Molecular Analysis of Naturally Occurring Copia Variation

9307220麦克唐纳自然发生的复制变异的分子分析（约翰F.麦克唐纳，P.I.）%%%越来越多的证据表明，逆转录病毒和逆转录病毒样转座因子是包括人类在内的高等真核生物突变的主要来源。这一事实的影响延伸到从医学到进化遗传学等广泛的生物学科。尽管我们现在对逆转录病毒样元素如何改变染色体基因表达的机制了解很多，但对逆转录病毒元素如何在物种内部和物种之间维持和传播知之甚少。此外，逆转录病毒元件插入突变通常是非适应性的，但如何随着时间的推移在某些物种中频率增加并最终成为“固定”（即达到1.00的频率），这仍然是一个谜。一种可能性是，能够抑制与逆转录病毒插入变异相关的突变表型的宿主染色体基因存在于自然种群中，并通过保护插入变异免受自然选择的影响来庇护它们。麦克唐纳博士假设，插入变异的频率可能会周期性地增加，这是由于“创始人事件”或其他类似的强迫近亲繁殖效应。在接下来的三年里，麦克唐纳博士将研究复制逆转录病毒样因子在果蝇自然种群中维持和传播的机制。果蝇是这些研究的理想系统，因为逆转录病毒元件在这种生物中被很好地理解，元件的频率和突变效应可以很容易地监测。麦克唐纳博士将专注于识别能够反式调节逆转录病毒元素的宿主基因，并研究它们在许多果蝇物种中的频率和作用方式。从许多果蝇种群和物种中分离的复制元件的DNA序列将被分析，以确定可能影响元件活性的结构差异在自然种群中是否可变。McDonald博士将通过将相同的复制型LTR报告基因结构引入几个菌株和物种并监测LTR介导表达的影响来寻找跨调控效应。结果将揭示决定逆转录病毒元素在自然种群和所有高等真核生物物种中维持和传播的因素。＊＊＊

9307220 McDonald Molecular Analysis of Naturally Occurring copia Variations (John F. McDonald, P.I.)%%% There is an ever growing body of evidence that retroviruses and retroviral-like transposable elements are a major source of mutation in higher eukaryotes including humans. The ramifications of this fact extend to a broad range of biological disciplines ranging from medicine to evolutionary genetics. Although we now know a great deal on the mechanisms of how retroviral-like elements alter the expression of chromosomal genes, little or nothing is known concerning how retroviral elements are maintained and spread within and between species. In addition, it remains a mystery as to how retroviral elements insertion mutations which are usually non-adaptive can nevertheless increase in frequency and eventually become "fixed" (i.e., attain a frequency of 1.00) in some species over time. One possibility is that host chromosomal genes capable of suppressing the mutant phenotype associated with retroviral insertion variants are present in natural populations and serve to harbor insertion variants by shielding them from natural selection. Dr. McDonald hypothesizes that insertion variants may periodically increase in frequency due to "founder events" or other such forced inbreeding effects.%%% Over the next three years Dr. McDonald will study the mechanisms by which the copia retroviral-like element is maintained and spread through natural populations of Drosophila. Drosophila is an ideal system for these studies because retroviral elements are well understood in this organism and element frequency and mutational effects can be easily monitored. Dr. McDonald will be concentrating on identifying host genes capable of trans-regulating retroviral elements and studying their frequency and mode of action in a number of Drosophila species. The DNA sequence of copia elements isolated from a number of Drosophila populations and species will be analyzed t o determine if structural differences which might affect element activity are variable in natural populations. Dr. McDonald will search for transregulatory effects by introducing the same copia LTR-reporter gene construct into several strains and species and monitoring the effect of LTR mediated expression. Results will shed light on the factors determining the maintenance and spread of retroviral elements in natural populations and species of all higher eukaryotes. ***