Chapter 1: case for evolutionary thinking: understanding HIV 04/02/2014
1.1 the natural history of HIV epidemic
AIDS was recognized in 1981 in US as forms of pneumonia/cnacer.
How does HIV spread, and how can it be slowed?
HIV infection start when body fluid with virus onto mucous membrane/blood stream (semen, vaginal, rectal,
breast milk). To reduce rate of HIV transmission: Antiviral drugs reduce transmission. Circumcision.
What is HIV?
Hiv is intracellular parasite incapable of reproducing on own, it invade specific cell in human immune
Life cycle: extracelluar phase and intracellular phase. During extracellular/infectious phase: virusmove from
one host cell to another and can be transmitted from hsot to host. The extracellular form of virus is called
virion/virus particule. In intracellular/replication phase: virus replicates. HIV initiates replication by latching
onto 2 protein on host cell ▯ CD4 and coreceptor ▯ fusion of virion’s envelope with host cell membrane and
virion into the cell. Contents include: viru’s genome (RNA) and viral enzyme (reverse transcriptase:
transcribe RNA genome into DNA, and integrase: splice DNA genome into host cell genome). ▯ once HIV
genome infiltrate host DNA, host RNA polymerase transcribe viral genome into viral mRNA ▯ ribocome
synthesize protein and new virone in host cell membrane into bloodstream. ▯ hiv protease enzyme cleave
viral protein into functional form to allow virions to mature and invade new cells.
Virus uses host cell’s enzyme: polymerase, ribosome, tRna. Challenge to find drug to interrupt viral life
cycle without interrupting host cell enzymes. Antiviral target enzymes specific to virus such as reverse
transcriptase and integrase.
How does the immune system react to HIV?
Senitels: dendritic cells patrol vulnerable tissue (digestive/reproduction tract). When dendritic cell capture
virus, it travels to lymph node or other lymphoid tissue and present virus protein to naïve helper T cells:
white blood cell. ▯ na ïve helper T cell carry Tcell receptor protein. When dendritic cell present t helper t cell
with viral protein, viral protein binds to T cell receptor, the helper t cell activates. Helper t cells
grows/divides/produce daughter clells called effector helper t cells which coordinate immune response ▯
effector helper t cell form cytokinese: mobilize immune cells to fight and induce b cells to masure into
plasma cells which produce antibodies that bind to invading virions and mark for elimination. B cell activate
killer t cells which destroy infected host cell ▯ macrophages destroy virus particles/kill infected cell. Most
effector helper t cell die in weeks, survivor becomes memory helper t cell so if same pathogen invades
again, memory cell produce new population of effector helper t cells
How does HIV cause AIDS?
Hiv invade host cell by latching onto 2 protein: Cd4 and coreceptors. Coreceptor form CCR5. Cells that
carry CD4 and ccr5 are vulnerable to hiv (macrophase, effector helper t cell, memory helper t cells).
Progress of hiv monitored by measuring hiv virion concentration in blood stream and CD4 t cells
concentration in blood stream and lymphoid. Untreated infection progresses in 3 phases.
Acute phase: hiv virion enter host cell ▯replicate explosively ▯virion concentration increase, dc4 t cells
concentration decrease when lymphoid ▯ host shows sympthoms of viral infection ▯ acut phase ends when
virla replication slows and virion concentration drop, cd4 t cells recovers.
Chronic phase: hiv replicate ▯ virion concentration falls ▯ AIDS begin when cd4 t cell in blood drop below
200 cell/ml ▯ immune system collapse and can’t fend off virus, bacteria, fungi ▯ without antihiv drug,
patient with aid live less than 3 years. Destruction of cd4 t cells explain acute phase of infection. But
immune system can regenerate these cells. Chronic phase: no more than 1 cd4 t cell is infected.
hiv infection to aids: hiv attack on cd4 t cells in gut ▯ destroy helper t cells/ damage other tissue in gut ▯
bacteria moves from but into blood ▯ trigger immune activation inducing b cell and t cell to increase. Anti hiv
killer t cell restrain hiv replication to produce new helper t cell allowing cd4 t cells concentration to recover.
In some case of hiv. Strong immune system comes in heavy cost. Hiv replicats in activated cd4 t cells ▯
immune system to stop hiv infection increases hiv infection. Hiv and immune system battles in lymph
nodes: place where naïve t cells activated. As patient t cell concentration fall due to infection, immune
system lose ability to fight pathogens ▯ aids.
How might hiv be stopped before it leads to aids? Stop replication. AZT drug
1.2 why does hiv therapy using just one drug ultimately fail?
To fight virus, try to inhibit enzymes that special to virus life cycle. For hiv, target the virus protease,
integrase, reverse transcriptase. AZE interfere with reverse transcriptase. Reverse transcriptase: enzyme
use virus rna as template to construct DNA (the DNA nucleotide stolen from host cell).
AZT stops reverse transcription. AZT is similar to nucleotide thymidine that it is used for reverse
transcriptase and cause reverse transcriptase to be stuck (unable to add more nucleotide). This stops
pathway of new viral protein/virions. Azt halts loss of t cell in aid patients by fooling dna polymerase,
interrupting normal dna synthesi.
does azt alter patient’s physiology?
Azt lose effectiveness in 2 ways: patient’s cellular physiology change. (after azt enter cell, long exposure
cause cell to make less thymidine kinase, less effective overtime).
Does act alter population of virions living in patient?
Second way azt lose effectiveness: population of virions living inside patient change so that virions
themselves would resist to disruption of AZT. Virions evolve and become resistant.
What makes hiv resistant to azt?
