QTL mapping in a mouse model of cardiomyopathy reveals an ancestral modifier allele affecting heart function and survival
QTL mapping in a mouse model of cardiomyopathy reveals an ancestral modifier allele affecting heart function and survival
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DOI：
10.1007/s00335-005-2468-7
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发表时间：
2005-06-01
期刊：
影响因子：
2.5
通讯作者：
Marchuk, DA
中科院分区：
文献类型：
--
作者：
Wheeler, FC;Fernandez, L;Marchuk, DA
从心肌肥厚到心力衰竭的进展是一个复杂的过程，涉及遗传和环境因素。阐明导致心力衰竭的遗传成分一直很困难，主要是因为人群的异质性。我们已经采用了一种策略，在转基因小鼠心肌病模型的心脏特异性过度表达的钙螯合蛋白，修改心力衰竭表型的遗传位点。当转基因转移到不同的近交系小鼠品系中时，观察到心脏功能和存活率的品系特异性差异。我们以前曾报道过C57/BL 6（BL 6）和DBA/2 J（DBA）之间的相互回交以及DBA/AKR和AKR之间的回交的连锁结果。本文报道了DBA/AKR和DBA之间的相互回交的全基因组连锁扫描结果。我们在18号染色体上发现了一个影响心脏功能的新位点，在3号染色体上发现了一个与生存和心脏功能有显著联系的新位点。有趣的是，AKR的Chr 3等位基因表现出对表型的易感性效应，而AKR遗传背景的总体效应是保护性的。Chr 3基因座也完全重叠的Hrtfm 2基因座，这是以前在DBA和BL 6之间的杂交映射。在两个不同的杂交中定位相同的QTL使我们能够使用祖先单倍型将候选基因的间隔从9 Mb缩小到2 Mb。在小鼠中鉴定这些QTL的基因将提供新的候选基因，可以评估它们在人类心力衰竭中的作用。
The progression from myocardial hypertrophy to heart failure is a complex process, involving genetic and environmental factors. Elucidating the genetic components contributing to heart failure has been difficult, largely because of the heterogeneity of human populations. We have employed a strategy to map genetic loci that modify the heart failure phenotype in a transgenic mouse model of cardiomyopathy caused by cardiac-specific overexpression of calsequestrin. Strain-specific differences in both cardiac function and survival are observed when the transgene is moved into different inbred mouse strains. We have previously reported linkage results from mapping in reciprocal backcrosses between C57/BL6 (BL6) and DBA/2J (DBA) and a backcross between DBA/AKR and AKR. Here we report the results of a genome-wide linkage scan in the reciprocal backcross between DBA/AKR and DBA. We identified one novel locus on Chromosome (Chr) 18 that affects heart function and a second on Chr 3 that shows significant linkage to both survival and heart function. Intriguingly, the Chr 3 allele of AKR shows a susceptibility effect on phenotype, whereas the overall effect of the AKR genetic background is protective. The Chr 3 locus also completely overlaps the Hrtfm2 locus, which was previously mapped in crosses between DBA and BL6. Mapping the same QTL in two different crosses allowed us to use ancestral haplotypes to narrow the candidate gene interval from 9 to 2 Mb. Identification of the genes at these QTLs in the mouse will provide novel candidate genes that can be evaluated for their role in human heart failure.