scholarly journals The Evolutionary History of Common Genetic Variants Influencing Human Cortical Surface Area

2020 ◽  
Author(s):  
Amanda K Tilot ◽  
Ekaterina A Khramtsova ◽  
Dan Liang ◽  
Katrina L Grasby ◽  
Neda Jahanshad ◽  
...  
Keyword(s):  
Human Brain ◽  
Surface Area ◽  
Brain Structure ◽  
Visual Processing ◽  
Large Scale ◽  
Structural Changes ◽  
Homo Sapiens ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Common Genetic Variants

Abstract Structural brain changes along the lineage leading to modern Homo sapiens contributed to our distinctive cognitive and social abilities. However, the evolutionarily relevant molecular variants impacting key aspects of neuroanatomy are largely unknown. Here, we integrate evolutionary annotations of the genome at diverse timescales with common variant associations from large-scale neuroimaging genetic screens. We find that alleles with evidence of recent positive polygenic selection over the past 2000–3000 years are associated with increased surface area (SA) of the entire cortex, as well as specific regions, including those involved in spoken language and visual processing. Therefore, polygenic selective pressures impact the structure of specific cortical areas even over relatively recent timescales. Moreover, common sequence variation within human gained enhancers active in the prenatal cortex is associated with postnatal global SA. We show that such variation modulates the function of a regulatory element of the developmentally relevant transcription factor HEY2 in human neural progenitor cells and is associated with structural changes in the inferior frontal cortex. These results indicate that non-coding genomic regions active during prenatal cortical development are involved in the evolution of human brain structure and identify novel regulatory elements and genes impacting modern human brain structure.

scholarly journals The Evolutionary History of Common Genetic Variants Influencing Human Cortical Surface Area

2019 ◽  
Author(s):  
Amanda K. Tilot ◽  
Ekaterina A. Khramtsova ◽  
Katrina Grasby ◽  
Neda Jahanshad ◽  
Jodie Painter ◽  
...  
Keyword(s):  
Surface Area ◽  
Visual Processing ◽  
Large Scale ◽  
Homo Sapiens ◽  
Genetic Screens ◽  
Molecular Variants ◽  
Common Genetic Variants ◽  
History Of ◽  
Cortical Regions ◽  
Key Aspects

AbstractStructural brain changes along the lineage that led to modern Homo sapiens have contributed to our unique cognitive and social abilities. However, the evolutionarily relevant molecular variants impacting key aspects of neuroanatomy are largely unknown. Here, we integrate evolutionary annotations of the genome at diverse timescales with common variant associations from large-scale neuroimaging genetic screens in living humans, to reveal how selective pressures have shaped neocortical surface area. We show that variation within human gained enhancers active in the developing brain is associated with global surface area as well as that of specific regions. Moreover, we find evidence of recent polygenic selection over the past 2,000 years influencing surface area of multiple cortical regions, including those involved in spoken language and visual processing.

Common genetic variation influencing human white matter microstructure

Science ◽  
2021 ◽  
Vol 372 (6548) ◽  
pp. eabf3736
Author(s):  
Bingxin Zhao ◽  
Tengfei Li ◽  
Yue Yang ◽  
Xifeng Wang ◽  
Tianyou Luo ◽  
...  
Keyword(s):  
White Matter ◽  
Complex Traits ◽  
Large Scale ◽  
Wide Spectrum ◽  
Genetic Correlations ◽  
Regulatory Elements ◽  
Brain Regions ◽  
Brain Diseases ◽  
White Matter Microstructure ◽  
Common Genetic Variants

Brain regions communicate with each other through tracts of myelinated axons, commonly referred to as white matter. We identified common genetic variants influencing white matter microstructure using diffusion magnetic resonance imaging of 43,802 individuals. Genome-wide association analysis identified 109 associated loci, 30 of which were detected by tract-specific functional principal components analysis. A number of loci colocalized with brain diseases, such as glioma and stroke. Genetic correlations were observed between white matter microstructure and 57 complex traits and diseases. Common variants associated with white matter microstructure altered the function of regulatory elements in glial cells, particularly oligodendrocytes. This large-scale tract-specific study advances the understanding of the genetic architecture of white matter and its genetic links to a wide spectrum of clinical outcomes.

scholarly journals Effects of Deafness and Sign Language Experience on the Human Brain: Voxel-based and Surface-based Morphometry

