The four Rs of RNA-directed evolution.

The way we quantify the human genome has changed markedly. The estimated percentage of the genome derived from retrotransposition has increased (now 45%; refs. 1,2), as have the estimates for alternative splicing (now 41-60% of multiexon genes), antisense transcription (now 10-20% of genes) and non-protein coding RNA (now approximately 7% of full-length cDNAs). Concomitantly, the estimated number of protein-coding genes (now approximately 24,500) has decreased. These numbers support an RNA-centric view of evolution in which phenotypic diversity arises through extensive RNA processing and widespread RNA-directed rewriting of DNA enables dissemination of 'selfish' RNAs associated with successful outcomes. The numbers also indicate important roles for sense-antisense transcription units (SATs) and coregulatory RNAs (coRNAs) in directing the read-out of genetic information, in reconciling different regulatory inputs and in transmitting epigenetic information to progeny. Together, the actions of reading, 'riting, 'rithmetic and replication constitute the four Rs of RNA-directed evolution.