Hiv virions epose to mutagenic chemical/ionizing radiation. ▯ hiv strains alter nucleotide sequence in
genome and alter protein adds into rverse trnsciptase. If reverse transcriptase remove azt and take in hiv
mutant, hiv replicates
Evolution by natural selection: process of change over time in composition of viral population.
Evolution by natural selection (4 step) 1 Replication errors produce mutation in reverse transcriptase gene. Virions carrying the differnet reverse
transcriptase genes produce versions of reverse transcriptase enzyme that vary in their resistanc to azt.
2 Mutant virion pass their reverse transcriptase genes, thad azt resistence to offspring. Azt resistance is
3 During treatment with aze, virions are abt to survive and reproduce.
4 Virion that persist in presence of azt are the ones with mutation in their reverse transcriptase genes that
Understanding evolution helps researchers design better therapies
Drugs: coreceptor inhibitor(prevent hiv from latching onto host ccr5). Fusion inhibitors (interfere hiv proteins
form entering host cell). Reverse inhibitors ( block hiv integrase from inserting hiv dna and interfere with
enzyme active site). Integrase inhibitors (block hiv integrase from insergin hiv dna and preventing
transcription of new viral rna). Protease inhibitors (prevent hiv protease enzyme from cleaving virla
precursor protein to produce mature virions).
To improve anti hiv therapy: increase number of mutations present in virion’s genome to render the virion
resistant. More mutation needed for resistance, lower probability that will occur in single virion. We need to
reduce genetic variation for resistance. Without genetic variation: without differences in survival/
reproduction that are passed from one generation to the next: viral population cannot evolve. To rais
number of mutation is to use more than 2 drugs. No cure hiv infection, hiv genomes remain hidden.
The evolution hiv strains resistant to multiple drugs
1.3 are human populations evolving as a result of hiv pandemic?
Some genetic variants offer protection against hiv
A missing coreceptor: ccr5 coreceptor for hiv. Unusual form of ccr5 32 allel confer strong protection against
hiv ccr5 32 allele common in northern Europe, less in sout/ease.
Genetic varion for hiv resistance in African population
Common nucldeotide at cd4 was at position 868. Alternative version was c868T.
A missing protective allele: loss of function mutations that increase our suspectivbility to HIV infection. (e.g
retrocyclin is protein that was found in apes which was joined to create protein. It protects human cd4+T cell
from hiv infection.
Practical applications. Ccr532 homozygotes: lack functional ccr5suffer fewer effects and resistant to HIV
yields benefits. Retrocyclin block hiv transmission
Unresolved mystery. Why is ccr532 common in Europe, rare everywhere else. Current hiv is young. Ccr5
32 allel may be favoured by natural selection in European population or allel could have risen to high
frequency by changed in process called genetic drift.
1.4 where did HIV come from?
Louisisana v Richard J Schmidt.
Reconstructing evolutionary history. New evolutionary tree with HIV transmission. Evolution as witness for prosecution.
The origin of hiv. First clue where hiv cmae from is viru’s genome and life cycle similar to simian
immundodeficiency virus (SIV). Family of virus infect primate. We got hiv from chimps and chimps got hiv
When did siv move from chimp to human?
Group M responsible for aid . group m strains of hiv originated in transfer of siv from chimps to human 70
years ago. Difference between siv infection in monkey vs siv in chimps and hiv infection in human is that
mokey siv infect natural hosts, they generally cuase little or no disease.
1.5 why is hiv lethal?
3 approaches that apply to the problem.
A correlation between lethality and transmission?
Virus will populate new host. First level of natural selection: there are difference among virions in ability to
survive and reproduce within a given host. Second level: whne viral strains differ in ability to move from one
host to another. Good strains become common, bad strain disappear.
Higher viral load, greater rate infection is pass on virus.
Hiv population within individual host evolve resistance to AZT . hiv also evolve ability to evade host immune
response. Antibodies and killer t cell recognize hiv cell by binding to epitopes: short pieces of viral protein
displayed on surface of virion/infect cell. Mutation affect epitope in protein called p24: capsule of hiv virion.
Infected host cell will have this epitope and human leucocyte antigen HLA. When kill t cell recognize foreign
epitope on hla protein, it destroys the infected cell.
Evolution of hiv population appears to contribute to death of host in 3 ways. 1. Continuous evolution toward
novel epitopes enable viral population to stay far enough ahead of immune reponse to avoid elimination. 2.
Viral population within host evolve toward ever more aggressive replication. Longer hiv in host, the more
virion. 3. Hiv evolve can infect naïve t cells. Infect given cell type is determined by coreceptior the virion
use. Most virion use ccr5 as coreceptor. Ccr5 is found in macrophages and effector t cells. Virion emerge to
exploit different coreceptor: x4 virus use cxcr4,cxcr4 found in naïve cell.
A surprising clue
Why would patient’s hiv lineages experience more rapid neutral evolution advance more quickyly to aids?
The infection triggers increase immune activation with proliferation of helper t cells. But helper t cell are
cells in which hiv replicates more efficiently. Patients whos immune system activate more aggressively
against hiv develop aid more quickly and higher rate of viral replication .more replication means more
mutation and more mutation means higher rate of neurtral evolution.
Unusual feature of hiv or humans? Vpu: extra gene. This extra gene appears to be risen from siv infect monkey. Vpu protein does block action
of host protein called tetherin. Tetherin ties maturing virions onto host cell membrane and preventing
release. In siv, vpu does not interfere with tetherine, another viral protein called nef. Human tetherin
resistant to nef and resistance is due to loss from deletion of tetherine gnee. Vpu blocks tetherin is why
group M spread so rapidly. Vpu block tetherin, allows production of virions form infected cells and induce
higher level of immune activation in host cell.
