Endogenous retrovirus insertion in the KIT oncogene determines white and white spotting in domestic cats.
Endogenous retrovirus insertion in the KIT oncogene determines white and white spotting in domestic cats.
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DOI：
10.1534/g3.114.013425
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发表时间：
2014-08-01
期刊：
影响因子：
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通讯作者：
Ryugo DK
中科院分区：
文献类型：
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作者：
David VA;Menotti-Raymond M;Wallace AC;Roelke M;Kehler J;Leighty R;Eizirik E;Hannah SS;Nelson G;Schäffer AA;Connelly CJ;O'Brien SJ;Ryugo DK
家猫的显性白色基因座（W）具有多效性，在无被毛时表现为完全显性，在耳聋和虹膜色素减退时表现为不完全显性。我们进行了连锁分析，使用谱系分离白色，以确定KIT（染色体B1）的猫W位点。分离和序列分析的KIT基因在两个家系（P1和P2）显示显着的逆转录转座和进化的猫内源性逆转录病毒（FERV 1）负责两个不同的表型的W位点，显性白色，和白色斑点。全长（7125 bp）的FERV 1元件与白色斑点相关，而FERV 1长末端重复序列（LTR）与所有显性白色个体相关。出于统计分析的目的，野生型序列、FERV 1元件和仅LTR的替代物定义了三等位基因标记。考虑到家系关系，耳聋是遗传连锁和相关的标记，估计P值的关联范围为0.007至0.10。逆转录转座中断了KIT内含子1中的DNA酶I超敏位点，该位点在哺乳动物中高度保守，并且先前被证明可调节小鼠造血细胞和黑素细胞中KIT的时间和组织特异性表达。一项对30个猫品种（n = 270）的大规模群体遗传调查支持了我们的发现，并证明了FERV 1 LTR和全长元件分别具有显性白色/蓝色虹膜（P < 0.0001）和白色斑点（P < 0.0001）的统计学显著性。
The Dominant White locus (W) in the domestic cat demonstrates pleiotropic effects exhibiting complete penetrance for absence of coat pigmentation and incomplete penetrance for deafness and iris hypopigmentation. We performed linkage analysis using a pedigree segregating White to identify KIT (Chr. B1) as the feline W locus. Segregation and sequence analysis of the KIT gene in two pedigrees (P1 and P2) revealed the remarkable retrotransposition and evolution of a feline endogenous retrovirus (FERV1) as responsible for two distinct phenotypes of the W locus, Dominant White, and white spotting. A full-length (7125 bp) FERV1 element is associated with white spotting, whereas a FERV1 long terminal repeat (LTR) is associated with all Dominant White individuals. For purposes of statistical analysis, the alternatives of wild-type sequence, FERV1 element, and LTR-only define a triallelic marker. Taking into account pedigree relationships, deafness is genetically linked and associated with this marker; estimated P values for association are in the range of 0.007 to 0.10. The retrotransposition interrupts a DNAase I hypersensitive site in KIT intron 1 that is highly conserved across mammals and was previously demonstrated to regulate temporal and tissue-specific expression of KIT in murine hematopoietic and melanocytic cells. A large-population genetic survey of cats (n = 270), representing 30 cat breeds, supports our findings and demonstrates statistical significance of the FERV1 LTR and full-length element with Dominant White/blue iris (P < 0.0001) and white spotting (P < 0.0001), respectively.