microRNA上の点変異で進行性難聴

An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice. Lewis MA et al. Nature Genetics. Epub online: 12 April 2009.

We report a new N-ethyl-N-nitrosurea (ENU)-induced mouse mutant, diminuendo, with a single base change in the seed region of Mirn96. Heterozygotes show progressive loss of hearing and hair cell anomalies, whereas homozygotes have no cochlear responses. Most microRNAs are believed to downregulate target genes by binding to specific sites on their mRNAs, so mutation of the seed should lead to target gene upregulation. Microarray analysis revealed 96 transcripts with significantly altered expression in homozygotes; notably, Slc26a5, Ocm, Gfi1, Ptprq and Pitpnm1 were downregulated. Hypergeometric P-value analysis showed that hundreds of genes were upregulated in mutants. Different genes, with target sites complementary to the mutant seed, were downregulated.

これはすごい。ENUで起こる点変異は全くランダムだから、たまたまmicroRNA（Mirn96）上で変異が起 こったが故にmicroRNA→進行性難聴の機構が判明したわけです。偶然って恐ろしい。
microRNAは遺伝子の発現を抑えると考えられているのですが、この変異体ではMirn96と相補配列を持 つ遺伝子の発現量が下がっていることが確認されました。さらに発現量が上がってる遺伝子も数百あ ったそうで、１つのmiRNAが複雑な転写制御ネットワークに及ぼす影響の大きさが判明したことになり ます。ゲノムって本当に面白い。