Exceptional expansion and conservation of a CT‐repeat complex in the core promoter of PAXBP1 in primates

Abstract

Adaptive evolution may be linked with the genomic distribution and function of short tandem repeats (STRs). Proximity of the core promoter STRs to the +1 transcription start site (TSS), and their mutable nature are characteristics that highlight those STRs as a novel source of interspecies variation. The PAXBP1 gene (alternatively known as GCFC1) core promoter contains the longest STR identified in a Homo sapiens gene core promoter. Indeed, this core promoter is a stretch of four consecutive CT-STRs. In the current study, we used the Ensembl, NCBI, and UCSC databases to analyze the evolutionary trend and functional implication of this CT-STR complex in six major lineages across vertebrates, including primates, non-primate mammals, birds, reptiles, amphibians, and fish. We observed exceptional expansion (≥4-repeats) and conservation of this CT-STR complex across primates, except prosimians, Microcebus murinus and Otolemur garnettii (Fisher exact P<4.1×10(-7)). H. sapiens has the most complex STR formula, and longest repeats. Macaca mulatta and Callithrix jacchus monkeys have the simplest STR formulas, and shortest repeat numbers. CT≥4-repeats were not detected in non-primate lineages. Different length alleles across the PAXBP1 core promoter CT-STRs significantly altered gene expression in vitro (P<0.001, t-test). PAXBP1 has a crucial role in craniofacial development, myogenesis, and spine morphogenesis, properties that have been diverged between primates and non-primates. To our knowledge, this is the first instance of expansion and conservation of a STR complex co-occurring specifically with the primate lineage.

Exceptionally long 5′ UTR short tandem repeats specifically linked to primates

“…We have recently reported human core promoter STRs that are exceptionally long, and may be of selective advantage (Darvish et al 2011;Ohadi et al, 2012a). This notion is supported by the emerging evidence of functionality for a number of those STRs, to modulate gene expression (Valipour et al, 2013;Heidari et al, 2012), and their differential evolution in the primate order vs. other mammals (Ohadi et al, 2015;Rezazadeh et al, 2014;Mohammadparast et al 2014). …”

“…At the top of that list, the PAXBP1 core promoter contains the longest STR identified in a human gene core promoter. This STR is functional and has been expanded exceptionally in primates (Mohammadparast et al 2014), indicating that exceptionally long STRs may confer selective advantage and adaptation in primates. Remarkably, PAXBP1 is involved in processes that have critically diverged from nonprimates to primates, such as craniofacial features (Paternoster et al, 2012) and spine morphogenesis (Guerreiro et al, 2013).…”

“…The emerging comparative genomics studies on short tandem repeats (STRs) support a role of those motifs in primate speciation (Ohadi et al, 2015;Rezazadeh et al, 2014;Mohammadparast et al 2014). STRs have recently been shown to have a prominent role in epistasis (Press et al, 2014).…”

Link Between Short tandem Repeats and Translation Initiation Site Selection

“…Genome-scale findings of the evolutionary trend of a number of STRs has begun to unfold their implications in respect with speciation and species-specific characteristics/phenotypes (Yuan et al 2018;Emamalizadeh et al 2017;Abe and Gemmell 2016;Bushehri et al 2016;Namdar-Aligoodarzi et al 2016;Nikkhah et al 2016;Bilgin Sonay et al 2015;Rezazadeh et al 2014;Khademi et al 2017;Mohammadparast et al 2014;Ohadi et al 2012;King et al 2012). The hypermutable nature of STRs and their large unascertained reservoir of functionality make them an ideal source of evolutionary adaptation, speciation, and disease (Hannan et al 2018;Bagshaw et al 2017;Press et al 2017;Ohadi et al2015;Valipour et al 2013;Heidari et al 2012).…”

Editorial: Could Speciation Across Evolution be Governed by Genetic Switch Codes at Short Tandem Repeats?

“…And if they could, would they consist of specific codes at different evolutionary crossroads? To this end, STRs have been identified, expansion or identical co-occurrence of which appear to be decisive in specific evolutionary divergence points [3][4][5][6] (Figure 1). In those instances, the threshold number of repeats for each STR seems to be crucial to species divergence (i.e.…”