Human-Specific Evolutionary Changes in the Biology of Siglecs

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.

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

Molecular Biology and Evolution ◽

10.1093/molbev/msz173 ◽

2019 ◽

Vol 36 (11) ◽

pp. 2432-2450 ◽

Cited By ~ 1

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.

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Species-specific mobile genetic elements in the gene of repair enzyme MGMT in new world monkeys

Faktori eksperimental'noi evolucii organizmiv ◽

10.7124/feeo.v28.1388 ◽

2021 ◽

Vol 28 ◽

pp. 128-134

Author(s):

O. V. Pidpala ◽

L. L. Lukash

Keyword(s):

New World ◽

Mobile Genetic Elements ◽

Nucleotide Sequences ◽

New World Monkeys ◽

Repair Enzyme ◽

Genetic Elements ◽

Mgmt Gene ◽

Evolutionary Changes ◽

Species Specific ◽

Human Specific

Aim.To analyze the distribution of species-specific mobile genetic elements (MGE) in orthologs of the MGMT gene in Platyrrhina. Methods. The homology between nucleotide sequences was determined by BLAST 2.6.1. The results of the search and identification of MGE were performed using the CENSOR program. Results. On the example of orthologs of the MGMT gene in New World monkeys, it has been shown that different species-specific MGE identified in their intron sequences may have different evolutionary chronologies. In the case of the element Alu2_TS, which originated in the Tarsiiformes representative, it was found that in evolutionarily close primates it undergoes deletion degradation, while fragments of the human-specific L1Hs element are found in the genomes of evolutionarily distant primates long before the formation and emergence of this retroelement. Conclusions. The chronology of evolutionary changes in the gene MGMT and its species-specific MGE can be of different nature and occur in parallele and independently. Keywords: Platyrrhina, MGMT gene, MGE, Alu2_TS, L1Hs.

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A Human Accelerated Region participates in early human forebrain patterning and expansion

10.1101/777235 ◽

2019 ◽

Author(s):

Sandra Acosta ◽

Jaydeep Sidhaye ◽

Luciano Fiore ◽

Isabel Rollan ◽

Giovanni Iacono ◽

...

Keyword(s):

Transgenic Mice ◽

Developmental Stages ◽

Regulatory Elements ◽

Mammalian Brain ◽

Enhancer Activity ◽

Evolutionary Changes ◽

Active Enhancer ◽

Phylotypic Stage ◽

Early Developmental ◽

Human Specific

AbstractThe expansion of the mammalian brain is associated with specific developmental processes; however, not much is known about how evolutionary changes participated in the acquisition of human brain traits during early developmental stages. Here we investigated whether enhancers active during the phylotypic stage show human-specific genomic divergence which could contribute to the evolutionary expansion of the forebrain. Notably, we identified an active enhancer containing a human accelerated region (HAR) located in the Chromosome 14q12, a region enriched with neurodevelopmental genes, such as Foxg1, Nkx2.1 and Nova1. Reporter analysis revealed that the human variant is active in the forebrain in transgenic mice and that it has stronger enhancer activity than the mouse or chimpanzee versions. Humanization of the mouse enhancer variant in transgenic mice and in mouse organoids resulted in an expansion of Foxg1 expressing domains in the forebrain early neural progenitors with a bias towards dorsal identities. Overall, our results suggest that human-specific mutations in critical regulatory elements controlling early brain development impact the expansion and patterning of the forebrain.

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

10.1101/256313 ◽

2018 ◽

Cited By ~ 13

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.

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