How Genetic Mutations Cause — And Prevent — Disease

Stephen Crohn, an artist from New York, lost a lot to the AIDS epidemic of the 1980s. He saw his partner and nearly all of his friends slowly grow sicker and die from this mysterious illness. But the one thing he didn’t lose during this scourge was his own life.

The reason he survived was not luck. Rather, he made it through because he carried a rare genetic mutation that made him virtually immune to HIV.

The 30,000 genes in your body not only dictate what color your eyes will be or whether you can curl your tongue; they also influence when, where, and how you will come down with an illness. Whether they directly cause an illness, make you more likely to develop a disease down the road, or protect you from health problems (like Mr. Crohn’s mutation), genes plays a role in virtually every facet of our health.

Since scientists first sequenced the human genome 15 years ago, they have come a long way in linking genetic mutations to various diseases. Doctors can now attribute conditions like hemophilia and cystic fibrosis to mutations in single genes, and just as importantly, researchers can also point to a mutation in people like Mr. Crohn and thank it for protecting him from HIV. Scientists are also finding that groups of genetic mutations contribute to more complex diseases, such as breast cancer and Alzheimer’s disease (which you can learn about in Part II of this series). Here, I will show how and why your life can either be upended or saved by mutations in single genes.

What’s a mutation?

First, let’s get something straight – a genetic mutation is not necessarily a bad thing. We often associate mutations with disease or disability but actually, a genetic mutation is merely any change in your genome that differentiates you from most other people. In other words, we are all mutants – if our DNA never changed, we wouldn’t possess the unique characteristics that make us who we are today. 

Mutations happen rather frequently. Your body is making new cells all the time by splitting your old cells into two, and every time this happens, your old cells need to replicate their DNA so each new cell gets a copy. But the copy machines in your cells aren’t perfect; your machinery can make errors and introduce new mutations into your DNA. Additionally, mutations can be caused by the sun, nuclear radiation, or toxins. Mutations that accumulate in certain parts of the body, such as the skin or liver, can cause a specific disease like liver cancer, but in you only — you won’t pass these mutations onto your kids.

However, if errors appear in sperm or egg cells (your “germline” or reproductive cells), and one of these cells ultimately leads to a baby, that child will carry these errors in every cell in their body.

But as I said, mutations aren’t all bad. Our genome mutates all the time without us noticing. In fact, genetic mutations led us to become who we are as humans; meanwhile, they make us all different from each other. Mutations create diversity in a species, which makes our population healthier overall. (For an example of what a lack of genetic diversity does to a species, look at the health problems among purebred dogs deal with, or at what happened to the royal families of Europe and Egypt).

How Do Genetic Mutations Affect Our Health?

Genes are the instruction manual for building proteins, the molecules responsible for giving you strong teeth, digesting your food, creating your memories, clotting your blood, growing your hair, replicating your DNA, and pretty much every other thing that happens in your body at any moment. Since proteins come from instructions in your DNA, genetic mutations can directly influence the structure, number, mobility, and activity of your proteins, which, in turn, determines the way your body develops and functions. And sometimes, these changes cause–or prevent–disease.

A Mutation in a Single Gene Can Make You Sick

The diseases we traditionally call genetic diseases are monogenic (mono = one) — they are caused by mutations in single genes. We have two copies (alleles) of each gene (one from our mother and one from our father), and mutations in one or both of these alleles can cause illness, depending on the effect they have on your body. Dominant disease mutations impact the body so greatly that they only have to come from one parent to make you ill. Recessive mutations have a lesser impact; therefore, someone has to inherit the mutation from both parents to see a difference in their own health.

Huntington’s disease is caused by a dominant mutation in a single gene: the HTT gene. A mutation in this gene causes progressive damage to the brain (learn more here). Since this mutation is dominant, someone only needs to inherit the disease-associated HTT allele from one of their parents to develop Huntington’s.

Sickle cell disease is also monogenic. People with sickle cell disease harbor a mutation in the hemoglobin gene (called HgbS) that causes red blood cells to turn sickle-shaped. This makes it difficult for red blood cells to carry oxygen, often leading to anemia (more here). But, unlike the mutation in HTT that causes Huntington’s disease, the HgbS mutation is recessive; a person needs to inherit the bad form of the gene from both parents to actually develop the disease.  If someone carries just one copy of the HgbS mutation, only half of their red blood cells will develop a sickle shape, which is not enough to cause symptoms.

Interestingly, the sickle cell gene can protect people from malaria: The microbe that causes malaria grows in red blood cells and cannot survive in sickle-shaped cells. Also, individuals who carry one copy of the bad form of the hemoglobin gene have an additional advantage: not only do they not have sickle cell disease, but they also don’t have enough healthy red blood cells to house the malaria microbe. In this situation, sickle cell carriers have the best of both worlds. This genetic oddity might explain why sickle cell disease is so common among people of African descent, given the prevalence of malaria-carrying mosquitoes in Sub-Saharan Africa.

Genetic Mutations Can Be Protective

The HgbS version of the hemoglobin gene is not the only protective gene in the body. In fact, at the top of this article, you learned that there’s a mutation out there that protects people from HIV. Here’s how it works:

The reason HIV is so deadly in most people is that it infects the very cells that protect your body from infection: T-cells. But HIV cannot get into these cells by themselves; they need to find a passageway that lets them get through. Fortunately for HIV, T-cells produce a protein called CCR5, which floats on their surface like a buoy in a pool, which HIV latches onto to dive into the cell and wreak havoc on its contents.

Mr. Crohn, the man who was immune to HIV, carried a rare mutation in the CCR5 gene called Delta23. This mutation makes T-cells produce a defective CCR5 protein that HIV doesn’t recognize. Since HIV has nothing to grab on to, it has no passageway into T-cells, and it can’t cause harm.

About 1% of northern Europeans are fortunate enough to harbor this mutation in both of their CCR5 alleles, which makes them effectively immune to HIV. Does this mean gene therapy for HIV is on the horizon? Maybe, but it’s too soon to tell.

Single Genes Make a Big Difference

With so many genes in our DNA, it’s amazing that a defect in only one of them can make someone chronically ill. At the same time, it’s pretty incredible that a single genetic mutation can protect someone from something as deadly as HIV. But while mutations in single genes can have a major impact on our lives, mutations don’t always directly cause disease. Most of the time, they have no effect, and sometimes it takes a combination of mutations to make someone ill. In Part II of this series, I discuss diseases such as breast cancer and Alzheimer’s disease that only develop in the presence of several mutations in multiple genes. If you think this article helps you wrap your head around the causes of monogenic disorders, just wait: Polygenic disorders, ones caused by mutations in multiple genes, are a whole new challenge.