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 Emerging Roles of Long Non-Coding RNAs as Drivers of Brain Evolution

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1399 ◽  
Author(s):  
Geraldine Zimmer-Bensch
Keyword(s):  
Human Brain ◽  
Cognitive Abilities ◽  
Brain Size ◽  
Expression Patterns ◽  
Brain Evolution ◽  
Relative Volume ◽  
Structural Reorganization ◽  
Protein Coding ◽  
Human Brain Evolution ◽  
Transcriptional Regulatory

Mammalian genomes encode tens of thousands of long-noncoding RNAs (lncRNAs), which are capable of interactions with DNA, RNA and protein molecules, thereby enabling a variety of transcriptional and post-transcriptional regulatory activities. Strikingly, about 40% of lncRNAs are expressed specifically in the brain with precisely regulated temporal and spatial expression patterns. In stark contrast to the highly conserved repertoire of protein-coding genes, thousands of lncRNAs have newly appeared during primate nervous system evolution with hundreds of human-specific lncRNAs. Their evolvable nature and the myriad of potential functions make lncRNAs ideal candidates for drivers of human brain evolution. The human brain displays the largest relative volume of any animal species and the most remarkable cognitive abilities. In addition to brain size, structural reorganization and adaptive changes represent crucial hallmarks of human brain evolution. lncRNAs are increasingly reported to be involved in neurodevelopmental processes suggested to underlie human brain evolution, including proliferation, neurite outgrowth and synaptogenesis, as well as in neuroplasticity. Hence, evolutionary human brain adaptations are proposed to be essentially driven by lncRNAs, which will be discussed in this review.

scholarly journals Emerging Roles of Long Non-Coding RNAs as Drivers of Brain Evolution

2019 ◽  
Author(s):  
Geraldine Zimmer-Bensch
Keyword(s):  
Human Brain ◽  
Cognitive Abilities ◽  
Brain Size ◽  
Expression Patterns ◽  
Brain Evolution ◽  
Relative Volume ◽  
Structural Reorganization ◽  
Protein Coding ◽  
Human Brain Evolution ◽  
Transcriptional Regulatory

Mammalian genomes encode tens of thousands of long-noncoding RNAs (lncRNAs), which are capable of interactions with DNA, RNA and protein molecules, thereby enabling a variety of transcriptional and post-transcriptional regulatory activities. Strikingly, about 40% of lncRNAs are expressed specifically in the brain in precisely regulated temporal and spatial expression patterns. In stark contrast to the highly conserved repertoire of protein-coding genes, thousands of new lncRNAs have appeared during primate nervous system evolution with hundreds of human-specific lncRNAs. Their evolvable nature and the myriad of potential functions make lncRNAs ideal candidates for drivers of human brain evolution. The human brain displays the largest relative volume of any animal species and the most remarkable cognitive abilities. In addition to brain size, structural reorganization and adaptive changes represent crucial hallmarks of human brain evolution. LncRNAs are increasingly reported to be involved in neurodevelopmental processes including proliferation, neurite outgrowth and synaptogenesis, as well as in neuroplasticity, suggested to underlie human brain evolution. Hence, evolutionary human brain adaptations are proposed to be essentially driven by lncRNAs, which will be discussed in this review.

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 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 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 Significant abundance of cis configurations of mutations in diploid human genomes

2017 ◽  
Author(s):  
Margret R. Hoehe ◽  
Ralf Herwig ◽  
Qing Mao ◽  
Brock A. Peters ◽  
Radoje Drmanac ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Genome Project ◽  
Personal Genome ◽  
Functional Interpretation ◽  
Protein Coding ◽  
Specific Distribution ◽  
Gene Sets ◽  
Human Genomes ◽  
Significant Enrichment ◽  
Coding Variants

AbstractTo fully understand human genetic variation, one must assess the specific distribution of variants between the two chromosomal homologues of genes, and any functional units of interest, as the phase of variants can significantly impact gene function and phenotype. To this end, we have systematically analyzed 18,121 autosomal protein-coding genes in 1,092 statistically phased genomes from the 1000 Genomes Project, and an unprecedented number of 184 experimentally phased genomes from the Personal Genome Project. Here we show that mutations predicted to functionally alter the protein, and coding variants as a whole, are not randomly distributed between the two homologues of a gene, but do occur significantly more frequently in cis-than trans-configurations, with cis/trans ratios of ∼60:40. Significant cis-abundance was observed in virtually all individual genomes in all populations. Nearly all variable genes exhibited either cis, or trans configurations of protein-altering mutations in significant excess, allowing distinction of cis- and trans-abundant genes. These common patterns of phase were largely constituted by a shared, global set of phase-sensitive genes. We show significant enrichment of this global set with gene sets indicating its involvement in adaptation and evolution. Moreover, cis- and trans-abundant genes were found functionally distinguishable, and exhibited strikingly different distributional patterns of protein-altering mutations. This work establishes common patterns of phase as key characteristics of diploid human exomes and provides evidence for their potential functional significance. Thus, it highlights the importance of phase for the interpretation of protein-coding genetic variation, challenging the current conceptual and functional interpretation of autosomal genes.

scholarly journals A Human-Specific De Novo Protein-Coding Gene Associated with Human Brain Functions

2010 ◽  
Vol 6 (3) ◽  
pp. e1000734 ◽  
Author(s):  
Chuan-Yun Li ◽  
Yong Zhang ◽  
Zhanbo Wang ◽  
Yan Zhang ◽  
Chunmei Cao ◽  
...  
Keyword(s):  
Human Brain ◽  
De Novo ◽  
Protein Coding ◽  
Brain Functions ◽  
Human Specific

scholarly journals Genes with human-specific features are primarily involved with brain, immune and metabolic evolution

2019 ◽  
Vol 20 (S9) ◽  
Author(s):  
Mainá Bitar ◽  
Stefanie Kuiper ◽  
Elizabeth A. O’Brien ◽  
Guy Barry
Keyword(s):  
Environmental Changes ◽  
Genomic Sequence ◽  
Brain Size ◽  
Current Knowledge ◽  
Average Height ◽  
Protein Coding ◽  
Metabolic Systems ◽  
Immune Challenges ◽  
Species Specific ◽  
Human Specific

Abstract Background Humans have adapted to widespread changes during the past 2 million years in both environmental and lifestyle factors. This is evident in overall body alterations such as average height and brain size. Although we can appreciate the uniqueness of our species in many aspects, molecular variations that drive such changes are far from being fully known and explained. Comparative genomics is able to determine variations in genomic sequence that may provide functional information to better understand species-specific adaptations. A large number of human-specific genomic variations have been reported but no currently available dataset comprises all of these, a problem which contributes to hinder progress in the field. Results Here we critically update high confidence human-specific genomic variants that mostly associate with protein-coding regions and find 856 related genes. Events that create such human-specificity are mainly gene duplications, the emergence of novel gene regions and sequence and structural alterations. Functional analysis of these human-specific genes identifies adaptations to brain, immune and metabolic systems to be highly involved. We further show that many of these genes may be functionally associated with neural activity and generating the expanded human cortex in dynamic spatial and temporal contexts. Conclusions This comprehensive study contributes to the current knowledge by considerably updating the number of human-specific genes following a critical bibliographic survey. Human-specific genes were functionally assessed for the first time to such extent, thus providing unique information. Our results are consistent with environmental changes, such as immune challenges and alterations in diet, as well as neural sophistication, as significant contributors to recent human evolution.

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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