I had an interesting conversation with my fifth grader son the other day. He is learning all about Evolution, Natural Selection, genes, and DNA. He asked me, “Dad, if the species with “good genes” has a better chance of survival why do “bad genes” don’t just go away? Wow…I’m in trouble.
First Things First.
OK, maybe we should start from the beginning and briefly explain some terms. DNA, the iconic double-helix, is where the genetic information is stored. Think of it as a gigantic library where the instructions to build an organism are stored. In simple terms, a GENE is a set of instructions to make a specific building block and the small “machines” that take care of specific tasks around the body; there are about 20,000 genes in the human genome (genome=collection of all the genes for an organism). These building blocks and machines are PROTEINS. Proteins are in charge of getting “the job done” around the body. A change in the gene that results in a “broken” protein is called a MUTATION.
One is Good; Two, Not So Much.
First off, we have two copies of many of our genes, one from our mother and the other from our father. The following figure shows how a couple that shows no symptoms of a disease can pass on genes to their children that may result in affected individuals. This kind of diseases is called “autosomal recessive”.
A good example of this is the gene CFTR. This protein is a little machine in charge of moving chloride (one of the elements that make sodium chloride, or table salt) across the membrane of cells. CFTR is important for making sweat, digestive juices and mucus. People that have two broken copies of CFTR have a disease called “cystic fibrosis”. People with this disease have difficulty breathing and develop frequent lung infections. They also have other health complications that result in them dying young. On the other hand, people with only one broken copy of CFTR do not have any of these symptoms. So, if having mutations in CFTR can be so bad why is it that 1 in 25 people of European descent, 1 in 46 Hispanics, 1 in 65 Africans and 1 in 90 Asians carry a broken copy of the CFTR gene? Also, why have these mutations been around for so long? It is believed that the most common CFTR mutation, ΔF508 (delta F 508), has been around for about 52,000 years! The answer might be that people with one working copy and one broken copy of the CFTR gene may have an advantage. These people are called “heterozygotes” for CFTR. It has been proposed that CFTR heterozygotes have some resistance (heterozygote advantage) to diseases such as typhoid, tuberculosis, cholera, and diarrhea. All of these diseases can claim a lot of lives and therefore people with even a small amount of extra resistance can survive and have children thus maintaining and potentially increasing the frequency of the mutation in the population.
Also, heterozygote advantage has been shown to be important in explaining the higher than expected mutation frequency in other diseases such as sickle-cell anemia and the so-called triosephosphate deficiency disease. It is likely that heterozygote advantage is the reason behind the higher than expected frequency of mutations in some other important genes.
Luck of the Draw.
Then there is the luck of the draw. Genetic diversity can be reduced when a new population is established by a very small number of individuals from a larger population. It is like getting candy out of a candy machine…depending on your luck, you may get more red candies or more blue candies…
I’d like to illustrate this phenomenon with one example of a mutation in BRCA1, the so-called breast cancer susceptibility gene 1 (yes, Angelina Jollie has a mutation in this gene). Mutations in BRCA1 result in a much higher chance of developing breast, ovarian and other types of cancer. The example is one of the so-called “Ashkenazi Jewish” BRCA1 mutations, 185delAG (also known as 187delAG and c.68_69delAG). This change results in a protein that cannot do its job. Work from talented scientists has shown that BRCA1 185delAG first appeared in the Middle East before the Jewish Diaspora (135 AD). At this point, it is believed that this mutation was not particularly common in the population of Israel as a whole.
Then History happened.
After many years of Roman oppression, the Jews revolted. As punishment, the Roman emperor banned the Jews from Jerusalem and implemented other measures that resulted in large numbers of people leaving Israel for other parts of the Roman empire. According to genetic data, about 600 to 800 years ago, a group of approximately 350 individuals of Jewish descent moved into Central Europe (Ashkenaz in Hebrew). These people are the ancestors of most of the Jewish population with roots in Central and Eastern Europe. Because of the small size of this population, some mutations were enriched due to chance. To this day, the BRCA1 185delAG mutation is found in about 1% of people of Ashkenazi Jewish heritage.
What Can We Do to Help?
“So Dad, what can we do to help?” Fortunately, I answered, we can help people in many ways. For example, we can test DNA from people before they have children and look for mutations that may result in affected children. We can also look for mutations that are known to cause diseases like cancer and, if found, guide them through their medical and family planning decisions. We can also look at DNA and find out if people are likely to benefit from one medication over another. However, I said, there is a LOT still to be learned. It will be up to your generation to learn even more about DNA and Genetics and understand how the interaction of DNA and the environment result in disease. I’m looking forward to seeing that future!
By: Adrian Vilalta, PhD