Every person starts with just one genome, the unique amalgam of paternal and maternal DNA in the fertilized egg. And researchers long thought that over a lifetime, pretty much all of the body’s diverse cells inherit that same genome. But large-scale DNA sequencing over the past decade or so has toppled that view, showing that human DNA starts to accrue mutations early in embryonic development and continues to change throughout life. “The genome you are conceived with is very different from the genome you die with,” says cardiovascular biologist Kenneth Walsh of the University of Virginia.
As a result, every person is actually a mosaic of genomes, varying across the body and often within the same organ or tissue. These DNA changes introduce a diversity to the body’s somatic, or nonreproductive, cells that may be as important to health as the more pervasive alterations inherited from parents. Now, the National Institutes of Health (NIH) has launched a 5-year, $140 million project to map this universe of genomic diversity—and probe why it matters.
Known as Somatic Mosaicism Across Human Tissues (SMaHT), the program will measure the baseline frequency of these mutations in an assortment of tissues to help researchers better understand how the alterations contribute to health and disease. SMaHT, which in May doled out its first 22 grants, aims to collect samples of 15 tissues from 150 healthy people who donated their bodies for research. It has funded five teams to sequence DNA from these samples—they should begin in the coming months—and is backing others to develop new technologies for analyzing genetic variants and probing their effects.
“The idea is to be able to at least catalog the mutations” so that researchers can delve into links with diseases, says genomicist Harsha Doddapaneni of Baylor College of Medicine, who helps lead one of the SMaHT sequencing groups.
For decades, the conventional wisdom held that a person’s somatic cells could pick up mutations but that these genome alterations were rare and not a major cause of health problems. Mutations in the skin, for example, occasionally resulted in unusual pigment patterns such as port-wine stain birthmarks.
But scientists now know that our genomes are riddled with somatic mutations. Even in young children, some cells already carry thousands of these alterations, and one study found that lung cells from a former smoker in her 70s boasted more than 15,000 mutations each. “We used to think about the genome. Now, we think about our genomes,” says oncologist Dan Landau of Weill Cornell Medicine.
The vast majority of these changes likely have no impact on our health. A portion can trigger cancers, however, and other mutations may drive different illnesses or cause premature deaths. Clonal hematopoiesis, a variety of mosaicism that affects blood-forming cells and becomes more common with age, almost doubles the likelihood of developing cardiovascular disease and boosts the risk of dying from any cause by 40%. As men get older, they become more vulnerable to another type of mosaicism in which the Y chromosome vanishes from some of their cells. Its absence may set them up for ailments such as cardiovascular disease and macular degeneration.
The brain can also incur damage as neurons and other cells accumulate mutations. “Somatic mutations are disease-causing in some proportion of patients with epilepsy,” says Alissa D’Gama, a clinical fellow at Boston Children’s Hospital. In addition, researchers estimate that fetal mutations that may modify brain development account for about 3% to 5% of the risk of developing autism spectrum disorder. Studies have also linked mosaic brain mutations to a variety of other neurological disorders, including schizophrenia and Alzheimer’s disease. “Somatic mosaicism is likely playing a role” in these conditions, D’Gama says. “What needs to be teased out is how big a role.”
Plenty of other mysteries about somatic mutations remain—for example, whether certain tissues accumulate more mutations than others. “Only a few types of tissues have been investigated,” notes developmental scientist Flora Vaccarino of Yale School of Medicine, who has SMaHT funding.
Researchers also want to determine whether some somatic mutations benefit us. Scientists have found that individual cells can gain from certain changes that give them and their descendants, known as a clone, a competitive advantage over other clones. However, what’s good for specific cells isn’t necessarily good for the tissues they inhabit—cancer is a prime example—and whether any somatic changes improve our overall health is unclear. But some evidence hints they can. For example, scientists have found that clones carrying certain mutations have an advantage in people with fatty liver disease, a condition in which fat accumulates in the organ and can cause it to fail. Those findings raise the possibility that the alterations help the liver cope with disease.
To test that idea, liver biologist Hao Zhu of the University of Texas Southwestern Medical Center and colleagues mimicked gene-disabling somatic mutations in mice with nonalcoholic steatohepatitis (NASH), a type of fatty liver disease that is increasingly common in people. The researchers deleted each of 63 genes linked to NASH from a subset of cells in the livers of the animals. Six months later, the team found, clones missing some of the genes had the upper hand. Because these elite clones grew faster, Zhu and colleagues next asked what would happen if one of them prevailed, expanding so much that it replaced its rivals. To find out, they deleted some of the genes throughout the rodents’ livers. For three of the genes, the mice gained protection against fatty liver disease, accumulating less fat and incurring less tissue damage. Liver clones probably grow too slowly in people to reverse fatty liver disease, Zhu says, but the discovery could point to new treatments.
By providing the first bodywide reference for somatic mutations, SMaHT will help scientists investigate their roles. However, finding these mutations is challenging. Researchers and clinical labs are adept at uncovering mutations in tumors, but those alterations are typically found in a large fraction of the abnormal cells. In contrast, some somatic mutations occur in less than 1% of cells in a tissue. Today’s DNA-decoding technology can miss such rare mutations because it has a relatively high error rate. Moreover, researchers often sequence DNA from multiple cells simultaneously, which can swamp rare changes. “You are looking for a signal that is hidden among noise,” says geneticist Martin Breuss of the University of Colorado School of Medicine.
For SMaHT, five groups of researchers plan to use several techniques to ferret out and verify these hidden signals. Doddapaneni, his Baylor colleague Rui Chen, and their team, for example, will deploy not just conventional whole genome DNA sequencing, but also two types of RNA sequencing, which can help confirm some variants and identify the types of cells carrying them. To weed out errors, they will also use duplex sequencing, a less common technique that decodes both strands of DNA’s double helix to reduce mistakes and pinpoint rare mutations.
The remaining SMaHT-funded teams will tackle a variety of projects. Geneticist Kathleen Burns of the Dana-Farber Cancer Institute and her colleagues want to better define the role of transposons, lengths of DNA that modify the genome by moving from place to place. The researchers will develop ways to identify restless elements that are primed to relocate and pin down where in the genome they insert. Work by other groups will include probing how somatic mutations affect gene activity and developing new approaches for sequencing the genomes of single cells.
SMaHT won’t answer every question about somatic mutations. Walsh notes that although the program will obtain tissues from people of different ages, it won’t include samples taken over time from the same person, making it harder to understand the mutations’ role in aging, he says. But it is a key next step in what Landau calls “a huge revolution in human genetics.” He is eager to see the results. “We are just at the beginning of this incredible adventure.”
