Molecular signatures of selection on the human GLI3 associated central nervous system specific enhancers

Hussain, Irfan; Raza, Rabail Zehra; Ali, Shahid; Abrar, Muhammad; Abbasi, Amir Ali

doi:10.1007/s00427-021-00672-1

Cited by 3 publications

(2 citation statements)

References 75 publications

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“…Three of the CNEs identified in this study drove reporter expression in forebrain (CNE17, CNE18, and CNE19), indicating involvement in early CNS regulation. Adding to our previously published studies, these results expand the number of in vivo validated Gli3 brain enhancers to 12 (Abbasi et al, 2010; Hussain et al, 2021) indicating that a complex and conserved Gli3 regulatory architecture is in place to drive Gli3 expression in brain subregions of mammals and fish (Hussain et al, 2021). Gli3 also acts as a mediator of Shh pathway activity in posterior second heart field cells during cardiac development, and GLI3 ‐A has been recently identified as an important component for intraventricular septum (IVS) formation through cilia‐mediated Platelet‐derived growth factor receptor alpha signaling during mouse heart development (Wiegering et al, 2020).…”

Section: Discussionsupporting

confidence: 68%

“…Transgenic reporter assays have been widely used as a method of choice to define tissue-specific transcriptional enhancer activities in vivo (Kvon, 2015) and multiple enhancer elements in the genomic vicinity of Gli3 have been identified in a number of species (Anwar et al, 2015;Coy et al, 2011;Hussain et al, 2021;Mannion et al, 2022;Osterwalder et al, 2018). In accordance with hotspots of Gli3 expression in vertebrate embryos, these enhancer activities were found enriched in the CNS, limb/fins, craniofacial regions, and internal organs (Abbasi et al, 2010(Abbasi et al, , 2013Anwar et al, 2015;Coy et al, 2011;Hussain et al, 2021;Osterwalder et al, 2014;Osterwalder et al, 2018). However, the mammalian Gli3-associated enhancer activities identified so far are not associated with the full spectrum of Gli3 expression domains.…”

Section: Introductionmentioning

confidence: 99%

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Identification of ancestral gnathostome Gli3 enhancers with activity in mammals

Ali,

Abrar,

Hussain

et al. 2023

Dev Growth Differ

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Abnormal expression of the transcriptional regulator and hedgehog (Hh) signaling pathway effector Gli3 is known to trigger congenital disease, most frequently affecting the central nervous system (CNS) and the limbs. Accurate delineation of the genomic cis‐regulatory landscape controlling Gli3 transcription during embryonic development is critical for the interpretation of noncoding variants associated with congenital defects. Here, we employed a comparative genomic analysis on fish species with a slow rate of molecular evolution to identify seven previously unknown conserved noncoding elements (CNEs) in Gli3 intronic intervals (CNE15–21). Transgenic assays in zebrafish revealed that most of these elements drive activities in Gli3 expressing tissues, predominantly the fins, CNS, and the heart. Intersection of these CNEs with human disease associated SNPs identified CNE15 as a putative mammalian craniofacial enhancer, with conserved activity in vertebrates and potentially affected by mutation associated with human craniofacial morphology. Finally, comparative functional dissection of an appendage‐specific CNE conserved in slowly evolving fish (elephant shark), but not in teleost (CNE14/hs1586) indicates co‐option of limb specificity from other tissues prior to the divergence of amniotes and lobe‐finned fish. These results uncover a novel subset of intronic Gli3 enhancers that arose in the common ancestor of gnathostomes and whose sequence components were likely gradually modified in other species during the process of evolutionary diversification.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Identification of ancestral gnathostome Gli3 enhancers with activity in mammals

Ali,

Abrar,

Hussain

et al. 2023

Dev Growth Differ

Self Cite

View full text Add to dashboard Cite

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Evolution and dysfunction of human cognitive and social traits: A transcriptional regulation perspective

Zug

Uller

2022

Evolut. Hum. Sci.

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Evolutionary changes in brain and craniofacial development have endowed humans with unique cognitive and social skills, but also predisposed us to debilitating disorders in which these traits are disrupted. What are the developmental genetic underpinnings that connect the adaptive evolution of our cognition and sociality with the persistence of mental disorders with severe negative fitness effects? We argue that loss of function of genes involved in transcriptional regulation represents a crucial link between the evolution and dysfunction of human cognitive and social traits. The argument is based on haploinsufficiency of many transcriptional regulator genes, which makes them particularly sensitive to loss-of-function mutations. We discuss how human brain and craniofacial traits evolved through partial loss of function (i.e., reduced expression) of these genes, a perspective compatible with the idea of human self-domestication. Moreover, we explain why selection against loss-of-function variants supports the view that mutation-selection-drift, rather than balancing selection, underlies the persistence of psychiatric disorders. Finally, we discuss testable predictions.

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NSD1 gene evolves under episodic selection within primates and mutations of specific exons in humans cause Sotos syndrome

Romero¹,

Arias-Almeida²,

Aguiar³

2022

BMC Genomics

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Background Modern human brains and skull shapes differ from other hominids. Brain growth disorders as micro- (ASPM, MCPH1) and macrocephaly (NFIX, GLI3) have been highlighted as relevant for the evolution in humans due to the impact in early brain development. Genes associated with macrocephaly have been reported to cause this change, for example NSD1 which causes Sotos syndrome. Results In this study we performed a systematic literature review, located the reported variants associated to Sotos syndrome along the gene domains, compared the sequences with close primates, calculated their similarity, Ka/Ks ratios, nucleotide diversity and selection, and analyzed the sequence and structural conservation with distant primates. We aimed to understand if NSD1 in humans differs from other primates since the evolution of NSD1 has not been analyzed in primates, nor if the localization of the mutations is limited to humans. Our study found that most variations causing Sotos syndrome are in exon 19, 22 and 10. In the primate comparison we did not detect Ka/Ks ratios > 1, but a high nucleotide diversity with non-synonymous variations in exons 10, 5, 9, 11 and 23, and sites under episodic selection in exon 5 and 23, and human, macaque/colobus/tarsier/galago and tarsier/lemur/colobus. Most of the domains are conserved in distant primates with a particular progressive development from a simple PWWP1 in O. garnetti to a complex structure in Human. Conclusion NSD1 is a chromatin modifier that suggests that the selection could influence brain development during modern human evolution and is not present in other primates; however, nowadays the nucleotide diversity is associated with Sotos syndrome.

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Molecular signatures of selection on the human GLI3 associated central nervous system specific enhancers

Cited by 3 publications

References 75 publications

Identification of ancestral gnathostome Gli3 enhancers with activity in mammals

Identification of ancestral gnathostome Gli3 enhancers with activity in mammals

Evolution and dysfunction of human cognitive and social traits: A transcriptional regulation perspective

NSD1 gene evolves under episodic selection within primates and mutations of specific exons in humans cause Sotos syndrome

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