Trim4a is like tetherin and block retroviral replication. Trim5a interact with contents of invading virion after
they have entered cell and before reverse transcription of viral genome. The protein can disrupt life cycle of
hiv. Trim5a cannot block hiv replication nearly as well. Sawyer’s arms race hypothesis: when monkey spry
is placed into human trim5a protein ability to block hiv replication. When human patch is played into
monkey, they cannot block hiv replication. Trim5a is adapted to fight not the recently hiv but extinct
retrovirus from ancetors before. Extinct retrovirus: pterv1. Trim5a does have storng resistance to pterv1.
The story of hiv demonstrates that evolutionary analysis has practical applications outside of textbooks and
classrooms. Hiv/aids has killed 30 million people, most of Africans.
Each time hiv virion invade host cell, virion reversetranscribes its rna genome into dna copy that serves as
template for next generation of virus particles. Because reverse trnascripiton is error prone, an hiv
population quickly develops substantial genetic diversity. Some genetic variants replicate raidly when others
die. As a result the composition of population change over time. That is, population evolves.
Hiv populations within patients quickly evolve resistance to any single antiretroviral drug and can even
evolve reistance to multidrug cocktails. Without effective antiretroviral therapy, hiv population also evolve to
evade host’s immune reponse. A process that ultimately contribute to collapse of immune system and onset
Just as hiv population evolve in response to slection imposed by host, so too host population may evolve in
reponse to selection imposed by virus. Human population harbor genetic variation for susceptibility to hiv
infection. If, during aids epidemic, susceptible individuals die at higher rate than resistant individuals, then
genetic composition of these popuplations will change over time. The search for genetic variation for
resistnce to hiv has leg to development of new antiretroviral drugas.
Hiv belongs to family of viruses that infect variety of primate. Evolutionary trees based on genetic
comparisons reveal that hiv 1 jumped to human from chimpanzees and has doen so more than once. Hiv 1
also may have mumped to humans formgorillas. The strains responsible for the bulk of hiv/aids pandemic,
hiv1 group m have a common ancestor that lived several decades ago. Comparison of hiv to evolutionarily related viruses, and of humans to related hosts, has provided insight into
why hiv infection is lethal. Hiv 1 possesses a gene not present in most sivs. This gene may have made it
advantageous for another hiv genes to lose its ability to suppress immune activation in host. Immune
activation plays crucial role in progression to aids. Human mya be susceptible to hiv due to genetic change
that evolved in ancestors because it conferred resistance to another retrovirus that is now extince.
By focusing in this chapter on adaptation and diversification in hiv, we introduced topics like mutation and
variation, competition, natural selection, evolutionary tree reconstruction, lineage diversification, and
applications of evolutionary theory to scientific and human problems. the pattern of evolution 1.
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Theory of descent
1. Microevolution: species change through time
2. Speciation: ancestral species split and diverge to increase number of species.
3. Macroevolution: over time new life can derive from earlier forms. Change over time
4. Species derive not independently from shared ancestors.
5. Earth and life are more than 6000 years old.
2.1 evidence of microevolution: change through time
After 24 generation of selective breeding,
Evidence from direct observation of natural populations.
Used field mustard where there were purebred and hybrids. In 1997 purebred had longer flowering time. In
2004, purebred had the shortest flowering time. This shows that plant evolved during drought.
Evidence form living anatomy: vestigial structures
Vestigial structures: useless version of body part that has an important function in other species. The kiwi
bird has stubby wing. Snake have hindlimbleg bone/hip. Human have tailbone called coccyx. Body hair
stand when we are cold. We have Goosebumps. Human have chromosome 6 in enzyme CMAH where
CMAH convert acidic sugar from one to another. Chimps can make a lot of CMAH, we can’t. this explains
why human and chimps are immune to each other ‘s malaria parasite.
In fish, the vestigial structure of body armor are controlled by 2 genes: ectodysplasinpelvic spine/
Why microevolution matters.
2.2 evidence of speciation: new lineages from old.
Evidence form laboratory experiments.
Wild type O6wt virus can effect P.syringae. O6Wt and O6E are different species. They cannot infect same
host and cannot interbreed. This shows virus can switch host.
Dodd flies that had different diet did interbreed (rarely but they did adapt). This shows that evolution occurs
slowly and isolation helps evolve faster.
Evidence from natural populations.
Speciation starts with single population among individuals. In lake, sticlebacks with longer rakers consume
richer diet than copepdpopulation dividing into subpopulation that still interbreed. Lake fish
sometimes lived with creek idistinct population with limited interbreeding. There were 2 types of
sticlebacks: benthic (specialize in bottom lake and limneticspecialize in plankton. The hybrid: benthic and
limnetic are poor compared to purebred that caused 2 form of diferdistinct populations whos
reproductive isolation is irreversible. Sticklefish has different appearance and genetic difference –sex
chromosome. (so: one populaiosubpopulatinlimited interbreeiirreversible change) the pattern of evolution 1.
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Ring species: one species can split into two. In birds, increase distance can cause genetic difference.
Why speciation matters
To find origin of human diseases. (from which host then evolves)
2.3 evidence of macroevolution: new forms from old.
Fossil; trace of organism that lived in the past
Fossil record: collection of fossil
Extinction and succession.
Georges curvier. Law of succession: general pattern of correspondence between fossil and living forms
from same location. 2 plants form different continents are similar.
Extinction and succession are patterns of descent with modification from ancestors.
Transitional form: traits typical of ancestral population and later descendants.
A living transitional form. .
Terrestrial fish: blennies: fish that can born from sea and live on land. They breathe through gills and skin.
There are 3 types: aquatic, amphibious, and terrestrial. It’s believed due to speciation, aquatic
amphibious terrestrial. Amphibious is transitional form because it is derived form and represent a
lineage. It is an intermediate species.
