Perhaps
the most striking feature of the higher organisms
is the massive amount of transcription of non-protein-coding
RNAs, which comprise about 98% of all genomic output
in mammals. At least half of the mammalian genome
is transcribed and at least half of mammalian genes
do not encode proteins, rather astounding facts
that are generally unappreciated. Where they have
been studied these RNAs have been found to be developmentally
regulated and to have function. Many of these RNAs
are processed to form smaller trans-acting species,
termed microRNAs. In addition, complex genetic phenomena
such as RNA interference, co-suppression, transgene
silencing, imprinting, and DNA methylation all involve
intersecting pathways based on or connected to RNA
signaling. Taken together the evidence suggests
that intronic and other noncoding RNAs comprise
a second tier of gene expression in the higher eukaryotes
which enables the integration of complex suites
of gene activity. Thus, while proteins are the fundamental
components and effectors of cellular structure and
function, the programming of eukaryotic complexity
and phenotypic variation may be primarily embedded
in an endogenous network of trans-acting RNAs that
relay state information required for the coordination
and modulation of gene expression via RNA-DNA, RNA-RNA
and RNA-protein interactions, acting to control
chromatin architecture and epigenetic memory, transcription,
alternative splicing, RNA turnover, translation
and other cellular processes. This regulatory network
has similarities to those underpinning advanced
information processing in other domains such as
computers and the brain (termed "the hidden
layer" in neural networks), and may have been
the essential prerequisite for the appearance of
developmentally complex multicellular organisms.
The hypothesis makes many predictions amenable to
bioinformatic and experimental testing, and provides
a platform for computational modeling of the regulatory
architecture underpinning the evolution and ontogeny
of higher eukaryotes.
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