A Hidden Inheritance Could Explain Disease Risks Beyond Dna

Newswise — When we think about genetic inheritance, we usually leap to DNA, the four-letter code containing the instructions for building a living organism. Scientists know that DNA encodes everything from hair and eye color to a person’s likelihood of developing hereditary diseases like cystic fibrosis or sickle cell anemia.

But genetics doesn’t always tell the whole story. For some traits—why one identical twin develops schizophrenia when the other doesn’t, why one sibling gets cancer while another carrying the same family risk never does—DNA sequence alone comes short of explaining the difference.

Lamia Wahba, assistant professor and head of the Laboratory of Epigenetics and Evolution at Rockefeller University, thinks the answer might lie in another layer of information called epigenetics. If DNA is the text of a book, epigenetics is the highlighter marks, the sticky notes, the pointers scrawled in the margins. It is instructions about how to read the book that aren’t part of the text itself.

Much of what we know about how epigenetic mechanisms work traces back to Rockefeller itself. The late C. David Allis, who spent the last two decades of his career at Rockefeller, was among the first to show how these mechanisms—in and of themselves—can turn genes on and off. Moreover, Allis’ work also established links between certain epigenetic changes and diseases like cancer, opening up the possibility of epigentic therapy.

Wahba’s lab builds on that foundation, investigating how epigenetic signals—proteins and chemical tags that dictate how DNA is read—can be passed from one generation of organism to the next. Using roundworms as a model system, her lab studies whether the environment can trigger changes to epigenetics that then persist across generations and potentially shape evolution.

We spoke to Wahba about what drew her to this field and how it could reshape our understanding of heredity.

What is epigenetics?

I often describe it as a layer of molecular information that sits on top of the DNA and helps determine how it is used by cells. It can come in the form of chemical modifications that decorate the DNA or the proteins that DNA is wrapped around. But there’s also a whole suite of mechanisms that are more dissociated from the DNA: RNA, proteins, and other biomolecules that may be floating around loosely in the interior of a cell. Any of these molecular signals can flip a gene on or off entirely, dial its activity up or down, or control the timing of when it gets read without altering the underlying DNA sequence. We want to better understand how those signals work and what factors—environmental or otherwise—turn them on.

What are the biggest questions about epigenetics right now?

What is very well established is that epigenetic molecules explain how an organism, like humans, can have many different cell types. Chemical marks on DNA control which genes are used in any given cell so that a kidney cell behaves like a kidney cell and not, say, a liver cell. We know that when cells within an organism divide, they pass those epigenetic marks on to their daughter cells. So a kidney cell reliably produces more kidney cells with the same chemical marks and the same genes turned on and off, instead of suddenly spawning liver or skin cells.

The more contested question is whether epigenetic changes can also influence traits at the evolutionary level, which operates across generations. If you’re exposed to an environmental factor that flips on a certain gene without changing the DNA sequence, does that “on switch” stay in the on-position for your children and their children? Or do all these epigenetic systems revert to a default state in eggs and sperm cells?

How do you study this?

We use C. elegans roundworms as our main model. One thing distinctive about how we work is that we use wild strains of worms collected from different parts of the world, rather than the single lab strain most researchers use. That gives us access to the genetic and epigenetic diversity that already exists in nature.

We also work with related roundworm species from the same family as C. elegans. These worms all look very similar, but their genetics are as different from each other as a human is from a zebrafish, which means we can ask how epigenetic mechanisms have changed over vast stretches of evolutionary time.

We’ve mapped out epigenetic differences between these strains of worms, and we’ve found that genes involved in defense against parasites and infection show a striking amount of variation in their epigenetic status. In other words, two worms might have the same genes but one worm might be actively reading that gene while another is not. That impacts how each animal is able to defend themselves against threats.

In some of our experiments right now, we’re looking at a drug called ivermectin, which is used to treat parasitic worm infections. Worms can develop what looks like epigenetic resistance to it, gaining resistance in just a few generations without any detectable genetic changes. We’re trying to figure out how that happens. If we can determine that, then we might be able to develop compounds that are less likely to lead to resistance.

Why would a cell pass something down epigenetically rather than just letting a genetic mutation arise?

I think it’s mostly a numbers game. Genetic mutation rates are very low—somewhere between one in one hundred thousand and one in one hundred million mutations per base pair each time a cell divides. Acquiring a useful mutation through chance is slow. Epigenetic change rates appear to be orders of magnitude higher, which means epigenetic mechanisms can allow an organism to adapt much faster, especially if the environment shifts suddenly and most offspring won’t survive otherwise. There’s also a hypothesis, still unproven, that epigenetic changes can be reversible in ways that genetic mutations are not: if the stressor goes away, you might be able to reset. That’s one of the things we’re actively studying.

How does epigenetics influence health and disease?

One compelling area is drug resistance. There’s growing evidence that the first wave of resistance to cancer drugs and treatments for autoimmune disease is caused by epigenetic changes to cells. A chemical tag might attach to a gene that makes cancer cells sensitive to a drug, for instance, silencing that gene entirely and nullifying the treatment without altering a single letter of its DNA sequence. Understanding those early epigenetic changes could lead to new ways of preventing or reversing drug resistance.

There are also implications for inherited disease risk. For conditions ranging from diabetes to schizophrenia, genetics accounts for only 20 to 30 percent of heritable risk. Most people who develop these diseases don’t have any known genetic variants explaining why they developed it. Companies that sell at-home DNA kits have done a great service in raising public awareness of genetics, but that’s also created the impression that your DNA sequence is more prescriptive and deterministic than it actually is. A significant part of that missing heritability may be epigenetic marks passed down from eggs and sperm at the same time as DNA sequence itself. If so, reading a person’s epigenetic marks alongside their DNA sequence could one day offer a far more complete picture of their disease risk, and potentially powerful new targets for intervening in complex conditions like cancer and heart disease.

Why is this such an exciting field to be in right now?

We now know quite a bit about the molecular mechanism of epigenetics—what all these molecules are that can act on DNA. But we don’t actually understand what the implications are for evolution, and that question feels very exciting right now. The classic view of heredity is Darwinian: genetic mutations drive adaptation. But decades before Darwin, a scientist named Jean-Baptiste Lamarck proposed that traits acquired during an organism’s lifetime could be passed to offspring. More than two centuries later, what we’re trying to understand is whether there are cases where an epigenetic change triggered by the environment can bypass the mechanisms that normally erase those marks between generations, because it’s adaptive enough to be worth preserving. In other words, epigentic changes may not just be shaping us as individual people; they may have helped shape us as a species. If true, the implications of that could be transformative.