Exploring the Genome

In light of last week’s article I thought it would be fun to share some
great genomics databases.
Here is a good place to start, with basic information on the human genome project: The Human Genome Project

Here is a page with general links to all sorts of gene related databases: NCBI gene databases

One of my favorite sites is
Online Mendelian Inheritance in Man (OMIM). This site will allow you to search any trait for possibly related genes. For example, if you type in “breast cancer” you will find all of the genes thought to have a link to the disease.

~A brief history of the study of genes~

Remember Gregor Mendel from high school biology? He was the monk with a certain love of peas who used probability to predict the expected ratio of traits in offspring. Mendel identified whether the physical traits of his pea plants were dominant (always expressed), partially dominant, or recessive (masked in the presence of dominant traits). If you were like me, you remember the "punnet square" method and getting stuck with any guy other than the one you liked, forced to make predictions about what eye color, brow line, etc., your offspring might have. Other uses of Mendel's findings are not always so traumatic. These methods can still sometimes be used to help predict the characteristics of offspring in breeding, research, and agriculture or anticipating a genetic disorder in humans. Although we now know that many traits are a result of multiple gene expression and most genes have more than just a dominant and a recessive allele (version), it was an amazing start and novel idea.

Archibald Garrod later used Mendel’s methods in humans to anticipate carriers of the rare genetic disease alkaptonuria (black urine) in 1902. This sparked a new interest in genetics and a revival of the monk’s work.

The famous Thomas Morgan (left) began his research career shortly after discovery of Garrod and others. Because humans don’t reproduce frequently and you certainly can't tell them who to breed with (unless they are high schoolers engaged in hypothetical crosses), Morgan thought his work would be better suited to a model organism: Drosophila melanogaster, the fruit fly. Working with the relatively simple genome of D. melanogaster, Thomas Morgan was able to demonstrate that genes are the carrier of traits and theorized that they resided in a linear fashion on “chromosomes.” The existence of actual genes was previously unknown, as Mendel had simply called them “heritable traits.” He and his student Alfred Sturtevant realized that these chromosomes underwent recombination—swapping of alleles on like chromosomes—before gametes (eggs or sperm) were produced. Sturtevant discovered he could utilize this meiotic property to reveal the relative location of individual genes on the chromosome. Genes that are closer to one another are less likely to be recombine, while genes lying far from one another are more frequently recombined. Recombinant frequencies were used to create the first genetic map of the Drosophila melanogaster X chromosome in 1913.

Later, in 1931, Harriet Creighton and Barbara McClintock (left) used corn to prove the physical existence of chromosomes and recombination. Using a chromosomal mutation in corn that made the ends of the chromosome distinguishable from one another under the microscope (one end with a “knob” and the other with extra length); they were able to show that recombination actually occurs. Genes more closely associated with the knobby end would recombine less frequently with one another and more frequently with those on the elongated end. McClintock’s research continued to contribute to genetics well into the 60’s, including her 1948 discovery of transposons (“mobile genes”) which she received a Nobel Prize for in 1983. Recombinant frequencies as well as other techniques are still used today to create relative genetic maps that aid in the sequencing process.

It would take longer before technology would advance in such a way to prove the physical characteristics of genes and pave the road for sequencing of whole genomes. 1947 papers by Chargaff revealed that nucleotides adenine and thymine, guanine and cytosine always appeared in equal proportions suggesting possible pair bonding. In 1948 Linus Pauling (my bio-chem instructor’s favorite chemist) discovered the alpha helical shape of proteins which could potentially be applied to nucleotides. Later x-ray diffraction data produced by Maurice Wilkins and Rosalind Franklin showed the possibility of DNA’s helical form. Putting all of this insight together, Francis Crick and James Watson (left) were able to publish the first structural model of DNA in 1953.

Advancements in molecular cloning via E. coli in the 1970s led to a desire to sequence genomes and discover the molecular components of genes. An eager effort to sequence the human genome was sparked in the 1980’s. Technology was such that it was slow going at first. In 1993, the invention of PCR (which can amplify DNA without the use of a living organism) by Kary Mullis greatly expedited the process. By the time the first draft of the human genome was published in 2000 (remember that year!); we had already sequenced the genomes of several other species with the now incredibly fast technology. Genomics is constantly growing with more genomes sequenced and better, more statistically accurate versions continue to come out. I may have teased a bit the “worship” of DNA, but genes are far from insignificant.

Sources: Benjamin Pierce. Genetics, A Conceptual Approach. 2005
www.wikipedia.org
Images:
DNA: http://www.chemicalgraphics.com/paul/images/DNA/
Mendel: http://www.blackwellpublishing.com/ridley/image_gallery/
Morgan: http://www.columbia.edu/cu/alumni/Magazine/Fall2002
McClintock: http://biology.kenyon.edu/slonc/bio3/people/
Watson and Crick: http://history.nih.gov/exhibits/nirenberg/images/photos/