We can learn about how they evolve from studies of sequence divergence between proteins from homologous organisms.

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2 We can learn about how they evolve from studies of sequence divergence between proteins from homologous organisms.

3 Refers to any similarity between characteristics that is due to their shared ancestry. Orthologs Homologs produced by speciation. They tend to have similar function. Paralogs Homologs produced by gene duplication. They tend to have differing functions. Xenologs Homologs resulting from horizontal gene transfer between two organisms.

4 Orthologous or Paralogous Homologs Early globin gene -chain gene ß-chain gene mouse human cattle cattle ß human ß mouse ß Orthologs ( ) Paralogs (cattle) Orthologs (ß) Homologs

5 The process of change in all forms of life over generations.

6 Four Force of Evolution Adaptation. Mutation (very slow). Natural selection (causes adaptive evolution). Nuetral drift (chance; causes nonadaptive evolution).

7 Adaptation Is the change in living organisms that allow them to live successfully in an environment. The Oxford Dictionary of Science defines adaptation as "Any change in the structure or functioning of an organism that makes it better suited to its environment ".

8 Mutation Change in primary amino acid sequence Type of Mutation A. Silent mutations B. Point mutations

9 Type of Mutation A. Silent mutations Code for the same amino acid. B. Point mutations Change in only one pair of nucleotid as follows:

10 Missense mutations: Code for a different amino acid. Nonsense mutations: Code for a stop, which stop protein formation(uaa, UGA, UAG). Frameshift mutation: Addition or deletion of bases leading to altered sequence beyond the sequence change.

11 Natural Selection a process causing heritable traits that are helpful for survival and reproduction to become more common in a population, and harmful traits to become more rare.

12 This occurs because individuals with advantageous traits are more likely to reproduce, so that more individuals in the next generation inherit these traits.

13 Neutral Drift Is an dependent process that produce random changes in the frequency of traits in a population. Genetic drift results from the role probability plays in whether a given trait will be passed on individuals survive and reproduce.

14 In a large population this will not have much effect in each generation because the random nature of the process will tend to average out. But in a small population the effect could be rapid and significant.

15 Evolution Chemical Evolution Structural Evolution

16 Chemical Evolution The evolutionary aspects of amino acid sequences. Evolutionary changes, which stem from random muational events, often alter a protein s primary structure.

17 Sickle Cell Anemia :The Influence of Natural Selection Hemoglobin Transport oxygen through body. Has 4 subunits: α2β2. Contained in red blood cells at high concentration. RBC is flexible biconcave disks and has to contort to fit through small sized capillary sections.

18 Sickle Cell Anemia :The Influence of Natural Selection Sickle cell anemia RBC assume crescent-like shape under low oxygen concentration. More rigid and hinders free passage. Molecular disease :Term coin by Linus Pauling. Caused by mutant hemoglobin.

19 Replacement of a negatively-charged glu in the standard HbA by a neutral val in HbS results in a protein with a slightly reduced negative charge.

20 Electrophoretic studies show that sickle cell hemoglobin HbS is two units more positive than HbA (normal).

21 Sickle cell confers resistance to malaria Sickle cell trait follow Mendelian genetics. Homozygotes have hemoglobin with all HbS Heterozygotes have approx. 40% HbS. Such people have sickle cell trait and can lead normal life. Anthony Allison Led to discovery that individuals heterozygote are resistant to malaria.

22 How does Sickle Cell Confer resistance to Malaria? Malaria caused by protozoan Plasmodium Falciparum. Plasmodia increase acidity of erythrocytes they infect by ~0.4 PH units. This causes erythrocytes to adhere to proteins lining capillary walls and thus avoid removal from spleen. Normally, ~2% of erythrocytes of those with sickle cell trait are sickle under low oxygen tension.

23 How does Sickle Cell Confer resistance to Malaria? With sickle cell trait, the decrease in ph causes increase in sickled cell shape of up to ~40%. This causes preferential removal of infected cells. The sickling induced by this low oxygen environment cells may mechanically and/or metabolically disrupt the parasite. Heterozygotes have advantage in surviving malaria.