2020 ◽  
Author(s):  
Stephen McCullough ◽  
Karen Emmorey
Keyword(s):  
Human Brain ◽  
Sign Language ◽  
Surface Area ◽  
Cortical Thickness ◽  
Structural Changes ◽  
Brain Regions ◽  
Language Experience ◽  
Signed Language ◽  
Native Signers ◽  
Surface Based Morphometry

We investigated, using voxel-based morphometry (VBM), how deafness and sign language experience affect the anatomical structures of the human brain by comparing gray matter (GM) and white matter (WM) structures across congenitally deaf native signers, hearing native signers, and hearing sign-naïve controls (n = 90). We also compared the same groups on cortical thickness, surface area, and local gyrification using surface-based morphometry (SBM). Both VBM and SBM results revealed deafness-related changes in visual cortices and right frontal lobe. The GM in the auditory cortices did not appear to be affected by deafness; however, there was a significant WM reduction in left Heschl's gyrus for deaf signers only. The SBM comparisons revealed changes associated with lifelong signing experience: expansions in the surface area within left anterior temporal and left occipital lobes, and a reduction in cortical thickness in the right occipital lobe for deaf and hearing signers. Structural changes within these brain regions may be related to adaptations in the neural networks involved in processing signed language (i.e., visual perception of face and body movements). Hearing native signers also had unique neuroanatomical changes (e.g., reduced gyrification in premotor areas), perhaps due to lifelong experience with both a spoken and a signed language.

scholarly journals Long-range promoter-enhancer contacts are conserved during evolution and contribute to gene expression robustness

2021 ◽  
pp. gr.275901.121
Author(s):  
Alexandre Laverre ◽  
Eric Tannier ◽  
Anamaria Necsulea
Keyword(s):  
Gene Expression ◽  
Long Range ◽  
Large Scale ◽  
Target Genes ◽  
Expression Profiles ◽  
Regulatory Element ◽  
Gene Expression Profiles ◽  
Evolutionary Conservation ◽  
Regulatory Elements ◽  
Regulatory Landscapes

Gene expression is regulated through complex molecular interactions, involving cis-acting elements that can be situated far away from their target genes. Data on long-range contacts between promoters and regulatory elements is rapidly accumulating. However, it remains unclear how these regulatory relationships evolve and how they contribute to the establishment of robust gene expression profiles. Here, we address these questions by comparing genome-wide maps of promoter-centered chromatin contacts in mouse and human. We show that there is significant evolutionary conservation of cis-regulatory landscapes, indicating that selective pressures act to preserve not only regulatory element sequences but also their chromatin contacts with target genes. The extent of evolutionary conservation is remarkable for long-range promoter-enhancer contacts, illustrating how the structure of regulatory landscapes constrains large-scale genome evolution. We show that the evolution of cis-regulatory landscapes, measured in terms of distal element sequences, synteny or contacts with target genes, is significantly associated with gene expression evolution.

scholarly journals Data-driven approaches for identifying links between brain structure and function in health and disease

2018 ◽  
Vol 20 (2) ◽  
pp. 87-99 ◽  
Keyword(s):  
Human Brain ◽  
Brain Structure ◽  
Structural Changes ◽  
Clinical Decision Making ◽  
Brain Regions ◽  
Structure And Function ◽  
Data Driven ◽  
Macroscopic Scale ◽  
Functional Changes ◽  
And Function

Brain imaging technology provides a powerful tool to visualize the living human brain, provide insights into disease mechanisms, and potentially provide a tool to assist clinical decision-making. The brain has a very specific structural substrate providing a foundation for functional information; however, most studies ignore the very interesting and complex relationships between brain structure and brain function. While a variety of approaches have been used to study how brain structure informs function, the study of such relationships in living humans in most cases is limited to noninvasive approaches at the macroscopic scale. The use of data-driven approaches to link structure and function provides a tool which is especially important at the macroscopic scale at which we can study the human brain. This paper reviews data-driven approaches, with a focus on independent component analysis approaches, which leverage higher order statistics to link together macroscopic structural and functional MRI data. Such approaches provide the benefit of allowing us to identify links which do not necessarily correspond spatially (eg, structural changes in one region related to functional changes in other regions). They also provide a “network level” perspective on the data, by enabling us to identify sets of brain regions that covary together. This also opens up the ability to evaluate both within and between network relationships. A variety of examples are presented, including several showing the potential of such approaches to inform us about mental illness, particularly about schizophrenia.

