Quantitative trait locus mapping for acute functional tolerance to ethanol in the L x S recombinant inbred panel
Quantitative trait locus mapping for acute functional tolerance to ethanol in the L x S recombinant inbred panel
复制标题
DOI：
10.1111/j.1530-0277.2006.00296.x
复制
发表时间：
2007-02-01
影响因子：
3.2
通讯作者：
Johnson, Thomas E.
中科院分区：
文献类型：
--
作者：
Bennett, Beth;Downing, Chris;Johnson, Thomas E.
背景：急性功能耐受性（Acute functional tolerance， AFT）是在给药后不久发生的，通过在2个行为或生理终点测量脑或血乙醇浓度（BEC）的变化来确定。一些啮齿动物的急性功能耐受性研究支持了一个长期存在的假设，即更敏感的菌株产生更多的期内耐受性。我们使用了新的74株L × S重组自交系（RI）小组，由自交系长睡眠（ILS）和自交系短睡眠（ISS）菌株开发，重新审视了这一假设，并绘制了AFT的数量性状位点（QTL）。我们报告了AFT早期研究报告的QTL区域的复制，并初步应用了粗单核苷酸多态性图谱分析，以限制后续候选基因假设的QTL间隔。方法：采用静止木销子失平衡和恢复平衡试验，测定急性功能耐受性。初始剂量为1.75 g/kg后，测定初始损失（BEC0）和恢复平衡（BEC1）时的BEC。第二次注射（2.0 g/kg），第二次恢复平衡（BEC2）时采血。急性功能耐受性通过两种方式计算为差异评分：(1)连续两次恢复平衡时的BEC (AFT(1))，或(2)最终恢复平衡和最初失去平衡时BEC的差异（AFT(2)）。我们绘制了BEC0的qtl图谱，BEC0是衡量初始灵敏度的指标，AFT评分也是如此。结果：所有4个亲本菌株（LS、SS、ILS和ISS）均产生耐受性，与先前报道的结果一致。其中3个菌株存在显著的性别效应。L x S组显示出128倍的耐受性范围，少数菌株表现出负耐受性（致敏）。ISS超过第二高的RI菌株55%，是SS的4倍多。两种AFT测量的遗传力估计在两性中都接近0.25。在12号染色体（AFT(1)）和16号染色体（AFT(2)）上分别鉴定出1个显著性QTL（占表型变异的18%）和1个暗示性QTL （16% V-P）。这些qtl复制了其他研究中报道的区域。建立了一个包含所有重要相互作用QTL效应的多QTL模型，解释了近60%的V-P。对12号染色体区域进行了进一步的单倍型分析，在置信区间内发现了许多非多态性区域，并在多态性区域中发现了可能的候选基因。结论：两种方法评估，SS和ISS均比LS和ILS发生更大的AFT；通过菌株比较，这种差异在几乎所有性别中都是显著的。在L x S RI中，在初始失去平衡时用BEC测量的初始灵敏度与固定销钉上的AFT测量值之间没有相关性。这些结果表明，在该模型系统中，初始灵敏度不能预测公差。鉴定了几个耐受性qtl；在12号染色体狭窄区域的候选基因，已经在另外两项作图研究中报道，值得进一步研究。
Background: Acute functional tolerance (AFT) develops shortly after ethanol administration, and is determined as the change in brain or blood ethanol concentration (BEC) measured at 2 behavioral or physiological endpoints. Acute functional tolerance studies in some rodent strains support a long-held hypothesis that more sensitive strains develop more within-session tolerance. We used the new, 74-strain L x S recombinant inbred (RI) panel, developed from inbred long-sleep (ILS) and inbred short-sleep (ISS) strains, to revisit this hypothesis and to map quantitative trait loci (QTLs) for AFT. We report replication of QTL regions reported by earlier studies of AFT and preliminary application of a coarse single nucleotide polymorphism map analysis to limit QTL intervals for subsequent candidate gene hypotheses.Methods: Acute functional tolerance was assayed using a test of ataxia: loss and regain of balance on a stationary wooden dowel. Following an initial dose of 1.75 g/kg, BEC was measured at initial loss (BEC0) and regain of balance (BEC1). A second injection (2.0 g/kg) was administered and blood taken at the second regain of balance (BEC2). Acute functional tolerance was calculated as a difference score in 2 ways: (1) between BEC at the 2 successive regains of balance (AFT(1)), or (2) as the difference in BEC at final regain and at initial loss of balance (AFT(2)). We mapped QTLs for BEC0, a measure of initial sensitivity, and both AFT scores.Results: All 4 parental strains (LS, SS, ILS, and ISS) developed tolerance, replicating previous published reports. There were significant sex effects for 3 of these strains. The L x S panel showed a 128-fold range in tolerance, with a few strains showing negative tolerance (sensitization). The ISS surpassed the next highest RI strain by 55% and was more than 4 times greater than SS. Heritability estimates for both AFT measures were close to 0.25 for both sexes. One significant QTL accounting for similar to 18% of phenotypic variance (V-P), on chromosome 12 (AFT(1)), and 1 suggestive QTL (16% V-P), on chromosome 16 (AFT(2)), were identified. These QTLs replicated regions reported in other studies. A multiple QTL model incorporating the effects of all significant interacting QTLs was developed, explaining almost 60% of V-P. The chromosome 12 region was further investigated by haplotype analysis, which identified many nonpolymorphic regions within the confidence interval, and possible candidate genes in the polymorphic regions.Conclusions: Both SS and ISS developed greater AFT, assessed by both methods, than LS and ILS; this difference was significant in virtually all sex by strain comparisons. In the L x S RI, there was no correlation between initial sensitivity, measured by BEC at initial loss of balance, and either measure of AFT, on a stationary dowel. These results indicate that in this model system, initial sensitivity does not predict tolerance. Several QTLs for tolerance were identified; candidates in the narrowed chromosome 12 region, which has been reported in 2 other mapping studies, merit additional study.