1. Motivations to study human genetic variation
The evolution of our species and its history. Understand the genetics of diseases, esp. the more common complex ones such as diabetes, cancer, cardiovascular, and neurodegenerative. To allow pharmaceutical treatments to be tailored to individuals (adverse reactions based on genetics). 1

2. Haplotype Map of the Human Genome
Goals:
Define patterns of genetic variation across human genome
Guide selection of SNPs efficiently to “tag” common variants
Public release of all data (assays, genotypes)
Phase I: M markers in 269 people
Phase II: M markers in 270 people

3. HapMap Project
The HapMap Project tests linkage between SNPs in various sub-populations.
For a group of linked SNPs recombination may be rare over tens of thousands of bases
A few "tag SNPs" can be used to identify genotypes for groups of linked SNPs
Makes it possible to survey the whole genome with fewer markers (1/3-1/10th)

4. Haplotype
Linkage is common in the human population, particularly in genetically isolated sub-populations.
A group of alleles for neighboring genes on a segment of a chromosome are very often inherited together.
Such a combination of linked alleles is known as a haplotype.
When linked alleles are shared by members of a population, it is called a linkage disequilibrium.

5. Haplotypes (example) .. A C T G
A chromosome region with only the SNPs shown. Three haplotypes are shown. The two SNPs in color are sufficient to identify (tag) each of the three haplotyes. For example, if a chromosome has alleles A and T at these two tag SNPs, then it has the first haplotype.

6. HapMap Samples
90 Yoruba individuals (30 parent-parent-offspring trios) from Ibadan, Nigeria (YRI)
90 individuals (30 trios) of European descent from Utah (CEU)
45 Han Chinese individuals from Beijing (CHB)
45 Japanese individuals from Tokyo (JPT)

7. Make Genetic Profiles
Scan these populations with a large number of SNP markers.
Find markers linked to drug response phenotypes.
It is interesting, but not necessary, to identify the exact genes involved.
Can work with “associated populations,” does not require detailed information on disease in family history(pedigree).

8. The 1000 Genomes Project submitted 17.3M SNPs
The SNP database today
March, ,098,087
The 1000 Genomes Project submitted 17.3M SNPs
The 2008 SNP Submissions for the James Watson Genome totaled ,542,364
The 2008 SNP Submissions for the J. Craig Venter Genome totaled ,018,050
The 2008 SNP Submissions for the Individual Chinese Genome totaled ,077,954
The 2008 SNP Submissions for the Individual Korean Genome totaled ,750,224
Derived from dbSNP release 130

9. SNP’s aren’t everything: Introducing Copy Number Variations
Redon et al. Nature 2006

10. Copy Number Variation Dataset
Genome Structural Variation Consortium
Array-CGH using a whole genome tile path array
Median clone size ~170 kb
All 270 HapMap individuals
Measures amount of DNA, not RNA
Comparison between two samples
‘Test’ sample vs ‘Reference’ sample 10

11. Array-CGH technology

12. Typical Analysis Procedure
Values are typically normalized so that the mean log2 value for the entire array (or an individual chromosome) is 0
Analysis consists of identifying segments where the test and reference samples have unequal copy number 12

13. Log(2) = (test/reference)13

14. 1,447 CNVRs from 270 HapMap samples

15. More than 10% of the genome sequence
Structural Variation Project
More than 10% of the genome sequence
Nature 447: , 2007 15

17. Copy Number Variations are ubiquitous in the human genome
The number of genome structural variants (>1 kb) that distinguish genomes of different individuals is at least on the order of 600–900 per individual.
J.O. Korbel et al., Science 318(2007), pp. 420–426

18. HapMap 3 Merged the results from Affymetrix and Illumina chips
Genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations
Sequenced ten 100-kilobase regions in 692 of these individuals

19. Centre d’Etude du Polymorphisme Humain collected in Utah, USA, with ancestry from northern and western Europe (CEU) Han Chinese in Beijing, China (CHB) Japanese in Tokyo, Japan (JPT) Yoruba in Ibadan, Nigeria (YRI) African ancestry in the southwestern USA (ASW) Chinese in metropolitan Denver, Colorado, USA (CHD) Gujarati Indians in Houston, Texas, USA (GIH) Luhya in Webuye, Kenya (LWK) Maasai in Kinyawa, Kenya (MKK) Mexican ancestry in Los Angeles, California, USA (MXL) Tuscans in Italy (Toscani in Italia, TSI)
CEU, ASW, MXL, MKK, and YRI

22. Computational detection of structural genomic variation
Direct comparison of genomes through sequence alignments
Advantages:
All types of genomic variation can be identified, including balanced variants (inversions or translocations)
No limit in the resolution and breakpoints can be defined at nucleotide level
Problems:
Generate a lot of false positives due to sequence misassembly and gaps

23. Out of Africa
Modern humans arose in Africa and replaced other human species across the globe.
Scientific American, August 1999)

24. Out of Africa again and again
Itai Yanai, 2003
Templeton, A. Nature 416 (2002):

26. The Human Genome Project cost ~USD 3,000,000,000
Illumina now offers a complete genome sequence from USD 50,000
Complete Genomics will offer a complete genome sequence from USD 5,000 soon
There are now an estimated 50 complete human genome sequences

27. •Craig Venter, Sanger, -$1 million
•James Watson, 454. $70 million
•Craig Venter, Sanger, -$1 million
•African -HapMap –Illumina & Solid, $100,000
•Five African –Penn State University
•Chinese, Illumina
•Two Koreans
•Prof. Quake -Stanford --Nature genetics paper -$50,000, 1 week, Helicos
Stanford team -Clinical annotation of genome from “patient Zero”

30. The 10-gen data set