Size-Associated NOTCH2NL Genes Proceeds toward Reduced Protein Levels

2020 ◽  
Vol 37 (9) ◽  
pp. 2531-2548
Author(s):  
Gerrald A Lodewijk ◽  
Diana P Fernandes ◽  
Iraklis Vretzakis ◽  
Jeanne E Savage ◽  
Frank M J Jacobs
Keyword(s):  
Human Brain ◽  
Brain Size ◽  
Modern Human ◽  
Copy Number Variations ◽  
Optimal Dosage ◽  
Protein Coding ◽  
Protein Levels ◽  
Human Genomes ◽  
Coding Variants ◽  
Human Specific

Abstract Ever since the availability of genomes from Neanderthals, Denisovans, and ancient humans, the field of evolutionary genomics has been searching for protein-coding variants that may hold clues to how our species evolved over the last ∼600,000 years. In this study, we identify such variants in the human-specific NOTCH2NL gene family, which were recently identified as possible contributors to the evolutionary expansion of the human brain. We find evidence for the existence of unique protein-coding NOTCH2NL variants in Neanderthals and Denisovans which could affect their ability to activate Notch signaling. Furthermore, in the Neanderthal and Denisovan genomes, we find unusual NOTCH2NL configurations, not found in any of the modern human genomes analyzed. Finally, genetic analysis of archaic and modern humans reveals ongoing adaptive evolution of modern human NOTCH2NL genes, identifying three structural variants acting complementary to drive our genome to produce a lower dosage of NOTCH2NL protein. Because copy-number variations of the 1q21.1 locus, encompassing NOTCH2NL genes, are associated with severe neurological disorders, this seemingly contradicting drive toward low levels of NOTCH2NL protein indicates that the optimal dosage of NOTCH2NL may have not yet been settled in the human population.

scholarly journals Proteolytic Activation of Human-specific Olduvai Domains by the Furin Protease

2021 ◽  
Author(s):  
Ashley Pacheco ◽  
Aaron Issaian ◽  
Jonathan Davis ◽  
Nathan Anderson ◽  
Travis Nemkov ◽  
...  
Keyword(s):  
Human Brain ◽  
Copy Number ◽  
Brain Size ◽  
Active Agent ◽  
Brain Evolution ◽  
Variable Number ◽  
Coding Region ◽  
Proteolytic Activation ◽  
Highly Correlated ◽  
Human Specific

Olduvai protein domains (formerly DUF1220) show the greatest human-specific increase in copy number of any coding region in the genome and are highly correlated with human brain evolution and cognitive disease. The majority of human copies are found within four NBPF genes organized in a variable number of a tandemly arranged three-domain blocks called Olduvai triplets. Here we show that these human-specific Olduvai domains are posttranslationally processed by the furin protease, with a cleavage site occurring once at each triplet. These findings suggest that all expanded human-specific NBPF genes encode proproteins consisting of many independent Olduvai triplet proteins which are activated by furin processing. The exceptional correlation of Olduvai copy number and brain size taken together with our new furin data, indicates the ultimate target of selection was a rapid increase in dosage of autonomously functioning Olduvai triplet proteins, and that these proteins are the primary active agent underlying Olduvai's role in human brain expansion.

scholarly journals Modeling Reveals Human–Rodent Differences in H-Current Kinetics Influencing Resonance in Cortical Layer 5 Neurons

2020 ◽  
Author(s):  
Scott Rich ◽  
Homeira Moradi Chameh ◽  
Vladislav Sekulic ◽  
Taufik A Valiante ◽  
Frances K Skinner
Keyword(s):  
Human Brain ◽  
Cell Model ◽  
Model Development ◽  
Compartment Model ◽  
Cell Types ◽  
Cortical Layer ◽  
Neuron Models ◽  
Cellular Models ◽  
Human Neurons ◽  
Human Specific

Abstract While our understanding of human neurons is often inferred from rodent data, inter-species differences between neurons can be captured by building cellular models specifically from human data. This includes understanding differences at the level of ion channels and their implications for human brain function. Thus, we here present a full spiking, biophysically detailed multi-compartment model of a human layer 5 (L5) cortical pyramidal cell. Model development was primarily based on morphological and electrophysiological data from the same human L5 neuron, avoiding confounds of experimental variability. Focus was placed on describing the behavior of the hyperpolarization-activated cation (h-) channel, given increasing interest in this channel due to its role in pacemaking and differentiating cell types. We ensured that the model exhibited post-inhibitory rebound spiking considering its relationship with the h-current, along with other general spiking characteristics. The model was validated against data not used in its development, which highlighted distinctly slower kinetics of the human h-current relative to the rodent setting. We linked the lack of subthreshold resonance observed in human L5 neurons to these human-specific h-current kinetics. This work shows that it is possible and necessary to build human-specific biophysical neuron models in order to understand human brain dynamics.

