High-resolution study of adaptation in haploid and diploid populations of yeast

 描述(申请人提供)：癌症是一种适应性疾病，在这种疾病中，一些细胞获得“有益的”突变，使它们能够在体内增殖。癌症和二倍体的适应通常是由有益的突变驱动的，这些突变必须至少部分显性才能被自然选择发现，甚至可能在适应度方面通常是超显性的(即作为杂合子比作为纯合子更有益)。因此，二倍体的适应很可能由与单倍体不同的一组性质不同的突变驱动，并可能遵循一套不同的规则。为了了解二倍体的适应动态并与单倍体进行比较，有必要(I)在单倍体和二倍体中鉴定大量的个体有益突变，(Ii)确定它们的分子性质，(Iii)在杂合子和纯合子中高精度地测量它们的适合度。不幸的是，这是不可能的，因为在任何系统中分离出少数几个大效应有益突变是困难的。在这里，我们将使用超高 分辨率条形码系统可以唯一地标记数十万个酵母细胞，从而能够在大型单倍体和二倍体酵母群体(约108个细胞/群体)中识别数千个适应性突变。我们将识别和测量在同一环境中出现的数百个不同的有益突变在单倍体和二倍体中的适合度、分子性质和杂合效应。我们将使用这些数据来检验关于单倍体和二倍体中出现和传播的适应性突变的显性的理论预测，并将产生数百个个体适应性突变的分子身份/适应效益/杂合子效应的第一个详细的联合分布。我们预计，从这个项目中获得的洞察力将(I)有助于我们理解在一个制度--大量人口--中的适应-- 这与癌症等人类疾病尤其相关；(Ii)揭示了单倍体和二倍体进化过程中可能存在的质的不同方式。

 DESCRIPTION (provided by applicant): Cancer is a disease of adaptation in which some cells acquire "beneficial" mutations that allow them to proliferate within the body. Cancer, and adaptation in diploids in general, is driven by beneficial mutations that must be at least partly dominant to be detected by natural selection and might even be commonly overdominant in fitness (i.e. more beneficial as heterozygotes than as homozygotes). It is therefore likely that adaptation in diploids will be driven by a qualitatively different set of mutations than in haploid and might obey a qualitatively different set of rules. In order to understand the dynamics of adaptation in diploids and to contrast it with that of haploids it is necessary to (i) identify a lrge number of individual beneficial mutations in both haploids and diploids, (ii) determine their molecular nature, and (iii) measure their fitness with high precision in both heterozygotes and homozygotes. Unfortunately this has not been possible due to the difficulty of isolating more than a handful of large-effect beneficial mutations in any system. Here, we will use an ultra- high resolution barcoding system to uniquely tag hundreds of thousands of yeast cells making it possible to identify thousands of adaptive mutations in large haploid and diploid yeast populations (~108 cells/population). We will identify and measure the fitness, molecular nature, and heterozygous effects of hundreds of distinct beneficial mutations arising in the same environment in haploids and diploids. We will use these data to test theoretical predictions about dominance of adaptive mutations arising and spreading in haploids and diploids and will generate the first detailed joint distribution of molecular identity/fitness benefit/heterozygote effect of several hundred individual adaptive mutations. We anticipate that the insight gained from this project will (i) inform our understanding of adaptation in a regime - large populations - that is especially relevant for human diseases such as cancer and (ii) reveal the likely qualitatively different ways in which evolution proceeds in haploids and diploids.