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Discussions – Optional

Discussions – Optional . I. Wednesday 3:30-4:20 p.m. Noland 342 II. Friday 1:20-2:10 p.m. Noland 539. Examples: Adaptation or not?. After high altitude training athletes have increased number of red blood cells (RBC)

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Discussions – Optional

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  1. Discussions – Optional I. Wednesday 3:30-4:20 p.m. Noland 342 II. Friday 1:20-2:10 p.m. Noland 539

  2. Examples: Adaptation or not? • After high altitude training athletes have increased number of red blood cells (RBC) • Tibetans and Sherpas have higher RBC than lowland (<2000 m) people (Yi et al. 2010, Science 329:75-78)

  3. Examples: Adaptation or not? • Weeds from a cornfield have been found to grow taller than those from soybean fields when both populations are reared in common-garden conditions • Taller weeds from the cornfields survive at a greater rate and leave more offspring

  4. EPIGENETICS

  5. WHAT IS EPIGENETICS? • Epigenetics – gene regulation changes that does not involve a change in DNA sequence • Epigenetic changes can be INHERITED!!

  6. EPIGENETICS Common mechanisms may include but not limited to: -DNA methylation -Histone modifications (De)Acetylation (De)Methyaltion, Ubiquitination, Phosphorylation -Regulatory non-coding RNAs

  7. DNA methylation

  8. Transgenerational inheritance of mothering style and stress in rat Youngson and Whitelaw (2008)

  9. Mechanisms of Adaptation Need Genetic variation upon which selection could act This variation could occur at many hierarchical levels: At different structural levels And at different steps leading to protein expression

  10. OUTLINE The origin of genetic variation Examples of structural and regulatory change by mutations Detection of selection (adaptation)

  11. The origin of genetic variation

  12. Sources of Variation Point Mutations nucleotide substitution Insertions or Deletions Insertions or deletions of nucleotides Gene duplications (insertions) or loss Chromosomal Duplications Whole Genome Duplications

  13. Where does the polymorphism (genetic variation) come from? • Mutations: change in genetic code • Recombination (sex): • Intragenic recombination • Gene conversion • Unequal crossing over – gene duplication • Changes by Transposable Elements

  14. Mutations Any change in the genetic code, including errors in DNA replication or errors in DNA repair

  15. Mutations Mutations that matter, in an evolutionary sense, are that get passed on to the next generation: i.e., those that occur in the cells that produce gametes (the “germ line”)

  16. Point Mutations

  17. Point Mutations: mistakes during DNA replication, or DNA repair

  18. RATE OF MUTATIONS In most species, mutation rate is LOW

  19. Mutations: Double-Edged Sword • Most mutations are ‘neutral’ with no effect on fitness • Most mutations that arise within functional genes are harmful • Mildly deleterious mutations persist longer in a population because it takes longer to select them out • Recessive mutations remain longer because they are eliminated when homozygous, not when heterozygous • Selection for favorable mutations leads to adaptation.

  20. Where does the polymorphism (genetic variation) come from? Mutations: change in genetic code Recombination (sex): Intragenic recombination Gene conversion Unequal crossing over – gene duplication Changes by Transposable Elements

  21. Gene Duplications

  22. Gene Duplications • Duplication of genes due to DNA replication error or recombination error (unequal crossing over) • Lynch and Connery 2000 • 0.01 duplications per gene per million years • Half life for a gene is 3-8 million years Crossing over

  23. Unequal crossing over

  24. Gene Duplications Duplicate genes in Eukaryotes are continuously created, tested, and discarded Duplicated genes either degenerate into pseudogenes (no function), become new genes, or subfunctionalize with an existing gene

  25. Pseudogene mutations New gene Each gene taking on subfunctions of the original gene

  26. Examples: Gene Families resulting from gene duplications • Olfactory receptors • Steroid hormone receptors • Heat shock proteins • Ion uptake enzymes • Hemoglobins • Opsins • Melanins • Detoxification enzymes (cytochrome P450s) • Hox genes

  27. Hierarchical processes that are affected by Mutations • STRUCTURAL • Primary: Amino Acid composition (Amino Acid substitutions) • Secondary, Tertiary, Quaternary structure • REGULATORY • Protein expression (transcription, RNA processing, translation, etc) • Protein activity (allosteric control, conformational changes)

  28. Diagram of eukaryotic gene

  29. Hierarchical processes that are affected by Mutations • REGULATORY • Protein expression • Transcription: Mutations at promoters, enhancers, (CIS) transcription factors (TRANS), etc • RNA Processing: Mutations at splice sites, sites of polyadenylation, sites controlling RNA export • Translation: Mutations in ribosomes, regulatory regions, etc • Protein activity (allosteric control, conformational changes)

