Evolutionary Changes in Transcriptional Regulation: Insights into Human Behavior and Neurological Conditions

2018 ◽  
Vol 41 (1) ◽  
pp. 185-206 ◽  
Author(s):  
Ryan N. Doan ◽  
Taehwan Shin ◽  
Christopher A. Walsh
Keyword(s):  
Population Data ◽  
Functional Information ◽  
Human Lineage ◽  
Medical Genetic ◽  
Noncoding Sequences ◽  
Noncoding Regions ◽  
Evolutionary Changes ◽  
Neurological Conditions ◽  
Human Accelerated Regions ◽  
Human Specific

Understanding the biological basis for human-specific cognitive traits presents both immense challenges and unique opportunities. Although the question of what makes us human has been investigated with several different methods, the rise of comparative genomics, epigenomics, and medical genetics has provided tools to help narrow down and functionally assess the regions of the genome that seem evolutionarily relevant along the human lineage. In this review, we focus on how medical genetic cases have provided compelling functional evidence for genes and loci that appear to have interesting evolutionary signatures in humans. Furthermore, we examine a special class of noncoding regions, human accelerated regions (HARs), that have been suggested to show human-lineage-specific divergence, and how the use of clinical and population data has started to provide functional information to examine these regions. Finally, we outline methods that provide new insights into functional noncoding sequences in evolution.

Transcriptional Enhancers in the FOXP2 Locus Underwent Accelerated Evolution in the Human Lineage

2019 ◽  
Vol 36 (11) ◽  
pp. 2432-2450 ◽  
Author(s):  
Alfredo Leandro Caporale ◽  
Catalina M Gonda ◽  
Lucía Florencia Franchini
Keyword(s):  
Developmental Stages ◽  
Evolutionary Process ◽  
Regulatory Sequences ◽  
Human Lineage ◽  
Coding Region ◽  
Transcriptional Enhancers ◽  
Accelerated Evolution ◽  
Evolutionary Changes ◽  
Human Specific

Abstract Unique human features, such as complex language, are the result of molecular evolutionary changes that modified developmental programs of our brain. The human-specific evolution of the forkhead box P2 (FOXP2) gene-coding region has been linked to the emergence of speech and language in the human kind. However, little is known about how the expression of FOXP2 is regulated and whether its regulatory machinery evolved in a lineage-specific manner in humans. In order to identify FOXP2 regulatory regions containing human-specific changes, we used databases of human-accelerated noncoding sequences or HARs. We found that the topologically associating domain determined using developing human cerebral cortex containing the FOXP2 locus includes two clusters of 12 HARs, placing the locus occupied by FOXP2 among the top regions showing fast acceleration rates in noncoding regions in the human genome. Using in vivo enhancer assays in zebrafish, we found that at least five FOXP2-HARs behave as transcriptional enhancers throughout different developmental stages. In addition, we found that at least two FOXP2-HARs direct the expression of the reporter gene EGFP to foxP2-expressing regions and cells. Moreover, we uncovered two FOXP2-HARs showing reporter expression gain of function in the nervous system when compared with the chimpanzee ortholog sequences. Our results indicate that regulatory sequences in the FOXP2 locus underwent a human-specific evolutionary process suggesting that the transcriptional machinery controlling this gene could have also evolved differentially in the human lineage.

scholarly journals Massively parallel dissection of human accelerated regions in human and chimpanzee neural progenitors

2018 ◽  
Author(s):  
Hane Ryu ◽  
Fumitaka Inoue ◽  
Sean Whalen ◽  
Alex Williams ◽  
Martin Kircher ◽  
...  
Keyword(s):  
Regulatory Elements ◽  
Neural Progenitors ◽  
Massively Parallel ◽  
Evolutionary Changes ◽  
Gene Regulatory Elements ◽  
Reporter Assays ◽  
Differentiation Stage ◽  
Almost All ◽  
Human Accelerated Regions ◽  
Human Specific

