Central Dogma, Selfish DNA and Noncoding RNAs: a Historical Perspective

Abstract

Major discoveries like the one gene-one enzyme hypothesis, demonstration of DNA as the genetic material and finally the elucidation of the double helical structure of DNA in 1940s and early 1950s set the stage for emergence of molecular biology. Parallel cell biological studies during this period also indicated a correlation between rate of protein synthesis in a cell and the amount of cytoplasmic RNA. Following the proposal of George Gamow, a physicist, about the tirplet genetic code and possible involvement of RNA in the transfer of information from DNA to proteins, Crick proposed the 'central dogma of molecular biology' to suggest the paths of information transfer between nucleic acids and proteins, with the limitation that the information cannot flow back from protein to nucleic acids.  With emphasis on proteins as the central phenotypic determinants and the continuing enigma of heterochromatin, which largely appeared to be ‘gene desert’, enriched in repetitive DNA sequences and claimed to be inert in transcription, the many observations in 1960s of a large variety of heterogeneous nuclear RNAs remained ignored. Curiosity in the nuclear RNAs that do not see the face of cytoplasm appeared to be quelled by concepts of ‘selfish’ or ‘junk’ DNA in the early 1980s, notwithstanding the fact that active transcription of typical heterochromatin regions and repetitive amd  other noncoding DNA sequences was well demonstrated in 1960s and 1970s. With a few exceptions like the hsrω and roX transcripts in Drosophila and the Xist RNAs in mammals, the noncoding RNAs remained largely ignored for nearly two decades. The discovery of RNA interference and sequencing of different eukaryotic genomes, including the human, led to revisits to possible significance of noncoding RNAs (ncRNAs) in the new millennium. The occasional identification of ncRNAs in early 2000s has in recent years transformed into a ‘tsunami’, resulting in concepts of ‘selfish’ or ‘junk’ DNA themselves becoming junk. There is now increasing realization that the subtle and large phenotypic effects of heterochromatin and the existence of diver nucleus-limited RNAs reported during the ‘pre-molecular biology’ period through painstaking genetic and biochemical studies can be largely related to the enormous diversity of short and long ncRNAs that all genomes, especially in eukaryotes, produce. Although Crick’s proposal of the Central Dogma was only about the directions of information transfer, its mis-interpretation due to the great emphasis on the central roles of proteins and the reductionist linear approach of molecular biology that led to widespread belief in concepts of 'selfish' or 'junk' DNA, delayed the appreciation of multi-dimensional roles that ncRNAs actually play in maintaining homeostasis in complex biological networks.