Your Genes Are Obsolete - Pacific Standard

Your Genes Are Obsolete

Genes don't consistently do what we once thought they would, so it's time to reconsider what we mean when we say the word.
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(Photo: Leigh Prather/Shutterstock)

(Photo: Leigh Prather/Shutterstock)

Today, DNA is central to modern biology, but scarcely a century ago biologists were debating whether or not genes actually existed. In his 1909 textbook on heredity, Danish botanist Wilhelm Johannsen coined the term gene to refer to that hereditary "something" that influences the traits of an organism, but without making a commitment to any hypothesis about what that "something" was. Just over a decade later, a prominent biologist could still note that some people viewed genes as "a convenient fiction or algebraic symbolism."

As the century progressed, biologists came to see genes as real physical objects. They discovered that genes have a definite size, that they are linearly arrayed on chromosomes, that individual genes are responsible for specific chemical events in the cell, and that they are made of DNA and written in the language of the Genetic Code. By the time the Human Genome Project was initiated in 1988, researchers knew that a gene was a segment of DNA with a clear beginning and end and that it acted by directing the production of a particular enzyme or other molecule that did a specific job in the cell. As real things, genes are countable, and in 1999 biologists estimated that humans had "80,000 or so" of them.

Giving a physical meaning to the concept of a gene was a triumph of 20th-century biology, but as it turns out, this scientific success hasn't solved the problems we hoped it would.

Yet, when the dust from the Human Genome Project cleared, we didn't have nearly as many genes as we thought. By the latest count, we have 20,805 conventional genes that encode enzymes and other proteins. Our inflated gene count, though, wasn't the only casualty of the Human Genome Project. The very idea of a gene as a well-defined segment of DNA with a clear functional role has also taken a hit, and as a result, our understanding of our relationship with our genes is changing.

One major challenge to the concept of a gene is the growing evidence that many genes are shapeshifters. Instead of a well-defined segment of DNA that encodes a single protein with a clear function, we should view a gene as "a polyfunctional entity that assumes different forms under different cellular states," according to University of Washington biologist John Stamatoyannopoulos. While researchers have long known that genes are made up of discrete subunits called “exons,” they hadn't realized until recently the degree to which exons are assembled—like Legos—into sometimes thousands of different combinations. With new technologies, biologists are cataloging these various combinations, but in most cases they don't know whether those combinations all serve the same function, different functions, or no function at all.

Our concept of a gene is also challenged by the fact that much of the function in our DNA is located outside of conventionally defined genes. These "non-coding" functional DNA segments regulate when and where conventional protein-coding genes operate. For our biology, non-coding regulatory DNA elements are asconsequential as genes, but their properties are even more difficult to define because their function isn't based on the well-understood Genetic Code and their boundaries are even fuzzier than gene boundaries. As a result, non-coding regulatory DNA elements are much more difficult to count. One consortium of researchers put the number of regulatory DNA segments in the human genome between 580,000 and 2.9 million, while just last month a different consortium claimed that there are only 43,000. Regardless of how you count them, it's clear that these non-gene regulatory DNA elements far outnumber conventional genes. It is hard not to wonder, then, what good is the concept of a gene if it doesn't include most of our functional DNA?

In the aftermath of the Human Genome Project, biologists are struggling with the definition of a gene, but why should this matter to anyone else? It matters because the molecular concept of the gene that has dominated biomedical research for the last half-century is increasingly ill-suited for our efforts to understand the role of genetics in human biology. Giving a physical meaning to the concept of a gene was a triumph of 20th-century biology, but as it turns out, this scientific success hasn't solved the problems we hoped it would.

The Human Genome Project was conceived as part of a research program to develop a set of clear molecular explanations for our biology. The idea was to inventory all of our genes and assign each of them a function; with this annotated inventory in hand, we would possess a molecular explanation of our genetic underpinnings and discover druggable target genes for specific diseases. While this gene-focused approach has been successful in many cases, it's increasingly clear that we will never understand the role of genetics in our biology by merely making an annotated inventory of those DNA entities that we call genes.

Life isn't so simple, and perhaps Wilhelm Johannsen's more agnostic definition of a gene is a better match to the mixed bag of genetic elements in our genomes. The molecular concept of a gene was supposed to explain the influence of our DNA on our biology, our behaviors, and our ailments. That explanation is much more elusive than we hoped, and the role of DNA in our lives is more complex and subtle than we expected.