24 Sickle Cell Anemia and Malaria Environment Without Malaria HbA HbA are normal HbS HbS die HbA HbS display symptoms of sickle cell anemia Environment With Malaria Parasite HbA HbA are normal but die of malaria HbS HbS die HbA HbS display symptoms of sickle cell anemia but are resistant to malaria

25 Species Variations in Homologous Protein :The Effects of Neutral Drift To examine homologous proteins and study an example of an orthologue. To apply genetic understanding to explain how different orthologues proteins can arise. To use the Biology Work Bench to comparin Cytochrome C from a variety of different species.

26 Cytochrome c: an Orthologue Cytochrome c has a single polypeptide chain an ancient protein, developed early in the evolution of life. It occurs in mitochondria as part of the electron transport chain. Consist of 103 or 104 residues, but in other phyla has up to 8 additional residues at its N-terminus. It has changed little in millions of years of evolution.

27 Elucidated the amino acid sequences of cytochromes c from over 100 widely diverse eukaryotic species ranging in complexity from yeast to humans. The sequences from 38 of these organisms are arranged in table so as to maximize the similarities between vertically aligned residues.

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29 Man, chimpanzee Rhesus monkey Horse Donkey Cow, pig, sheep Dog Rabbit Calif. gray whale Great gray kangaroo Chicken, turkey Pigeon Pekin duck Snapping turtle Rattlesnake Bullfrog Tuna Dogfish Samia cynthia (moth) Tobacco hornworm moth Screwworm fly Drosophila (fruit fly) Baker s yeast Candida krusei (yeast) Neurospora crassa (mold) Wheat germ Buckwheat seed Sunflower seed Mung bean Cauliflower Pumpkin Sesame seed Castor bean Cottonseed Abutilon seed DTLMEYLENPKKYIPGTKMIFVG DTLMEYLENPKKYIPGTKMIFVG ETLMEYLENPKKYIPGTKMIFAG ETLMEYLENPKKYIPGTKMIFAG ETLMEYLENPKKYIPGTKMIFAG ETLMEYLENPKKYIPGTKMIFAG DTLMEYLENPKKYIPGTKMIFAG ETLMEYLENPKKYIPGTKMIFAG DTLMEYLENPKKYIPGTKMIFAG DTLMEYLENPKKYIPGTKMIFAG DTLMEYLENPKKYIPGTKMIFAG DTLMEYLENPKKYIPGTKMIFAG ETLMEYLENPKKYIPGTKMIFTG DTLMEYLENPKKYIPGTKMVFTG DTLMEYLENPKKYIPGTKMIFAG DTLMEYLENPKKYIPGTKMIFAG ETLRIYLENPKKYIPGTKMIFAG DTLFEYLENPKKYIPGTKMVFAG DTLFEYLENPKKYIPGTKMVFAG DTLNPKLENPKKYIPGTKMIFAG DTLFEYLENPKKYIPGTKMIFAG NNMSEYLTNPKKYIPGTKMAFGG PTMSDYLENPKKYIPGTKMAFGG NTLFEYLENPKKYIPGTKMAFGG NTLYDYLLNPKKYIPGTKMVFPG DTLYEYLLNPKKYIPGTKMVFPG NTLYDYLENPKKYIPGTKMVFPG KTLYDYLENPKKYIPGTKMVFPG KTLYDYLENPKKYIPGTKMVFPG KTLYDYLENPKKYIPGTKMVFPG NTLYDYLENPKKYIPGTKMVFPG NTLYAYLENPKKYIPGTKMVFPG NTLYDYLENPKKYIPGTKMVFPG NTLYDYLENPKKYIPGTKMVFPG