A fossil transitional bird.
Dinosaur then archaeopeteryx(gliding feathers) then modern bird with reduced tail. Feathers came first
Transitional forms allow predictive tests of evolutionary hypotheses
Transitional form give us a way to test macroevolution. With more fossil evidence we know. Dinosaur then
sinosauroteryx then similcaudipteryx then archaeopteryx then modern bird. The addition of where the
feathers and faned feathers came from.
A transitional turtle.
Amniotes: mammals/reptiles/bird. Ribs that curve of body wall. Ain odontochelys: rib
expand modern turtle: rib fan apart.
Why macroevolution matters.
Hiccup. Hiccup begins with strong muscle inhalation at diaphragm and sharp breath and active glottis. . we
think like how tadpoles breathe water, they pump it across the will while closing the glottis to keep it out of
lungs. the pattern of evolution 1.
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2.4 evidence of common ancestry: all life forms are related
homology: study of likeness. The same organ in different animals under variety of form and function
structural homology. What causes vertebrate forelimbs to be similar, shark/wale to have same short
fine/flipper, plants to have similar position sigma/anther. Darwin says that descent from common ancestor
(they share common ancestor)
using homology to test the hypothesis of common ancestry
snail lineage. Speciidaughter has no further changes isother lineage with long shell
underwent speciatin daughter lineage evolve band on shell then noc other lineage evolve
pink shell and sl daughter lineage evolve highs the other has spike on shell then no change.
Humans: tetrapod then primate then ape then human.
In a test if person A sat with B and both got all right answers, no problem. But if person A sat with B and
both got all wrong answers, something’s wrong. When chromosome 17 sit near protein22, it causes
repeats that cause abnormal chromosome.
A predictive test of common ancestry using molecular homologies.
Processed pseudogenes.: flaw in molecular homology. Pseudogenes do not have intron/extron. DNA and
RNA has retrotransposon. Pseudogenes are nonfunctional that attach mRNA to reverse transcribe to DNA.
From this we can estimate the age of psudogens. So those with pseudogens will have diversity and
Universal molecular homologies.
All organisms use the same nucleotide triplets/codon.
The modern concept of homology
Homology are similarities due to inheritance of traits from common ancestor. Correct.
Incorrect: homology is similarity in structure despite difference in function
Why common ancestry matters.
Gene team: when we look for common ancestor, we do not find same genes in creatures, but same groups
of genes working together to carry out function. Mice and yeast have gene team. In mice, phenotype cause
disease. In yeast, sensitive to drug cause disease. In mice, gene 8 affect blood vessel.
2.5 the age of earth
uniformitarianism: geological process taking place now work similrl catastrophism: todays’
geological formation are form catastrophi e Pangaea
the geologic time scale. the pattern of evolution 1.
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Used relative dating: to determine how old each rock formation was. Geologic time scale: geologic history
Radiometric dating: using unstable isotope of elements. Isotope decay and they either change into different
element of different isotope. Earth is 3 billion years old.
Why earth’s age matter.
Before Charles Darwin published on the origin on species in 1859, special creation was the lading
explanation for where earth’s organism came from. Arguing from evidence, Darwin advocated a different
view of patter of life’s history. All organisms are descended, with modification from common ancestor.
Darwin’s evidence was persuasive.
The evidence showing that Darwin’s view is correct. The results of laboratory selection experiment, the
selective breeding of domestic plants and animals, direct observation of change in natural populations and
vestigial structures all demonstrate that population changes across generations. Change in population from
one generation to next is called microevolution.
The results of laboratory experiments involving selection for divergence, observation of natural populations
with different degrees of reproductive isolation and studies of ring species establish that lineages split and
diverge. The separation of one species into two is called speciation.
Extinction, succession and transitional forms include transitional fossils predicted before they were found
show that over long time spans, new life forms can arise form old lineages. This is macroevolution.
Structural and genetic homologies indicate and predictive tests using fossil record and shared genetic flaws
confirm that all organisms are related by common ancestry. There is but one tree of life.
Finally, relative and absolute dating show that the earth and life are billions of years old.
In addition to establishing the fact of evolution, Darwin had set himself a second goal in on the origin of
species. That was to call the mechanism responsible for evolution. The mechanism Darwin identified was
natural selection. In contrast to rapid acceptance of fact of descent with modification, natural selection was
not widely accepted as mechanism of adaptive evolution until 1930. Estimating Evolutionary Trees
4.1: how to read an evolutionary tree
evolutionary tree: phylogenetic tree: phylogeny : diagram showing history of divergence/evolutionary change
leading form single ancestral lineage to descendants. It shows group of organisms genealogical
relationships as they understood according to Darwin’s theory of descent with modification from common
How to read time on an evolutionary tree.
Root is bottom then branches and nodes.
Transitions: evolutionary modifications as lineage diverges.
How to read relationships on evolutionary tree.
Evolutionary relationships: relative time elapsed since they shared common ancestors. Sister species:
species that share more recent last common ancestor with each other than other species. (last nodes)
Evolutionary trees do not show everything.
It may show coat color/ tail length during evolution. It does not show change in body size or evolution of the
mane, genetic, behavioral, physiological changes.
Evolutionary trees can be drawn in various style. 4 styles.
Evolutionary trees are hypotheses.
4.2 the logic of inferring evolutionary trees.
Phylogeny inference in an ideal case.
Derived characters: unique to one species and which are shared. E.g in birds: long bills/ dark tails.
Key concepts in phylogeny inference
Apomorphy: derived character (separate form).
Plesiomorphy: ancestral character (near form).
Synapomorphy: derived character shared by 2 or more lineages: similar separate form
Monophyletic: clade: ancestor +all of descendents.
