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4: Genome evolution. break. Why should we care about genome evolution? Comparing the human and the chimp genomes. Genome evolution – why is it interesting?. The first working draft of the Human genome was released in 2000. (The first paper was published in the 15 february 2001 in Nature)

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  1. 4: Genome evolution break

  2. Why should we care about genome evolution? Comparing the human and the chimp genomes

  3. Genome evolution – why is it interesting? The first working draft of the Human genome was released in 2000. (The first paper was published in the 15 february 2001 in Nature) September 01, 2005: the full genome of the Chimpanzee is published in Nature.

  4. Genome evolution – why is it interesting? • The biggest question for molecular evolutionists: • WHAT MAKES US HUMAN? • By comparing the human and chimp • genomes we can search for the genetic • differences responsible for the • human characteristics such as • Large cranial capacity • Bipedalism • Developed brain

  5. Types of differences – at the molecular level • What are the kind of differences between the genomes? • Single-nucleotide substitutions • Insertions and deletions (indels) • Genes and genomes (partial) duplications • Rearrangements

  6. Types of differences – at the molecular level Human are Chimp are both 3 billion (3,000,000,000) nucleotides long. There are about: 35,000,000 nucleotide differences (~1.2%) 5,000,000 indels (insertions and deletions) Many chromosomal rearrangements Most of these differences are probably neutral. The challenge: find the few that are meaningful!

  7. Known differences 1: Diseases/Pathogens HIV progression to AIDS is common in humans and very rare in great apes. Humans are susceptible to Plasmodium falciparum malaria. Great apes are resistant Carcinomas (epithelial cancer) is common in humans and rare in great apes.

  8. Known differences 2: Karyotype Human karyotype

  9. Karyotype All members of Hominidae except humans have 24 chromosomes. Humans have only 23 chromosomes.

  10. Karyotype: fusion Human chromosome 2 is widely accepted to be a result of an end-to-end fusion of two ancestral chromosomes. from Yunis, J. J., Prakash, O., The origin of man: a chromosomal pictorial legacy. Science, Vol 215, 19 March 1982, pp. 1525 - 1530

  11. Karyotype: invertion There are large inversions on human chromosomes 4 and 5 relative to the chimp. There are hundreds of invertions of smaller size

  12. Known differences 2: Karyotype • Chimps have an additional chromosome compared to human because the genetic material on human chromosome 2 is split between chimpanzee chromosomes 12 and 13. • There are large inversions on human chromosomes 1, 4, 5 and 18 relative to the chimp. • The heterochromatic genome segments are distributed differently on several chromosomes in the two species (heterochromatin is the part of the genome that is not transcribed, and has a structural rather than functional role).

  13. Known differences 3: Gene expression • Transthyretin is a protein responsible for transporting thyroid hormones in the blood. (Thyroid hormones effect metabolic rate and have an effect on embryonic brain development). • It was found that humans have lower levels of transthyretin expression compared to chimpanzees. • Studying expression differences between human and chimps is problematic because of the huge potential for artifacts in such studies (e.g., rate of tissues deterioration after death).

  14. 3 theories Protein evolution: Most meaningful changes are due to amino-acid replacements in proteins. Gene regulatory evolution: Most meaningful changes are in non-coding regions that are responsible for gene regulation. Less is more hypothesis: Most meaningful changes are due to deletions, stop codons in coding proteins (loss of coding regions) and deletions of entire genes.

  15. 4: Genome evolution break

  16. An example of “protein evolution” in the lineage leading to humans: The story of FOXP2: a speech and language related gene

  17. Humans can talk • Why can humans talk and chimps cannot? • Two possible explanations • Culture • Genetics • Because chimps that are raised in human environments do not acquire human linguistic competence, even with intensive tuition, we believe there is a strong genetic background underlying this difference.

  18. Humans can talk From the anatomical point of view: Humans have a longer oral cavity and a lower larynx than other primates. This is crucial for modern human speech.

  19. Humans can talk • It is expected that there are genetic differences that have impact on neurological development, for example: • The ability to control the articulators (one of the organs of speech, such as the lips or tongue). • Higher order of cognitive processing involved in language acquisition. Source: Marcus GF, and Simon EF. 2003. TRENDS in Cognitive Sciences 7:257-261.

  20. The KE family This is a unique family, 3 generations, in which 15 out of 24 members suffer from severe speech and language difficulties. Remaining relatives are unaffected.

  21. The gene is found The single gene was found by correlating the distribution of the disorder among members of the KE family with a set of DNA markers (gene hunt!)

  22. The gene is found The gene is in human chromosome 7 and is a transcription factor. The name is FOXP2. It works in a dominant fashion.

  23. The gene: a FOX transcription factor The FOXP2 is a transcription factor: it activates genes in specific tissues and/or specific physiological conditions.

  24. What’s the phenotype – a debated issue 1990. Hurst et al. Problematic verbal development (verbal dyspraxia). 1990,1991. Miriam Gopnik. More specifically, the problem is in grammar: tenses, gender, numbers, and such. (Big splash, a gene for grammar). 1995. Faaneh-Vargha-Khadem et al. Not only grammar. Also problems in face and mouth movements which impede their speech. (Maybe this is a motor problem?) 2002. Watkins et al. Against the motor problem. They also have problems in writing and in understanding.

  25. The gene: a FOX transcription factor The name FOX is for “forkhead” as mutations in the first gene from this family that was studied in the fruit fly had unusual spiked-head structures in the embryo. All FOX proteins share a 80-100 amino-acid motif (the forkhead box) responsible for DNA binding. In the KE family, the mutation is in this forkhead box. FOX are found only in animals and fungi. Yeasts have 4 FOX genes, nematode 15, fruit flies 20, and 40 in humans. This increase is suggested to be correlated with body-plan complexity.

