Phylogenetic%20Analysis

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What is phylogenetic analysis and why should we
perform it? Phylogenetic analysis has two major
components (1) Phylogeny inference or tree
building the inference of the branching
orders, and ultimately the evolutionary
relationships, between taxa (entities such as
genes, populations, species, etc.) (2)
Analyzing change in traits (phenotypes, genes)
using phylogenies as analytical frameworks
for rigorous understanding of the evolution of
various traits or conditions of interest
Germline and somatic evolution included!
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• Uses of Phylogenetics in the Study of
• Health Disease
• Evolutionary history of humans, between and
  within species
• Analysis of evolution of phenotypic and genetic
  traits in humans, especially human-specific
  traits - evolved when, where, why, how
• Evolution of parasites and pathogens, in relation
  to their hosts (us)
• Evolution of cancer cell lineages, and somatic
  evolution more generally.
• (5) Study of adaptation in humans and other taxa

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• What you will learn in this lecture
• About phylogenies, terminology, what they are,
• how they work, tree thinking
• (2) How to infer phylogenies
• (3) How we can use phylogenies to answer
  questions
• related to human adaptation, health and disease

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Common Phylogenetic Tree Terminology
Terminal Nodes
Branches or Lineages
A
Represent the TAXA (genes, populations, species,
etc.) used to infer the phylogeny
B
C
D
Ancestral Node or ROOT of the Tree
E
Internal Nodes or Divergence Points (represent
hypothetical ancestors of the taxa)
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Phylogenetic trees diagram the evolutionary
relationships between the taxa
((A,(B,C)),(D,E)) The above phylogeny as
nested parentheses
These say that B and C are more closely related
to each other than either is to A, and that A, B,
and C form a clade that is a sister group to the
clade composed of D and E. If the tree has a
time scale, then D and E are the most closely
related.
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Three types of trees
Cladogram Phylogram
Ultrametric tree
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Taxon B
Taxon B
Taxon B
1
1
Taxon C
Taxon C
Taxon C
3
1
Taxon A
Taxon A
Taxon A
Taxon D
Taxon D
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Taxon D
no meaning
genetic change
All show the same evolutionary relationships, or
branching orders, between the taxa.
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A major goal of phylogeny inference is to resolve
the branching orders of lineages in evolutionary
trees
Completely unresolved or "star" phylogeny
Partially resolved phylogeny
Fully resolved, bifurcating phylogeny
RESOLUTION AND SUPPORT for nodes
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There are three possible unrooted trees for four
taxa (A, B, C, D)
Phylogenetic tree building (or inference) methods
are aimed at discovering which of the possible
unrooted trees is "correct". We would like this
to be the true biological tree that is, one
that accurately represents the evolutionary
history of the taxa. However, we must settle for
discovering the computationally correct or
optimal tree for the phylogenetic method of
choice.
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The number of unrooted trees increases in a
greater than exponential manner with number of
taxa
(2N - 5)!! unrooted trees for N taxa
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Inferring evolutionary relationships between the
taxa requires rooting the tree
To root a tree mentally, imagine that the tree is
made of string. Grab the string at the root
and tug on it until the ends of the string (the
taxa) fall opposite the root
Unrooted tree
TIME
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Now, try it again with the root at another
position
B
C
Root
Unrooted tree
D
A
A
B
C
D
Rooted tree
Note that in this rooted tree, taxon A is most
closely related to taxon B, and together they are
equally distantly related to taxa C and D.
Root
TIME
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An unrooted, four-taxon tree theoretically can be
rooted in five different places to produce five
different rooted trees
A
C
The unrooted tree 1
D
B
These trees show five different evolutionary
relationships among the taxa!
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All of these rearrangements show the same
evolutionary relationships between the taxa
Rooted tree 1a
D
C
A
B
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Main way to root trees
By outgroup Uses taxa (the outgroup) that
are known to fall outside of the group of
interest (the ingroup). Requires some prior
knowledge about the relationships among the taxa.

outgroup







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Molecular phylogenetic tree building
methods Are mathematical and/or statistical
methods for inferring the divergence order of
taxa, as well as the lengths of the branches that
connect them. There are many phylogenetic
methods available today, each having strengths
and weaknesses. Most can be classified as
follows
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Types of data used in phylogenetic
inference Character-based methods Use the
aligned characters, such as DNA or protein
sequences, directly during tree inference.
Taxa Characters Species
A ATCGCTAGTCCTATAGTGCA Species
B ATCGCTAGTCCTATATTGCA Species
C TTCGCTAGACCTGTGGTCCA Species
D TTGACCAGACCTGTGGTCCG Species
E TTGACCAGTTCTGTGGTCCG ETC ETC