Paraphyletic: ancestor +some (not all) descendants.
Polyphyletic: some descendants. Estimating Evolutionary Trees
Synapomorphies identify monophyletic groups. (e.g dog belong to mammal that belong to amniotes(share
egg with membrane) that belong to tetrapod.
Polytomy: 3 way split. Lizard, snake, bird, crocodile lineage.
Phylogeny inference in nonideal cases.
Problems with reconstruct evolutionary history:
1. Do not know characteristic of common ancestor that species derive from
2. Similar evolutionary novelties sometimes evolve independently from lineage
3. Evolutionary novelties, once they evolve are lost.
Outgroup: historical reconstruction one or more additional species. Realtives of ingroupspecies whose
relationship we with to infer.
Ingroup is monophyletic. In simple outgorup analysis, we add outgroup of just one species and assume no
evolutionary change in outgorup lineage.
To see if A,b,c which two are sister species (AB,AC, BC).
Parsimony analysis: fewest evolutionary changes in the characters of interest. We look at each character,
total number of evolutionary change require and find lowest possibility.
Uninformative characters: different changes. (e.g in the 3 antelopsingroup, cowoutgroup. All 3 ingroup
have brown legs. Cow and 2 ingroup have rump.
Informative: dark tail, loss of color tail.
The number of possible trees.
convergent and reversal
Convergent evolution: independent appearance in different lineages of similar derived characters
Reversal: loss of derived traits in lineage, resulting in return to ancestral condition.
Homoplasy: similarity in character states due to convergence/reversal. Wings, nostrils above
(hippo/crocodile), snake/legless lizard, fins.
Reversal may be caused by environmental changes . loss of limb, eye sight
Homologous=inherited form common ancestor=synapomorphies=monophyletic groups.
Homoplasy: protein contain 10 protein. All the frogs produce the protein, but different frogs produce it from
a different gene. So this is convergence.
4.3 molecular phylogeny inference and origin of whales.
Whales, dolphins, porpoises are monophyletic group. Clade cetacean.
What is catacea?
Catecea is monophyletic group of synapomorphies in the skull that use hearing underwater. variation among individuals
Genetic variation: mutation that generate new alleles, genes, chromosomes. variation among individuals
5.1 3 kinds of variation
genetic variation, environment variation, genotypebyenvironment interaction.
The machinery of life.
Genome: genetic instruction.
Genetic variation is result of differences among individuals that encode DNA. E.g different proteins at
Environmental variation arises when external factors influence how much protein is made from gene and
how protein work.
Genotype by environment interaction is result of differences among individuals that are encoded into DNA
that make them differ in their sensitivity to environment influences.
PTC: phenylthiocarbamide. Used for tasting.
Alleles: different genes.
Genotype: combination of alleles
Taste receptor type 2: TAS2R are receptor protein for bitter flavor. 2 common TAS2R are AVI and pAV.
AVI/APAV are genotype. PAV/PAv are most sensitive in phenotype. AVI/AVI are least sensitive.
Ability to taste bitter in genotype is inherited. On chromosome 7 there is AVI/PAV alleles. Best is AVI/PAV
because the genotype allows us to taste bitter and eat it. PAV makes ppl hate bitter and not eat it.
Genetic variation and evolution
Daphnia. Inducible defense: increase armor. Daphnia use inducible defense against predators. Expression:
production of proteins in daphnia. TBM is an enzyme that increase neurotransmitters as catalyze to
Environmental variation and evolution. Protein can change in environment. E.g athletes live in low altitude
and train in high altitudes have more capillary growth.
Non genetic influences/ phenotype has chance. Coli bacteria affects green fluorescent protein.
Genotypebyenvironment interaction variation among individuals
Reaction norm: pattern of phenotypes an individual may develop upon exposure to different environments.
# offspring, temperature sensibility.
Genotype by environment interaction and evolution
Genotype ll serotonin transporter gene does not affect depression. Genotype ss affect depression.
Genotype ss make less serotonin.
Phenotypic plasticity: different phenotypes in different environment. Using a new strain of black caterpillars,
they were given heat shock. Very sensitive to heat=high plasticity. Low sensitivity to heat=low plasticity.
After a few more trials of heat, the low plasticity black caterpillars lost sensitivity to heat shock. High
plasticity became extremely sensitive. The reason: protein.
Mutation: change in genome. Gain/loss of chromosomes.
5.2 where new alleles come form.
New alleles come from change in existing alleles.
Mutation create new alleles when DNA alteration that escape before repair or replication occur. E.g ATCG.
BUT if the TG is not repaired and enters the replication then mutation occurs.
Premutations: when DNA goes through chemical degradation and replication errors not repaired.
Premutations are fixed by enzymes. Mice without DNA polymerase lacked ability to correct/proofread DNA
How mutation alter protein function.
When cell encoded in a gene it makes 2 step.
1) transcription: using DNA as template and copy sequence bases into mRNA
2) translation: use mRNA as template to create protein.
The cell reads mRNA as codons for amino acid.
Point mutation: small mutation at of one base(ATCG).
AG (agony) purine. CT pyrimidines.
Transition: purine substitute purine / pyrimidine substitute pyrimidines
Transversion: purine substitute pyrimidine,
Silent/synonymous substitution: when mutation leaves protein unaltered
Nonsynonymous/replacement substitute. Switching amino acid will change protein function. Transversion. variation among individuals
Nonsense mutation: protein become nonfunctional. Stop codon.
Introns: intervening sequences. Exon=coding sequences.
Intron transcribed into mRNA and spliced before translation.
Like point mutations, indels (insertions/deletions).
