Phylogeny and Molecular Evolution

Introduction part I

1 Credit

• Serafim Batzoglou (UPGMA slides) http://www.stanford.edu/class/cs262/Slides • Notes by Nir Friedman, Dan Geiger, Shlomo Moran, Ron Shamir, Sagi Snir, Michal Ziv-Ukelson • Durbin et al. • Jones and Pevzner’s lecture notes • Bioinformatics Algorithms book by Phillip Compeau and Pavel Pvzner.

2/62 3/62 4/62 5/62 Characterizing Evolution • Anatomical and behavioral features were the dominant criteria used to derive evolutionary relationships between species since Darwin

• Equipped with analysis based on these relatively subjective observations, the evolutionary relationships derived from them were often inconclusive and/or later proved incorrect

6/62 How did the panda evolve?

• For roughly 100 years scientists were unable to figure out which family the giant panda belongs to • In 1870 Père Armand David, returned to Paris from China with the bones of the mysterious creature which he called simply “black and white bear.” Biologists examined the bones and concluded that they more closely resembled the Giant panda bones of a red panda (raccoons) than those of bears. • In 1985, Steve O’Brien et al. solved the giant panda classification problem using DNA sequences (the giant panda is a bear) Red panda

7/62 Evolutionary Tree of Bears and Raccoons (O’Brien 1985)

O’Brien’s study used about 500,000 nucleotides to construct the evolutionary tree of bears and raccoons.

Note that bears and raccoons diverged just 35 million years ago and they share many morphological features.

8/62 Human closer to Dog or Mouse?

9/62 Human closer to Dog or Mouse?

10/62 11/62 12/62 13/62 14/62 Human closer to Dog or Mouse?

Which Monkey is Human Closest to? 15/62 Evolutionary Trees: DNA-based Approach

• In the 1960s, Emile Zuckerkandl and Linus Pauling brought reconstructing evolutionary relationships with DNA into the spotlight • In the first few years after Zuckerkandl and Pauling proposed using DNA for evolutionary studies, the possibility of reconstructing evolutionary trees by DNA analysis was hotly debated • Now it is a dominant approach to study evolution. Emile Zuckerkandl on human-gorilla evolutionary relationships: From the point of hemoglobin structure, it appears that gorilla is just an abnormal human, or man an abnormal gorilla, and the two species form actually one continuous population.

Emile Zuckerkandl, Classification and Human Evolution, 1963 Gaylord Simpson vs. Emile Zuckerkandl:

From the point of hemoglobin structure, it appears that gorilla is just an abnormal human, or man an abnormal gorilla, and the two species form actually one continuous population.

Emile Zuckerkandl, Classification and Human Evolution, 1963 From any point of view other than that properly specified, that is of course nonsense. What the comparison really indicate is that hemoglobin is a bad choice and has nothing to tell us about attributes, or indeed tells us a lie. Gaylord Simpson, Science, 1964 Who are closer? Different Trees Obtained Based on Different Genes

Betta Globin Dopamine D4 receptor 20/62 Human-Chimpanzee Split? Chimpanzee-Gorilla Split? Three-way Split? Sequence Comparison and Homology

When two protein sequences are being compared and the similarity is considered statistically significant, it is highly likely that the two proteins are evolutionary related.

Proteins are homologous if they are related by divergence from a common ancestor.

Two kinds of biological homology relationships:

Orthologs - Proteins that carry out the same function in different species.

Paralogs - Proteins that perform different but related functions within one organism

24 25 Copy of a gene inserted next to the original

Two copies mutate independently Each can take on separate functions

All or part can be transferred from one part of genome to another

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30/62 Evolutionary Tree of Humans (mtDNA)

Vigilant, Stoneking, Harpending, Hawkes, and Wilson (1991) Evolutionary Tree of Humans

• Around the time the giant panda riddle was solved, a DNA-based model of the human evolutionary tree lead to the Out of Africa Hypothesis:

• Claims our most ancient ancestor lived in Africa roughly 200,000 years ago

32/62 Human Evolutionary Tree (cont’d)

