Bio263 Lecture 2: Becoming human

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Lecture 2: Becoming human
What have comparisons between human and ape genomes taught us about what it means to be human?

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  • Two distinct experimentally supported secondary structure models for HAR1 RNAs. (A) The cloverleaf-like model of the human HAR1 RNA. (B) The chimpanzee HAR1 RNA adopts a hairpin structure. The length and thickness of the symbols represent the intensity of the cleavages. Bases reactive to DMS or CMCT under native conditions are circled; weak reactivities are depicted by dotted circles. Bases modified by CMCT under semidenaturing conditions only are displayed with a green background. H, helix; IL, internal loop; L, loop.
  • Bio263 Lecture 2: Becoming human

    1. 1. Human Evolution Genes and Genomes Lecture 2: Becoming Human <ul><li>Professor Mark Pallen </li></ul>
    2. 2. Humans are not chimps <ul><li>Bipedalism, with resulting changes in post-cranial anatomy (S-shaped spine, bowl-like pelvis) </li></ul><ul><li>Brain size increased, head shape changed (strong chin, small snout, larger brain case) </li></ul><ul><li>Smaller canines, less robust musculature </li></ul><ul><li>Loss of thick body hair </li></ul><ul><li>Differences in disease susceptibility </li></ul>
    3. 3. What can genes and genomes hope to tell us? <ul><li>Exact genome-wide divergence (& its variation across the genome) </li></ul><ul><ul><li>Estimation of time of divergence from the closest relatives </li></ul></ul><ul><ul><li>The mode of genome evolution </li></ul></ul><ul><ul><li>The mode of speciation </li></ul></ul><ul><li>Human-specific changes in the genome </li></ul><ul><ul><li>What differences in our genome make us human? </li></ul></ul><ul><ul><li>Genes involved in evolution of brain and speech </li></ul></ul><ul><ul><li>Discovery of genetic variants that might contribute to disease susceptibility in humans </li></ul></ul>
    4. 4. Genomes sequenced Human genome: complete Chimp genome: draft Orang genome: in progress Macaque genome: draft Neanderthal genome sample sequenced
    5. 5. Single male chimp: Clint
    6. 6. What makes us human? <ul><li>Candidate gene approach </li></ul><ul><ul><li>examine genes likely to be involved in specific traits of interest </li></ul></ul><ul><li>Comparative genomics approach </li></ul><ul><ul><li>Look for differences in genome, especially regions that have undergone positive selection </li></ul></ul><ul><ul><li>BUT 35 million bp of difference and needle in a haystack problem </li></ul></ul>
    7. 7. What makes us human? <ul><li>No easy answer! </li></ul><ul><li>Most evolutionary change is due to neutral drift </li></ul><ul><li>Adaptive changes constitute only a small fraction of the changes between species </li></ul><ul><li>No simple linear relationship between morphological changes and sequence variation </li></ul><ul><ul><li>gross morphological differences human/chimp >> differences between two mouse species with same %DNA difference </li></ul></ul><ul><ul><li>marked variation among dogs, but all show little sequence variation (0.15%) </li></ul></ul>
    8. 8. Human & Chimp Genomes <ul><li>The number of chromosomes differs </li></ul><ul><li>Changes in chromosome structure </li></ul><ul><li>Multiple insertions and deletions: about 90Mb of DNA is either human or chimp-specific </li></ul><ul><li>Gene duplication </li></ul><ul><li>Gene loss </li></ul><ul><li>Evolution of gene expression </li></ul>
    9. 9. Changes in chromosome structure Human Chromosome 2 Chimpanzee Chromosomes 2a & 2b Chromosome fusion: Segmental duplications: Humans: 13.7% Chimps: ~5% of the genome is segmentally duplicated Inversions: Multiple inversions between humans and chimpanzees Translocations: In humans an X=>Y translocation resulted in formation of the second pseudo- autosomal region
    10. 10. Modes and models of evolution
    11. 14. Evolution of gene expression Search for human-specific changes in gene expression Human bonobo chimp gorilla A set of genes with human-specific changes in expression Pollard et al Nature 2006
    12. 15. Human & Chimp Genomes <ul><li>Single nucleotide substitutions occur at rate of 1.23% </li></ul><ul><li>Orthologous proteins on average differ by only two amino acids, one in each lineage </li></ul><ul><ul><li>29% of proteins identical </li></ul></ul><ul><li>Differences in endogenous retroviruses </li></ul><ul><ul><li>HERV-K in humans; PtERV1 and 2 in chimp </li></ul></ul><ul><li>More Alu repeat activity in humans </li></ul>
    13. 17. Differences in biology <ul><li>Apoptosis </li></ul><ul><ul><li>caspase-12 disrupted in humans; intact in mice and chimps </li></ul></ul><ul><ul><li>?related to susceptibility to Alzheimer’s? </li></ul></ul><ul><li>Inflammation </li></ul><ul><ul><li>IL1F7, IL1F8, ICEBERG all missing in chimps </li></ul></ul><ul><li>Parasite resistance </li></ul><ul><ul><li>APOL1/APOL4 missing in chimps; altered resistance to Trypanosomes? </li></ul></ul><ul><li>Sialic acid biology </li></ul><ul><ul><li>CMAH gene </li></ul></ul><ul><ul><li>underlies differences in susceptibility to malaria and AIDS? </li></ul></ul>