5.3 where new genes come from
2 mechanisms for gene duplication
1. unequal crossing over: error in genetic recombination that happens during meiosis. In
normal crossing over, homologous chromosome align in prophase of Meiosis I in 1 loci. In
unequal crossing over, homologous chromosome align incorrectly. This occurs because the
nucleotide occurs in more than one place on the chromosome causing many loci.
2. Retroposition / retroduplication. Retroposition begins when mRNA after intron spliced is
reversetranscribed by enzyme reverse transcriptase to form DNA. If DNA is combined into the
main chromosome, the genome duplicate gene. In many cases, the new copy is nonfunctional
psudogene because it lacks regulatory sequences that cause it to be transcribed. If the
duplicate inserts near existing regulatory sequence, then it become functional gene.
Retroposition and unequal crossing. Retroduplicated genes lack intron and far from original gene. Unequal
crossing gene has some intron and found in same chromosome.
A new gene generated by unequal crossing over. mendelian genetics in populations I
selection and mutation (214/216) 04/02/2014
When we know starting allele frequency and genotype fitness, model can predict how allel frequency will
change under controlled conditions. Gigord study of elder flower orchids show model can be applied in
natural situation. Eugenic sterilization sought to reduce fitness of particular genotype to zero and reduce
rrequency of allels responsible for undesirable phenotype.
Normal mindedness is dominant. Feeblemindedness recessive. If recessive is q then square root q. if all
individuals are sterilized, then fitness of genotype is zero.
3 problems: 1. Individuals whose case are highly diverse groups (in down syndrome ppl could be deaf or
just uneducated). 2) goddard’s data relied on family members that died. 3) goddard’s method of analysis
separated his cases into: definitely heridatry, probably hereditary, accidents. He only analyzed from
definitely heridatry. Mendelian genetics in population I:
selection and mutation (180217)
Population genetics: evolution by natural selection with mendelian genetics.
6.1 mendelian genetics in populations: hardyweinberg equilibrium
population: group of interbreeding individuals and offspring.
Adult in mouse are diploid and carry 2 copy of A o meiosis mendel’s law of segregation: each
gamete receive one copy of A locus.
Genetic drift: chance cause population to evolve unpredictably.
A numerical calculation.
The general case
The hardy Weinberg equilibrium principle
1) the allele frequencies in population will not change, generation after generation
2) if the allele frequencies in a population are given by p and q , the genotype frequencies will be given by
p2, 2pq, q2.
What use is the hardyweinberg equilibrium principle?
1. There is no selection. Equal survival rate and equal gamete in gene pool. If one survives more than the
other then Hardyweinberg is violated and allele frequency may change
2. There is no mutation. No new alleles created. If violated, some have higher mutation rate than other.
3. There is no migration. No one moves in/out
4. There are no chance events. So no individuals will have more genotypes of alleles passed on than
others. The model population is infinite large. If violated, then genetic drift or more alleles contribute to new
5. Individuals choose their mates at random. When violated, individuals choose mate with same genotype
causing alleles frequency to not change through generations.
Changes in frequency of CCR532 allele. Mendelian genetics in population I:
selection and mutation (180217)
All ccr5 genotypes survive and reproduce at equal rate, no mutation, no migration, large population and
people choose mates random. The frequency of CCR5 allele will not change.
violation of hardyweinberg isselection : when individuals of phenotypes survive to sexual maturity at
higher rates than those with other phenotypes / when individuals with phenotypes produce more offspring
during reproduction than those with different phenotype. Selection leads to evolution and is heritable, when
phenotype associated with genotypes.
Adding selection to hardyweinberg analysis.
Empirical research on allele frequency change by selection
When fruitflies had different diet that is already violation of Hardy=Weinberg.
Adding selection to the hardyweinberg analysis: calculation of genotype frequency.
Empirical research on selection and genotype frequencies.
Mother pregnant is susceptible to malaria. So this is violation to assumption 2: no mutation.
Changes in frequency of CCR532 allele revisited.
Heterozygous are susceptible to infection, these copies are hidden from selection.
6.3 patterns of selection: testing predictions of population genetics theory.
Selection on recessive and dominant alleles
Dominance and allele frequency interact to determine the rate of evolution. When recessive allele is
common ( and dominant allele is rare), evolution by natural selection is rapid. When recessive is rare,
dominant allele is common, evolution by natural selection is slow. It is because if dominant is common, then
there will be little change since Aa + AA has always shown.
Dominant and recessive describes genotype and phenotype not genotype/fitness
Selection on heterozygotes and homozygotes.
Selection favoring heterozygotes.
Heterozygote superiority/ overdominance: heterozygotes have higher fitness than homozygous. At
equilibrium the selective advantage enjoyed by lethal allele when it is heterozygous balances disadvantage
it suffers when it is in homozygotes. The favored allele will reach 100% while other will disappear.
Selection favoring homozygotes.
Homologous chromosomes of fruit flies. Underdominance: when fitness of genotypes are in mixed
population. Equilibrium of p2 is 0.5 q2 is 0.5. even when its p2=0.25, q2=1, one kind of homozygote will
have higher fitness than the other.
Leads to loss of genetic diversity within. By driving different allele to fixation in different population,
heterozygotes inferiority help maintain genetic diversity among populations. Mendelian genetics in population I:
selection and mutation (180217)
Frequency dependent selection.
Frequency dependent selection: selection favors one alleles until it becomes too common, then favors the
other allele. Both frequency dependent selection and heterozygote superiority help maintain genetic
diversity in population
Most serious genetic diseases are recessive, sterilization would have little impact on frequency at which
new affected individuals are born. Mainstream attitudes about reproductive rights have changed in favor
individual autonomy over societal mandates. Growing list of diseases alleles are known to maintain
population by heterozygote superiority. It would be futile to reduce frequency of alleles by preventing
affected individuals from reproducing.
