Evolutionary dynamics of tRNA genes

tRNA基因的进化动力学

• 批准号: 9904124
• 负责人: Bryan Patrick Thornlow
• 金额: $ 2.95万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904124
• 关键词: Anticodon; Architecture; Base Pairing; Behavior; Biological Models; Cell physiology; Chromatin; Codon Nucleotides; Complex; DNA Sequence; Data; Data Set; Development; Disease; Drosophila genus; Enzymes; Evolution; Exhibits; Gene Dosage; Gene Duplication; Gene Expression; Gene Family; Genes; Genetic Transcription; Genetic Variation; Genome; Genome Mappings; Germ-Line Mutation; Human; Individual; Laboratories; Lead; Life; Mammals; Modeling; Modification; Mutagenesis; Mutation; Output; Pathologic Mutagenesis; Pathway interactions; Pattern; Phenotype; Population; Population Genetics; Positioning Attribute; Primates; Process; Production; Proteins; Rodent; Role; Source; Structure; Synteny; Testing; Tissues; Transcript; Transfer RNA; Translations; Variant; base; combat; comparative genomics; disorder risk; epigenomics; experience; fitness; genome wide association study; genome-wide; genomic variation; human disease; interest; placental mammal; population based; preference; rare variant; risk variant; simulation; tRNA Precursor; theories; tool development; transcriptome sequencing; virtual

Abstract Transfer RNAs (tRNAs) are fundamental to life due to their vital roles in protein translation. tRNAs are needed in large abundance for normal cellular functions, which requires that they are among the most highly transcribed loci in the genome. Because of their rigidly defined structure and interactions with many other molecules, each base within tRNA genes is highly conserved. Pre-tRNA transcripts also include leader and trailer sequences, which have minimal functionality in most cases and are quickly processed out as part of the tRNA maturation process. Nonetheless, their high levels of transcription can lead to extremely high levels of variation, likely due to transcription-associated mutagenesis (TAM). TAM at tRNA loci has important implications. tRNA genes exist in many copies throughout the genome, and while many of these genes are constitutively transcribed, epigenomic data shows that a majority appear to be completely inactive. Variation in tRNA gene expression within and between species make annotation of expression essential for interpreting the potential effects of natural variants in populations. Greater understanding of tRNA locus variation could enable prioritization of risk loci in genome-wide association studies, as variants in active tRNA genes could have pronounced fitness consequences. However, annotation of tRNA expression levels is difficult for many reasons, including post-transcriptional modifications that impede RNA sequencing, as well as their high levels of redundancy at the gene level. I will develop a predictive classifier, which will use only DNA sequence data, to infer and annotate tRNA gene expression across mammals. There are strong evolutionary implications of increased tRNA transcription as well. Virtually all eukaryotic genomes contain upwards of 200 tRNA genes. Theory predicts that duplicated genes will quickly diverge in function and sequence, generally by neo- or sub-functionalization. However, these predictions assume low and equal germline mutation rates among genes. Therefore, elevated mutation rates at tRNA loci may drive the conservation of hundreds of functionally redundant genes. I will develop an individual-based population genetic simulator framework, using estimations of the per-locus mutation rates at tRNA genes, as well as their duplication and deletion rates. I will then compare simulation results to the actual human tRNA distribution to quantitatively test each component of this model. Adding additional complexity, modifications to the wobble base position on mature tRNAs often alters tRNAs’ decoding repertoire and are essential for proper translation. Differences in tRNA modification between species may lead to differences in wobble potential, and thus change codon usage bias. For example, several closely related Drosophila species exhibit drastic shifts in codon preference despite no changes in tRNA gene copy number. To investigate the evolutionary influence of anticodon base pairing, I will analyze the relative effects of modification enzymes and determine their effects on codon preference shifts, using Drosophila as a model.

摘要 转运RNA（transfer RNA，tRNA）是生命的基础，因为它们在蛋白质翻译中起着重要作用。需要tRNA 在正常的细胞功能，这就要求他们是最高度转录 基因组中的位点。由于它们严格定义的结构和与许多其他分子的相互作用， tRNA基因内的碱基高度保守。前tRNA转录物还包括前导序列和尾随序列， 其在大多数情况下具有最小的功能性，并且作为tRNA成熟的一部分被快速加工出来， 过程尽管如此，它们的高水平转录可能导致极高水平的变异，这可能是由于 转录相关诱变（TAM）。 TAM在tRNA位点具有重要意义。tRNA基因在整个基因组中以许多拷贝存在， 虽然这些基因中有许多是组成型转录的，但表观基因组数据显示，大多数基因似乎是组成型转录的。 完全不活跃。种内和种间tRNA基因表达的变异对 表达对于解释种群中自然变异的潜在影响至关重要。更大的理解 tRNA基因座变异可以使风险基因座在全基因组关联研究中的优先顺序， 活跃的tRNA基因可能具有明显的适应性后果。然而，tRNA表达的注释 由于许多原因，包括阻碍RNA测序的转录后修饰， 以及它们在基因水平上的高冗余度。我将开发一个预测分类器，它仅使用 DNA序列数据，以推断和注释哺乳动物之间的tRNA基因表达。 tRNA转录的增加也有很强的进化意义。几乎所有的真核生物 基因组包含超过200个tRNA基因。理论预测，重复的基因将很快发生分歧， 功能和序列，通常通过新功能化或亚功能化。然而，这些预测假设低， 基因之间的生殖细胞突变率相等。因此，tRNA基因座突变率的升高可能会导致 数百个功能冗余基因的保存。我将开发一个基于个体的群体遗传学 模拟器框架，使用tRNA基因的每个位点突变率的估计，以及它们的重复 和删除率。然后，我将模拟结果与实际的人类tRNA分布进行比较， 测试该模型的每个组件。 增加额外的复杂性，对成熟tRNA上摆动碱基位置的修饰经常改变tRNA的结构。 解码剧目，并为正确的翻译必不可少的。物种间tRNA修饰的差异 可能导致摆动电位的差异，从而改变密码子使用偏好。例如，几个密切 尽管tRNA基因拷贝没有变化，但相关的果蝇物种表现出密码子偏好的剧烈变化 number.为了研究反密码子碱基配对的进化影响，我将分析 修饰酶，并确定其对密码子偏好的转变，使用果蝇作为模型的影响。