Critical Evaluation of Imprinted Gene Expression by RNA-Seq: A New Perspective

被引:165
作者
DeVeale, Brian [1 ,2 ]
van der Kooy, Derek [1 ,2 ]
Babak, Tomas [3 ]
机构
[1] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada
[2] Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Toronto, ON, Canada
[3] Stanford Univ, Dept Biol, Stanford, CA 94305 USA
来源
PLOS GENETICS | 2012年 / 8卷 / 03期
关键词
ALLELE-SPECIFIC EXPRESSION; MOUSE-BRAIN; DIFFERENTIAL EXPRESSION; WIDE IDENTIFICATION; AMPLIFICATION-FREE; GENOME; ANNOTATION; RESOLUTION; IMBALANCE; PROTEIN;
D O I
10.1371/journal.pgen.1002600
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
In contrast to existing estimates of approximately 200 murine imprinted genes, recent work based on transcriptome sequencing uncovered parent-of-origin allelic effects at more than 1,300 loci in the developing brain and two adult brain regions, including hundreds present in only males or females. Our independent replication of the embryonic brain stage, where the majority of novel imprinted genes were discovered and the majority of previously known imprinted genes confirmed, resulted in only 12.9% concordance among the novel imprinted loci. Further analysis and pyrosequencing-based validation revealed that the vast majority of the novel reported imprinted loci are false-positives explained by technical and biological variation of the experimental approach. We show that allele-specific expression (ASE) measured with RNA-Seq is not accurately modeled with statistical methods that assume random independent sampling and that systematic error must be accounted for to enable accurate identification of imprinted expression. Application of a robust approach that accounts for these effects revealed 50 candidate genes where allelic bias was predicted to be parent-of-origin-dependent. However, 11 independent validation attempts through a range of allelic expression biases confirmed only 6 of these novel cases. The results emphasize the importance of independent validation and suggest that the number of imprinted genes is much closer to the initial estimates.
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页数:12
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