    14. 19. FOXP2 <ul><li>Identified as site of Mendelian dominant mutation in human KE family, afflicted with speech difficulties </li></ul><ul><ul><li>missense mutation (R553H) in the forkhead domain of FOXP2 cosegregates with the disorder in this family </li></ul></ul><ul><ul><li>Regulatory protein; contains forkhead domain; shown to regulate hundreds of genes in brain, including CNTNAP2(Spiteri et al 2007). </li></ul></ul><ul><li>Often dubbed “the language gene” </li></ul><ul><ul><li>but also involved in motor co-ordination </li></ul></ul><ul><ul><li>Neuroimaging studies show anomalies in basal ganglia morphology and activity. </li></ul></ul><ul><ul><li>Embryological studies then showed that in mouse and human FOXP2 modulates development of the basal ganglia </li></ul></ul><ul><li>Convergent evolution in bird song (and bat echolocation?) </li></ul>
    15. 20. Evolution of human FOXP2 gene Mutations in the human FOXP2 gene are associated with an autosomal dominant form of dysarthria (difficulty in articulating speech). The human FOXP2 gene shows changes in amino acid coding and a pattern of nucleotide polymorphisms that suggest this gene has undergone positive selection during recent human evolution (Enard et al 2002 Nature )
    16. 21. FOXP2 in mice <ul><li>FoxP2 knock-outs in mice: </li></ul><ul><ul><li>developmental delays; defects in ultrasonic communication; effects on basal ganglia </li></ul></ul><ul><ul><li>Severe in homozygotes; less so in heterozygotes </li></ul></ul><ul><li>FoxP2 R553H knock-in mice: </li></ul><ul><ul><li>Homozygous: severe developmental problems; defects in ultrasonic communication; similar but less severe in heterozygotes </li></ul></ul><ul><li>Humanised FoxP2 knock-in mice: </li></ul><ul><ul><li>generally healthy, </li></ul></ul><ul><ul><li>different ultrasonic vocalizations, decreased exploratory behavior, decreased dopamine concentrations in brain </li></ul></ul><ul><ul><li>increased dendrite lengths and increased synaptic plasticity in striatum/basal ganglia. </li></ul></ul><ul><li>Note of caution in interpreting these changes </li></ul>
    17. 22. HAR1 <ul><li>Human accelerated region 1 </li></ul><ul><ul><li>2/118 differences chicken-chimp </li></ul></ul><ul><ul><li>18/118 differences chimp-human </li></ul></ul><ul><li>Non-protein-coding RNA gene </li></ul><ul><li>Expressed during cortical development </li></ul>
    18. 23. Two distinct experimentally supported secondary structure models for HAR1 RNAs Beniaminov A et al. RNA 2008;14:1270-1275
    19. 24. AMY1 <ul><li>Encodes amylase </li></ul><ul><li>Multiple copies in mammalian genomes </li></ul><ul><ul><li>But many more copies in humans </li></ul></ul><ul><li>People with most copies produce most amylase in saliva </li></ul><ul><ul><li>People with high-starch diets have, on average, more AMY1 copies than those with traditionally low-starch diets </li></ul></ul><ul><li>Provides immediate access to glucose from starch </li></ul><ul><ul><li>?role in recovering more calories from diet more quickly </li></ul></ul><ul><ul><li>? Protection against effects of GI upset </li></ul></ul>
    20. 25. “ Brain-building” genes <ul><li>ASPM and Microcephalin identified in microcephaly patients </li></ul><ul><ul><li>Along with MCPH1, CDK5RAP2 and CENJ </li></ul></ul><ul><ul><li>ASPM crucial for control of cell division in neuroepithelial cells </li></ul></ul><ul><li>Both experienced bursts of change during primate evolution, including in human lineage since divergence from chimps </li></ul>
    21. 26. <ul><li>Two controversial Science papers from Sep 9, 2005 </li></ul>variants more common in Eurasians than in Africans…
    22. 27. Subsequent studies find no links found between microcephalin variant and IQ or brain size AND these genes are also expressed outside the brain Merely tracking out of Africa migration?
    23. 29. MYH16
    24. 30. MYH16
    25. 31. KRTHAP1
    26. 32. HAR2/HACNS1 “ The dexterity of the human hand is due to morphological differences compared with other primates that include rotation of the thumb toward the palm and an increase in the length of the thumb relative to the other digits. Human-specific changes in hindlimb morphology, such as the characteristic inflexibility and shortened digits of the human foot, facilitated habitual bipedalism. The gain of function in HACNS1 may have influenced the evolution of these or other human limb features by altering the expression of nearby genes during limb development.”
    27. 37. Summary <ul><li>Chimpanzee genome </li></ul><ul><ul><li>Differences of many sorts from SNPs to chromosome structure </li></ul></ul><ul><ul><li>Some key differences in biology </li></ul></ul><ul><ul><li>Chimp allele is a disease allele in humans in several genes </li></ul></ul><ul><li>Candidate Genes: FoxP2, Amy1, Har1/2, Microcephalin, ASPM </li></ul><ul><li>Macaque Genome </li></ul><ul><ul><li>Triangulation allows determination of polarity of human-chimp changes </li></ul></ul><ul><ul><li>Macaque allele is a disease allele in humans in several genes </li></ul></ul><ul><ul><li>Genes undergoing positive selection identified </li></ul></ul>

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