SUMMARYHow mutations in gene regulatory elements lead to evolutionary changes remains largely unknown. Human accelerated regions (HARs) are ideal for exploring this question, because they are associated with human-specific traits and contain multiple human-specific variants at sites conserved across mammals, suggesting that they alter or compensate to preserve function. We performed massively parallel reporter assays on all human and chimpanzee HAR sequences in human and chimpanzee iPSC-derived neural progenitors at two differentiation stages. Forty-three percent (306/714) of HARs function as neuronal enhancers, with two-thirds (204/306) showing consistent changes in activity between human and chimpanzee sequences. These changes were almost all sequence dependent and not affected by cell species or differentiation stage. We tested all evolutionary intermediates between human and chimpanzee sequences of seven HARs, finding variants that interact both positively and negatively. This study shows that variants acquired during human evolution interact to buffer and amplify changes to enhancer function.

scholarly journals Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhongbo Chen ◽  
◽  
David Zhang ◽  
Regina H. Reynolds ◽  
Emil K. Gustavsson ◽  
...  
Keyword(s):  
Neurological Diseases ◽  
Purifying Selection ◽  
Whole Genome Sequencing Data ◽  
Human Lineage ◽  
Sequencing Data ◽  
Protein Coding ◽  
Potential Association ◽  
High Depth ◽  
Specific Sequences ◽  
Human Specific

AbstractKnowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer’s disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease.

scholarly journals Positive Selection in Gene Regulatory Factors Suggests Adaptive Pleiotropic Changes During Human Evolution

2021 ◽  
Vol 12 ◽  
Author(s):  
Vladimir M. Jovanovic ◽  
Melanie Sarfert ◽  
Carlos S. Reyna-Blanco ◽  
Henrike Indrischek ◽  
Dulce I. Valdivia ◽  
...  
Keyword(s):  
Positive Selection ◽  
Human Evolution ◽  
Target Genes ◽  
Population Data ◽  
Great Ape ◽  
Human Lineage ◽  
Regulatory Factors ◽  
Site Model ◽  
Branch Site ◽  
Gene Regulatory

Gene regulatory factors (GRFs), such as transcription factors, co-factors and histone-modifying enzymes, play many important roles in modifying gene expression in biological processes. They have also been proposed to underlie speciation and adaptation. To investigate potential contributions of GRFs to primate evolution, we analyzed GRF genes in 27 publicly available primate genomes. Genes coding for zinc finger (ZNF) proteins, especially ZNFs with a Krüppel-associated box (KRAB) domain were the most abundant TFs in all genomes. Gene numbers per TF family differed between all species. To detect signs of positive selection in GRF genes we investigated more than 3,000 human GRFs with their more than 70,000 orthologs in 26 non-human primates. We implemented two independent tests for positive selection, the branch-site-model of the PAML suite and aBSREL of the HyPhy suite, focusing on the human and great ape branch. Our workflow included rigorous procedures to reduce the number of false positives: excluding distantly similar orthologs, manual corrections of alignments, and considering only genes and sites detected by both tests for positive selection. Furthermore, we verified the candidate sites for selection by investigating their variation within human and non-human great ape population data. In order to approximately assign a date to positively selected sites in the human lineage, we analyzed archaic human genomes. Our work revealed with high confidence five GRFs that have been positively selected on the human lineage and one GRF that has been positively selected on the great ape lineage. These GRFs are scattered on different chromosomes and have been previously linked to diverse functions. For some of them a role in speciation and/or adaptation can be proposed based on the expression pattern or association with human diseases, but it seems that they all contributed independently to human evolution. Four of the positively selected GRFs are KRAB-ZNF proteins, that induce changes in target genes co-expression and/or through arms race with transposable elements. Since each positively selected GRF contains several sites with evidence for positive selection, we suggest that these GRFs participated pleiotropically to phenotypic adaptations in humans.

scholarly journals Genetic diversity on the human X chromosome does not support a strict pseudoautosomal boundary