  30. Once these mutations have occurred creating genetic variation, selection could act on genes, gene expression, and on genetic architecture (allelic and gene interactions)

  31. OUTLINE The origin of genetic variation Examples of structural and regulatory changes by mutations Detection of selection (adaptation)

  32. Example: temperature adaptation in Fundulus heteroclitus

  33. LDH

  34. LDH is a glycolytic enzyme which catalyzes the reaction between Pyruvate and Lactate

  35. Protein function STRUCTURE • Amino acid composition (AA substitutions) • Secondary, Tertiary, Quaternary structure REGULATORY • Protein expression (transcription, translation, etc) • Protein activity (allosteric control, conformational changes, receptors)

  36. Fundulus heteroclitus Populations in Maine and Georgia have different proportions of alleles (isozymes) at LDH-B

  37. Difference in alleles (isozymes) in North vs South North: LDH-B b allele (cold-adapted) South: LDH-B a allele (warm-adapted) The two alleles have a difference of 2 amino acids

  38. Place and Powers, PNAS 1979 1° latitude change = 1°C change in mean water temperature Place and Powers, PNAS 1979

  39. Catalytic efficiency (kcat/km) is higher for the b allele at low temperature, and higher for the a allele at higher temperature a allele homozygote b allele homozygote Place and Powers, 1979

  40. Catalytic efficiency (kcat/km) is higher for the b allele at low temperature, and higher for the a allele at higher temperature • The two allele products (the enzymes) show genetic differences in catalytic efficiency (adaptive differences) • They also show genotype by environment interaction: they differ in the their optimal environments (differences in plasticity) Place and Powers, 1979

  41. Protein function STRUCTURAL • Amino acid composition (AA substitutions) • Secondary, Tertiary, Quaternary structure REGULATORY • Protein expression (transcription, translation, etc) • Protein activity (allosteric control, conformational changes, receptors)

  42. activity Crawford and Powers, 1989 Common Garden Experiment: The Northern isozyme has BOTH higher activity and higher level of expression in fish at constant lab conditions (20°C temperature) protein mRNA

  43. Higher Gene Expression of LDH-B in the Northern Maine population Maine Florida Georgia New Jersey Schulte et al. 2000

  44. Transcriptionalcontrol • What controls differences in gene expression of LDH in F. heteroclitus? • Mutations within Promoter or Enhancer? Doug Crawford: Promoter Patricia Schulte: Enhancer

  45. Gene expression • Transcription Cis-regulation (at or near the gene) Examples: • RNA polymerase and promoter • Enhancers Trans-regulation(somewhere else in the genome) Examples: • Gene regulatory proteins (transcription factors)

  46. TEMPERATURE ADAPTATIONin F. heteroclitus • Cis-acting sequence ~ 500 bp upstream of the start site of transcription of LDH-B • S-population - a 7-bp site identical to a mouse mammary tumor virus glucocorticoid responsive element (MTV-GRE) repressor • N-population - this site differs from S population sequence by 1 bpand does not repress expression of LDH gene • MTV-GRE repressor inhibits transcription in the absence of stress hormones. • When stress hormone levels are high, the repression is removed and transcription increases • The putative element within the F. heteroclitus LDH-B gene might behave in a similar way.

  47. Schulte et al. 2000 GRE present control (GRE absent) Transgenic Fish Regulatory sequence (an enhancer) was injected into Northern and Southern Fish An enhancer, located within a 500 base pair sequence,significantly increased gene expression of LDH GRE present control (GRE absent)

  48. Protein function STRUCTURE • Amino acid composition (AA substitutions) • Secondary, Tertiary, Quaternary structure REGULATORY • Protein expression (transcription, translation, etc) • Protein activity (allosteric control, conformational changes)

  49. Gillichthys mirabilis sloughs and estuaries Gulf of California to Tomales Bay (38.16°N) 9–30 °C Gillichthysseta High rocky intertidal Gulf of California 5° - 41°C

  50. A4-LDHs from Gillichthys seta and G. mirabilis have identical amino acid sequences (no structural differences) • But show potentially adaptive differences in substrate affinity for Pyruvate (Km) and thermal stability Fields and Somero, 1997, Fields et al. 2002 Pyruvate Km (mmol/l) G. seta more tolerant of a broad temperature range; LDH less sensitive to temperature Temperature °C

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