The Theme of Levels of Organization in Genetics
We now know so much about the human genome: it is made of approximately 3.2 billion base pairs of DNA, which contain the information for about 25,000 genes. Less than 0.1% of the genome varies across humans, and thus this incredibly small fraction is responsible for many of the differences we observe across races and individuals (US Department of Genome Programs, 2010)! In the not so distant future, it will be possible to have your own genome sequenced, and you will be able to look at many, many pages covered in As, Ts, Cs, and Gs, containing all the genetic information about you - your very own genetic blueprint. But can you learn everything about you from looking at these pages? No, not really. Variation in the series of base pairs making up your genome does determine a lot about you, but because of the complex processes that lead from genotype to phenotype, and because not all characters have a genetic basis, it is impossible to know everything about someone simply from a printout of their genome. For example, we would definitely know your blood type, and whether you might be able to taste the bitterness of Brussels sprouts, and we'd be able to take an educated guess at your height and your hair color. But we wouldn't know what your favorite kind of music is, or what languages you speak just from looking at your DNA.
Let's pick a well-studied gene to see how small changes in sequence might lead to major differences in phenotype, while affecting many processes. Fibroblast growth factor receptor 3, or FGFR3, is involved in bone development and maintenance. A common point mutation at nucleotide 1138 in this gene replaces a G with an A. This mutation, or SNP (single nucleotide polymorphism), changes a codon, originally GGA, into AGA (National Center for BiotechnologyInformation, 2010). This also changes the corresponding amino acid from a glycine into an arginine, and thus affects the structure of the proteins FGFR3 codes for. This modification in structure affects how these proteins function. Because the FGFR3 products behave differently, bone development does not follow the usual trajectory. Individuals born with this mutation have a genetic disorder called achondroplasia: short stature because of shortening of the limbs, amongst other symptoms. Achondroplasia is the most common genetic disorder associated with short stature and occurs between 1 in 15,000 to 1 in 40,000 births. Most often (approximately 80% of the cases) it is a "de novo" mutation – not inherited from the parents, but appearing in the offspring. The mutation usually occurs in the father's sperm (National Center for Biotechnology Information, 2010).
So one little change, a single letter in 3.2 billion that constitute the human genome, can affect many levels of organization in an organism; this single nucleotide base difference changes codon identity, protein structure and function, bone development, and overall physical appearance. And yet, because of the many factors involved in the translation of genotype into phenotype, not every variation in the coding sequence results into such a dramatic and predictable phenotypic effect.