scholarly journals Where the genome meets the connectome: understanding how genes shape human brain connectivity

2021 ◽  
Author(s):  
Aurina Arnatkeviciute ◽  
Ben Fulcher ◽  
Mark Bellgrove ◽  
Alex Fornito
Keyword(s):  
Human Brain ◽  
Phenotypic Variation ◽  
Molecular Mechanisms ◽  
Brain Connectivity ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Brain Dysfunction ◽  
Brain Network ◽  
Clinical Disorders ◽  
And Function

The integration of modern neuroimaging methods with genetically informative designs and data can shed light on the molecular mechanisms underlying the structural and functional organisation of the human connectome. Here, we review studies that have investigated the genetic basis of human brain network structure and function through three complementary frameworks: (1) the quantification of phenotypic heritability through classical twin designs; (2) the identification of specific DNA variants linked to phenotypic variation through association and related studies; and (3) the analysis of correlations between spatial variations in imaging phenotypes and gene expression profiles through the integration of neuroimaging and transcriptional atlas data. We consider the basic foundations, strengths, limitations, and discoveries associated with each approach. We present converging evidence to indicate that anatomical connectivity is under stronger genetic influence than functional connectivity and that genetic influences are not uniformly distributed throughout the brain, with phenotypic variation in certain regions and connections being under stronger genetic control than others. We also consider how the combination of imaging and genetics can be used to understand the ways in which genes may drive brain dysfunction in different clinical disorders.

scholarly journals Establishing Cerebral Organoids as Models of Human-Specific Brain Evolution

2018 ◽  
Author(s):  
Alex A Pollen ◽  
Aparna Bhaduri ◽  
Madeline G Andrews ◽  
Tomasz J Nowakowski ◽  
Olivia S Meyerson ◽  
...  
Keyword(s):  
Human Brain ◽  
Regulatory Networks ◽  
Radial Glia ◽  
Brain Size ◽  
Metabolic Stress ◽  
Brain Evolution ◽  
Cell Types ◽  
Segmental Duplications ◽  
Systematic Analysis ◽  
Human Specific

Direct comparisons of human and non-human primate brain tissue have the potential to reveal molecular pathways underlying remarkable specializations of the human brain. However, chimpanzee tissue is largely inaccessible during neocortical neurogenesis when differences in brain size first appear. To identify human-specific features of cortical development, we leveraged recent innovations that permit generating pluripotent stem cell-derived cerebral organoids from chimpanzee. First, we systematically evaluated the fidelity of organoid models to primary human and macaque cortex, finding organoid models preserve gene regulatory networks related to cell types and developmental processes but exhibit increased metabolic stress. Second, we identified 261 genes differentially expressed in human compared to chimpanzee organoids and macaque cortex. Many of these genes overlap with human-specific segmental duplications and a subset suggest increased PI3K/AKT/mTOR activation in human outer radial glia. Together, our findings establish a platform for systematic analysis of molecular changes contributing to human brain development and evolution.

scholarly journals Accelerated evolution of oligodendrocytes in the human brain

2019 ◽  
Vol 116 (48) ◽  
pp. 24334-24342 ◽  
Author(s):  
Stefano Berto ◽  
Isabel Mendizabal ◽  
Noriyoshi Usui ◽  
Kazuya Toriumi ◽  
Paramita Chatterjee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Brain ◽  
Molecular Mechanisms ◽  
Rhesus Macaques ◽  
Brain Evolution ◽  
Neuropsychiatric Disorders ◽  
Cell Types ◽  
Accelerated Evolution ◽  
Expression Evolution ◽  
Human Specific

Recent discussions of human brain evolution have largely focused on increased neuron numbers and changes in their connectivity and expression. However, it is increasingly appreciated that oligodendrocytes play important roles in cognitive function and disease. Whether both cell types follow similar or distinctive evolutionary trajectories is not known. We examined the transcriptomes of neurons and oligodendrocytes in the frontal cortex of humans, chimpanzees, and rhesus macaques. We identified human-specific trajectories of gene expression in neurons and oligodendrocytes and show that both cell types exhibit human-specific up-regulation. Moreover, oligodendrocytes have undergone more pronounced accelerated gene expression evolution in the human lineage compared to neurons. We highlighted human-specific coexpression networks with specific functions. Our data suggest that oligodendrocyte human-specific networks are enriched for alternative splicing and transcriptional regulation. Oligodendrocyte networks are also enriched for variants associated with schizophrenia and other neuropsychiatric disorders. Such enrichments were not found in neuronal networks. These results offer a glimpse into the molecular mechanisms of oligodendrocytes during evolution and how such mechanisms are associated with neuropsychiatric disorders.

