New consortium to catalog DNA mutations across human lifetime

From the time we are conceived and through old age, genetic mutations accumulate in all our tissues, eluding the body’s typically efficient DNA repair machinery and potentially affecting our health and well-being.

In a new project, a team of researchers from multiple institutions, including Yale, will catalog these changes, known as somatic mutations, more than two decades since scientists first logged snapshots of 3 billion DNA base pairs that make up the human DNA. The project will focus specifically on mutations across 19 tissue sites in 150 individuals without disease.

The project, called the Somatic Mosaicism across Human Tissues (SMaHT) Network, and which will include more than 300 researchers, is described today in the journal Nature.

“We want to know how many mutations there are in as many tissues of the body we can to understand how our body changes over time,” said Flora Vaccarino, the Harris Professor at the Yale Child Study Center, professor of neuroscience at Yale School of Medicine, and co-corresponding author of the perspective paper.

There is a general belief that people are born with an immutable set of DNA sequences inherited from their parents that dictate almost all aspects of their biology. But even a few days after fertilization, cells of the embryo develop somatic mutations which can affect development.

In the embryo, mutations of single nucleotides within a cell, known as SNVs (single nucleotide variants), occur at a rate of about 1 to 5 SNVs per cell division. These mutations slow after birth to 2 to 65 SNVs per year, depending on the tissue, and so steadily accumulate in our cells as we age. Larger structural DNA mutations are much less frequent but potentially could have a larger impact.

(Intriguingly, there are 10 times fewer mutations in germ line cells, the reproductive cells in sexually reproducing organisms, than in other post-conception cells.)

Most of these somatic mutations have little effect on our health—and some may even be advantageous. Other mutations, however, including those which occur in many forms of cancer, can be life-threatening. While cancer is the most well-known disease associated with somatic mutations, recent studies have linked these mutations to developmental syndromes, neurological diseases and inflammatory disorders.

However, there is no largescale reference database for mutations in different tissue types in a large general population that is needed to begin understanding their impact on development, aging, and disease.

For the new project, collaborators will seek to define the prevalence and types of somatic mutations in healthy individuals in order to better identify those which may cause harm.

“Until we understand what is happening in healthy people, we can’t understand what is happening in disease,” Vaccarino said.

Specifically, the research consortium will look at somatic mutations in multiple tissue types, including in the skin, brain, skeleton, heart, lungs, and blood. Finding these mutations in human tissues, however, is challenging, researchers say.

“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,” said Tim Coorens, co-lead and co-corresponding author from the Broad Institute of MIT and Harvard and currently a research group leader at the European Bioinformatics Institute in Cambridge, UK.

To overcome these challenges, the consortium is developing and applying state-of-the-art technological advances, including sequencing approaches with ultra-low error rates and sequencing the DNA of single cells. This will allow them to track mutations of single nucleotides within a single cell and, at the same time, to monitor RNA that carry out instructions encoded within the DNA.

“It is like a super-personal genome overtime,” Vaccarino said.