scholarly journals Similar evolutionary trajectories for retrotransposon accumulation in mammals

2016 ◽  
Author(s):  
Reuben M Buckley ◽  
R Daniel Kortschak ◽  
Joy M Raison ◽  
David L Adelson
Keyword(s):  
Large Scale ◽  
Regulatory Element ◽  
Insertion Site ◽  
Regulatory Elements ◽  
Site Preference ◽  
Open Chromatin ◽  
Short Interspersed Elements ◽  
Evolutionary Trajectories ◽  
Mammalian Genomes ◽  
Retrotransposon Activity

AbstractThe factors guiding retrotransposon insertion site preference are not well understood. Different types of retrotransposons share common replication machinery and yet occupy distinct genomic domains. Autonomous long interspersed elements accumulate in gene-poor domains and their non-autonomous short interspersed elements accumulate in gene-rich domains. To determine genomic factors that contribute to this discrepancy we analysed the distribution of retrotransposons within the framework of chromosomal domains and regulatory elements. Using comparative genomics, we identified large-scale conserved patterns of retrotransposon accumulation across several mammalian genomes. Importantly, retrotransposons that were active after our sample-species diverged accumulated in orthologous regions. This suggested a similar evolutionary interaction between retrotransposon activity and conserved genome architecture across our species. In addition, we found that retrotransposons accumulated at regulatory element boundaries in open chromatin, where accumulation of particular retrotransposon types depended on insertion size and local regulatory element density. From our results, we propose a model where density and distribution of genes and regulatory elements canalise retrotransposon accumulation. Through conservation of synteny, gene regulation and nuclear organisation, mammalian genomes with dissimilar retrotransposons follow similar evolutionary trajectories.

scholarly journals Long-range promoter-enhancer contacts are conserved during evolution and contribute to gene expression robustness

2021 ◽  
Author(s):  
Alexandre Laverré ◽  
Eric Tannier ◽  
Anamaria Necsulea
Keyword(s):  
Gene Expression ◽  
Long Range ◽  
Large Scale ◽  
Target Genes ◽  
Expression Profiles ◽  
Regulatory Element ◽  
Gene Expression Profiles ◽  
Evolutionary Conservation ◽  
Regulatory Elements ◽  
Regulatory Landscapes

AbstractGene expression is regulated through complex molecular interactions, involving cis-acting elements that can be situated far away from their target genes. Data on long-range contacts between promoters and regulatory elements is rapidly accumulating. However, it remains unclear how these regulatory relationships evolve and how they contribute to the establishment of robust gene expression profiles. Here, we address these questions by comparing genome-wide maps of promoter-centered chromatin contacts in mouse and human. We show that there is significant evolutionary conservation of cis-regulatory landscapes, indicating that selective pressures act to preserve regulatory element sequences and their interactions with target genes. The extent of evolutionary conservation is remarkable for long-range promoter-enhancer contacts, illustrating how the structure of regulatory interactions constrains large-scale genome evolution. Notably, we show that the evolution of cis-regulatory landscapes, measured in terms of distal element sequences, synteny or contacts with target genes, is tightly linked to gene expression evolution.

scholarly journals Characterizing higher order structures of chromatin in human cells

2018 ◽  
Author(s):  
Uwe Schwartz ◽  
Attila Németh ◽  
Sarah Diermeier ◽  
Josef Exler ◽  
Stefan Hansch ◽  
...  
Keyword(s):  
Large Scale ◽  
Structural Changes ◽  
Computer Modelling ◽  
Regulatory Elements ◽  
Higher Order ◽  
Chromatin Organization ◽  
Transcription Start Sites ◽  
Irregular Structure ◽  
Genomic Regions ◽  
Order Structures

AbstractPackaging of DNA into chromatin regulates DNA accessibility and, consequently, all DNA-dependent processes, such as transcription, recombination, repair, and replication. The nucleosome is the basic packaging unit of DNA forming arrays that are suggested, by biochemical studies, to fold hierarchically into ordered higher-order structures of chromatin. This defined organization of chromatin has been recently questioned using microscopy techniques, proposing a rather irregular structure. To gain more insight into the principles of chromatin organization, we applied an in situ differential MNase-seq strategy and analyzed in silico the results of complete and partial digestions of human chromatin. We investigated whether different levels of chromatin packaging exist in the cell. Thus, we assessed the accessibility of chromatin within distinct domains of kb to Mb genomic regions by utilizing statistical data analyses and computer modelling. We found no difference in the degree of compaction between domains of euchromatin and heterochromatin or between other sequence and epigenomic features of chromatin. Thus, our data suggests the absence of differentially compacted domains of higher-order structures of chromatin. Moreover, we identified only local structural changes, with individual hyper-accessible nucleosomes surrounding regulatory elements, such as enhancers and transcription start sites. The regulatory sites per se are occupied with structurally altered nucleosomes, exhibiting increased MNase sensitivity. Our findings provide biochemical evidence that supports an irregular model of large-scale chromatin organization.