Sterilization sought to reduce the fitness of particular genotype to zero and reduce frequency of alleles
responsible for undesirable phenotypes.
Adding mutation to the hardyweinberg analysis: mutation as an evolutionary mechanism.
Mutation is not a rapid mechanism of evolution.
Mutation and selection
Inbreeding cause rapid loss of genetic variation.
Mutation selection balance.
Selection tend to eliminate deleterious mutation from population. When the rate at which copies of
deleterious allele are being eliminated = new copies created by mutation, the frequency of allele are at
equilibrium: mutationselection balance.
M=q2s. Mendelian genetics in population II:
Migration, drift & nonrandom mating. 04/02/2014
In Hardyweinberg equilibrium: when population has no selection, no mutation, no migration, an infinite
number of individuals, and random choice of mates then 1) allele frequency do not change from on
generation to the next 2. The genotype frequencies can be calculated by multiplying allele frequency.
migration: evolutionary movement of alleles between population. Migration can be caused by anything that
moves alleles far enough to go form one population to another.
Adding migration to hardyWeinberg analysis: gene flow as mechanism of evolution.
Migration as homogenizing evolutionary process.
Flower. Less variation in allele frequencies among population of intermediate age than among young/old
population. The low diversity among intermediate populations reflect homogenizing influence of gene flow.
High diversity of young/old population represent genetic drift.
Empirical research on migration VS selection
Snakes. Migration is movement of alleles form population to population. Within a participating population,
migration can cause allele frequency to change from one generation to the next. For small population
receiving immigrants from large population, migration can cause evolution. Across groups of population
gene flow tends to homogenize allele frequencies, preventing evolutionary divergence of population, unless
it is balanced by opposed mechanism of evolution.
7.2 genetic drift.
Nonselective mechanism of evolution, genetic drift is random.
Model of genetic drift.
Finite population. Sampling error: discrepancy between theoretical and actual results.
Random genetic drift: sampling error in production of zygotes from a gene pool/ genetic drift. It is
Genetic drift cannot produce adaptation, it can cause allele frequency to change.
Genetic drift and population size.
Sampling error decrease as sample size increase. Genetic drift powerful in small population, but declines in
Empirical research on sampling error as mechanism of evolution: the founder
Founder effect: allele frequencies in new population by chance to be different from what they were in
Found effect is direct result of sampling error. Cricket.
Random fixation of alleles and loss of heterozygosity.
Genetic drift: Mendelian genetics in population II:
Migration, drift & nonrandom mating. 04/02/2014
Fluctuations in allele frequency form one generation to the next caused by random sampling error, every
population follows a unique evolutionary path.
Genetic drift has more rapid dramatic effect on allele frequencies in small population than large population
Given sufficient time, genetic drift can produce substantial change in allele frequencies even in populations
that are fairly large. Genetic drift occurs if: no selection, mutation, migration. Sampling error causes allele
frequencies to be between 01 .
Eventually, alleles drift to fixation or less and frequency of heterozygotes decline.
Random fixation of alleles. When one allel become fixed, other one will lost
Loss of heterozygoisty.
As allele frequency in finite population drift toward fixation/loss, frequency of heterozygotes decrease.
Heterozygosity: frequency of heterozygotes in a population
Fixation index: when one allele= 1 , other allele = 0
An experiment an random fixation and loss of heterozygosity.
Effective population size: lost heterozygosity as though they contained fewer individuals.
Genetic drift allows us to make accurate prediction about behavior of alleles in finite population.
Random fixation and loss of heterozygosity in natural populations
Lizards genotype. When loci is fixed in single alleles, genetic variation should be low. When allele become
fixed in population there should be genetic diversity among population.
Genetic drift leads to random fixation and reduced heterozygosity. The loss of genetic diversity in small
populations: genetic diversity is for adaptive evolution. Loss of heterozygosity shows increase
homozygosity. Increase homozygosity lead to reduce fitness in population. Inbreeding depression: exposes
deleterious alles in selection.
7.4 nonrandom mating
inbreeding: nonrandom mating. Mating among genetic relatives. It increases freuqncy of homozygotes.
Empirical research on inbreeding.
Inbreeding produce large homozygotes.
deficient of heterozygotes could result form selection against them and in favor of homozygotes.
General analysis of inbreeding Mendelian genetics in population II:
Migration, drift & nonrandom mating. 04/02/2014
Coefficient of inbreeding: F: probability that two allels in individual are identical by descent.
Inbreeding depression: result form exposure of deleterious recessive alleles to selection. There are no
fitness consequences in heterozygotes, inbreeding increases frequency with which deleterious recessives
Inbreeding depression various among family lineages. Some show some don’t.
Nonrandom mating does not alter allele frequencies, it is not mechanism to evolution.
Nonrandom mating does alter frequency of genotype that change distribution of phenotypes in population
and alter pattern of natural selection and evolution of population. For example, inbreeding increases
frequency of homozygotes and decrease frequency of heterozygotes. This can expose deleterious
recessive alleles to selection, leading to inbreeding depression.
7.5 conservation genetics of Florida panther
inbreeding depression. Use extinction vortex hypothesis.
To help: reintroduction of lost alleles should reverse effects of drift and eliminate inbreeding
depression. Migration. evolution at multiple loci:
quantitative genetics (343353) 04/02/2014
9.3 measuring heritable variation
darwin’s theory of evolution by natural selection: If there is heritable variation among individuals in
population, if differneces in survival/reproduction among variatnts, then population will evolve. Quantitative
genetics include tools for easuring heritable variation, tools for measuring idfferences in
survival/reproductive success, predicting evolutionary response to selection.
