1. Introduction Basic Genetic Mechanisms Eukaryotic Gene Regulation The Human Genome Project Test 1 Genome I - Genes Genome II – Repetitive DNA Genome III - Variation Test 2 Monogenic and Complex Diseases Finding ‘Disease’ Genes Pharmacogenomics Test 3 Your Presentations Happy New Year! Molecular Genetics The Human Genome: Biology and Medicine http://priede.bf.lu.lv/http://priede.bf.lu.lv/ Studiju materiāli / MolekularasBioloģijas / MolGen / EN

2. Gene density is low in the human genome Molecular Biology of the Gene, 6th Edition

3. Comparison of chromosomal gene density for different organisms Molecular Biology of the Gene, 6th Edition

4. Genomes, 2nd Edition Genes and other elements in a segment of the human genome

5. The sequence content of the human genome

6. >5% of the human genome contains segmental duplications: 1000 – 1500000 bp; >90% identity Intrachromosomal un interchromosomal duplications in chromosome 22 Genomes, 2nd Edition

7. Segmental duplications result in (at least some of the) microdeletion syndromes Emery’s Elements of Medical Genetics, 13th Edition (modified) - +

8. Genomes, 2nd Edition (origin - transpositions) There are two types of repetitive DNA (origin - replication) [SSR - simple sequence repeats] [genome-wide repeats]

9. Variation in the distribution of interspersed repeats Interspersed repeatsExons

10. The human genome is filled with copies of ancient transposons

11. (LTR elements) Classes, organisation and number of transposable elements in the human genome (poli-A elements) LINE – Long Interspersed Nuclear Element SINE – Short Interspersed Nuclear Element LTR – Long Terminal Repeat P P P P P – promoter ORF - (open-reading frame) 1 – gene encoding RNA binding protein ORF2 – gene encoding reverse transcriptase and endonuclease gag: gene for a protease pol: gene encoding reverse transcriptase and integrase (env): gene for envelope proteins - absent in retro-virus like elements, present in retroviruses LTR (endogenous retroviruses) RETROTRANSPOSONS

12. Genomes, 2nd Edition Groups and copy number of interspersed repeats in the human genome

13. Genomes, 2nd Edition Human Molecular Genetics, 2nd Edition; modifiied SINEs LINEs LTR elements RT - reverse transcriptase The three main classes of the human trasposable elements (retrotransopons) transpose through an RNA interemdiate

14. Transposition of LINE elements Molecular Biology of the Gene, 5th Edition nucleus cytoplasm nucleus

15. LINE insertions are known in cases of 34 different human diseases Recombinant DNA, 3rd Edition

16. Molecular Biology of the Gene, 5th Edition Origin and expansion of the human Alu repeat and the mouse B1 repeat Alu (and B1) contains an internal RNA Pol III promoter (a and b elements) and it can therefore be transcribed Human Molecular Genetics, 2nd Edition

17. Alu have also been proved to cause genetic disease Recombinant DNA, 3rd Edition

18. Satellites: 5 - 171 bp unit; large clusters (> 100 000 bp) – heterochromatin regions of centromeres; not transcribed – function not known; likely – the formation of centromeres (  satellite) Minisatellites: 6 - 64 bp unit; medium-size clusters (100 - 20 000 bp) – heterochromatin regions of telomeres or their vicinity; not transcribed – telomere repeats – the structure and replication of chromosomes Microsatellites: 1 - 4 bp unit; short clusters (<150 bp ) – scattered along the genome; no known function; widely used as markers – if located within or nearby a gene can cause ‘triplet expansion dieseases’..........CACACACACACACACA...........................................................CACACACACACA................... Genomes, 2nd Edition Classes of tandem repeats

19. Location of different classes of tandem repeats Human Molecular Genetics, 2nd Edition

20. The End Replication Problem Molecular Biology of the Gene, 6th Edition

21. Solving the end replication problem: TELOMERES & TELOMERASE Molecular Biology of the Gene, 5th Edition

22. Promoter of FMR1 gene (component of translational regulation in nerve cells) Unstable expanding repeats cause disease Life The Science of Biology, 7th Edition Promoter of FMR1 gene (the encoded protein regulates translation in nerve cells)

23. Unstable expanding repeats cause disease Emery’s Elements of Medical Genetics, 13th Edition  CAG – glutamine (Gln); (CAG) n – poliglutamine tract within the gene product  Forms toxic aggregates within certain cells  There is a critical threshold repeat size above which the repeat causes disease  Late-onset neurodegenerative diseases, dominantly inherited  The larger the repeat, the earlier is the age of onset