Identifying the Genomic Basis of Biological Variation: Home

Under the “central dogma” of molecular biology, a concept developed by Francis Crick in the 1950s, information flows unidirectionally from the genetic information encoded in DNA—the genome of an organism—to guide the production of proteins. Proteins, in turn, include structural elements such as muscle fibers, and actors such as the enzymes that mediate conversion of ingested food into energy forms directly accessible to cells. Horace Freeland Judson’s The Eighth Day of Creation provides an engaging, comprehensive history of key experiments in the discovery of the molecular basis of genetics.

Some seventy years later, it has become clear that this central dogma is both useful as a broad summary of a subset of genetic processes and incomplete in its portrayal of biological information. The Human Genome project, an ambitious, early-2000s project to discover the human DNA sequence, led ultimately to the unanticipated discovery of two patterns that undermine the capacity of the central dogma alone to explain the bulk of biological variation both within and among species. First, genes—the areas of DNA that encode proteins—constitute a very small fraction of a human’s total genome, indicating either that most of an organism’s DNA has no function, or that genes alone do not account for phenotype, the full set of characteristics of an organism. Second, a very large fraction of the genes present in the human genome are also present in the genomes of mammalian species whose structures and behaviors differ greatly from our own. Walter Bodmer and Robin McKie provide a useful overview of this project in The Book of Man. In short, the Human Genome Project both successfully discovered approximately 20,000 genes encoded in human DNA, and found that these genes on their own are wholly insufficient to explain observed biological diversity. Prescott Deininger, in his Scientific American article “What Does the Fact That We Share 95 Percent of Our Genes with the Chimpanzee Mean? And How Was This Number Derived?” offered a broadly accessible consideration of this paradox, pointing to what we can and cannot infer from the observation that the human genome is about 95 percent identical to that of our closest relative, the chimpanzee.

These essential findings from the Human Genome Project have raised both challenges and hopes. On the one hand, if variation in phenotype cannot be explained by the presence or absence of a given gene, then we need to learn more about the vast, non-genic expanses of the genome that were initially assumed to be irrelevant to health—a major undertaking, to be sure. On the other hand, if many health-related genetic changes occur outside of genes, then even individuals discovered to have a disease traceable to a genetic alteration may still have a “normal” copy of the gene that encodes an essential protein, thus raising hopes that activating an abnormally dormant gene could be a promising therapeutic path. This bibliographic essay offers a selection of resources focused on helping students to both appreciate the history of our understanding of the genomic basis of biological diversity and to survey contemporary approaches to identifying the genetic components of biological variation.

Diane P. Genereux is a scientist at the Broad Institute of Harvard and MIT in Cambridge, Massachusetts. She studied biology at Brown University, Emory University, and the University of Washington, and previously taught undergraduate and graduate courses in genetics, genomics, and mathematical biology. Her research focuses on the genomic basis of flexible homeostasis.