250+ Scientists Are Building The Most Complex Map Of Human Genetic Mutations Ever Created

NIH’s SMaHT Network will chart trillions of somatic mutations to reveal how our DNA changes over a lifetime.

BETHESDA, Md. — Your body is quietly collecting genetic changes right now, and scientists want to map every single one. A massive new research network is launching the most ambitious genetic study since the Human Genome Project, but this time they’re tracking the thousands of DNA alterations that pile up throughout your lifetime.

The Somatic Mosaicism across Human Tissues (SMaHT) Network, backed by the National Institutes of Health, plans to catalog genetic changes that happen after conception. These aren’t mutations inherited from your parents, rather, they’re DNA alterations that accumulate as you live, making each person’s tissues genetically distinct by adulthood.

These quadrillions of genetic changes help explain why identical twins grow more genetically different with age, and why diseases like cancer can seemingly appear from nowhere. “A typical cell may acquire hundreds to thousands of somatic mutations in a lifetime,” the researchers write in their paper published in Nature. “There are trillions of cells in a human body and so the total number of somatic mutations acquired in a single individual may well exceed quadrillions.”

Your Body’s Daily DNA Changes

Your cells face constant attack from environmental toxins, UV radiation, and normal cellular processes. Most DNA changes are harmless, but some dramatically alter cell behavior. Cancer represents the most extreme example, though these mutations also factor into heart disease, neurological disorders, and aging.

Different body parts collect mutations at wildly different rates. Brain cells, which rarely divide after birth, gather about 16-20 new mutations yearly. Rapidly dividing colon cells rack up approximately 44 mutations annually. Sun-exposed skin shows clear UV damage patterns, while smokers’ lung tissue bears molecular tobacco scars.

These patterns, called mutational signatures (distinct patterns that reveal what caused specific DNA changes), work like genetic fingerprints revealing specific environmental exposures or cellular processes that caused particular DNA changes.

“Specific mutations can be present in very small numbers of cells or even single cells, and so detecting them is like looking for a needle in a haystack,” says co-lead author Tim Coorens, from the Broad Institute of MIT and Harvard and currently a research group leader at the European Bioinformatics Institute, in a statement.

The Largest Genetic Study Ever Attempted

SMaHT researchers plan to analyze tissue samples from 150 deceased donors, examining 19 different tissue types from each person. Samples will include organs from all three developmental layers forming the human body: brain, skin, and adrenal glands; heart, blood, and muscle; plus lungs, liver, and intestines.

Advanced DNA sequencing methods will detect mutations present in just single cells among millions. One technique, duplex sequencing (a method that sequences both strands of DNA to reduce errors), reduces error rates to less than one in 100 million, allowing scientists to spot authentic mutations that would otherwise disappear in sequencing noise.

Over 250 researchers from 52 institutions are involved, organized into five genome characterization centers and 14 technology development projects. Each donor gets extensive analysis, with researchers collecting tissue samples plus detailed medical histories, environmental exposure data, and demographics.

Game-Changing Discoveries Already Emerging

Early SMaHT research has revealed unexpected insights about human development and disease. Studies tracking these mutations show that when a fertilized egg first divides, one of the two resulting cells often gives rise to twice as many descendant cells in the adult body as its sibling—explaining developmental patterns scientists observed for decades.

More surprisingly, normal tissues often harbor mutations typically associated with cancer. In healthy 60-year-olds, approximately 90% of endometrial tissue contains driver mutations that could theoretically cause cancer, while only about 1% of colon tissue shows similar changes, despite colon cells having much higher mutation frequency (the rate at which mutations occur).

This contradiction demonstrates how context determines whether mutations cause disease. The endometrium goes through monthly cycles of shedding and regrowth that may prevent dangerous cell populations from establishing, while colon tissue faces different biological pressures.

SMaHT’s comprehensive mapping could transform medical practice by establishing baselines for normal mutation patterns, helping doctors distinguish between harmless age-related changes and early disease signs. The research might also predict which patients face higher risks for specific cancers or other mutation-driven diseases.

Beyond medicine, the project promises insights into fundamental biological questions about aging, longevity, and how environmental exposures leave lasting cellular marks. Rather than having one static genome, each person carries millions of subtly different genetic variants distributed across tissues, a discovery that could revolutionize approaches to human health and personalized medicine.

The cells in our bodies constantly acquire mutations. But what are the patterns of mutations across tissues? How do mutations in normal cells lead to disease? These and other questions we will tackle within the SMaHT Network, now described in @Nature https://t.co/5c1mfZOrOR

— Tim Coorens (@TimCoorens) July 3, 2025