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Sequencing extinct human ancestors

Sequencing extinct human ancestors. The Hominid Lineage. Archaeology. Archaeology – “the scientific study of material remains (as fossil relics, artifacts, and monuments) of past human life and activities” Studies the time period starting at the Paleolithic time until the advent of literacy .

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Sequencing extinct human ancestors

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  1. Sequencing extinct human ancestors

  2. The Hominid Lineage

  3. Archaeology • Archaeology – “the scientific study of material remains (as fossil relics, artifacts, and monuments) of past human life and activities” • Studies the time period starting at the Paleolithic time until the advent of literacy • Slide Credits to Vanessa Patel

  4. The Neanderthal Genome • From bones, compared genomes of three different Neanderthals with five genomes from modern humans from different areas of the world • Figure 1- R. E. Green et al., Science 328, 710-722 (2010) • Slide Credits to Vanessa Patel

  5. Genomic Analysis Stoneking, Krause, Nature Reviews Genetics 2011

  6. Genomic Analysis Stoneking, Krause, Nature Reviews Genetics 2011

  7. Neanderthal Genome

  8. Neanderthal Genome

  9. Model-based analyses Stoneking, Krause, Nature Reviews Genetics 2011

  10. Neanderthal Genome

  11. Neanderthal Genome

  12. Denisovan– Another human relative

  13. Denisovan– Another human relative

  14. Out of Africa Refined Stoneking, Krause, Nature Reviews Genetics 2011

  15. Denisovan

  16. DenisovanAdmixture

  17. Denisovan Admixture

  18. Aboriginal Australian

  19. Aboriginal Australian

  20. Archaic African Admixtures

  21. Archaic African Admixture Signature Haplotypes: • Highly diverged • High LD over a long region

  22. Fixation, Positive & Negative Selection How can we detect negative selection? How can we detect positive selection? Negative Selection Neutral Drift Positive Selection

  23. How can we detect positive selection? Ka/Ks ratio: Ratio of nonsynonymous to synonymous substitutions Very old, persistent, strong positive selection for a protein that keeps adapting Examples: immune response, spermatogenesis

  24. How can we detect positive selection?

  25. Mutations and LD X X X Slide Credits:Marc Schaub

  26. Slide Credits:Marc Schaub

  27. Extended Haplotype Homozygozity S1 S2 S3 S4 S5 S6 Slide Credits:Marc Schaub

  28. Extended Haplotype Homozygozity Core C Slide Credits:Marc Schaub

  29. Extended Haplotype Homozygozity Core C • 3 core haplotypes: ch0 = 101 ch1 = 111 ch2 = 100 Slide Credits:Marc Schaub

  30. Extended Haplotype Homozygozity Core C • 3 core haplotypes: ch0 = 101 ch1 = 111 ch2 = 100 Slide Credits:Marc Schaub

  31. Extended Haplotype Homozygozity Core C • 3 core haplotypes: ch0 = 101 ch1 = 111 ch2 = 100 Slide Credits:Marc Schaub

  32. Extended Haplotype Homozygozity • Given a core haplotype (101) and a SNP (S6) • EHH is the conditional probability of two randomly chosen chromosomes to be homozygous from the core to S6 given that they include core haplotype 101 Core C

  33. Extended Haplotype Homozygozity • EHH is the conditional probability of two randomly chosen chromosomes to be homozygous from the core to S6 given that they include core haplotype 101 Core C Slide Credits:Marc Schaub

  34. Extended Haplotype Homozygozity • EHH is the conditional probability of two randomly chosen chromosomes to be homozygous from the core to S6 given that they include core haplotype 101 Core C Slide Credits:Marc Schaub

  35. Extended Haplotype Homozygozity Core C Slide Credits:Marc Schaub

  36. Application: Malaria • Study of genes known to be implicated in the resistance to malaria. • Infectious disease caused by protozoan parasites of the genus Plasmodium • Frequent in tropical and subtropical regions • Transmitted by the Anophelesmosquito Slide Credits:Marc Schaub Image source: wikipedia.org

  37. Application: Malaria Slide Credits:Marc Schaub Image source: NIH - http://history.nih.gov/exhibits/bowman/images/malariacycleBig.jpg

  38. Application: Malaria Slide Credits:Marc Schaub Image source: CDC - http://www.dpd.cdc.gov/dpdx/images/ParasiteImages/M-R/Malaria/malaria_risk_2003.gif

  39. Results: G6PD Slide Credits:Marc Schaub Source: Sabeti et al. Nature 2002.

  40. Results: G6PD Slide Credits:Marc Schaub Source: Sabeti et al. Nature 2002.

  41. Results: G6PD Slide Credits:Marc Schaub Source: Sabeti et al. Nature 2002.

  42. Results: TNFSF5 Slide Credits:Marc Schaub Source: Sabeti et al. Nature 2002.

  43. Results: TNFSF5 Slide Credits:Marc Schaub Source: Sabeti et al. Nature 2002.

  44. Malaria and Sickle-cell Anemia • Allison (1954): Sickle-cell anemia is limited to the region in Africa in which malaria is endemic. Distribution of malaria Distribution of sickle-cell anemia Slide Credits:Marc Schaub Image source: wikipedia.org

  45. Malaria and Sickle-cell Anemia • Hypothesis: mutation causing sickle-cell anemia positively selected for the resistance to malaria. • Currat (2002) and Ohashi (2004) identify the mutations in the African respectively Asian populations. Slide Credits:Marc Schaub

  46. Malaria and Sickle-cell Anemia • Single point mutation in the coding region of the Hemoglobin-B gene (glu → val). • Heterozygote advantage: • Resistance to malaria • Slight anemia. Slide Credits:Marc Schaub Image source: wikipedia.org

  47. Slide Credits:Marc Schaub

  48. Lactose Intolerance Slide Credits:Marc Schaub Source: Ingram and Swallow. Population Genetics of Encyclopedia of Life Sciences. 2007.

  49. Lactose Intolerance LCT, 5’ LCT, 3’ Slide Credits:Marc Schaub Source: Bersaglieri et al. Am. J. Hum. Genet. 2004.

  50. Lactose Intolerance Slide Credits:Marc Schaub Source: Catherine Janet Ellen Ingram and Dallas Mary Swallow. Population Genetics of Lactase Persistence and Lactose Intolerance advanced. Encyclopedia of Life Sciences. 2007.

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