Journal Club 11705 Phil Bourne

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Journal Club 11/7/05 Phil Bourne
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Phenotype Chimp Human Comparison

• Human
• Habitual bipedality
• Enlarged brain
• Speech
• Specific diseases -

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Phenotype Chimp Human Comparison it is
regulation that differs leading to differing
rates of development - the genetic complement is
very similar

• Brain grows more slowly in chimps rapid fetal
  growth rates in humans differing size of
  cranial vault in adults
• Faster face growth in chimps protruding
  forehead and muzzle
• Position of the foramen magnum (hole is skull
  base through which spinal cord emerges position
  and growth suited to quadraped vs biped
• Late closure of skull for post natal expansion
  skeletal formation significantly post natal
• Chimp big toe begins as humans but later moves to
  a rotated opposable position for grasping human
  does not develop in this way and facilitates
  upright walking
• ..

Stephen Jay Gould
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What is Covered - Genotype Chimp Human Comparison

• So close therefore study differences rather than
  similarities have accurate alignment
• Each base change is likely a single event not
  multiple changes over time
• Indels are different to nucleotide replacements
• Differences in the rates of transposable elements
  and Short INdispersed Elements (SINEs)
• Differences little different to variations
  between humans positive selection limited
• Where there are differences they are localized
  and may reflect strong selective sweeps during
  human history

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Differences at the Nucleotide Level
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Comparative Comparisons Hominids vs Murids
(diverged 75M years ago)

• Substitution rates between each is consistent,
  except..
• Substitution rates in subtelomeric regions
  (highly repetitive regions at the ends of
  chromosomes) elevated in hominids
• Amino acid substitutions higher in hominids

Note Hominids diverged about 6M years ago
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Lab. Motivation
903/1558
26/53
2/20
SCOP Superfamilies / Families SCOP 1.69
1539 / 2845
True differences or currently undetected in
respective genomes? If true differences what do
they tell us?
Data from Song
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Lab Motivation

• Can we in any way relate differences at the
  protein family and superfamily levels (which may
  have gone undetected by conventional sequence
  methods) to either differences in the genotype or
  through possible implication in different forms
  of regulation having a phenotypic outcome?

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Major features Covered by the Paper

• Generation and assembly of the chimp genome
• Mutational processes at work in the human genome
• Evolution of protein coding genes to understand
  the nature of selection
• Initial insights into human and chimp
  population genetics not discussed

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Nucleotide Divergence Rates

• Not constant across the genome
• Variation not accounted for by genetic drift
  (population too large?)
• Positive or negative selection discounted
  natural selection is not believed to account for
  genetic variability in humans
• Thus differences a result of regional variation
  in mutation rate.

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CpG Islands

• CpG islands located in promotor regions
  associated with gene silencing also associated
  with housekeeping genes
• Show substantially elevate divergence rates 25
  of substitutions only 2 of all bases

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Influence of Large Scale Chromosomal Structure

• Larger divergence in distal regions
• Comprise 15 of the genome

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Sequence divergence rates are influenced by
factors which are stable across all of mammalian
evolution and also lineage specific factors eg
proximity to telomere which change with
chromosomal rearrangements
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Insertions/Deletions

• 40-45 Mb of species specific euchromatic sequence
  thus 90Mb indel differences based on 5M events
• Corresponds to 3 of genome cf 1.23 from
  nucleotide substitution based on 35M events
• Large insertions gt 15kb 163 unique human regions

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Transposable Element Insertions

• Endogenous retroviruses nearly extinct in the
  human lineage only HERV-K still active in chimp
  and human lineages -73 human specific insertions
  45 chimp after other persistent RVs - 9 human
  only
• 2 RVs unique to chimp infected the germ line
  after the split

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Short INdispersed Elements (SINEs)

• Definition repetitive sequences (300bp) that
  occur every 3000-5000
• Include Alu repeats implicated in disease
• Reminder So named since recognized by AluI
  endonuclease
• 3 fold more Alu repeats in human
• Alu repeat inserted in approx 1 in 200 births
• Chimp Alu repeats belong to a subfamily believe
  to exist before the split
• Human has 2 new subfamilies
• Baboon 1.6 the human repeats implies decline in
  chimp
• Murid genomes do not show this changing
  distribution

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Large scale rearrangements

• Human chromosome 2 results from fusion of 2A and
  2B in chimp
• 9 other inversions some experimentally confirmed

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Summary - Genotype Chimp Human Comparison

• So close therefore study differences rather than
  similarities have accurate alignment
• Each base change is likely a single event not
  multiple changes over time
• Indels lead to 1.5 of each genome being
  specific otherwise 1 different
• Differences in the rates of transposable elements
  humans 3x the Short INdispersed Elements
  (SINEs) Chimp 2 new retroviral elements
• Orthologs 29 identical rest 1-2 aa different
• Differences little different to variations
  between humans positive selection limited
• Where there are differences they are localized
  and may reflect strong selective sweeps during
  human history
• What constitutes phenotypic changes relative to
  random mutation?