scholarly journals Modeling reveals human-rodent differences in h-current kinetics influencing resonance in cortical layer 5 neurons

2020 ◽  
Author(s):  
Scott Rich ◽  
Homeira Moradi Chameh ◽  
Vladislav Sekulic ◽  
Taufik A. Valiante ◽  
Frances K. Skinner
Keyword(s):  
Human Brain ◽  
Cell Model ◽  
Model Development ◽  
Compartment Model ◽  
Cell Types ◽  
Cortical Layer ◽  
Neuron Models ◽  
Cellular Models ◽  
Human Neurons ◽  
Human Specific

AbstractWhile our understanding of human neurons is often inferred from rodent data, inter-species differences between neurons can be captured by building cellular models specifically from human data. This includes understanding differences at the level of ion channels and their implications for human brain function. Thus, we here present a full spiking, biophysically-detailed multi-compartment model of a human layer 5 (L5) cortical pyramidal cell. Model development was primarily based on morphological and electrophysiological data from the same human L5 neuron, avoiding confounds of experimental variability. Focus was placed on describing the behavior of the hyperpolarization-activated cation (h-) channel, given increasing interest in this channel due to its role in pacemaking and differentiating cell types. We ensured that the model exhibited post-inhibitory rebound (PIR) spiking considering its relationship with the h-current, along with other general spiking characteristics. The model was validated against data not used in its development, which highlighted distinctly slower kinetics of the human h-current relative to the rodent setting. We linked the lack of subthreshold resonance observed in human L5 neurons to these human-specific h-current kinetics. This work shows that it is possible and necessary to build human-specific biophysical neuron models in order to understand human brain dynamics.

scholarly journals Dump the “dimorphism”: Comprehensive synthesis of human brain studies reveals few male-female differences beyond size

2020 ◽  
Author(s):  
Lise Eliot ◽  
Adnan Ahmed ◽  
Hiba Khan ◽  
Julie Patel
Keyword(s):  
Human Brain ◽  
Brain Size ◽  
Brain Mri ◽  
Size Difference ◽  
Human Populations ◽  
Female Brain ◽  
Brain Structure And Function ◽  
Size Task ◽  
Meta Analyses ◽  
And Function

With the explosion of neuroimaging, it is clear that sex/gender is a key covariate influencing brain structure and function. Here we synthesize three decades of human brain MRI and postmortem data, emphasizing meta-analyses and other large studies, but the result is few reliable sex/gender findings and many unreplicated claims. Males' brains are larger than females' from birth, stabilizing around 11% in adults. This size difference accounts for other reproducible male/female brain differences: gray/white matter ratio (larger in F), inter- versus intrahemispheric connectivity ratio (greater in F), and regional cortical and subcortical volumes (greater in M). However, regional cortical and subcortical sex/gender differences are highly unreliable and explain only about 1% of volume variance. Connectome studies of sex/gender difference are conflicted and rarely control from brain size. Task-based fMRI has also failed to find reproducible brain activation differences between men and women in verbal, spatial, or emotion processing due to high rates of false discovery. In sum, male/female brain differences are non-binary and trivial relative to the total variance across human populations. Properly speaking, the human brain is not sexually-dimorphic.

scholarly journals Feature Article: A Connectomic Hypothesis for the Hominization of the Brain

2020 ◽  
Author(s):  
Jean-Pierre Changeux ◽  
Alexandros Goulas ◽  
Claus C Hilgetag
Keyword(s):  
Human Brain ◽  
Cognitive Abilities ◽  
Brain Size ◽  
Brain Connectivity ◽  
Feature Article ◽  
Primate Brain ◽  
Gene Level ◽  
Small Set ◽  
The Brain ◽  
Human Specific

Abstract Cognitive abilities of the human brain, including language, have expanded dramatically in the course of our recent evolution from nonhuman primates, despite only minor apparent changes at the gene level. The hypothesis we propose for this paradox relies upon fundamental features of human brain connectivity, which contribute to a characteristic anatomical, functional, and computational neural phenotype, offering a parsimonious framework for connectomic changes taking place upon the human-specific evolution of the genome. Many human connectomic features might be accounted for by substantially increased brain size within the global neural architecture of the primate brain, resulting in a larger number of neurons and areas and the sparsification, increased modularity, and laminar differentiation of cortical connections. The combination of these features with the developmental expansion of upper cortical layers, prolonged postnatal brain development, and multiplied nongenetic interactions with the physical, social, and cultural environment gives rise to categorically human-specific cognitive abilities including the recursivity of language. Thus, a small set of genetic regulatory events affecting quantitative gene expression may plausibly account for the origins of human brain connectivity and cognition.

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