2015 ◽  
Author(s):  
Daniel J Cotter ◽  
Sarah M Brotman ◽  
Melissa A Wilson Sayres
Keyword(s):  
Genetic Diversity ◽  
X Chromosome ◽  
Sex Chromosomes ◽  
Sex Chromosome ◽  
Gradual Reduction ◽  
Noncoding Regions ◽  
Pseudoautosomal Regions ◽  
Linked Selection ◽  
Human Specific ◽  
Pseudoautosomal Boundary

Unlike the autosomes, recombination between the X chromosome and Y chromosome often thought to be constrained to two small pseudoautosomal regions (PARs) at the tips of each sex chromosome. The PAR1 spans the first 2.7 Mb of the proximal arm of the human sex chromosomes, while the much smaller PAR2 encompasses the distal 320 kb of the long arm of each sex chromosome. In addition to the PAR1 and PAR2, there is a human-specific X-transposed region that was duplicated from the X to the Y. The X-transposed region is often not excluded from X-specific analyses, unlike the PARs, because it is not thought to routinely recombine. Genetic diversity is expected to be higher in recombining regions than in non-recombining regions because recombination reduces the effect of linked selection. In this study, we investigate patterns of genetic diversity in noncoding regions across the entire X chromosome of a global sample of 26 unrelated genetic females. We observe that genetic diversity in the PAR1 is significantly greater than the non-recombining regions (nonPARs). However, rather than an abrupt drop in diversity at the pseudoautosomal boundary, there is a gradual reduction in diversity from the recombining through the non-recombining region, suggesting that recombination between the human sex chromosomes spans across the currently defined pseudoautosomal boundary. In contrast, diversity in the PAR2 is not significantly elevated compared to the nonPAR, suggesting that recombination is not obligatory in the PAR2. Finally, diversity in the X-transposed region is higher than the surrounding nonPAR regions, providing evidence that recombination may occur with some frequency between the X and Y in the XTR.

scholarly journals Human-lineage-specific genomic elements: relevance to neurodegenerative disease and APOE transcript usage

2020 ◽  
Author(s):  
Zhongbo Chen ◽  
David Zhang ◽  
Regina H. Reynolds ◽  
Emil K. Gustavsson ◽  
Sonia García Ruiz ◽  
...  
Keyword(s):  
Neurological Diseases ◽  
Purifying Selection ◽  
Whole Genome Sequencing Data ◽  
Human Lineage ◽  
Sequencing Data ◽  
Protein Coding ◽  
Genomic Features ◽  
High Depth ◽  
Specific Sequences ◽  
Human Specific

ABSTRACTKnowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript/s to be more abundant in Alzheimer’s disease with more severe tau and amyloid pathological burden. Thus, we demonstrate the importance of human-lineage-specific sequences in brain development and neurological disease. We release our annotation through vizER (https://snca.atica.um.es/browser/app/vizER).

scholarly journals Human core duplicon gene families: game changers or game players?

2019 ◽  
Vol 18 (6) ◽  
pp. 402-411 ◽  
Author(s):  
Cemalettin Bekpen ◽  
Diethard Tautz
Keyword(s):  
Positive Selection ◽  
Protein Domains ◽  
Gene Families ◽  
Specific Gene ◽  
Gene Duplications ◽  
Human Lineage ◽  
Protein Families ◽  
Cellular Pathways ◽  
Human Specific

Abstract Illuminating the role of specific gene duplications within the human lineage can provide insights into human-specific adaptations. The so-called human core duplicon gene families have received particular attention in this respect, due to special features, such as expansion along single chromosomes, newly acquired protein domains and signatures of positive selection. Here, we summarize the data available for 10 such families and include some new analyses. A picture emerges that suggests broad functions for these protein families, possibly through modification of core cellular pathways. Still, more dedicated studies are required to elucidate the function of core-duplicons gene families and how they have shaped adaptations and evolution of humans.

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