QTL MAPPING FOR ALCOHOL PREFERENCE IN SELECTED MICE

高酒精偏好和低酒精偏好(HAP和LAP)小鼠品系是根据酒精偏好的不同而选择性培育的。这些品系是现存的唯一为酒精偏好而培育的选择性繁殖的小鼠品系。因此，它们提供了一个独特的机会来潜在地确认BXD RI研究中假定确定的QTL或F2验证研究中确认的QTL。这些品系还将提供一个机会来检查小鼠的共线区域，其中QTL已经在偏爱酒精和不偏爱酒精的(P和NP)大鼠品系以及高和低饮酒(HAD和LAD)大鼠品系中暂时被发现。由于连锁不平衡预计将局限于与选择系中的QTL非常接近的小区域(约1-2 cM)，因此有必要使用高密度的标记来检测从其他研究中已知存在的QTL。这项工作的目的是获得QTL存在的确凿证据，并获得比Belnuap等人在F2中可能获得的更高的作图分辨率。(1997)在两个相反选择的品系中，只要标记上的等位基因频率的差异比遗传漂移和等位基因频率估计误差预期的大得多，就可以获得QTL存在的证据。我们也提出了类似的分析在第二个重复集，(HAP2/LAP2)线起始于第二代。这将使我们能够检查在动物被选择时等位基因频率变化的进展。衍生HAP和LAP系的异源群体可能导致检测和定位新的QTL，这些QTL在其他动物系中没有分离，例如来自B6和D2祖代的那些(例如，BXD RI品系)。因此，我们还建议做一个有趣的基因组筛选，通过使用HAP1X LAP1杂交产生的F2动物来寻找新的QTL。我们将首先使用Haley和Knott(1994)开发的一种新方法对HAP1 X LAP1 F2动物进行连锁分析，该方法专门为非近交动物品系的连锁分析而设计。此外，我们将使用为人类研究中的标记图开发而设计的程序来创建大鼠标记图(CRI-MAP；Green，1990)，我们将使用最近开发的可用于数量性状的方差分量连锁分析方法(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).