  26. FOXP2 • It is currently unknown: • Which genes is FOXP2 activating or repressing? • Which genes activate/repress FOXP2? • Which genes work with FOXP2?

  27. FOXP2 – where is it expressed? FOXP2 is expressed in the brain, lung, gut, and heart. Many transcription factors have multiple jobs, sometimes at diverse time points during development. Why do we only see speech problems in the KE family? Maybe because other mutations are recessive.

  28. FOXP2 – evolutionary perspective • FOXP2 is also found in mouse. • There are almost no differences in the amino-acid sequence between mouse FOXP2 and human FOXP2 (3 aa differences, p-distance for nucleotides = 0.065). • Mice don’t talk. • Conclusion: FOXP2 is finally not related with speech… ?

  29. FOXP2 – evolutionary perspective • Francois Jacob: evolution is like molecular tinkering… Uses what it can find around... • There are 3 aa differences between human and mouse but two of them occurred after the divergence of chimpanzee.

  30. FOXP2 – evolutionary perspective Comparing a model of Ka/Ks in which this ratio is the same in all lineages versus a model in which the branch to humans evolves with a different Ka/Ks ratio, showed that there was a change in selection pressure in the lineage leading to modern human Source: Enard W. et al (Svante Paabo group). 2002. Nature 418:869-872.

  31. Conclusions A classical example of “Protein Evolution”- the first source of variation that can explain why species A is different from species B… In genomic scale, it could be interesting to detect all proteins with positive Darwinian selection in the lineage leading to human (and to a lesser extant, in other organisms).

  32. A remark Although this was a classical example of “Protein Evolution”- it is also an example of “Gene Regulatory Evolution”, because it involves transcription factors. These two theories have a lot in common, if protein evolution acts mainly on transcription factors…

  33. More on FoxP2 In 1972 it was discovered that rodents produce noise at ultrasonic frequencies (that human ears cannot hear). Mice do not talk but they sing…

  34. FOXP2 – evolutionary perspective

  35. FOXP2 – evolutionary perspective Knockout mice with only one functional copy of the FOXP2 gene have significantly reduced vocalizations as pups. [Shu W. et al. (2005). "Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene“ Proc Natl Acad Sci U S A 102 (27): 9643–8]

  36. FOXP2 – evolutionary perspective Bird also sing… Songbirds also require a properly functioning FoxP2 gene if they are to sing their song accurately and completely [Haesler S, Rochefort C, Georgi B, Licznerski P, Osten P, et al. (2007) Incomplete and Inaccurate Vocal Imitation after Knockdown of FoxP2 in Songbird Basal Ganglia Nucleus Area X. PLoS Biol 5(12): e321. ]

  37. Haesler S, et al. (2007) Incomplete and Inaccurate Vocal Imitation after Knockdown of FoxP2 in Songbird Basal Ganglia Nucleus Area X PLoS Biol 5(12): e321 • In bird, FoxP2 is up-regulated in Area X, a brain region important for song plasticity. In the paper they reduced FoxP2 levels in Area X before zebra finches started to learn their song, using virus-mediated RNA interference.

  38. short interfering hairpin RNA (shRNA)

  39. Haesler S, et al. (2007) Incomplete and Inaccurate Vocal Imitation after Knockdown of FoxP2 in Songbird Basal Ganglia Nucleus Area X PLoS Biol 5(12): e321 • Birds with experimentally lowered levels of FoxP2 imitated their tutor's song imprecisely and sang more variably than controls. FoxP2 thus appears to be critical for proper song development.

  40. More on FoxP2 • There have been many studies on FoxP2 in the last 5 years. • FoxP2 of bat (do animal that use echolocation use FoxP2?) • FoxP2 of Neandertal (were they talking?) • And many more….

  41. 4: Genome evolution break

  42. Story 3: The “less is more” hypothesis.

  43. The theory The claim is that loss-of-function mutations are important in recently evolved novel lineages such as humans. This theory is counter-intuitive as it suggests that humans are “degenerate apes”.

  44. The theory The theory was first suggested by MV Olson in 1999.

  45. Points in favor Deleterious mutations are very common. In yeast, 85% of the genes are not essential (knock out experiments). In some cases, knocking out a gene increased growth relative to the w.t.

  46. Points in favor • Loss of function mutations can protect against pathogens. For example, human with double mutant to CCR5 are immune to HIV-1. • The frequency of the CCR5 deleterious allele is ~15% in certain area of northern Europe, but • It is probably not the result of HIV-1 which is a new emerging pathogen. • It is difficult to separate “founder effect” from “selective advantage”.

  47. Human vs. other primates • Degenerative phenotypes in humans compared to chimpanzees are: • Delayed postnatal development • Loss of muscle • Loss of strength of hair

  48. A molecular example Humans, unlike great apes cannot synthesize a form of the cell-surface sialic acid.

  49. A molecular example Specifically, humans cannot synthesize the sialic acid N-glycolyl-neuraminic acid (Neu5Gc). This results in an excess of the precursor Neu5Ac. The “problem” in humans is that the enzyme that catalyzes the reaction: Neu5Gc → Neu5Ac does not function. Neu5Ac Neu5Gc

  50. A molecular example The defective enzyme is CMAH (it hydroxylates CMP-Neu5Ac). In humans, it is inactivated by a 920bp deletion that occurred in the lineage leading to humans after the divergence from chimpanzees. Neu5Ac Neu5Gc

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