Genotype Browser Exercise
This exercise will introduce you to Perlegen's genotype browser, which allows you to view and navigate the haplotype structure of the human genome. You'll start by first downloading and reading Perlegen's most recent paper, Whole-Genome Patterns of Common DNA Variation in Three Populations. This is a little trickier than the first paper by David Cox, as it involve more genetics, including linkage disequilibrium calculations. However, it builds on the haplotype browser, which you should have already explored. You may also wish to read a paper by Applied Biosystems which is also very helpful. The time you take to read these articles now will help you in navigating these data later - so be advised!
This area of haplotype studies is very new, hence you will probably have very little experience with either the concepts or the data. However, if you think of alleles as being defined by SNPs, and haplotypes as being defined as 'blocks of associated SNPs' you can combine the concept of linkage disequilibrium to broader your notion as to what an allele is. Technically, we are talking about haplotypes here, but the 'outcome' of haplotypes affects our notion of alleles.
From the Genotype Browser page, you will navigate the COMT gene, and access the SNP that is responsible for the now infamous Val/Met substitution in codon 158 (and also 108). In order to find that SNP, you really need to know the Perlegen SNP identifier. But here's a little secret, you can enter the NCBI SNP ID, and it will take you there (I finally found a short cut that worked!). So type in rs4680 in the Perlegen SNP identifier box, press submit, and the page that is returned is this. Navigate to the block marked by afd0106026 which will take you to this link.
At the top of the page you will see the allele distribution by lineage, which we have shown below:
Reference_Allele_Frequency_African_American:
0.326
Reference_Allele_Frequency_Chinese: 0.271
Reference_Allele_Frequency_European_American: 0.375
Scroll down to the block that shows the allele distributions by lineage (column) and by person (row). The SNPs you are reading are the alleles for each person. Take a careful look at the data below, and remember that each data point represents a person, at their alleles for this key SNP. The Val / Met substitution is based on Val, whose codon is GTG, changing to Met, whose codon is ATG. A simple G to A transition.
The three key outcomes for this lesson are:
1) You can find a SNP of interest in most of the biological literature in the last 5 years. Get the rs number (reference SNP) and take that to Perlegen to see how the distribution looks in the Genome browser (you can also see this in the UCSC genome browser).
2) In your story centered or problem posing exercise, think about finding a key SNP, like BRCA1, sickle cell anemia. Can you find those SNPs, and possibly build a lesson plan around that? Be prepared to hunt, and don;t give up! Let the story be bigger than the task!
3) As you consider the Val/Met and other key nonsynonymous substitutions, remind yourself, and be humbled, by the power of just one letter!
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European American
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African American
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Chinese
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| Sample Name | Genotype | Sample Name | Genotype | Sample Name | Genotype |
| NA06990 (F) | AG | NA17102 (M) | AG | NA17733 (F) | GG |
| NA07019 (F) | GG | NA17103 (M) | GG | NA17734 (F) | AG |
| NA07348 (F) | AG | NA17104 (M) | AA | NA17735 (F) | AG |
| NA07349 (M) | GG | NA17105 (M) | GG | NA17736 (M) | AG |
| NA10830 (M) | AG | NA17106 (M) | AG | NA17737 (M) | AA |
| NA10831 (F) | AG | NA17107 (M) | GG | NA17738 (F) | AG |
| NA10842 (M) | AA | NA17108 (M) | AG | NA17739 (F) | GG |
| NA10843 (F) | GG | NA17109 (M) | GG | NA17740 (F) | GG |
| NA10844 (F) | GG | NA17110 (F) | GG | NA17741 (F) | AG |
| NA10845 (M) | GG | NA17111 (M) | AG | NA17742 (M) | AG |
| NA10848 (M) | AG | NA17112 (F) | GG | NA17743 (M) | GG |
| NA10850 (F) | AA | NA17113 (F) | AG | NA17744 (F) | GG |
| NA10851 (M) | AG | NA17114 (M) | AG | NA17745 (F) | GG |
| NA10852 (F) | GG | NA17115 (M) | AG | NA17746 (F) | GG |
| NA10853 (M) | AA | NA17116 (F) | GG | NA17747 (F) | AG |
| NA10854 (F) | GG | NA17133 (F) | AA | NA17749 (M) | GG |
| NA10857 (M) | GG | NA17134 (F) | GG | NA17752 (F) | AG |
| NA10858 (M) | AG | NA17135 (F) | AG | NA17753 (M) | AG |
| NA10860 (M) | AG | NA17136 (F) | GG | NA17754 (F) | GG |
| NA10861 (F) | AG | NA17137 (F) | GG | NA17755 (M) | GG |
| NA12547 (M) | GG | NA17138 (F) | AG | NA17756 (F) | AG |
| NA12548 (F) | GG | NA17139 (F) | AG | NA17757 (F) | AG |
| NA12560 (M) | AA | NA17140 (F) | AG | NA17759 (M) | GG |
| NA17201 (M) | AG | NA17761 (M) | GG | ||
This lesson is copyrighted using an Educational Common License, and may be used freely without restriction for academic purposes.
Robert D. Cormia