QTL MAPPING FOR ALCOHOL PREFERENCE IN SELECTED MICE

高酒精偏好和低酒精偏好（HAP和LAP）小鼠系已经选择性地培育了酒精偏好的差异。这些系是唯一现存的选择性繁殖的小鼠系，为酒精偏好而发展。因此，它们提供了一个独特的机会来潜在地确认在BXD RI研究中推定确定的qtl或在F2验证研究中确认的qtl。这些品系还将提供一个机会来检测小鼠体内的合成区域，在这些区域中，在嗜酒和非嗜酒（P和NP）大鼠品系以及高酒精和低酒精（HAD和LAD）大鼠品系中暂时鉴定出了qtl。由于连锁不平衡预计仅限于选择系中非常接近QTL的小区域（约1至2 cM），因此有必要在其他研究中已知存在QTL的区域使用高密度标记来检测QTL。这项工作的目的是获得qtl存在的确凿证据，并获得比Belknap等人（1997）在F2中可能获得的更高的定位分辨率。每当一个标记的等位基因频率在两个相反选择的株系中差异显著大于遗传漂变和等位基因频率估计误差所预期的结果时，就可以获得qtl存在的证据。我们还对第二个重复集（HAP2/LAP2）进行了类似的分析，从第二代开始。这将使我们能够在选择动物时检查等位基因频率变化的进展。来自HAP和LAP系的异质源可能会导致在其他动物系中无法分离的新qtl的检测和定位，例如来自B6和D2祖系的qtl（例如，BXD RI菌株）。因此，我们还建议使用HAP1与LAP1杂交产生的F2只动物进行有趣的基因组筛选，以寻找新的qtl。我们将首先使用Haley和Knott（1994）开发的新方法对HAP1 X LAP1 F2动物进行连锁分析，该方法专门用于非近交系动物系的连锁分析。此外，我们将使用为人类研究中的标记图谱开发而设计的程序来创建大鼠标记图谱（CRI-MAP; Green, 1990），我们将使用最近开发的方差成分连锁分析方法，该方法可用于数量性状（Almasy & Blangero, 1998）。

The High- and Low-Alcohol Preferring (HAP and LAP) mouse lines have been selectively bred for differences in alcohol preference. These lines are the only extant selectively bred mouse lines developed for alcohol preference. Therefore, they provide a unique opportunity to potentially confirm the QTLs putatively identified in the BXD RI studies or confirmed in the F2 verification studies. These lines will also provide an opportunity to examine syntenic regions in the mouse where QTLs have been provisionally identified in the Alcohol-Preferring and Non- preferring (P and NP) rat lines and the High and Low-Alcohol Drinking (HAD and LAD) rat lines. Because linkage disequilibrium is expected to be restricted to small regions very close to a QTL (approximately 1 to 2 cM) in the selection lines, it will be necessary to use a high density of markers to detect QTLs in regions where they are known to exist from other studies. The purpose of this effort is to obtain confirmatory evidence for the existence of QTLs, and to obtain much higher mapping resolution than is possible in F2 after that of Belknap et al. (1997) Evidence for the presence of QTLs is gained whenever the allele frequencies at a marker diverse significantly more in the two oppositely- selected lines than is expected by genetic drift and allele frequency estimation error. We also propose a similar analysis in the second replicate set, (the HAP2/LAP2) line staring in the 2nd generation. This will allow us to examine the progression of changes in allele frequency as the animals are being selected. The heterogenous stock from which the HAP and LAP lines were derived will likely result in the detection and mapping of novel QTLs not segregating in other animal lines, such as those derived from B6 and D2 progenitors (e.g., the BXD RI strains). Thus, we also propose to do a fun genome screen to search for novel QTLs by using F2 animals generated from a HAP1 X LAP1 cross. We will initially perform linkage analyses for the HAP1 X LAP1 F2 animals using a novel method developed by Haley and Knott (1994), specifically designed for linkage analysis in non-inbred animal lines. In addition, we will use a program designed for marker map development in human studies to create rat marker maps (CRI-MAP; Green, 1990) and we will use a recently developed variance component linkage analysis method which may be used for quantitative traits (Almasy & Blangero, 1998).