Gene & Genome Evolution Chapter 9 You will not be responsible for:

1. Gene & Genome Evolution Chapter 9 You will not be responsible for: Read the How We Know section on Counting Genes, and be able to discuss methodologies for doing so. Questions in this chapter you should be able to answer: Chapter 9- #1 -7 , 9, 10 - 16, 18 Gene & Genome Evolution

2. Trends in genome evolution 1) Genome expansion 2) Accumulation of Repetitive DNA 3) Accumulation of transposable elements 4) Intron Expansion 5) Loss of GC pairs 6) Accumulation of SNPs Figures 9-32 & 9-33 Gene & Genome Evolution

3. Base pairs# Genes Viruses Hepatitis-B 3,200 4 HIV 9,700 9 Influenza 13,500 10-11 Ebola 19,000 7 Epstein-Barr virus 172,282 80 Bacteria Mycoplasma genitalium 580,073 517 Treponema pallidum 1,138,011 1,039 E. coli 5,440,000 5,416 Single celled eukaryotes Yeast 12,495,682 5,770 Chlamydomonas 111,000,000 17,700 Insect Fruit fly 122,653,977 15,000 Plants Soybean 950,000,000 46,430 Norway Spruce 196,000,000 28,354 Corn 5,000,000,000 39,000 Animals Mouse 2,800,000,000 23,000 Humans 3,300,000,000 21,000 Sizes of genomes Gene & Genome Evolution

4. ~50% of the human genome is repetitive DNA Two main types: “Tandem repetitive DNA”: 1 - 100+ base sequences “CAG CAGCAGCAGCAG… “GGAAT GGAATGGAAT… “Interspersed Nuclear Elements”: 100s – 104 base sequences -- most are “transposable elements” -- make copies of themselves . . . repeated 10s  106s of times Gene & Genome Evolution

5. Tandem Repetitive DNA is linked to several genetic diseases -- “Trinucleotide repeat expansion” disorders Huntington’s disease -- neurodegenerative -- late onset -- inheritance is Dominant -- Repeat #  onset age & severity Gene & Genome Evolution

6. Transposable Elements have accumulated over time Examples LINE (Long) elements, e.g., ‘L1’ -- 1000s Bp long ~ 500,000 copies = ~20% of genome -- encode genes for own movement SINE (short) elements, e.g, ‘Alu’ – 300 Bp long -- 106 copies = ~ 13% of genome Tick and Sick - 7

7. Transposable Elements are fascinating -- and disconcerting! DNA that moves around “Jumping genes” Some move via “Cut and Paste” (no longer active in humans) Some move via “Copy and Paste” -- still active!! Tick and Sick - 7

8. Inverted sequences How do transposable elements move? 1) DNA-only mechanism -- common in bacteria, plants, yeast, insects Mechanism of cut and paste transposition 2) Alu and Li are retrotransposons -- Pass through RNA form -- Use reverse transcriptase Gene & Genome Evolution

9. TE movements have been linked to human diseases -- estimated to cause 0.3% of human genetic disorders Belancio et al (2008) Genome Res. 18: 343-358 Genetic analysis of mutated genes in individuals BRCA1 gene:42% of gene is Alu sequences in introns Tick and Sick - 7

10. The Good News: TEs are not running rampant Most are inactive – mutated ‘fossils’ – host suppressive mechanisms ~ 80-100 active L1s Beneficial roles -- not fully understood Roles in regulating gene expression -- the space between genes matters -- changes alter patterns of gene expression -- TE RNAs appear to have functions Have given rise to new genes --e.g., telomerase; RAG enzymes -- Intron/Exon diversity Roles in neurological development? Tick and Sick - 7

11. How do genes evolve over time? Mutation of coding regions Mutation of regulatory regions Chromosome/Gene/Exon duplications Exon/intron shuffling & Transposition Horizontal gene transfer Gene & Genome Evolution

12. How do new genes evolve? Exon duplication & shuffling is common Gene & domain duplications occurred during evolution of the “Ig-Superfamily” Exon shuffling & duplication has occurred during evolution of these genes Gene & Genome Evolution

13. Gene duplications are common Divergence of function e.g. Fetal/human hemoglobin Families of related genes Pseudogenes can result Gene & Genome Evolution

14. Horizontal Gene Transfer -- can move blocks of genes Asexual transfer of genes between organisms Most common in single-celled organisms -- why? Bacterial genetic recombination -- spread of Ab resistance Gene & Genome Evolution

15. Simple mutations to regulatory genes can cause dramatic changes in development Explains “Punctuated Equilibrium” Mutations to “master regulatory gene” Antennapedia (antp) -- antennae transformed to legs bithorax (bx) + postbithorax (pbx) -- extra set of wings Gene & Genome Evolution

16. Loss of GC pairs in Vertebrates ‘ Cytosine methylation and gene regulation CpG’ vs ‘GC’ bp Methylation of CpG leads to loss of GC bp’s Deamination of methyl-C yields T – G mismatch Gene & Genome Evolution

17. Creation of CpG islands CpG remains in ‘islands’ Where found? housekeeping genes non-coding regions Frequencies GroupGCCpG Fish & amphibians 44% 1.8% Birds and mammals 42% 1.13% “GC-islands” 4-6% Jabbari, et al. 1997 Gene 205:109-118 Gene & Genome Evolution

18. Introns have gotten bigger Genome sizes Puffer fish: 400,000,000 Human: 3,000,000,000 Huntingtin gene – mutations cause Huntington’s Disease Gene size Puffer fish: 22,000 bases Human: 170,000 bases Both produce proteins of ~ 3000 AAs!!! All expansion is in Introns! Every exon and intron align exactly Gene & Genome Evolution

19. 4) Intron expansion Genome sizes Puffer fish: 4 x 108 Human: 3 x 109 Huntingtin gene size Puffer fish: 2.4 x 104 Human: 1.8 x 105 All 67 exons align!! Expansion and mobile elements occur in introns Gene & Genome Evolution

20. Accumulation of single-nucleotide polymorphisms (SNP) distinguish individual genomes Consequence of “point mutations” 107+ documented in humans Can influence: Our individual physical traits Disease susceptibility Risk factors for disorders e.g., Macular Degeneration SNP in Complement factor H His  Tyr 5 – 7x >risk Gene & Genome Evolution

21. What is a “silent mutation”? And why are they not always silent? Sometimes: Wobble position Non-coding regions Sometimes not: regulatory sites chromosome codon usage Arginine tRNA occurrence Codon tRNA [tRNA]1 CGU arg2 5.54 CGC arg2 CGG arg3 1.45 AGA arg4 2.64 AGG arg5 1.61 1tRNA abundance in E. coli: Burg & Kurland (1997) J. Mol. Biol. 270: 544 2Frequency in E. coli O127:H6 http://www.kazusa.or.jp/codon/ What would be the expected effect on translation rate of … … CGU CGC mutation? … CGU CGG mutation? Gene & Genome Evolution