Genomes as Complex Systems

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Genomes as Complex Systems

• Richard v. Sternberg

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The Atomistic or Bean-bag View of the Genome

• Most of us are familiar with this model of the
  genome

Genetic Program

Protein 3
Protein 1
Protein 2

Gene 3
Gene 2
Gene 1
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The Atomistic View of the Genome

• This classical model of the genome emerged as a
  synthesis of four things
• Mendelian laws of inheritance
• Chromosomal theory of inheritance
• The distinction between germline and soma
  (genotype-phenotype difference)
• Population genetics

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The Atomistic View of the Genome

• This view of the genome ensured the primacy of
  natural selection as the mechanism of
  evolutionary change.

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The Atomistic View of the Genome

• First, it assumes that the genome alone
  determines organismal characters
• information flow is one-way genotype ?
  phenotype (contra higher-order laws of form).

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The Atomistic View of the Genome

• Second, because information in the genome is
  context-independent, constraints are not
  operative at the genome-level no internal
  tendencies are present in the genome.

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The Atomistic View of the Genome

• Third, genetic change is the result of random
  errors in the chromosomal material, and the
  recombination of existing variation.

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The Atomistic View of the Genome

• Finally, natural selection provides the mechanism
  for evolution by sieving mutated and recombined
  genetic information.

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The Atomistic View of the Genome

• Yet many genetic and cytological observations
  contradicted the premises of the atomistic genome
  model
• a. Position effects (i.e., gene location
  affects gene expression)
• b. Paramutation (R. A. Brink)
• c. Transposable controlling elements (B.
  McClintock)
• d. Chromatin diminution (e.g., in Cyclops)
• e. Non-random, large chromosomal changes in
  hybrids
• f. C-value paradox/repetitive DNA
• g. Transvection
• h. Obscure connections between genes and
  anatomical homologies
• I. Other inexplicable effects

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The Atomistic View of the Genome

• Molecular data then emerged (late 1970s-80s)
  that complicated the reductionistic genome model
• prokaryotic and eukaryotic genomes are organized
  differently
• eukaryotic, archaeal genes divided into introns
  and exons
• reverse transcription (RNA ? DNA)
• RNA splicing, including alternative and
  trans-splicing
• RNA editing
• most eukaryotic chromosomal DNA consists of
  transposable genetic elements
• molecular drive of repetitive DNA elements
• non-random distribution of DNA segments
• complexity of genomic regulatory elements
• et cetera

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The Atomistic View of the Genome

• In addition, a host of phenomena were discovered
  in the 1980s and90s
• A. Transgene chromosomal position effects
• B. Prions
• C. Paternal/maternal genome imprinting
• D. Germline inheritance of epigenetic states
• E. Genomes can be induced to reorganize during
  times of cellular/organismal stress
• F. Genes and genomes are hierarchically
  organized systems (see below)

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• Lets examine then some basic principles of
  eukaryotic genome organization to see what
  impact, if any, these may have on evolutionary
  theory.

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Genome Organizational Rules in Eukaryotes

• All known eukaryotic genomes reveal the
  following organizational rules
• Genomic components (genes and various structural
  units) are hierarchies of modules.
• Highly nonrandom placement of gene structures and
  loci along the chromosome.
• Genes and chromosomes occupy distinct territories
  in the nucleus.

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Protein-coding regions are hierarchies of modules
Exons
Protein-coding segments of gene
zinc-finger domain
a-helix domain
a-helix domain
zinc-finger domain
Protein domains
Codons
(ACG)(CGT)(CAG)
(AGC)(GTT)(CCT)
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Protein-coding regions are hierarchies of modules

• The average human transcribed region of a gene is
  
• 95 intronic.
• Exons account for only 1.5 of the human (and
• mammalian) genome.

Protein-coding region of gene
Exon 4
Exon 1
Exon 2
Exon 3
/
/
Introns (nonprotein-coding)
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Regulatory regions are also hierarchies of modules
Regulatory element
factor-binding regions
Regulatory domains
trans-factor binding motifs
(GAGA)(GAGA)(GAGA)
AATAAGCAATAGGC
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Genes are concatenations of regulatory and
protein-coding modules
Tissue-specific enhancers
Nuclear matrix attachment site
snoRNA gene
Promoters
Exon 1
Exon 2
microRNA genes
Exon 3
Silencer
Terminator
Exon 4
Nuclear matrix attachment site
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Loci are often concatenations of genes
Locus-control regions
Gene 3
Gene 4
Gene 2
Gene 1
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Co-expressed loci are clustered together along
chromosomes and in the nucleus
Nuclear compartment with concentrated transcriptio
n factors
Chromosome 5 loop
Chromosome 21 loop
Chromosome 2 loop
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Chromosomes are divided into distinct sequence
compartments
GC rich isochore (house-keeping genes, early
replication, dense with SINEs, few LINEs)
AT rich isochore (some tissue-specific genes,
late replication, dense with LINEs, few SINEs)
Centromeric DNA (localized tandem repeats,
retrotransposons, few-to-no genes)
Telomeric DNA (localized short tandem repeats,
retrotransposons, few-to-no genes)
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The chromosomal neighborhood of a locus
influences its expression
Locus Xgh
100
Xgh expression level
0
Pancreas
Lung
Testes
Heart
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The chromosomal neighborhood of a locus
influences its expression
Locus Xgh
100
Xgh expression level
0
Pancreas
Lung
Testes
Heart
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The chromosomal neighborhood of a locus
influences its expression
Locus Xgh
100
Xgh expression level
0
Pancreas
Lung
Testes
Heart
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The chromosomal neighborhood of a locus
influences its expression
Locus Xgh
100
Xgh expression level
0
Pancreas
Lung
Testes
Heart
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Genome Organization and Information Flow

• Eukaryotic gene expression is a complex affair
• Many gene products can be encoded by one gene.
• Gene expression is regulated at multiple levels.
• Gene-encoded information is compressed and
  overlapping.
• Genes are fuzzy entities.

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One gene many transcripts
/
/
Gene
transcription
/
/
AAUAAAA
Primary transcripts
/
/
AAUAAAA
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Alternative and trans-splicing of transcripts
generates yet more gene products
/
/
AAUAAAA
/
/
AAUAAAA
RNA splicing
AAUAAAA
AAUAAAA
AAUAAAA
AAUAAAA
AAUAAAA
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Exons assembled by alternative, trans, and
normal splicing
AAUAAAA
AAUAAAA
AAUAAAA
AAUAAAA
AAUAAAA
mRNAs
Translation
Proteins (catalytic, signaling, structural, and
regulatory)
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Intron and exon RNA also encodes small regulatory
RNAs
AAUAAAA
AAUAAAA
AAUAAAA
AAUAAAA
AAUAAAA
Processing of exons and introns
snoRNAs (RNA editing)
ncRNAs (various roles)
microRNAs (regulatory)
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Genomes as Complex Systems

• Given all the evidence we now have available, a
  computational systems model of the genome is now
  emerging.

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21st Century View of the Genome
From Shapiro (2002), Genome organization and
reorganization in evolution. Annals NY Acad. Sci.
981 111-134.
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Genomes as Complex Systems

• Yet all these discoveries have had almost no
  impact on the neoDarwinian model of the genome.
  Why?