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Your life history is written in your cells' mutations

New study traces developmental history of the human body using small differences in DNA between each of our cells

April 13, 2021

NoneA new study traces human development from adults all the way back to embryos when they were just a few cells. Shown here, an 8-cell human embryo used for in vitro fertilization.

When you were very, very small, something went wrong in your cells.

Not very wrong, just a little bit wrong. Before you were born, when you were a bundle of a few cells, one of those cells made a small mistake copying its DNA as it divided into two.

The mistake was so minor as to be inconsequential. If it was a major mistake, you might not exist right now. But as the daughters of that first mistake-bearing cell kept growing and dividing, all the other cells they begat contained the same DNA mistake.

Even if that small mistake has no discernible effect on your life, it marks your personal cellular history like a trail of breadcrumbs, showing how one cell from the earliest periods of your development influenced the fate of the rest of your body. It turns out our bodies are riddled with thousands and thousands of such mostly innocuous — but potentially revealing — little mistakes.

That’s the finding from a new study led by researchers at the Allen Discovery Center for Human Brain Evolution in Boston, which was published last month in the journal Science. Our life’s history is written in each of our cells, thanks to those tiny mutations.

The center’s director, Christopher Walsh, M.D., Ph.D., and other scientists at Harvard Medical School and Boston Children’s Hospital used those mutations to decode the early history of human development, looking all the way back to eight-cell and even two-cell embryos.

These DNA mistakes are also termed somatic mutations, meaning mutations that arise once the body is already formed (soma is the ancient Greek word for body). That’s in contrast to a germline mutation, a mutation in a sperm or egg cell that would pass onto the next generation and appear in every cell alike. Inherited mutations, such as a genetic disease that’s passed from parent to child, are germline mutations.

While most somatic mutations don’t have obvious immediate effects, the gradual accumulation of these cell-to-cell differences over a lifetime adds up. Some researchers think they are the driving force behind aging, and, under the right circumstances, they can trigger cancer. Whatever their ultimate toll, the sheer number of these mutations means that people don’t just have one genome; we are each a complex patchwork of different genomes.

Walsh’s work is making clear just how complicated that patchwork is. Although his research in this area originally focused on brain disease — some forms of epilepsy are linked to somatic mutations in neurons — he soon realized these mutations also served as coded histories of our past.

“We recognized in the course of that epilepsy work that these mutations occur ubiquitously,” said Walsh, who is also a neurologist and geneticist at Boston Children’s Hospital and Harvard Medical School and an investigator of the Howard Hughes Medical Institute. “They represent a permanent forensic map of the whole cell lineage of the whole human body.”

Our cellular biographies

NoneChristopher Walsh, M.D., Ph.D., presents his research at the 2017 Allen Frontiers Symposium in San Francisco.

To sketch that detailed map, the researchers captured the complete DNA sequences from thousands of different cells from more than 70 people who had died and donated their bodies to science. Most of the cells were brain cells, but they also studied liver, heart and spleen cells from one donor. A team of computational biologists led by Harvard bioinformatics researcher Peter Park, Ph.D., used machine learning to make sense of those thousands of different DNA sequences.

Using about 500 different somatic mutations from the donors’ cells, the researchers were then able to back-construct their life histories. They looked at mutations that cropped up very early in development, Walsh said, as those mutations are present in larger numbers in the body. In next phases of the work, they plan to refine their techniques to find more rare mutations that represent later stages of someone’s developmental history.

Looking at the mutations that crop up when we are just two cells big, the researchers found that those cells don’t always evenly contribute to our adult bodies. That is, if you call those two cells A and B, some of us are made up of about half cells that came from A and half that came from B, but some of us seem to be closer to 70% A descendants and 30% B descendants. That distribution seems to be somewhat random, in contrast to the development of some commonly studied laboratory animals like flies and worms, which is very tightly scripted. Our own early growth may be more flexible, these findings indicate.

The team also found that cell lineages mix and mingle in the body. They saw that descendants of our first eight cells grew mixed together in every organ they studied. Walsh thinks that could be an evolutionary adaptation that protects our organs from being overwhelmed by potentially harmful DNA mistakes. If one of our first eight cells happens to mutate such that it can’t give rise to working heart cells, for example, there are seven other cell lineages that can.

Again, not all animals develop this way. To Walsh, these findings imply the importance of studying humans directly to learn the most about our own biology.

“We’re uncovering aspects of human developmental biology that haven’t been discovered by studying cells in a dish or by studying other animals,” Walsh said. “There’s nothing better than just studying the actual human form itself.” — written by Rachel Tompa, Ph.D.

Rachel Tompa is Senior Writer at the Allen Institute. She covers news from all scientific divisions at the Institute. Get in touch at rachelt@alleninstitute.org.


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