30 Human Gly Asp Val Glu Lys Gly Lys Lys Ile Phe Ile Met Lys Cys Ser Gln Cys His Thr Val Glu Lys Pig Val Gln - - Ala Chicken - - Ile Val Gln Dogfish Val - Val Gln - - Ala Asn Drosophi la << < Leu Val Gln Arg Ala Ala Wheat << < - Asn Pro Asp Ala - Ala Lys Thr - - Ala Asp Ala Yeast << < - Ser Ala Lys - - Ala Thr Leu - Lys Thr Arg - Glu Leu

31 In table indicates that cytochromes c is an evolutionarily conservative protein. a total of 38 of its 105 residues (23 in all that have ben sequenced)are invariant and most of the the remaining residues are conservative substituted. In contrast, there are 8 position that each accommodate six or more different residue and, accordingly, are described as being hypervariable. However, the biochemical significance of most of the invariant or conservatively substituted residues of cytochrom c can only be profitable assessed in term of the protein s three dimensional structure.

32 The easiest way to comare the evolutionary differnces between two homologous protein is simply to count the amino acid differences between them. we can tabulation of amino acid sequances differences among 22 of the cytochromes c listed in table.

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34 Thus primate cytochromes c more nearly resemble those of other mammale than they dof,or example, those of insect(8-12 differences for mammals vs for insect).similarly, the cytochromes c of fungi differ as much from those of mammals (41-47) or higher plants (47-54). We can analysis of data such as those in table aphylogenetic tree can be constructed that indicates the ancestral relationships among the organisms which produced the protein.

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36 Displays a phylogenetic tree (a diagram illustrating the evolutionary relationships among a group of organisms) constructed from the sequences of cytochrome c. The tree has been deduced by computer analysis of these sequences to find the minimum number of mutational changes connecting the branches. Similar tree have been derived for other protein. Each branch point of a tree indicates the probable existence of common ancestor for all the organisms above it.

37 The relative evolutionary distances between neighboring branch point are expressed as the number of amino acid differences per 100resides of the protein. This furnishes a quantitative measure of the degree of relatedness of the various species that macroscopic toxonomy cannot provide. Evolutionary trees constructed in this manner, that is, solely on the basis of amino acid differences occurring in the primary sequence of one selected protein, show remarkable agreement with phylogenetic relationships derived from more classic approaches and have given rise to the field of molecular evolution.

38 Mammals Birds/Reptiles Pliocene Oligocene Miocene Eocene aleocene Cretaceous Jurassic Triassic Permian Carboniferous Devonian Silurian Ordovician Cambrian Algonkian Huronian Corrected amino acid changes per 100 residues Mammals/ Reptiles Reptiles/Fish Carp/Lamprey Insects ab cd e f g h i V ertebrates/ j Evolution of the globins Millions of years since divergence

39 References 1.X. Gu, "Statistical methods for testing functional divergence after gene 2.duplication" Mol. Biol. Evol. 16: (1999). 3.www_bio_mtu_edu-campbell-401l10f4_gif. 4.http--www_asa3_org-aSA-PSCF-1992-PSCF12-92MillsFig3_jpg.mht 5.http--anthro_palomar_edu-synthetic-images-map_of_sickle_cell_frequencies_gif.mht 6.http--fig_cox_miami_edu-~cmallery-150-gene-sf12x16_jpg.mht 7. http--mvl_chem_tu-berlin_de-ak_hildebrandt-hildebrandt-images-cyt_1_jpg.mht. 8. http--www_detectingdesign_com-images-methinks cytochrome%20c_jpg.mht 9. http--dbs_umt_edu-courses-fall2006-bioc380-lectures-009-images-cyt-c-seq_jpg.mht 10.http--www_muhlenberg_edu-depts-biology-courses-bio152 BioinformaticsLabsymptoms_gif.mht 11.http--academic_brooklyn_cuny_edu-biology-bio4fv-pag molecular%20biologymutation-neutral_jpeg.mht lhttp://philosophy.wisc.edu/forster/220/notes_4.html

40 Thank you