Point your Web browser to http://genome.perlegen.com/haplotype/ Download the paper by David Cox Blocks of Limited Haplotype Diversity Revealed by High-Resolution Scanning of Human Chromosome 21 Science 294: 1719-1723 (2001): (You can right click on this link to download the paper). You should also download the second paper Whole Genome patterns of Common DNA Variation in Three Human Populations. (You can right click on this link to download the paper). Both these papers are a tricky read, so plan to spend some time with them later. The notes from it are summarized in ten slides near the end of the PPT lecture. The image in the Cox paper is key. Take some time to look at this figure, and additionally work through the PPT lecture. This is a tricky concept!
Next, scroll down with your mouse over the length of the chromosome. Watch the entries change as you move up and down. I have chosen to look at the block: Chromosome 21 -- NT_002836, position 17600000 to 17700000 You can access it from either of these links.
http://genome.perlegen.com/cgi-bin/lookup.cgi?search=13722711&sequence_id=2
You can also enter 17642120 into the open search box and choose contig NT_002836 from the Perlegen Haplotype browser page.
You're now looking at a 100,000 base pair run along chromosome 21, and at eight blocks along that run. Take time to scan down the blocks. You are looking at a map of alleles as determined by the identity of SNPs at each location.
block_id start_pos end_pos tiled snp_used pi theta
B001082
17591424 17613467 11407 12 0.000553 0.000508
B002691
17613468 17613938 471 1 0.001439 0.001401
B002692
17613939 17614299 361 1 0.000462 0.001017
B001951
17614300 17618397 2104 2 0.000659 0.000703
B000649
17618398 17631369 9075 7 0.000512 0.000559
B002690
17631370 17632561 417 1 0.000939 0.000954
B000003
17632562 17664902 16478 49 0.001544 0.001310
B000011
17664903 17779396 85268 114 0.000722 0.000666
Click in the top block B001082 in the haplotype image . That link will take you to http://genome.perlegen.com/haplotype/blk/82/B001082.html where you'll see the image below. Note the start and and positions of the haplotype block, and the link to the contig NT_002836.
Now you are looking at Chromosome 21 -- Haplotype Block B001082
This block shows six distinct haplotype patterns, of which four represent over 80% of the 20 individuals who were sequenced along this chromosome. These SNPs are linked, SNP by SNP, to the 12 links in the block below. Follow any of the 12 SNPs into NCBI.
Polymorphism data: Each of the links below will take you to a SNP entry at NCBI. Take time to look at a few, and follow the RS and SS links.
snp_id position ref_base alt_base ref_calls alt_calls
P00217216
17591877 t c 13 4 TSC0960078
P00217217
17593884 t c 8 9
P00217219
17594528 c t 16 2
P00217220
17595241 a g 14 3
P00217221
17596334 a g 7 11
P00217223
17597082 a g 3 15 TSC0063080
P00217224
17597474 t c 8 10
P00217225
17602744 g a 12 4
P00217226
17602899 g a 4 12
P00217228
17611243 c t 15 2
P00217229
17612457 c t 15 2
P00217230
17613248 a g 5 12
Follow any of the links (for example http://www.ncbi.nlm.nih.gov/SNP/snp_retrieve.cgi?subsnp_id=4011663) , and examine both rs and ss SNP entry links. These links go to rs (Reference SNP) and ss (Submitted SNP) entries for each SNP entry in NCBI dbSNP.
Can you find the allele (bp) identities and SNP location for any of the SNP entries? Here's a hint, read slowly down the page. It's all there.
Review questions:
1) What is a SNP?
2) Why are SNPs important?
3) Are SNPs considered to be a mutation or a polymorphism? What is the difference?
4) What is a haplotype block?
5) How are SNPs and haplotype blocks related? How many SNPs (on average) are needed to define the identity of a haplotype?
6) What is the HapMap project?
7) How are SNPs (and haplotypes) related to alleles and polymorphic diversity?
8) Explain the number of haplotypes in the human genome (250,000), and how just four haplotypes account for 80% of the human diversity along a haplotype block. How many combinations of haplotypes do you think there are? (this is a question that we will have answered in two years).
9) Demonstrate how the Perlegen Haplotype browser works. Use the links above as a guide, and practice, practice, practice.
10) Follow the haplotype browser SNP entries into NCBI dbSNP. Explain as best as you can the difference between an rs and ss dbSNP entry.
11) (Bonus) Explain the myth of race, or how you might define race in terms of haplotype patterns. How many 'races' do you think there are?
Better yet, go to part II of this amazing new field (genotype.htm), and follow the links to Perlegen's new genome browser!.
References:
International HapMap Project - http://www.hapmap.org/
International HapMap Project Tutorials - http://www.hapmap.org/tutorials.html
This lesson is copyrighted using an Educational Common License, and may be used freely without restriction for academic purposes.
Robert D. Cormia