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).
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: 1.3 M markers in 269 people • Phase II: +2.8 M markers in 270 people
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 "tagSNPs" 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)
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.
Haplotypes (example) 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.
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)
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).
The SNP database today March, 2010 105,098,087 The 1000 Genomes Project submitted 17.3M SNPs The 2008 SNP Submissions for the James Watson Genome totaled 3,542,364 The 2008 SNP Submissions for the J. Craig Venter Genome totaled 4,018,050 The 2008 SNP Submissions for the Individual Chinese Genome totaled 5,077,954 The 2008 SNP Submissions for the Individual Korean Genome totaled 1,750,224 Derived from dbSNP release 130 http://www.ncbi.nlm.nih.gov/SNP/
SNP’s aren’t everything: Introducing Copy Number Variations Redon et al. Nature 2006
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
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
More than 10% of the genome sequence Structural Variation Project Nature 447: 161-165, 2007
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., Science318(2007), pp. 420–426
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 • http://www.broadinstitute.org/~debakker/p3.html
ASW African ancestry in Southwest USA CEU Utah residents with Northern and Western European ancestry from the CEPH collection CHB Han Chinese in Beijing, China CHD Chinese in Metropolitan Denver, Colorado GIH Gujarati Indians in Houston, Texas JPT Japanese in Tokyo, Japan LWK Luhya in Webuye, Kenya MXL Mexican ancestry in Los Angeles, California MKK Maasai in Kinyawa, Kenya TSI Toscani in Italia YRI Yoruba in Ibadan, Nigeria
SNP allele frequency estimation Population differentiation Linkage disequilibrium analysis SNP Tagging Imputation efficiency Genomic locations of human CNVs Genotypes for CNVs Population genetic properties of CNVs (allele frequencies, population differentiation, etc.) Mutation rate (frequency of de novo CNV) and potential mutational mechanisms Linkage disequilibrium properties of CNVs Tagging and imputation of CNVs Signals of selection around CNVs Association of SNPs and CNVs with expression phenotypes
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
Out of Africa Scientific American, August 1999) Modern humans arose in Africa and replaced other human species across the globe.
Out of Africa again and again Itai Yanai, 2003 Templeton, A. Nature 416 (2002): 45 - 51
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 ? complete human genome sequences
•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”