Hereditary Consequences of Small RNAs

小RNA的遗传后果

• 批准号: 437407415
• 负责人: Professor Dr. Björn Schumacher
• 金额: --
• 依托单位: Department of Neurobiology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/437407415?language=en
• 关键词: Hereditary; Consequences; Small; RNAs

The “Modern synthesis”, which is a combination of Darwinian evolution with Mendelian and population genetics, dismisses the possibility that responses to environmental challenges can become heritable. According to this prevailing conceptual paradigm, genomes evolve due to selection or drift of mutations that accumulate randomly. Nonetheless, experiments conducted with C. elegans over the last 20 years have shown that small RNA-induced RNA interference (RNAi) mechanisms can transmit parental gene regulatory responses across generations; thus, while the original naïve ideas of Lamarck were dismissed, tractable genetic models now allow proper investigation of new mechanisms that, in certain cases, enable direct transgenerational transfer of acquired non-DNA-encoded information about the ancestral environment. Indeed, insight from multiple studies elucidated the conditions under which RNAi in C. elegans can trigger silencing effects that proceed for many generations, and the genetic mechanisms that enable this type of inheritance. Transcription is known to affect the capacity of DNA repair mechanisms, such as transcription-coupled nucleotide excision repair (TC-NER), to prevent mutations, and also the probability that a given locus would undergo recombination. Different mechanisms discovered in a wide range of organisms raise the provocative possibility that silencing genes over long periods of time could lead to a change in the number of mutations on the target, or alternate recombination frequencies. We present here a plan for testing the provocative hypothesis that small RNA inheritance affects genome evolution; Specifically, we will examine if small RNAs can change the propensity of genes to accrue germline mutations thus altering the genetic plasticity of their targets, ultimately giving rise to “hardwired” changes in the DNA sequence. We decided to synergize our expertise in RNAi mechanisms in transgenerational inheritance (Rechavi) and DNA repair mechanisms, specifically TC-NER (Schumacher), to addresses the fundamental question: Can temporary epigenetic responses become fixated in the genome? We will (1) examine whether heritable small RNA-induced silencing affects the likelihood that the target would acquire specific types of mutations, (2) test whether small RNA inheritance affects recombination frequencies, (3) perform a genome-wide assessment of the contribution of small RNAs in the germline to DNA repair and recombination, and (4) assess whether the levels of small RNAs, which are inherited as a response to environmental stress, correlate with DNA sequence changes.

“现代综合”是达尔文进化论与孟德尔和种群遗传学的结合，它否定了对环境挑战的反应可以遗传的可能性。根据这种流行的概念范式，基因组的进化是由于随机积累的突变的选择或漂移。尽管如此，在过去20年里对秀丽隐杆线虫进行的实验表明，小RNA诱导的RNA干扰（RNAi）机制可以将亲本基因调控反应传递给后代；因此，虽然Lamarck最初的naïve想法被驳回，但可处理的遗传模型现在允许对新机制进行适当的调查，在某些情况下，可以直接跨代传递获得的关于祖先环境的非dna编码信息。事实上，来自多项研究的见解阐明了秀丽隐杆线虫中的RNAi可以触发多代沉默效应的条件，以及使这种遗传成为可能的遗传机制。众所周知，转录会影响DNA修复机制的能力，如转录偶联核苷酸切除修复（TC-NER），以防止突变，也会影响给定位点进行重组的可能性。在广泛的生物体中发现的不同机制提出了一种令人兴奋的可能性，即长时间沉默基因可能导致目标突变数量的变化，或者交替重组频率。我们在这里提出了一个计划，以测试小RNA遗传影响基因组进化的挑衅性假设；具体来说，我们将研究小rna是否可以改变基因积累生殖系突变的倾向，从而改变其目标基因的遗传可塑性，最终导致DNA序列的“硬连接”变化。我们决定将我们在RNAi机制跨代遗传（Rechavi）和DNA修复机制（特别是TC-NER）方面的专业知识协同起来，以解决基本问题：暂时的表观遗传反应能否在基因组中固定？我们将(1)研究可遗传的小RNA诱导的沉默是否会影响目标获得特定类型突变的可能性，(2)测试小RNA遗传是否会影响重组频率，(3)对种系中小RNA对DNA修复和重组的贡献进行全基因组评估，以及(4)评估作为环境应激反应而遗传的小RNA水平是否与DNA序列变化相关。