The Motherlode: Mitochondrial DNA
WHY YOU SHOULD CARE
Every mother transmits a second genetic legacy to her children…and within it may be the a chance to alter future generations.
You know what DNA is. You’ve heard of 23andMe. You’re following news about the human genome, and you’ve come to understand how its sequence of nucleotide bases writes the playbook for our lives. But surprise! Did you know that we have not just one but two genomes within each of our cells?
The vast and famous human genome that resides in the nucleus of our cells clearly runs the show with its 25,000 genes arranged in pairs — one from Mom and one from Dad. But there’s a second genome, small and beautiful and much less appreciated, living in our cells within structures known as mitochondria and directing functions that are absolutely essential. Author Nick Lane writes about these little beauties in most powerful terms in his book Power, Sex, Suicide: Mitochondria and the Meaning of Life. Not 3,000,000,000 but just 16,000 nucleotide bases of DNA, and not 25,000 but only 13 genes. And finally — here’s the shocker — we inherit all of our mitochondrial DNA from our mothers. Dad’s mitochondria get stripped away as the sperm carries his nuclear genes to match up with Mom’s, and the oocyte (egg) is fertilized.
There’s a second genome, small and beautiful and much less appreciated, living in our cells within structures known as mitochondria.
Only 13 genes, but if any become defective, things can really go south, particularly for high-energy organs such as the brain, heart and muscles. Mitochondria are the energy factories for our cells, and mutations in mitochondrial genes can cause a broad spectrum of serious problems that may appear at birth or much later in life. Mitochondrial DNA mutations forced the retirement of Tour de France champion Greg Lemond when he was only 33.
The disconcerting truth is that our mitochondrial genes go bad all the time. Year by year as we age, our cells acquire an increasing number of mutated mitochondrial genomes, even in apparently healthy persons. The good news is that each of our cells includes dozens or even hundreds of copies of mitochondrial DNA (MtDNA), and usually cells work just fine unless 80 percent or more of these become defective. Most of us never approach that threshold, but for those who do, it’s a sobering reality: There are no current cures for diseases caused by defects in mitochondrial DNA.
However, a bold new biotechnology that would allow mothers to replace defective mitochondrial genomes in their offspring is currently under consideration for approval by British lawmakers. The procedure involves removing the nucleus from a fertilized oocyte from such a mother and inserting it into an enucleated oocyte (nucleus removed) from a second female with normal mitochondrial DNA. If approved, it would represent the first germ-line gene replacement in human beings, meaning that the genome would be altered not only in the individual but in all of the individual’s descendants as well.
Mitochondrial genes go bad all the time. There are no current cures for diseases caused by defects in MtDNA.
As Marcy Darnovsky, of the Center for Genetics and Society in Berkeley, California, wrote in Nature, this new germ-line modification would go against current international consensus on gene therapy: ”Genetic-engineering tools may be applied…to treat an individual’s medical condition, but should not be used to…manipulate the characteristics of future children.” A number of European parliamentarians have also raised objections, arguing that a therapy which combines the genetic material of more than two persons ”is incompatible with human dignity.” So, while there is considerable excitement in the scientific community about replacing mitochondrial DNA, some worry that we’re moving too quickly into an unknown frontier.
In considering mitochondrial DNA as the second human genome, things grow curiouser and curiouser, as Alice found in Wonderland. The nuclear and mitochondrial genomes each employ a distinct genetic code to provide instructions on how to make specific proteins. All life forms, from microbes to humans, use an identical code, except for their mitochondria. Far from being an independent structure, mitochondria can’t last long outside of the cell because most of the hundreds of proteins required to build and maintain them are provided by the cell nucleus.
How did this happen? Why two separate genomes? Here’s the skinny on what seems the most likely explanation. Around 2 billion years ago in the primordial ooze, one bacterium swallowed another. But instead of the predator digesting its prey, the two played Jonah and the Whale as one learned to live happily and successfully inside the other, becoming what is called an endosymbiont. Thanks to this bit of bacterial indigestion, the resulting critter went on to sire all subsequent creatures that have ever crawled, walked, swum or flown on the planet — and caused us, along with zebras, yeasts, barn swallows, night crawlers and octopi, to have two genomes.
The curious maternal inheritance of mitochondrial DNA has given rise to important insights about human evolution.
The curious maternal inheritance of mitochondrial DNA has given rise to important insights about human evolution and migration across the globe. Without dilution from mixing with paternal genes, as is true for the nuclear genome, the strictly maternal inheritance of mitochondrial genes can be used to track lines of relatedness more faithfully over many generations. Statistical methods applied to mitochondrial DNA sequences from persons around the world suggest that all modern humans are the descendants of one female (or perhaps a very few) who lived in Africa several hundred thousand years ago (Eve?). Focusing on more recent history, it’s interesting to consider how different the succession of British royalty from Queen Victoria would be if rules of maternal inheritance had been applied (Prince George, move aside!).
There may be no current cures for diseases caused by defects in mitochondrial DNA, but the new biotechnology offers hope to mothers with mitochondrial DNA mutations that their children — and their children’s children — can be free of disease. The concept is being criticized on scientific grounds, questions of safety and matters of ethics, but stay tuned. The first medical alteration of the human germ line could well be applied to Mother’s little secret, the diminutive but mighty mitochondrial genome.
R. Sanders (Sandy) Williams, MD, is president of the Gladstone Institutes and a professor of medicine at the University of California San Francisco. Formerly dean of Duke University’s medical school, he has served on various boards and professional associations, including the board of reviewing editors of Science magazine.