Evolution of codon usage bias in the genus Drosophila

描述(申请人提供)：在相当长的一段时间里，沉默或同义突变(不改变DNA编码的氨基酸的突变)被假定为相对于自然选择是中性的。最近对各种生物体的分析表明，这种假设并不总是正确的。几乎可以肯定的是，由于同义密码子在翻译消息的效率上存在差异，选择可以检测到同义突变。然而，理论和实证研究都表明，选择的水平非常弱，可能处于漂移或选择主导决定动态的边缘。因此，对分子进化的一个主要特征--这种略微有害的突变--的大多数研究都局限于分析统计审查(而不是经验实验操作)。12种众所周知的果蝇的完整基因组序列的出现，为研究分子进化的这一重要特征提供了一个迄今无法获得的机会。在这项建议中，我们关注决定密码子使用的因素，特别是非随机或有偏见的密码子使用。研究包括，首先，确定十二种果蝇的最佳密码子，以记录在大约40-50年的进化过程中密码子的使用发生了多少变化。我们将探索密码子使用偏向程度与基因表达水平和表达时间(通过发育)的关系，假设高表达的基因具有更大的密码子使用偏向，这与等接受tRNA池的水平有关，而tRNA池有时会在发育阶段发生变化。这将需要分析特定的氨基酸。系统发生学观点将解决诸如选择、突变和漂移在决定密码子使用变化中的相对作用等问题。密码子使用偏向的一个假说断言，氨基酸的错误结合是使用最佳密码子的主要驱动因素；这一假说将通过对新出现的完整基因组的分析来检验。最后，我们将研究重组水平对包括密码子使用在内的分子变异水平和模式的作用。这是因为在大多数物种中，一条染色体上的基因(点)几乎不会重组，但在威利斯多尼的染色体上，基因已经整合到正常重组的染色体中，这是正在测序的物种之一。

DESCRIPTION (provided by applicant): For a considerable time, silent or synonymous mutations (mutations that do not change the amino acid being coded by DNA) were assumed to be neutral with respect to natural selection. Recent analyses of a variety of organisms indicate that this assumption is not always correct. Almost certainly due to the fact that synonymous codons confer differences in efficiency of translation of messages, selection can detect synonymous mutations. However, both theoretical and empirical studies indicate that the level of selection is very weak, probably on the border of when drift or selection predominates in determining the dynamics. Thus, most studies of such slightly deleterious mutations, a major feature of molecular evolution, are confined to analytical statistical scrutiny (as opposed to empirical experimental manipulations). The emerging set of complete genome sequences for twelve species of well understood Drosophila provides a heretofore unavailable opportunity to study this important feature of molecular evolution. We focus in this proposal on the factors that determine codon usage, especially non-random or biased codon usage. Studies include, first, defining optimal codons for the twelve species of Drosophila to document how much codon usage has changed during the approximately 40-50 MY of evolution. The relationship of level of codon usage bias to both the level and timing (through development) of expression of genes will be explored, with the hypothesis that genes with higher expression have greater codon usage bias as well as this being related to levels of isoaccepting tRNA pools that sometimes change across developmental stages. This will require analysis of specific amino acids. A phylogenetic perspective will address issues such as the relative role of selection, mutation, and drift in determining changes in codon usage. One hypothesis for codon usage bias asserts that misincorporation of amino acids is a major driving factor for usage of optimal codons; this hypothesis will be tested by analysis of the emerging new complete genomes. Finally, we will examine the role of levels of recombination on level and patterns of molecular variation including codon usage. This is made possible by the fact that genes on one chromosome (the "dot") are nearly non- recombining in most species, but have been incorporated into a normally recombining chromsome in D. willistoni, one of the species being sequenced.