A missense mutation in PPARD causes a major QTL effect on ear size in pigs.
A missense mutation in PPARD causes a major QTL effect on ear size in pigs.
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DOI：
10.1371/journal.pgen.1002043
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发表时间：
2011-05
期刊：
影响因子：
4.5
通讯作者：
Huang L
中科院分区：
文献类型：
--
作者：
Ren J;Duan Y;Qiao R;Yao F;Zhang Z;Yang B;Guo Y;Xiao S;Wei R;Ouyang Z;Ding N;Ai H;Huang L
中国二花莲是世界上产量最高的猪品种。这个品种的耳朵特别大，松软。为了确定这一典型特征的基因，我们之前对白杜洛克×二花莲进行了大规模的基因组扫描，并将一个与耳朵大小有关的主要QTL定位在7号染色体上2厘米的区域。我们在此进行了一个相同的血统分析，定义了750-kb区域内的QTL。历史上，二花莲猪的祭祀文化选择了大耳朵特征。通过选择性扫描分析，我们将关键区域细化为包含9个注释基因的630-kb区间。9个基因中有4个在仔猪耳组织中表达。在这4个基因中，PPARD因其在皮肤稳态、软骨发育和脂肪代谢中的作用而被认为是最强的候选基因。PPARD在大耳二花莲和小耳杜洛克猪不同生长阶段的耳组织中表达无差异。我们进一步筛选了PPARD基因的编码序列变异，并在一个保守的功能重要区域发现了一个错义突变（G32E）。该蛋白改变突变与白杜洛克×二花莲杂交的19只创始动物的QTL基因型完全一致（100%），并且只在中国大耳品种中发生。此外，该突变具有功能意义；它介导β-连环蛋白及其靶基因表达的下调，而β-连环蛋白对皮肤脂肪沉积至关重要。此外，该突变与实验杂交和不同近交系群体的穗大小显著相关。一项对单倍型多样性的全球调查显示，突变事件起源于中国，可能是在驯化之后。综上所述，我们提供的证据表明PPARD G32E是这一主要QTL的变异。当前生物学的一个核心但具有挑战性的目标是剖析数量性状的遗传基础。许多数量性状位点（QTL）已经在模型动物和农场动物中被发现，为复杂性状的生物学提供了意想不到的见解。然而，只有少数QTL的因果变异被明确地识别出来。通过一系列的遗传和功能分析，我们在此表明，对猪耳大小的主要QTL效应很可能是由PPARD基因进化保守区域的单碱基替换引起的。这种蛋白质改变的突变具有重要的功能意义，并解释了不同猪种之间耳朵大小变化的比例。一项全球调查显示，耳朵增大的突变等位基因来自中国猪的一个共同祖先，可能是在驯化之后。这些发现首次证实了PPARD在耳朵发育中的重要作用，并强调了农场动物中自然发生的突变对哺乳动物生物学的巨大潜力。此外，对PPARD致病突变的了解增加了家畜数量性状基因和数量性状核苷酸的有限列表。
Chinese Erhualian is the most prolific pig breed in the world. The breed exhibits exceptionally large and floppy ears. To identify genes underlying this typical feature, we previously performed a genome scan in a large scale White Duroc × Erhualian cross and mapped a major QTL for ear size to a 2-cM region on chromosome 7. We herein performed an identical-by-descent analysis that defined the QTL within a 750-kb region. Historically, the large-ear feature has been selected for the ancient sacrificial culture in Erhualian pigs. By using a selective sweep analysis, we then refined the critical region to a 630-kb interval containing 9 annotated genes. Four of the 9 genes are expressed in ear tissues of piglets. Of the 4 genes, PPARD stood out as the strongest candidate gene for its established role in skin homeostasis, cartilage development, and fat metabolism. No differential expression of PPARD was found in ear tissues at different growth stages between large-eared Erhualian and small-eared Duroc pigs. We further screened coding sequence variants in the PPARD gene and identified only one missense mutation (G32E) in a conserved functionally important domain. The protein-altering mutation showed perfect concordance (100%) with the QTL genotypes of all 19 founder animals segregating in the White Duroc × Erhualian cross and occurred at high frequencies exclusively in Chinese large-eared breeds. Moreover, the mutation is of functional significance; it mediates down-regulation of β-catenin and its target gene expression that is crucial for fat deposition in skin. Furthermore, the mutation was significantly associated with ear size across the experimental cross and diverse outbred populations. A worldwide survey of haplotype diversity revealed that the mutation event is of Chinese origin, likely after domestication. Taken together, we provide evidence that PPARD G32E is the variation underlying this major QTL. A central but challenging objective in current biology is to dissect the genetic basis of quantitative traits. Numerous quantitative trait loci (QTL) have been uncovered in model and farm animals, providing unexpected insights into the biology of complex traits. However, only a few causal variants underlying the QTL have been explicitly identified. By using a battery of genetic and functional assays, we herein show that a major QTL effect on pig ear size is most likely caused by a single base substitution in an evolutionary conserved region of the PPARD gene. The protein-altered mutation is of functional significance and explains a proportion of variation in ear size across diverse pig breeds. A worldwide survey showed that the mutant allele for increased ear size was derived from a common ancestor in Chinese pigs, likely after domestication. These findings establish, for the first time, an essential role of PPARD in ear development and highlight the great potential of naturally occurring mutations in farm animals to gain insights into mammalian biology. Moreover, the knowledge of the PPARD causal mutation adds to the limited list of quantitative trait genes and quantitative trait nucleotides characterized in domesticated animals.
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影响因子：
64.8
作者：
Rubin, Carl-Johan;Zody, Michael C.;Andersson, Leif
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0308518100
发表时间：
2004-02-24
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
56.9
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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