I Contain Multitudes
Our bodies are a genetic patchwork, possessing variation from cell to cell. Is that a good thing?
Olena Shmahalo for Quanta Magazine
Even healthy brains harbor genetic diversity, though scientists disagree over the extent.
By: Kat McGowan
August 21, 2014
Your DNA is supposed to be your blueprint, your unique master code, identical in every one of your tens of trillions of cells. It is why you are you, indivisible and whole, consistent from tip to toe.
But that’s really just a biological fairy tale. In reality, you are an assemblage of genetically distinctive cells, some of which have radically different operating instructions. This fact has only become clear in the last decade. Even though each of your cells supposedly contains a replica of the DNA in the fertilized egg that began your life, mutations, copying errors and editing mistakes began modifying that code as soon as your zygote self began to divide. In your adult body, your DNA is peppered by pinpoint mutations, riddled with repeated or rearranged or missing information, even lacking huge chromosome-sized chunks. Your data is hopelessly corrupt.
Most genome scientists assume that this DNA diversity, called “somatic mutation” or “structural variation,” is bad. Mutations and other genetic changes can alter the function of the cell, usually for the worse. Disorderly DNA is a hallmark of cancers, and genomic variation can cause a suite of brain disorders and malformations. It makes sense: Cells working off garbled information probably don’t function very well.
Most research to date has focused on how aberrant DNA drives disease, but even healthy bodies harbor genetic disorder. In the last few years, some researchers report that anywhere from 10 to 40 percent of brain cells and between 30 and 90 percent of human liver cells are aneuploid, meaning that one entire chromosome is either missing or duplicated. Copy number variations, in which chunks of DNA between 100 and a few million letters in length are multiplied or eliminated, also seem to be widespread in healthy people.
The exact extent of cell-to-cell diversity is still unclear and a matter of some debate. It’s only in the last two years that scientists have been able to look carefully at just one genome at a time, with the advent of new methods of single-cell DNA sequencing. (Earlier methods averaged the results of thousands or millions of cells and could only detect huge aberrations or relatively common ones.) Because this work is so new, each study includes surprises: A single-cell genome sequencing study of 97 neurons from healthy brains, published today by Christopher Walsh, a neurologist at Boston Children’s Hospital and Howard Hughes Medical Institute, and the postdoctoral researcher Xuyu Cai found few that were aneuploid — less than 5 percent. But most had at least one good-sized copy number variation.
Walsh’s findings and others mark a third phase in human genomics. When the complete DNA of one human being was first sequenced in 2000, it was considered to be “the” human genome. Soon after, researchers began to explore the differences between individuals, launching the era of the “personal genome.” Now science is entering the age of the microgenome, in which research begins to explore the worlds within us, examining our inherent imperfections and contradictions, the multitudes we contain.
With that third phase comes a deeper question. What do our genetic contradictions mean? Do they play an important role in our biology? At this point, just about every genome scientist has a slightly different take. One surprising theory suggests that DNA diversity might be good for you. It’s a feature, not a bug.
According to this idea, genetic heterogeneity allows bodies to be more adaptive and resilient. The logic comes from evolutionary biology. Genetic diversity is clearly beneficial for a population or species, because a few individuals will likely be randomly equipped to survive unpredictable environmental changes, such as a drought or an epidemic. Along similar lines, some biologists have proposed that genetic diversity might also be beneficial within the individual. If new conditions demand new abilities or functions, such as surviving an environmental toxin or learning a new skill, genetic heterogeneity increases the odds that at least some cells will be able to thrive in this new situation. “I think of the body as a population of cells, similar to the population of human organisms walking this earth,” said James Lupski, a geneticist at Baylor College of Medicine, who studies how DNA alterations shape human traits. In any such population, “there’s a lot to be said for generating variation, and allowing the most fit variation to be selected out.”
Courtesy of Fred Gage
Our genetically diverse brains might be one reason we are all so different, suspects Salk Institute neurobiologist Fred Gage.
The most radical version of this argument comes from Fred Gage, a Salk Institute neurobiologist best known for pioneering studies in neuroplasticity, the adult brain’s ability to adapt. His team has found several types of genetic variation to be common in normal adult human brains, and he thinks this diversity could help explain the organ’s amazingly complex structure and remarkable flexibility. “We can’t predict what will happen to us in our 80 years of life,” he said. “We have to build in mechanisms of diversity that will help us adapt to the things that happen to us.” Experts in liver biology propose a similar idea. They even have preliminary evidence that genetic diversity actually can make the organ more resilient.
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