scholarly journals Personality and local brain structure: their shared genetic basis and reproducibility

2019 ◽  
Author(s):  
Sofie L. Valk ◽  
Felix Hoffstaedter ◽  
Julia A. Camilleri ◽  
Peter Kochunov ◽  
B.T. Thomas Yeo ◽  
...  
Keyword(s):  
Personality Traits ◽  
Surface Area ◽  
Brain Structure ◽  
Large Scale ◽  
Local Variation ◽  
Total Surface Area ◽  
Frontal Surface ◽  
Cortical Structure ◽  
Human Connectome Project ◽  
Local Brain

AbstractLocal variation in cortical architecture is highly heritable and distinct genes are associated with specific cortical regions. Total surface area has been shown to be genetically correlated with complex cognitive capacities, suggesting cortical brain structure is a viable endophenotype linking genes to behavior. However, to what extend local brain structure has a genetic association with cognitive and emotional functioning is incompletely understood. Here, we study the genetic correlation between personality traits and local cortical structure in a large-scale twin sample (Human Connectome Project, n=1106, 22-37y). We found a genetic overlap between personality traits and local cortical structure in 10 of 17 observed phenotypic associations in predominantly frontal cortices. To evaluate the robustness of observed personality-brain associations we studied two independent age-matched samples (GSP: n=926, age=19-35y, eNKI: n=210, age: 19-39y). We observed anecdotal to moderate evidence for a successful replication of the negative association between surface area in medial prefrontal cortex and Neuroticism in both samples. Quantitative functional decoding indicated this region is implicated in emotional and socio-cognitive functional processes. In sum, our observations suggest that associations between local brain structure and personality are, in part, under genetic control. However, associations are weak and only the relation between frontal surface area and Neuroticism was consistently observed across three independent samples of young adults.

scholarly journals Common genetic variation influencing human white matter microstructure

2020 ◽  
Author(s):  
Bingxin Zhao ◽  
Tengfei Li ◽  
Yue Yang ◽  
Xifeng Wang ◽  
Tianyou Luo ◽  
...  
Keyword(s):  
White Matter ◽  
Genetic Variants ◽  
Complex Traits ◽  
Large Scale ◽  
Genetic Correlations ◽  
Neuropsychiatric Disorders ◽  
Regulatory Elements ◽  
Functional Principal Component Analysis ◽  
White Matter Microstructure ◽  
Common Genetic Variants

AbstractBrain regions communicate with each other via tracts of myelinated axons, commonly referred to as white matter. White matter microstructure can be measured in the living human brain using diffusion based magnetic resonance imaging (dMRI), and has been found to be altered in patients with neuropsychiatric disorders. Although under strong genetic control, few genetic variants influencing white matter microstructure have ever been identified. Here we identified common genetic variants influencing white matter microstructure using dMRI in 42,919 individuals (35,741 in the UK Biobank). The dMRIs were summarized into 215 white matter microstructure traits, including 105 measures from tract-specific functional principal component analysis. Genome-wide association analysis identified many novel white matter microstructure associated loci (P < 2.3 × 10−10). We identified shared genetic influences through genetic correlations between white matter tracts and 62 other complex traits, including stroke, neuropsychiatric disorders (e.g., ADHD, bipolar disorder, major depressive disorder, schizophrenia), cognition, neuroticism, chronotype, as well as non-brain traits. Common variants associated with white matter microstructure alter the function of regulatory elements in glial cells, particularly oligodendrocytes. White matter associated genes were enriched in pathways involved in brain disease pathogenesis, neurodevelopment process, and repair of white matter damage (P < 1.5 × 10−8). In summary, this large-scale tract-specific study provides a big step forward in understanding the genetic architecture of white matter and its genetic links to a wide spectrum of clinical outcomes.

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