Ultraconserved cDNA segments in the human transcriptome exhibit resistance to folding and implicate function in translation and alternative splicing.
Ultraconservation, defined as perfect human-to-rodent sequence identity at least 200-bp long, is a strong indicator of evolutionary and functional importance and has been explored extensively at the genome level. However, it has not been investigated at the transcript level, where such extreme conservation might highlight loci with important post-transcriptional regulatory roles. We present 96 ultraconserved cDNA segments (UCSs), stretches of human mature mRNAs that match identically with orthologous regions in the mouse and rat genomes. UCSs can span multiple exons, a feature we leverage here to elucidate the role of ultraconservation in post-transcriptional regulation. UCS sites are implicated in functions at essentially every post-transcriptional stage: pre-mRNA splicing and degradation through alternative splicing and nonsense-mediated decay (AS-NMD), mature mRNA silencing by miRNA, fast mRNA decay rate and translational repression by upstream AUGs. We also found UCSs to exhibit resistance to formation of RNA secondary structure. These multiple layers of regulation underscore the importance of the UCS-containing genes as key global RNA processing regulators, including members of the serine/arginine-rich protein and heterogeneous nuclear ribonucleoprotein (hnRNP) families of essential splicing regulators. The discovery of UCSs shed new light on the multifaceted, fine-tuned and tight post-transcriptional regulation of gene families as conserved through the majority of the mammalian lineage.
Department of Medical Genome Sciences, Graduate School of Frontier Sciences, the University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan. fsathira@fas.harvard.edu
J Fah
JF
Sathirapongsasuti
Nuankanya
N
Sathira
Yutaka
Y
Suzuki
Curtis
C
Huttenhower
Sumio
S
Sugano
D020121:5' Untranslated Regions; D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D018387:Codon, Initiator; D018389:Codon, Nonsense; D017124:Conserved Sequence; D018076:DNA, Complementary / Q000737:chemistry*; D004194:Disease / Q000235:genetics; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D009690:Nucleic Acid Conformation; D014176:Protein Biosynthesis; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry*; D016601:RNA-Binding Proteins / Q000235:genetics; D051381:Rats; D038621:Regulatory Sequences, Ribonucleic Acid; D000068103:Serine-Arginine Splicing Factors
D020121:5' Untranslated Regions; D018387:Codon, Initiator; D018389:Codon, Nonsense; D018076:DNA, Complementary; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D038621:Regulatory Sequences, Ribonucleic Acid; D000068103:Serine-Arginine Splicing Factors