1. YOUR FUTURE STARTS WITH HOPE YOUR FUTURE STARTS WITH HOPE Genome Biology & Applied Bioinformatics Human Genome Mehmet Tevfik DORAK, MD PhD

2. Schedule

3. Outline Genome size, composition and function Genetics and epigenetics 1D vs 3D genome Gene expression regulation

4. Human Genome in Numbers

5. Human Genes in Numbers

6. Evolving Concepts in Genetics

7. ENCODE Project

8. Genetics vs Epigenetics

10. DNA double helix (2-nm diameter) (metaphase chromosome) 700 nm Tight helical fiber (30-nm diameter) Nucleosome (10-nm diameter) Histones “Beads on a string” Supercoil (200-nm diameter) Campbell NE et al (Eds): Biology: Concepts & Connections 4 th Edition, 2003 Chromosomes are usually depicted as they appear during metaphase of cell division. They are densely packed DNA-histone complexes called nucleosomes. If the DNA from a single cell is straightened out, it would be 2 meters long. Thus, to fit the DNA into the cell nucleus, it has to be packaged at multiple levels. Genetics vs Epigenetics

11. NIH Epigenetics & DNA/Chromatin

12. Epigenetics & RNA > > >

13. Epigenetics & DNA/Chromatin

14. Gene Expression Regulation: Enhancers

15. Gene Expression Regulation From 1G to 3D Genome

16. Gene Expression Regulation: 3D

18. The eukaryotic nucleus is a complex three-dimensional environment in which genome function depends not only on the linear arrangement of regulatory sequence elements but also on their spatial organization for effective control of gene expression. Analysis of the role of chromatin 3D organization in gene expression is progressing rapidly, largely due to the development of chromosome conformation capture methods such as Hi-C. Sequences within these Topologically Associated Domains (TADs) interact more frequently with sites inside than outside the domain. TADs with a median size of 880 kb have been found in mammals. Gene Expression Regulation: 3D

21. Gene Expression Regulation: Genetics

22. Gene Expression Regulation: Epigenetics

26. Key Points - From linear sequence-based view of the genome, we have moved to a 3D genome - Epigenetics mechanisms (DNA methylation, histone modifications and non-coding RNA-based ones) are now appreciated as important as genetic mechanisms - Even pseudogenes can be transcribed, and may have a role in gene expression regulation - Genetic and epigenetic variation influencing each one of these mechanisms cause alterations in genome biology and modify disease risk - There are bioinformatics tools to assess the effect of genetic variation on each process in genome biology (purely computational results need to be experimentally validated)

27. YOUR FUTURE STARTS WITH HOPE YOUR FUTURE STARTS WITH HOPE … Looking forward … Looking forward …..

28. YOUR FUTURE STARTS WITH HOPE YOUR FUTURE STARTS WITH HOPE