Tandem Repeats and Repeatomes: Delving Deeper into the 'Dark Matter' of Genomes.
Tandem Repeats and Repeatomes: Delving Deeper into the 'Dark Matter' of Genomes.
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DOI：
10.1016/j.ebiom.2018.04.004
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发表时间：
2018-05
期刊：
影响因子：
11.1
通讯作者：
Hannan AJ
中科院分区：
文献类型：
--
作者：
Hannan AJ
对人类生物学和疾病的理解，以及现代医学的实践，正在被基因组学所改变。大约20年前的人类基因组测序（来自少数健康个体）仅仅是个开始。超过一半的人类基因组，大约30亿个碱基对的DNA，涉及构成重复组的重复DNA序列（Hannan, 2012），可以被认为是基因组的“暗物质”。这是因为它的大部分内容仍未得到充分研究，注释不足，功能也很神秘。对于重复组内的大量重复序列，我们仍然不确定它们是“垃圾DNA”（如果实际上我们基因组的任何部分都值得这样一个贬义的描述），还是它们的进化功能在这一点上仍然不透明。重复组的一个关键组成部分包括串联重复序列，它占人类基因组的3%以上。人类基因组中有超过150万个短串联重复序列（STRs），由DNA 1-6个碱基对基序的重复单元组成，最近的证据支持它们在一系列分子和细胞过程中发挥作用（Gymrek等人，2016;Hannan, 2018）。虽然在过去的三十年中，关于串联重复序列扩增导致特定孟德尔人类疾病的证据已经积累，但串联重复序列多态性（TRPs）在调节复杂人类特征和疾病中的潜在作用在很大程度上仍未被探索（Hannan, 2018）。《电子生物医学》杂志上的一篇新文章（Lee et al., 2018）描述了亨廷顿蛋白（HTT）基因中的CAG串联重复多态性与认知的特定测量（他们称之为“一般智力”）之间非常有趣的关联。这项工作是新颖的，并增加了迅速扩大的串联重复序列遗传学领域。25年前，当编码聚谷氨酰胺束的CAG重复序列在亨廷顿舞蹈病（HD）患者中被发现扩增时，HTT基因首次受到关注。然而，像许多str一样，它在一般人群中是高度多态的，在那里它可能构成功能多态性。本研究（Lee et al., 2018）涉及一组有HD风险的儿童（6-18岁）和年龄匹配的健康对照。这项研究最重要的方面是，在正常范围内（低于HD的阈值），CAG重复长度与一般智力之间存在关联。作者承认，这项研究的主要局限性是，它需要对更大的独立健康对照人群以及HD突变基因阳性人群进行随访。针对此类复杂性状（或多基因疾病）的全基因组关联研究（利用基于snp的微阵列）现在通常涉及非常大的队列，以便在面对广泛的多基因性和异质性时提供统计能力。因此，目前的研究（n= 316），适当地为儿童症状前HD基因阳性研究（该研究的主要目的）提供了支持，但作为复杂性状的候选基因关联研究（这可能不是研究者的初衷）并没有得到很好的支持。然而，它确实为更大规模的复制研究提供了一个重要的框架。另一个关键点是，对于高HD范围内的重复长度（也是本研究的一部分），即使预测儿童多年后不会出现症状，一些认知变化可能反映了早期HD相关的认知变化。另外，成人发病的HD（约95%的病例）可能至少部分是一种发育障碍。因此，HD患者的大脑可能经历……
The understanding of human biology and diseases, and the practice of modern medicine, is being transformed by genomics. The sequencing of the human genome (from a handful of healthy individuals) almost two decades ago was only a beginning. Over half of the human genome, approximately 3 billion base pairs of DNA, involves repetitive DNA sequences which constitute the repeatome (Hannan, 2012) and could be considered the ‘dark matter’of the genome. This is because much of it remains under-studied, poorly annotated and functionally mysterious. For large tracts of repetitive sequences within the repeatome, we remain uncertain as to whether they are ‘junk DNA’(if in fact any part of our genome deserves such a pejorative description) or whether their evolved functions simply remain opaque at this point in time. A key component of the repeatome involves tandem repeats, which constitute over 3% of the human genome. There are over 1.5 million short tandem repeats (STRs), which consist of repeating units of 1–6 basepair motifs of DNA, in the human genome and recent evidence supports their roles in a range of molecular and cellular processes (Gymrek et al., 2016; Hannan, 2018). Whilst the evidence for tandem repeat expansions causing particular Mendelian human disorders has accumulated in the past three decades, the potential roles of tandem repeat polymorphisms (TRPs) in modulating complex human traits and disorders remain largely unexplored (Hannan, 2018). A new article (Lee et al., 2018) in EBioMedicine describes a very interesting association between a CAG tandem repeat polymorphism in the huntingtin (HTT) gene and specific measures of cognition (which they refer to as ‘general intelligence’). This work is novel and adds to the rapidly expanding tandem repeat genetics field. The HTT gene first came to prominence 25 years ago, when the CAG repeat, encoding a polyglutamine tract, was found to be expanded in patients with Huntington's disease (HD). However, like many STRs, it is highly polymorphic in the general population, where it may constitute a functional polymorphism. The present study (Lee et al., 2018) involved a cohort of children (6–18 years) at risk of HD and age-matched healthy controls. The most significant aspect of this study is that in the normal range (below the threshold for HD) there was an association between CAG repeat length and general intelligence. The major limitation of this study, acknowledged by the authors, is that it needs to be followed up with larger independent cohorts of healthy controls, as well as those genepositive for the HD mutation. Genome-wide association studies (utilising SNP-based microarrays) for such complex traits (or polygenic disorders) now generally involve very large cohorts, to provide statistical power in the face of extensive polygenicity and heterogeneity. Therefore, the present study (n= 316), which was appropriately powered for a gene-positive presymptomatic HD study in children (the primary aim of the study), is not well powered as a candidate gene association study of a complex trait (which presumably was not the original intention of the investigators). Nevertheless, it does provide an important framework for larger replication studies. The other key point is that for repeat lengths within the higher HD range (also part of this study), even though the children were not predicted to become symptomatic for many years, some of the cognitive changes could reflect very early HD-associated cognitive changes. Alternatively, or additionally, it is possible that adult-onset HD (~ 95% of cases) is at least partly a developmental disorder. Thus, the HD brain may undergo …
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影响因子：
6.8
作者：
Gardiner, S. L.;van Belzen, M. J.;Aziz, N. A.
通讯作者：
Aziz, N. A.
影响因子：
17.7
作者：
Perlis, Roy H.;Smoller, Jordan W.;Gusella, James
通讯作者：
Gusella, James
影响因子：
11.1
作者：
Lee JK;Conrad A;Epping E;Mathews K;Magnotta V;Dawson JD;Nopoulos P
通讯作者：
Nopoulos P
影响因子：
30.8
作者：
Gymrek M;Willems T;Guilmatre A;Zeng H;Markus B;Georgiev S;Daly MJ;Price AL;Pritchard JK;Sharp AJ;Erlich Y
通讯作者：
Erlich Y
影响因子：
6.8
作者：
Gardiner SL;van Belzen MJ;Boogaard MW;van Roon-Mom WMC;Rozing MP;van Hemert AM;Smit JH;Beekman ATF;van Grootheest G;Schoevers RA;Oude Voshaar RC;Roos RAC;Comijs HC;Penninx BWJH;van der Mast RC;Aziz NA
通讯作者：
Aziz NA