The Institute for Molecular Bioscience

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The Institute for Molecular Bioscience
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The Institute for Molecular Bioscience
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Challenges in bioinformatics and computational
biology

• Representation of biology in silico

• Genomes as information systems

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Molecular genetic networks and the architecture
of biological complexity
__________ The evolution of controlled
multitasked molecular networks a role for
introns and other noncoding RNAs
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The complexity problem

• Gene numbers do not increase as much as expected
  with complexity
• - worm and fly gene numbers (12-14,000) are
  only about twice those of yeast (6,000) and P.
  aeruginosa (5,500)
• - mammalian (human, mouse) gene numbers
  (30,000) are only about twice those of
  invertebrates.

• Phenotypic variation in mammals is primarily
  associated with noncoding regions
• - only 10,000 out of 3,000,000 polymorphisms
  between individual humans (0.3) occur in
  protein coding sequences
• - only 1 of genes are different between humans
  and mice.

• This suggests that
• - animals have a relatively stable core
  proteome, whose components are multitasked in
  differentiation and development
• - variations in phenotype occurs mainly by
  variation in the control architecture (unlike
  prokaryotes)

• 98 of transcriptional output in humans is
  noncoding RNA

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Eukaryotic gene structure
Mosaic "gene" (protein coding sequence)
Transcription
pre-mRNA
Splicing
Nucleus
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mRNA (alt)
Cytoplasm
Translation
protein (alt)
Possibility 1 intronic RNA is non-functional
Possibility 2 intronic RNA is functional
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Hypothesis

• Introns and other eRNAs are involved in gene-gene
  communication and networking in real time in
  eukaryotic cells

• This RNA network forms a parallel processing
  system / neural net / cellular memory of recent
  transcriptional events

• This system evolved ad hoc from a mosaic gene
  structure (derived from the invasion of
  eukaryotes by group II introns and the subsequent
  evolution of the spliceosome) and radically
  increased the power of the genetic operating
  system in eukaryotes, compared to that in
  prokaryotes

• This in turn allowed the development of much more
  sophisticated multitasked genetic programming and
  the integration and regulation of much larger
  genomic datasets, which underlie multicellular
  and neural development in the higher organisms,
  including (esp.) humans

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SINGLE OUTPUT
MULTIPLEX OUTPUT
SIMPLE OPERATING SYSTEM
PARALLEL PROCESSING
Prokaryotic gene
Eukaryotic gene
networking
mRNA
mRNA eRNA
functions
protein
protein
catalytic function
catalytic function
structural role
structural role
regulation
regulation
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• Introns comprise, on average, 90-95 of the
  primary sequence of protein coding transcripts in
  mammals

• hnRNA is 30 times more complex (unique sequence)
  than mRNA - perhaps up to two-thirds of all
  transcripts in the mammalian nucleus do not code
  for any protein at all and only 2-3 of RNA
  sequences are protein coding

• The frequency and size of introns and noncoding
  RNAs correlates with developmental complexity

• Noncoding RNAs have all of the signatures of
  information
• - largely comprised of unique sequence of high
  complexity
• - non-random nucleotide composition

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• Some introns / noncoding RNAs are highly
  conserved, e.g.
• - Drosophila adh gene intron 1, tra gene intron
  2, let-7
• - Mouse/human T-cell receptor gene
• - Human / Xenopus g-actin intron 3 - but
  most not sequenced.

• Excised introns and other noncoding RNAs appear
  to be relatively stable (not degraded rapidly as
  is usually thought)

• Evidence for RNA-mediated gene regulation
• - lin4/lin14 and let7/lin41 in C. elegans
• - small nucleolar RNAs
• - H19, XIST, roX1/roX2
• - Drosophila bithorax - abdominal A/B locus of
  Drosophila - 200kb, 7 major transcripts - only
  3 code for protein, all 7 are developmentally
  regulated and all have genetic signatures

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• Unexplained genetic and molecular genetic
  phenomena involving RNA
• - co-suppression
• - transgene silencing
• - position effect variegation
• - imprinting
• - methylation
• - RNAi
• - transvection (role of polycomb/zeste)

• Other observations
• - antisense transcripts, intergenic
  transcripts
• - zinc-finger transcription factors have high
  affinity for RNA
• - chromodomains are RNA-binding modules

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SINGLE OUTPUT
MULTIPLEX OUTPUT
SIMPLE OPERATING SYSTEM
PARALLEL PROCESSING
Prokaryotic gene
Eukaryotic gene
networking
mRNA
mRNA eRNA
functions
protein
protein
catalytic function
catalytic function
structural role
structural role
regulation
regulation
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Molecular Biology and Evolution 18 1611-1630
(2001)