Exploiting natural genetic variation to map QTLs of telomere properties in Yeast: Length silencing ageing and senescence

生物体的大多数特性是由许多基因而不是单个主要基因控制的。在过去的100年里，遗传学被分成了两种分析模式。第一种是育种遗传学，它通常处理复杂的遗传性状，如产蛋量、产奶量和作物产量，但不是以简单的方式遗传的。在过去的几十年里，已经产生了非常复杂的统计分析来处理这些特征的遗传。第二种分析模式处理简单的单基因效应，其中变异或突变具有可见的表型效应。现代分子遗传学通常处理这种单基因方法，其中基因的敲除或突变已被评估对特定表型的影响。这已经发展到大规模的全基因组方法，其中对每个基因敲除的特定表型的影响进行评估。现在有一致的努力来评估许多（如果不是全部的话）双基因敲除，以观察基因的相互作用。复杂的数量性状与现代分子方法的有效结合还没有实现，尽管已经有一些努力取得了有限的成功。单核苷酸多态性和其他变异的全基因组图谱的出现，改善了涉及复杂性状的基因图谱，但这仍然是一项缓慢而艰巨的任务。大自然为我们提供了必要的实验材料，以现代分子方法来研究在序列和表型特征上存在分歧的群体形式的复杂特征。在酵母种群中，我们发现高达4.5%的序列差异，以及端粒长度等许多表型的差异。我们可以证明，这种表型差异是由许多基因而不是几个主要基因造成的。对所有单基因敲除的全球筛选已经在一种酵母菌的实验室菌株上完成，该菌株已经确定了大量可能与端粒长度有关的基因。我们将利用自然遗传变异来绘制所有参与端粒长度控制的基因，其中将包括在以前的研究中未检测到的必要基因，以及它们之间的相互作用。通过将我们的方法与之前的方法进行比较，我们将确定新的遗传因素，但更重要的是这些因素如何相互作用。我们将评估我们的方法相对于之前的基因敲除方法的效率，也将评估确定端粒长度的遗传因素以及衰老和附近基因抑制的相关表型所需的相对工作量。这种方法肯定会进一步揭示与这些性状有关的遗传因素，但如果它被证明是可行的，我们将把它应用于一般的复杂表型，并使材料可供社区使用。

Most properties of an organism are under the control of many genes rather than single major genes. Genetics in the past 100 years has been split into two modes of analysis. The first is breeding genetics which generally dealt with complex traits that were inherited, such as egg production, milk yield and crop yields, but were not inherited in a simple fashion. Very complex statistical analyses have been generated over the decades to deal with the inheritance of these traits. The second mode of analysis deals with the simple single gene effects where a variant or mutant has a visible phenotypic effect. Modern molecular genetics has generally dealt with this single gene approach where a knockout or mutation of a gene has been assessed for the effect on particular phenotypes. This has grown to large scale genome wide approaches where the effect on a particular phenotype of every gene knockout is assessed. There are now concerted efforts to assess many if not all double gene knockouts to look at gene interactions. There hasn't yet been an effective marriage of the complex quantitative traits with the modern molecular approach though there have been some efforts with limited success. The advent of genome wide mapping of SNPs and other variation has improved the mapping of genes involved in complex traits but it is still a slow and arduous task. Nature has provided us with the necessary experimental material to undertake a modern molecular approach to complex traits in the form of populations that have diverged in sequence and phenotypic characteristics. In yeast populations we have found up to 4.5% sequence divergence as well as divergence in a number of phenotypes such as the length of telomeres. We can show that this difference in phenotypes is due to a number of genes rather than a few major genes. A global screen of all single gene knockouts has already been done on a laboratory strain of yeast which has identified a large number of genes that may be involved in telomere length. We will use the natural genetic variation to map all the genes involved in telomere length control, which will include essential genes not detectable in the previous studies, as well as their interactions. By comparing our approach to the previous approach we will identify new genetic factors but more importantly how these factors interact. We will assess the relative efficiency of our approach to the previous gene knockout approach and will also assess the relative workload required to determine the genetic factors of telomere length as well as related phenotypes of aging and nearby gene repression. The approach will definitely reveal further genetic factors involved in these traits but if it proves to be as feasible we will apply it to complex phenotypes in general and make the materials available to the community.