As the Human Genome Project moves into the 21st Century, the emphasis of the project is no longer the tedious job of sequencing the nucleotide sequences of all the genes, but determining where genes for various characteristics are located on the chromosomes, what other scientists have discovered concerning those genes, what alleles exist for those genes, and whether similar (homologous) genes have been characterized in other species. To answer these questions, molecular biologists turn to the World Wide Web, where the individual efforts of deciphering the human genetic code is being put together piece by piece. Whereas sequencing nucleotides is relatively easy, the real work on the Human Genome Project is being conducted on the WWW, in the hope of determining a gene's function based on the work of previous investigators and the rich body of literature they have produced.

The purpose of this exercise is to explore the data available in the Human Genome Project concerning a gene of interest. The combined repository of human genome information is at the Genome Database at Johns Hopkins University (http://gdbwww.gdb.org/gdb). We will also use the resources of the Mouse Genome Database Project (http://www.informatics.jax.org:80/searches/homology_form.shtml), based at the Jackson Laboratory in Bar Harbor, Maine, which contains information on mammalian homology (similarities between genes in different species). You will prepare a report describing the research and resources available in the Human Genome Database for a gene of interest.

How to use the Human Genome Database:

1. Pick any gene of interest to you. Do NOT use the Huntington's Disease gene HD (this will be used in our example).
   
2. Read through this list quickly, then check out the Assignment Example to see what I'm talking about.
   
3. Go to the Genome Database at Johns Hopkins University (http://gdbwww.gdb.org/gdb).
   
4. Type the gene abbreviation (if known) into the box below and to the right of the heading "Simple Search." Click on the "Submit" button (or hit your "Enter" key). If the gene abbreviation is not known, click on the "All Biological Data" button at the lower left, type the trait's name (such as a disease name) followed by a star (*) into the box, and click on the "Submit" button.
   
5. You may receive a list of clones, probes, genes, and other DNA segments. Use the gene (one that is labeled as a "Gene") that looks most promising.
   
6. Which chromosome and chromosome segment is the gene located on? Scroll down to the table titled "Cytogenetic Localization."
   
7. Scroll back to the top. You will see a button labeled "View Maps of Region." Click on this button.
   
8. You will get a screen that says "Check maps to display." Put a check by "GDB Comprehensive Map," but UNCHECK all the other boxes EXCEPT where it says "Genes." If you do not uncheck all the other boxes, you will get an incredibly busy map that is several megabytes in size and will probably crash your computer. We are only interested in seeing what some of the nearby genes are.
9. After you have unchecked those boxes, click on the "Display Map" button. The map will show you the exact location of the gene in question on its chromosomes, and its relationship to nearby markers and genes.

   WARNING: This step requires you to have Java-capable Netscape 3.0 or higher or Internet Explorer 3.0 or higher. In addition, this step will require several minutes for the map to download, and you will need quite a bit of memory. A Pentium or Power Mac works best. If your normal computer (i.e. at home) does not have these capabilities, you can access this data at a school lab, extension office, or library. If all else fails, the OMIM Database (see the Genetic Diseases Assignment, Module 3) has much of the same data in text format. It will take some work to format that data, however, in a way that it is meaningful to you.
   

10. Look at the structure of the chromosome on the map. How is the genome organized? Look up the identity of some of the nearby genes on the Genome Database. Are nearby genes associated with the same organ or system? Is there a nearby centromere or chromosome end? How will this affect expression of the gene?
    
11. Go to the Mammalian Homology Query Form at the Mouse Genome Informatics page (http://www.informatics.jax.org:80/searches/homology_form.shtml). Under "Primary Species," click on "Human (Homo sapiens)." Scroll down to "Marker Symbol" and "Chromosome" and fill in the necessary information. Under "Comparison Species," click on "Any," and then click on the "Retrieve" button at the bottom.
    
12. If there are any homologous genes listed in any other species, explore some of the links listed. Is the entire chromosome region conserved throughout evolution? Are the conservation of chromosomal regions important in gene function? How homologous are these animal genes with this human gene? 20%? 50%? 95%? If there are no homologous genes listed, speculate about what we can conclude from this finding. Does this mean that the animals have no similar genes? Speculate about what effects this gene might have on evolution. In both cases, what can we learn about human genes by studying animal genes? Use your intuition, imagination, logic, and reason. You don't need advanced classes in evolutionary genetics in order to speculate!

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Report on your Research (100 points):

• Review of the clinical features of the gene in question (10 points).
  
• Discuss your gene's location on a chromosome and on a chromosome segment. Also include a discussion on genome organization, nearby genes, and chromosome structure in the area of the gene (a good place to reference your map [see below]). Does the function of nearby genes or chromosome structure suggest a certain kind of organization for the genome? (20 points)
  
• Include a hard copy (see below) of the chromosome map with a brief caption titled "Figure 1" (or whatever Figure number it is in your paper) and a brief description including the gene's name and the chromosome it is on. On the map itself should be the labels of chromosome regions, the abbreviation and location of the gene in question, and the labels and locations of nearby genes of interest (such as the ones you investigated to check on genome organization) (15 points).

  Ways to make a hard copy of a very *big* map:
  a) You can try printing it. Click on "Print" (under "File" in toolbar). About 1/3 of the way down, it will show you how many pages there are to print. Try shrinking the "Set Size" to 30%, and see how many pages that is. If you are ready to print, and have Postscript software, then click on the "Generate Post Script" button. If it prints, cool. If you don't have Postscript software, click on the "Help" button, and there will be a link for you to get it. If you can't get it to print for any reason, and if you have Printshop or Adobe Photoshop or similar software, you can save the file when it prompts you, and then print it out on your program.
  b) The old-fashioned way. Draw it freehand. I'm looking for a rough approximation of the cytogenetic map (the drawing with the chromosome and the white and dark bands in that area), and the relative positions of the gene in question, and a few of the nearby genes you looked at in Part 10. I'm not an art teacher; I don't take off for quality. As long as it shows the chromosome segments, genes clearly labeled as to what and where they are. Do not include any amplimers or bins or clones or fragile sites....only genes.
  

• What other species have genes that are homologous to the gene in question? Describe some of the research done on these genes in other species. How homologous are these animal genes to their human counterparts? Comment on chromosome segment conservation through evolution, and whether this is important in gene function. If no homologous genes were found, what does this mean? Does this mean the animals do not have any genes similar to this gene? What effect would this gene have on the survival of humans if we lived wild and had no medicine or modern technology? How does this gene affect evolution and selection of the fittest? In either case, talk about what we can learn about human genes from studying genes from other species (30 points).
  Hint: You don't need an advanced degree or even a class in evolutionary genetics in order to speculate. Stretch your imagination, and your powers of intuition, logic, and deduction!
  
• Originality and creativity in research or style of paper (10 points).
  
• Readability, grammar, spelling, etc. (5 points).
  
• All sources (including the databases) MUST be referenced (10 points).
  

TOTAL POINTS: 100 POINTS.

Submit your paper via the usual means.

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