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

Abstract

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.

Identification of Novel NSD1 variations in four Pediatric cases with sotos Syndrome

“…The missense variant, NSD1 (NM_022455): c.6397T > G(p.C2133G), in Case 4 resides in the plant homeodomain (PHD) 5 domain of the NSD1 protein, exhibiting considerable conservation across species. PHD acts as a C4HC3 zinc finger-like motif within nuclear proteins that are involved in chromatin modulation and epigenetics [ 29 ]. This variant significantly influenced local hydrogen bond formation, potentially compromising the stability of the protein’s three-dimensional structure.…”

Chromatin modifiers in human disease: from functional roles to regulatory mechanisms

“…Recently published studies have confirmed that patients with HMT SETD2 mutations present with intellectual disability, developmental delay, and skeletal system abnormalities as the main clinical manifestations [ 101 ]. However, mutations in the domain between HMT NSD1 exon 10 and 22 are associated with microcephaly [ 102 ]. The above evidence suggests that histone methyltransferases are closely associated with neurodevelopmental disorders.…”