Global Variation in Copy Number in the Human Genome

1. Global Variation in Copy Number in the Human Genome Presentation by Julian Reoyo & Andrea Pastores

2. Introduction/Background Copy Number Variation (CNV): a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals in the human population. It can include deletions, duplications, combination of deletions/duplications, multi-allelic, and complex genes. Copy Number Variation Region (CNVR): Region in which CNV are found, they are determined by overlapping CNVs within the genome HAPMAP: Haplotype mapping (haplotypes are a set of DNA variations, or polymorphisms, that tend to be inherited together)

3. Populations Groups Being Studied & Why • Yoruba from Nigeria (YRI) • European descent from Utah, USA (CEU) • Japanese from Tokyo, Japan (JPT) • Han Chinese from Beijing, China (CHB) • Trios & the Unrelated

4. The Importance of CNV • Used to find genes related to genetic mutational diseases and medical conditions. • Alzheimer’s disease, Parkinson’s (tauopathies) • Mapping non-coding regions • Finding SNPs not easily found through locating a nearby CNV. • Discovering genotype linkages between populations, or species.

5. Two methods for CNV Mapping and Detection Whole Genome TilePath Array Affymetrix GeneChip Human Mapping 500K EA • Good for large CNVs • Hybridizes genomic DNA from a cell line to a reference DNA • Data presented on a log2 scale • Good for short CNVs • Hybridizes HAPMAP DNA to SNP Chip • Data is also presented on a log2 scale

6. Whole Genome Tile Path Array • Label Genomic DNA from cell line and hybridize with differently labeled Reference DNA • Measure Fluorescence Intensity of Hybridized Samples • Compare Intensity of Test DNA to Reference on Log Scale

7. Affymetrix 500K Early Access Analysis • Uses a whole genome analysis SNP Chip that hybridizes with the HAPMAP genome. • The hybridized HAPMAP test DNA with SNP chip and compared it to hybridized ref DNA SNP chip to create log scale • In both methods log scales greater or less than 0 indicate CNVS

8. Inheritance of CNVS in families • This figure shows how often they would see a certain CNV (homozygous deletion, heterzygous deletion, or duplication) in a cetain region. • The pedigree shows how this CNV would be normally inherited.

9. How CNVs Regions were determined • Since CNVS can be duplications, deletions, or complex they would overlap matching regions of CNVs.

10. CNVS in Chromosomes, Lengths, Association

11. How they determined Gene Class • They determined Gene Class based on the log2 scale of test DNA to reference DNA (X- axis) and the relative frequency (Y-axis). • Percentage relates to how many times the CNV was duplicated.

12. Positive Selection of Gene Duplications in CNVRs

13. SNPs vs CNVs to detect Disease Related Genes • Linkage Disequilibrium (LD): the non-random association of alleles at two or more loci in a general population

14. Poor Prediction of CNVs using SNPs 13 Multi-allelic CNVs as a quantitative trait (phenotypes) to test neighboring SNPs to predict the trait in the WGTP method

15. Frequency of genetic differentiation for CNVs

16. Summary • Through both methods, WGTP and 500K EA, and previous literature they found 1,447 CNVRs in human genome. • Hundreds of genes, disease loci, functional elements and segmental duplication • CNVRs encompassing more nucleotide content per genome than SNPS • Similar populations or ethnicities share CNV genotypes. • CNVs used to identify genetic phenotypic variation and disease related genes among populations Cons • Procedural understanding of HAPMAP and SNP Chip • Difficulty assessing the isolated statements made regarding their findings (CNVs being located in ultra-conserved elements being stronger than their analysis can determine).

17. Additional Reading

18. Questions