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Similarity vs. Evolutionary Relationship
Similarity and relationship are not the same
thing, even though evolutionary relationship is
inferred from certain types of similarity. Simila
r having likeness or resemblance (an
observation) Related genetically connected
(an historical fact) Two taxa can be most
similar without being most closely-related
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Main computational approach
Optimality approaches Use either character or
distance data. First define an optimality
criterion (minimum branch lengths, fewest number
of events, highest likelihood), and then use a
specific algorithm for finding trees with the
best value for the objective function. Can
identify many equally optimal trees, if such
exist. Warning Finding an optimal tree is not
necessarily the same as finding the "true tree.
Random data will give you an optimal (best )
tree!
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Parsimony methods

• Optimality criterion The most-parsimonious
  tree is the one that
• requires the fewest number of evolutionary events
  (e.g., nucleotide
• substitutions, amino acid replacements) to
  explain the sequences.
• Advantages
• Are simple, intuitive, and logical (many
  possible by pencil-and-paper).
• Can be used on molecular and non-molecular
  (e.g., morphological) data.
• Can be used for character (can infer the exact
  substitutions) and rate analysis.
• Can be used to infer the sequences of the
  extinct (hypothetical) ancestors.
• Disadvantages
• Not explicitly statistical
• Can be fooled by high levels of parallel
  evolution

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Use parsimony to infer the optimal (best)
tree Character-based methods Use the aligned
characters, such as DNA or protein sequences,
directly during tree inference. Taxa
Characters Species A ATCG
CTAGACCTATAGTGCA Species B ATCG
CTAGACCTATATTGCA Species C TTCG
CTAGACCTGTGGTCCA Species D TTGA
CCAGACCTGTGGTCCG Species E TTGA
CCAGTTGTGTGGTCCG OUTGROUP TTAC
CCATTTGTGTCCTCCG Infer maximum parsimony tree
using first four characters Quality of trees
(how likely it is that they reflect the one True
Tree) can be evaluated in various ways (random
data will give you a low-quality best tree)
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We can Statistically Compare alternative trees,
corresponding to specific biological
hypotheses of the history of some set of lineages
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Timescales on trees molecular clocks
Why such different profiles? Variation in
mutation rate?
Variation in selection. Genes coding for some
molecules under very strong stabilizing selection.
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Dates for calibrating molecular clocks can come
from geology, fossils, or historical data
From known ages of islands, for two genes
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Calibrating using fossil data
chimps
6 substitutions
humans
whales
60 substitutions

hippos
56 mya
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Calibrating from known dates of the ages of
samples for very fast-evolving taxa such as HIV
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• Uses of Phylogenetics in the Study of
• Health Disease
• Evolutionary history of humans, between and
  within species
• Analysis of evolution of phenotypic and genetic
  traits in humans, especially human-specific
  traits - evolved when, where, why, how
• Taxonomy and evolution of parasites and
  pathogens, and evolution in relation to their
  hosts
• Evolution of cancer cell lineages, and somatic
  evolution more generally.
• Study of adaptation in humans and other taxa, via
  analysis of divergence and convergence

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EMERGING VIRUSES - THE GREATEST KNOWN HEALTH
THREAT TO HUMANITY
VIRUS - what IS it? Sequence its DNA and relate
sequence to known viruses Evolution of SIV and
HIV viruses multiple transfers to humans, from
chimps and from green monkeys
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SARS (severe acute respiratory syndrome) what
causes it and where did it come from?
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HIV phylogeny within humans in different
regions Haiti as stepping stone to North
America
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HIV evolves very rapidly WITHIN hosts, as a
result of interactions with the immune
system Can do phylogenetics -Pathogens within
individuals, -Pathogens between Individuals (eg
in different or same regions) How originate?
From other species? How spread? How does
resistance to Antibiotics evolve in pathogens,
resistance to chemotherapeutic agents evolve in
cancer?
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Cancer evolves genetically in the body during
carcinogenesis, allowing the inference of
oncogenetic trees Cytogenetic data Gains and
losses of Chromosomal regions During evolution
of cancers Lose tumor suppressor gene copies,
gain Oncogene copies Involves losses of
heterozygosity and losses of imprinting
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Cancer Evolutionary Phylogenomics Compare
primary cancer with metastatic tumors
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• What you learned in this lecture
• About phylogenies, terminology, what they are,
• how they work, tree thinking
• (2) How to infer and evaluate phylogenies
• (3) How to use phylogenies to answer questions
• related to human adaptation, health
• and disease (viruses, cancer, etc)
• (4) How to THINK in terms of evolutionary trees
• (historical patterns of evolution), within and
  between species