Today we will start in the present,
by looking at the first of a number of inherited diseases that we will investigate
during the semester. Then, we will get into our time machine, go back 150 years,
and start forward again.
From the genotype to phenotype overview last class, we see that the complicated events of translation determine the "amino acid sequence" of the protein, and the protein folds into its 3-D shape as it is being synthesized. The specific physical interactions between the amino acid side chains determine how the protein folds into a detailed structure, and it is a protein's 3-D structure which gives it its function.
If, for example, there is a base pair mutation in the gene (a change in genotype), thus giving a single nucleotide change in the mRNA, there might be a single amino acid difference in the protein. If this amino acid change causes a significant difference in the shape of the protein, the protein's functionality might be significantly altered, thus giving us a noticeably different phenotype.
1. At the molecular level, what is "wrong" in people who have the inherited disease phenylketonuria?
Page 25 shows the 3-D structure of the enzyme PAH (composed of four identical polypeptide chains, each 452 amino acids in length). A person has the disease phenylketonuria (PKU) if this enzyme is defective due to mutations in both alleles of the PAH gene that codes for this enzyme. Two examples of mutations found in people with this disease are shown in Figures 1.17 and 1.18. For the M1V mutation (Fig. 1.17), translation cannot begin, and so no PAH enzyme is produced. For the R408W mutation (Fig. 1.18), a single base pair difference in codon 408 results in a PAH enzyme that has just this one amino acid difference (out of the 452), but the resultant protein has no enzymatic activity.
So, a person whose two PAH alleles are M1V and R408W (or any two defective alleles) has phenylketonuria.
2. Where are we if we do a "knowledge re-wind" of 150 years?
Let's get into our time
machine, and turn the dial to 1855. Here we are in the middle of the 19'th century, nearly a hundred
years before Watson and Crick's discovery of the double helical structure of
DNA. What does the biological science knowledge frontier look like? The world
(of 1855) does not yet know it, but there are two people whose biological insights
are going to revolutionize things and set the stage for 20'th century biology.
These two people are Charles Darwin and Gregor Mendel.
Darwin, in England, is already quite well known in 1855. He had earlier published an account of his voyage on the Beagle, during which his detailed observations in the Galapagos Islands and elsewhere convinced him that species are directly influenced by their environments. He is at work on the book for which he will become both famous and infamous four years later, "The Origin of Species by Means of Natural Selection". This work will become the foundation that will lead to 20'th century thinking about evolutionary processes. In the most general terms, our current understanding of the relationship between genetics and evolution is that evolution occurs due to a combination of two things: (First) Random genetic changes (mutations) guarantee that large populations will be heterogeneous at the genotype level; & (Second) Organisms of various phenotypes will have different levels of reproductive success. Thus, natural selection can lead to changes in the average genotype in the population as generations go by.
Mendel, in central Europe, is (in 1855) getting ready to start some cross-breeding experiments on pea plants of various different characteristics (Figure 3.1). Mendel had shown that peas usually reproduce by self-pollination. He has just figured out how to cross-pollinate (Figure 3.3), and will spend the next seven years carrying out experiments and analyzing the results. This work will then remain obscure until early in the 20'th century, when it will be "re-discovered" and become the foundation of genetics.