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对乙醇镇静/催眠敏感性进行定量性状基因座的遗传剖析:利用区间特异性同源重组系进行定位

Genetic dissection of quantitative trait loci specifying sedative/hypnotic sensitivity to ethanol: mapping with interval-specific congenic recombinant lines.

作者信息

Bennett Beth, Beeson Mary, Gordon Lena, Carosone-Link Phyllis, Johnson Thomas E

机构信息

Institute for Behavioral Genetics, University of Colorado, Boulder 80309-0447, USA.

出版信息

Alcohol Clin Exp Res. 2002 Nov;26(11):1615-24. doi: 10.1097/01.ALC.0000037136.49550.B3.

Abstract

BACKGROUND

Linkage studies alone do not produce sufficient resolution to narrow the location of a quantitative trait locus (QTL) to a small-enough chromosomal region for gene identification. One solution to this problem is to use interval-specific congenic recombinant (ISCR) lines to narrow the chromosomal interval known to contain the QTL. In previous work, we mapped four QTLs for differential ethanol sensitivity in the inbred long-sleep (ILS) and inbred short-sleep (ISS) strains and generated reciprocal congenic strains in which each full QTL interval from ILS was bred onto the ISS background and vice versa.

METHODS

ISCR lines were derived by identifying mice carrying recombination events in the congenic interval during backcrossing of the ISS.ILS.Lore congenics to ISS. Recombinant mice were backcrossed to ISS, and progeny carrying the ISCR chromosome were identified and tested to determine whether the ISCR region carried the donor Lore QTL.

RESULTS

We developed multiple ISCR lines for each Lore QTL, in which the QTL interval was broken into a number of smaller intervals. For all four QTLs, we reduced the size of the interval, in one case to 3.7 cM.

CONCLUSIONS

Use of ISCR lines can narrow each Lore candidate region to a few centimorgans. Such an interval size is conducive to brute-force approaches to identify candidate genes, entailing bioinformatics, gene expression, and DNA sequencing strategies.

摘要

背景

仅靠连锁研究无法产生足够的分辨率,将数量性状基因座(QTL)的位置缩小到足够小的染色体区域以进行基因鉴定。解决这个问题的一种方法是使用区间特异性同源重组(ISCR)品系来缩小已知包含QTL的染色体区间。在之前的工作中,我们在近交长睡眠(ILS)和近交短睡眠(ISS)品系中定位了四个影响乙醇敏感性差异的QTL,并构建了相互同源品系,即将来自ILS的每个完整QTL区间导入ISS背景中,反之亦然。

方法

通过在ISS.ILS.Lore同源品系与ISS回交过程中,鉴定在同源区间携带重组事件的小鼠来获得ISCR品系。将重组小鼠与ISS回交,鉴定并测试携带ISCR染色体的后代,以确定ISCR区域是否携带供体Lore QTL。

结果

我们为每个Lore QTL开发了多个ISCR品系,其中QTL区间被分解为多个较小的区间。对于所有四个QTL,我们都缩小了区间大小,在一个案例中缩小到了3.7厘摩。

结论

使用ISCR品系可以将每个Lore候选区域缩小到几厘摩。这样的区间大小有利于采用强力方法来鉴定候选基因,包括生物信息学、基因表达和DNA测序策略。

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