Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA.
Adv Exp Med Biol. 2017;1042:489-526. doi: 10.1007/978-981-10-6955-0_21.
Chromosome fragile sites are a fascinating cytogenetic phenomenon now widely implicated in a slew of human diseases ranging from neurological disorders to cancer. Yet, the paths leading to these revelations were far from direct, and the number of fragile sites that have been molecularly cloned with known disease-associated genes remains modest. Moreover, as more fragile sites were being discovered, research interests in some of the earliest discovered fragile sites ebbed away, leaving a number of unsolved mysteries in chromosome biology. In this review we attempt to recount some of the early discoveries of fragile sites and highlight those phenomena that have eluded intense scrutiny but remain extremely relevant in our understanding of the mechanisms of chromosome fragility. We then survey the literature for disease association for a comprehensive list of fragile sites. We also review recent studies addressing the underlying cause of chromosome fragility while highlighting some ongoing debates. We report an observed enrichment for R-loop forming sequences in fragile site-associated genes than genomic average. Finally, we will leave the reader with some lingering questions to provoke discussion and inspire further scientific inquiries.
染色体脆性位点是一种引人入胜的细胞遗传学现象，现在广泛涉及从神经紊乱到癌症等多种人类疾病。然而，通向这些发现的道路远非直接，并且已经用已知与疾病相关的基因对少数脆性位点进行了分子克隆。此外，随着越来越多的脆性位点被发现，对一些最早发现的脆性位点的研究兴趣逐渐减弱，导致染色体生物学中存在许多未解之谜。在这篇综述中，我们试图回顾一些早期的脆性位点发现，并强调那些尚未受到深入研究但对我们理解染色体脆性机制仍然极其重要的现象。然后，我们查阅文献，列出了一份全面的脆性位点疾病相关性列表。我们还回顾了最近研究染色体脆弱性潜在原因的研究，同时强调了一些正在进行的争论。我们报告在与脆性位点相关的基因中观察到富含 R 环形成序列，而不是基因组平均水平。最后，我们将为读者留下一些悬而未决的问题，以引发讨论并激发进一步的科学探究。