Based on 53 individuals’ mitochondrial DNA (16,587bp ) http://www.mun.ca/biology/scarr/Out_of_Africa2.htm 33/62 The Origin of Humans: ”Out of Africa” vs Multiregional Hypothesis Out of Africa: Multiregional: • Humans evolved in • Humans evolved in the last two Africa ~150,000 million years as a single species. years ago Independent appearance of modern • Humans migrated out of Africa, traits in different areas replacing other • Humans migrated out of Africa humanoids around mixing with other humanoids on the the globe way • There is no direct descendence from • There is a genetic continuity from Neanderthals Neanderthals to humans Human Migration Out of Africa

http://www.becominghuman.org Evolutionary Tree of Humans (mtDNA)

The evolutionary tree separates one group of Africans from a group containing all five populations.

Vigilant, Stoneking, Harpending, Hawkes, and Wilson (1991) mtDNA analysis supports “Out of Africa” Hypothesis • African origin of humans inferred from: • African population was the most diverse (sub-populations had more time to diverge) • The evolutionary tree separated one group of Africans from a group containing all five populations. • Tree was rooted on branch between groups of greatest difference. Evolutionary Tree of Humans (mtDNA)

The evolutionary tree separates one group of Africans from a group containing all five populations.

Vigilant, Stoneking, Harpending, Hawkes, and Wilson (1991) Two Neanderthal Discoveries

Feldhofer, Germany

Mezmaiskaya, Caucasus

Distance: 25,000km Two Neanderthal Discoveries

•Is there a connection between Neanderthals and today’s Europeans? •If humans did not evolve from Neanderthals, whom did we evolve from? Multiregional Hypothesis?

• May predict some genetic continuity from the Neanderthals through to the Cro- Magnons up to today’s Europeans

• Can explain the occurrence of varying regional characteristics Sequencing Neanderthal’s mtDNA

•mtDNA from the bone of Neanderthal is used because it is up to 1,000x more abundant than nuclear DNA •DNA decay over time and only a small amount of ancient DNA can be recovered (upper limit: 100,000 years) •PCR of mtDNA (fragments are too short, human DNA may mixed in) Neanderthals vs Humans: surprisingly large divergence

• AMH vs Neanderthal: • 22 substitutions and 6 indels in 357 bp region

• AMH vs AMH • only 8 substitutions

AMH = Anatomically Modern Human 44/62 New Fossil (Manot Cave) Supports OOA This means several things. 1. First, unless and until other fossil evidence is found, AMHs once they left Africa came though the Sinai and Levant region stopping in what is now modern day Israel before migrating outwards into Europe and the rest of Asia. 2. Secondly, this discovery conclusively shows that AMHs were indeed living near and perhaps even next to Neanderthals as early as 60,000 years ago. 3. Thirdly, the Out of Africa (OOA) hypothesis becomes the best evidenced hypothesis regarding how early humans migrated and conquered the planet.

45/62 Phylogenetic Trees applied as Crime Evidence

46/62 Phylogenetic Analysis of HIV Virus

• Lafayette, Louisiana, 1994 – A woman claimed her ex-lover (who was a physician) injected her with HIV+ blood • Records show the physician had drawn blood from an HIV+ patient that day • But how to prove the blood from that HIV+ patient ended up in the woman?i

HIV is the virus causing AIDS !!! HIV Transmission

• HIV has a high mutation rate, which can be used to trace paths of transmission • Two people who got the virus from two different people will have very different HIV sequences • Three different tree reconstruction methods (including parsimony) were used to track changes in two genes in HIV (gp120 and RT)

HIV is the virus causing AIDS !!! HIV Transmission

• Took multiple samples from the patient, the woman, and controls (non-related HIV+ people) • In every reconstruction, the woman’s sequences were found to be evolved from the patient’s sequences, indicating a close relationship between the two • Nesting of the victim’s sequences within the patient sequence indicated the direction of transmission was from patient to victim • This was the first time phylogenetic analysis was used in a court case as evidence (Metzker, et. al., 2002)

HIV is the virus causing AIDS !!! Evolutionary Tree Leads to Conviction 51/62 52/62 End Lecture

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