Cis- and Trans-Modifiers of Repeat Expansions: Blending Model Systems with Human Genetics

Abstract

Over 30 hereditary diseases are caused by the expansion of microsatellite repeats. The length of the expandable repeat is the main hereditary determinant of these disorders. They are also affected by numerous genomic variants that are either nearby (cis) or physically separated from (trans) the repetitive locus, which we review here. These genetic variants have largely been elucidated in model systems using gene knockouts, while a few have been directly observed as single-nucleotide polymorphisms (SNPs) in patients. There is a notable disconnect between these two bodies of knowledge: knockouts poorly approximate the SNP-level variation in human populations that gives rise to medically relevant cis- and trans-modifiers, while the rarity of these diseases limits the statistical power of SNP-based analysis in humans. We propose that high-throughput SNP-based screening in model systems could become a useful approach to quickly identify and characterize modifiers of clinical relevance for patients.

Targeted Oligonucleotides for Treating Neurodegenerative Tandem Repeat Diseases

“…G-rich sequences can form G-quadruplex (G4) structures consisting of π–π stacking of planar G-tetrads. These conformations are implicated in NRDs even if this has not been equally substantiated for all structures [ 2 , 5 ].

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“…It is believed that changes in the repeat number in normal cells mainly occur during replication, transcription, or under DNA repair (reviewed in [ 3 – 5 ]). In addition, they may occur when translocations take place.…”

“…Related repair proteins were also found in other studies [ 127 ]. Cis - and trans -modifiers of repeat expansions were recently reviewed [ 5 ]. Collectively, this shows that there are numerous cellular components, which influence the propensity to expand tandem repeats, although considerably less is known about what ignites these processes.…”

“…The number of inherited repeats varies between the different disease genes and among individuals within the same patient group. Even if premutations with an increased number of repeats are inherited, further expansion still occurs in somatic cells, and another critical feature is that the expansion is tissue-specific, suggesting that phenotypic differences among cell types may determine the repeat instability [ 3 – 5 ]. The most studied are trinucleotide repeat (TNRs) sequences; however, larger repeats also exist in the human genome, such as tetra-, penta-, and hexanucleotide repeats.…”

Detours to Replication: Functions of Specialized DNA Polymerases during Oncogene-induced Replication Stress

“…Below, we summarize evidence for the effect of DiToRS on replication obtained through in vitro studies of purified polymerases, ex vivo studies using reporter plasmids and two-dimensional (2D) gel analyses of fork progression, and in vivo studies analyzing replication progression within individual DNA molecules. Such DiToRS are linked mechanistically to genome variations that underlie inherited microsatellite expansion diseases [ 31 ], de novo genomic disorders [ 32 , 33 ], cancer genome instability [ 34 , 35 , 36 ], and genome evolution [ 37 ]. Evolutionarily, conserved repetitive elements prone to breakage or viral integration provide ideal regions for chromosomal rearrangement and species divergence [ 38 ].…”