Selection pressure on human STR loci and its relevance in repeat expansion disease

Abstract

Short Tandem Repeats (STRs) comprise repeats of one to several base pairs. Because of the high mutability due to strand slippage during DNA synthesis, rapid evolutionary change in the number of repeating units directly shapes the range of repeat-number variation according to selection pressure. However, the remaining questions include: Why are STRs causing repeat expansion diseases maintained in the human population; and why are these limited to neurodegenerative diseases? By evaluating the genome-wide selection pressure on STRs using the database we constructed, we identified two different patterns of relationship in repeat-number polymorphisms between DNA and amino-acid sequences, although both patterns are evolutionary consequences of avoiding the formation of harmful long STRs. First, a mixture of degenerate codons is represented in poly-proline (poly-P) repeats. Second, long poly-glutamine (poly-Q) repeats are favored at the protein level; however, at the DNA level, STRs encoding long poly-Qs are frequently divided by synonymous SNPs. Furthermore, significant enrichments of apoptosis and neurodevelopment were biological processes found specifically in genes encoding poly-Qs with repeat polymorphism. This suggests the existence of a specific molecular function for polymorphic and/or long poly-Q stretches. Given that the poly-Qs causing expansion diseases were longer than other poly-Qs, even in healthy subjects, our results indicate that the evolutionary benefits of long and/or polymorphic poly-Q stretches outweigh the risks of long CAG repeats predisposing to pathological hyper-expansions. Molecular pathways in neurodevelopment requiring long and polymorphic poly-Q stretches may provide a clue to understanding why poly-Q expansion diseases are limited to neurodegenerative diseases.

Androgen receptor polyglutamine repeat length (AR‐CAGn) modulates the effect of testosterone on androgen‐associated somatic traits in Filipino young adult men

“…Here, the same extremes of T and AR‐CAGn relate to the lowest levels of androgen‐associated somatic traits. Because the combination and high T and short AR‐CAGn and low T and long AR‐CAGn are also associated with risk for prostate cancer and infertility, respectively, selection arising from other traits, diseases, or molecular processes could act to counter‐balance these extremes to maintain the high variability in AR‐CAGn among humans (Ryan & Crespi, ; Shimada et al, ).…”

Diverse single-amino-acid repeat profiles in the genusCryptosporidium

“…One of the argument in support of this view is the differential evolution of human short tandem repeats (syn. microsatellites) located in genes and in intergenic regions (Shimada et al 2016).…”

Repeat RNA expansion disorders of the nervous system: post-transcriptional mechanisms and therapeutic strategies

“…Collectively, the repeat sequences that give rise to neurological MREs are diverse in nucleotide composition and intragenic location. One striking bias, however, is the preponderance of trinucleotide ( Rodriguez et al 2020 ) repeat expansions compared to other short RNA repeats, such as di-, tetra-, penta-, and hexanucleotide sequences ( McMurray 2010 ; Shimada et al 2016 ; Paulson 2018 ). Another general feature of MRE sequences includes the prevalence of C and G, compared to A or U, and the ability of MRE RNA to form higher order A-form like duplexes, alternative secondary structures, or even G-quadruplexes ( Fratta et al 2012 ; Cammas and Millevoi 2017 ; Hale et al 2019 ).…”

“…>1000 in DM1, SCA10, or SCA36) compared to those within coding sequences (e.g. 35–80 in many polyQ disorders), which may be a consequence of evolutionary pressures to maintain functional open reading frames of host genes key to neuronal homeostasis ( Shimada et al 2016 ; Paulson 2018 ). Moreover, the length of repeat expansions often inversely correlates with disease severity and onset, especially for polyQ disorders, but varies based on several factors ( Orr and Zoghbi 2007 ; Shimada et al 2016 ).…”