Is height heritable? Genes and environment both play role in heritability. Heritability of trait: fraction of total
variation in trait that is due to variation in gene. Phenotypic variation: vp=total variation in a trait. Genetic
variation: vg: variation among individuals due to variation in gene. Ve: environmental variation: variation
among individual. . heritability: vg/vp=vg/(vg+ve)
Broad sense heritability: degree of genetic determination. Heritability is between 01.
Estimating heritability from parents and offspring.
Midparent: average of parents. Midoffspring: average offspring.
Difference between narrow sense and broad sense heritability: distinguish between genetic variation:
additive genetic variation vs dominance genetic variation.
Va additive genetiv variation is variation among individuals due to additive effects of genes.
vd dominance genetic variation is variation among individuals due to gene interactions such as dominance.
Vg=va + vd. H^2=va/vp=va/(va+vd+ve)
Narrow sense heritability allow us to predict how population wll respond to sleeciton because it describes
extent to which offspring resemble parents. Make sure no correlation between environment experienced by
parents and experienced by offspring. To measure if beak depth is heritable: place baby egg into foster
parent and see if their beaks will be differnet from real parents. Baby bird similar to real parent beak.
Heritability is .98. winnign running horse is because of environment, not genetics: heritability is .095+.034.
Estimating heritability from twins.
Another method to estimate heritability: regression of offspring on paretns, and studying twins. If heritability
is high, variation among individuals is due mostly to variation in genes, then monozygotic twins will be more
similar than dizygotic twin. If heritability is low, variation among individuals is due mostly to variation in
environment, then monozygotic twin will be different than dizygotic twins. Cognitive ability is heritabile .62.
cognitive ability heritability increases with age because individuals with differnet genotypes may choose
differnet life experiences.
9.4 measuring differences in survival and reproductive successes.
Measuring strength of selection. Once we measure heritable variation and strength of selection, we predict
evolutionary change in response t oselection. Individuals with some trait value survive higher rate/ produce
more offspring with individual of other trait value. To measure strength of selection: ntoe who
survives/reproduce and who fials. evolution at multiple loci:
quantitative genetics (343353) 04/02/2014
I. Assign absolute fitness to mice in population. Think of fitness as survival to reproductive age.
In population, 1/3 mice survived to reproduce. Short tail 2/3 have fitness of 0. Long tial have
fitness of 1.
II. Convert absolute fitness to relative fitness. Mean fitness of population is: (20x 0) + (10 x 1 ) / 30
= 0.33 . then relative fitness of short tail mice is 0/.33=.33 relative fitness of long tial mice is
III. Make a stterplot of relative fitness as function of tial length and calculate slope of regression
line. Slope of this best fit line is selction gradient.
In selection gradient we can calculate for measure of fitness, not just survival.
9.5 predicting evolutionary response to selection
R=h^2 s used to study evolution of quantitative traid under natural selection and estimate how much
variation in trait is due to variation in genes, quantify the strength of selection that result from differences in
survival/reproduction and predict how population will change from one generation to the next.
Alpine skypilots and bumblebees. In timberline, skypilot flowers pollinated by differnet insects. In tundra,
flower only pollinated by bumblebee.
2 control to see that bumble bee select larger flowers: she pollinate skypilot by hand and allow skypilot to
be pollinated by others but bee. neither was there relationship between flower size and fitness. Only bumble
bees select larger flower. Found that flowers pollinated by bees were bigger than flower pollinated by hand.
Throughbred racehorses and breeding fees.
Selection on multiple traits and correlated characters.
9.7 the bell curve fallacy and other misinterpretations of heritability.
A key point os formula for heritability includes genetic vraition bg and environmental variation ve. Heritability
is specific to population living in particular environment. It tells us nothing about cuase of differnces
between population living in different environment. Achillea: wildflower: grow from cutting and making
clones. When plants had the same environment, differences in height is because of genetic variation.
Heritability size of population is 1 in Stanford location. In mather population, plants in Stanford taller than
mather. Does it mean that plants in Stanford more superior than mather? No. heritability is high in each
population tells us nothing about cuase of differences in mean between them because they’re in differnet
Unsupported claims about IQ.
Iq heritable tells us nothing about origin of differences between group.
Why measure heritability? evolution at multiple loci:
quantitative genetics (343353) 04/02/2014
If heritability is greater than 0, it tells us that selecting on trait will cause population to evolve. If heritability is
less 1, it tells us that latering environment can shift a population’s trait distribution.
Quantitative traits show continuous variation among individuals. They are influenced by the genotype at
many loci as well as environment.
Sometimes we can identify loci that contribute to a quantitative triat. We strt with phenotypically distinct
parental stains or sepcies in which we have identified marker loci where different alleles are fixed in each
parental population. We then generat a larg population of f2 individuals and look for associations between
gentype at the marker loci vs phenotype. Such associations indicate that marker is linked to a locus that
influences the trait of interest . if known proteinencoding genes are nearby, they may warrant futher
Often we do not know the identity of loci that influence a quantitative triat. Quantitative genetics gives us
tools for analyzigng the evolution of such traits, anyway. Heritability, the fration of overall variation due to
genetic cuases, can be estimated by examining similarities among relatives. The strength of selection can
be measured by analyzing the relationship between phenotypes and finesss.
When we know both the heritability of trait and the strength of selection on trait,j we can predict how the
population will evolve in response to selection.
Selection on quantitative traits can follow a variety of patterns, including directional slection, stabilitizing
selection, and disruptive selection. Directional selection and stabilizing selction reduce gentic variation in
populations. Nonetheless, genetic variation persists in most populations , even for traits closely related to
Genetic variation for fitnessrelated traits may persist because most populations are not in equilibirium,
because there a balance between mutation and selection, or because disruptive selection ( and related