A Comprehensive Genetic Analysis of Candidate Genes Regulating Response to Trypanosoma congolense Infection in Mice
A Comprehensive Genetic Analysis of Candidate Genes Regulating Response to Trypanosoma congolense Infection in Mice
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DOI：
10.1371/journal.pntd.0000880
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发表时间：
2010-11-01
影响因子：
3.8
通讯作者：
Noyes, Harry A.
中科院分区：
文献类型：
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作者：
Goodhead, Ian;Archibald, Alan;Noyes, Harry A.
背景：非洲锥虫是一种原生动物寄生虫，可引起人类的“昏睡病”和家畜的类似疾病。锥虫也感染实验室小鼠和三个主要的数量性状基因座（QTL），调节生存时间后感染T。在易感的A/J和BALB/c小鼠与抗性的C57 BL/6之间的两个独立杂交中鉴定了刚果金单抗。这些被指定为Tir 1，Tir 2和Tir 3的锥虫感染反应，和范围的大小从0.9-12 cM。在另一个交叉中的刚果金单胞菌感染揭示了易感的C3 H/HeJ小鼠在Tir 1和Tir 3 QTL处具有减少感染后存活时间的等位基因，但在Tir 2处没有。下一代小鼠17号染色体6.2 Mbp区域（包括Tir 1）的重测序确定了1，632个常见的单核苷酸多态性（SNP），包括Pram 1（PML-RAR α调节衔接分子1）中可能具有破坏性的非同义SNP，这是Tir 1中最合理的候选QTL基因。全基因组比较基因组杂交鉴定了12个与差异基因表达相关的拷贝数变异（CNV）位点，包括Cd 244（自然杀伤细胞受体2B 4），其位于Tir 3c的峰值附近，并且具有与CNV和表型相关的基因表达，使其成为该位点的强候选QTL基因。通过系统地结合下一代DNA捕获和测序，基于阵列的比较基因组杂交（aCGH），基因表达数据和SNP注释，我们已经开发出一种策略，可以生成候选QTL基因中的多态性的短列表，可以进行功能测试。
Background: African trypanosomes are protozoan parasites that cause "sleeping sickness" in humans and a similar disease in livestock. Trypanosomes also infect laboratory mice and three major quantitative trait loci (QTL) that regulate survival time after infection with T. congolense have been identified in two independent crosses between susceptible A/J and BALB/c mice, and the resistant C57BL/6. These were designated Tir1, Tir2 and Tir3 for Trypanosoma infection response, and range in size from 0.9-12 cM.Principal Findings: Mapping loci regulating survival time after T. congolense infection in an additional cross revealed that susceptible C3H/HeJ mice have alleles that reduce survival time after infection at Tir1 and Tir3 QTL, but not at Tir2. Next-generation resequencing of a 6.2 Mbp region of mouse chromosome 17, which includes Tir1, identified 1,632 common single nucleotide polymorphisms (SNP) including a probably damaging non-synonymous SNP in Pram1 (PML-RAR alpha-regulated adaptor molecule 1), which was the most plausible candidate QTL gene in Tir1. Genome-wide comparative genomic hybridisation identified 12 loci with copy number variants (CNV) that correlate with differential gene expression, including Cd244 (natural killer cell receptor 2B4), which lies close to the peak of Tir3c and has gene expression that correlates with CNV and phenotype, making it a strong candidate QTL gene at this locus.Conclusions: By systematically combining next-generation DNA capture and sequencing, array-based comparative genomic hybridisation (aCGH), gene expression data and SNP annotation we have developed a strategy that can generate a short list of polymorphisms in candidate QTL genes that can be functionally tested.