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Gene Evolution

• Identified 13,454 pairs of orthologs
• Close to whole complement of human genes but
  under represents families that have undergone
  recent expansion eg immunoglobulins and olfactory
  receptors
• 7,043 orthologous between hominid and murid
  genomes

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Terminology

• KA The number of coding base substitutions that
  result in amino acid change as a fraction of all
  possible sites
• This needs to be normalized across the whole
  genome if we are to use it for comparison
  purposes
• Ks synonymous substitution rate
• KA/Ks ltltlt 1 most aa changes removed by purifying
  selection
• KA/Ks ? gt implies positive selection

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Hominid higher rate of change Murid higher
turnover rates
Rate of amino acid change
Evolutionary constraint
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Gene Evolution

• Encoded proteins are identical in 29 of cases
• Medium number of non-synonymous and synonymous
  substitutions are 2 and 3, respectively
• 77 of amino acid substitutions in hominids are
  sufficiently deleterious to be eliminated by
  natural selection
• 25 of the deleterious amino acid alterations may
  reach detectable frequencies
• Synonymous substitutions are also constrained
  other signals may be encoded eg splice sites
  which require this constraint

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Rapid Evolution in Individual Genes

• 4.4 of the 13,454 orthologs are considered under
  positive selection
• Glycophorin C which mediates Plasmodium
  falciparum invasion pathways in human
  erythrocytes
• Granulysin mediates antimicrobial activity
  against eg tuberculosis
• Protamines and semenogelins involved in
  reproduction (chromatin packing in
  spermiogenesis)
• Mas-related gene family involved in nociception
  (sensory component of pain)

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Evolution of Gene Clusters in human and chimp
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Evolution According to Gene Ontology

• Broadly the same categories known to be
  undergoing accelerated evolution in all mammals
• With regard to purifying selection ie lower rates
  - brain location, cellular signaling, metabolism,
  neurogenesis and synaptic transmission

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Gene Evolution Hominid vs Murid

• Selective pressures largely proportional, but
  there are exceptions
• 59 categories show non-syn acceleration in murid
  (11 by chance) linage specific specialization
  in the immune system in murids
• 58 categories show acceleration in hominids (14
  by chance) transport, synaptic transmission,
  spermatogenesis, perception of sound

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Gene Evolution Human vs Chimp

• 7 show accelerate in human (4 by chance)
• None show acceleration in chimp
• Strongest outlier is transcription factor
  activity based on 348 human genes accumulating
  47 more changes than chimp
• No strong disease associations established
• strong evidence of positive selection unique to
  the human lineage is limited to a handful of
  genes

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Gene Disruption Human vs Chimp

• 53 human genes deleted (36) or partially (17) in
  chimp 15 confirmed by experiment
• The reverse human disruptions cf chimp is limited
  by the gene prediction currently in chimp

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Manifestations of Genetic Differences

• Apoptosis caspase-12 inactive form in human,
  active in murid and chimp may lead to amyloid
  induced neurotoxicity in humans linked to the
  pathology of AD
• Inflammatory response
• Parasite resistance
• Sialic acid biology

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Human Disease Alleles

• Look for those which are wild type in chimp
  found 16 cases which had support in the
  literature
• 6 cases are human mutations associated with
  disorders- might be the result of adaptive
  differences
• Eg the Asn 29 allele of cationic tripsyogen
  causes autosomal dominant pancreatitis in humans
  could be a digestion related molecular adaption
• Implies human specific risk factors due to
  changes in physiology and environment

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What Makes Us Human?

• Most evolutionary change is due to (apparent)
  neutral drift. Adaptive changes are only a small
  part that is gross phenotypic variation is not
  directly related to genomic differences
• Eg Dogs little genomic difference large
  phenotypic difference
• Hominids accumulate deleterious mutations that
  are eliminated by purifying selection in murids
  decreases overall fitness but allows exploration
  of a larger fitness landscape, ultimately leading
  to improved adaption.