Thermodynamically stable and genetically unstable G-quadruplexes are depleted in genomes across species
Thermodynamically stable and genetically unstable G-quadruplexes are depleted in genomes across species
复制标题
DOI：
10.1093/nar/gkz463
复制
发表时间：
2019-07-09
影响因子：
14.9
通讯作者：
Londono-Vallejo, Arturo
中科院分区：
文献类型：
--
作者：
Lombardi, Emilia Puig;Holmes, Allyson;Londono-Vallejo, Arturo
G-四链体在多种生物过程中发挥各种作用，当G4参与基因表达的调节时，G-四链体可以是积极的，或者当稳定的G4的折叠损害DNA复制促进基因组不稳定性时，G-四链体可以是有害的。这种二元性质疑它们在基因组中存在的意义。为了解决G4基序的潜在偏向进化，我们分析了它们在大范围物种中的发生，特征和多态性。我们发现了短环G4基序的极端偏差，这是最稳定的体外，从而携带最高的折叠潜力在体内。在人类基因组中，存在单核苷酸环G4基序（G4-L1）的过度表达，其在人类中高度保守，并且显示出在生物学上最不稳定的G4-L1 A（G（3）AG（3）AG（3））序列的显著过量。在酵母中的功能测定表明，G4-L1 A引起的自发和G4-配体诱导的不稳定性的最低水平。对600个物种的分析显示，在大多数基因组中最稳定的G4-L1 C/T四链体的消耗有利于脊椎动物中的G4-L1 A或其他真核生物中的G4-L1 G。我们讨论了这些趋势如何可能是与针对最稳定基序的负选择相关的物种特异性突变过程的结果，从而中和它们对基因组稳定性的有害影响，同时保留G4相关的积极生物学作用。
G-quadruplexes play various roles in multiple biological processes, which can be positive when a G4 is involved in the regulation of gene expression or detrimental when the folding of a stable G4 impairs DNA replication promoting genome instability. This duality interrogates the significance of their presence within genomes. To address the potential biased evolution of G4 motifs, we analyzed their occurrence, features and polymorphisms in a large spectrum of species. We found extreme bias of the short-looped G4 motifs, which are the most thermodynamically stable in vitro and thus carry the highest folding potential in vivo. In the human genome, there is an over-representation of single-nucleotide-loop G4 motifs (G4-L1), which are highly conserved among humans and show a striking excess of the thermodynamically least stable G4-L1A (G(3)AG(3)AG(3)AG(3)) sequences. Functional assays in yeast showed that G4-L1A caused the lowest levels of both spontaneous and G4-ligand-induced instability. Analyses across 600 species revealed the depletion of the most stable G4-L1C/T quadruplexes in most genomes in favor of G4-L1A in vertebrates or G4-L1G in other eukaryotes. We discuss how these trends might be the result of species-specific mutagenic processes associated to a negative selection against the most stable motifs, thus neutralizing their detrimental effects on genome stability while preserving positive G4-associated biological roles.