Mutations in DNA are natural occurrences which can lead to diseases, sometimes have no effect on a person’s health, at all, or even result in advantageous traits. Mutations arise as a part of DNA replication and cell division, and have lead to evolution and diversification of organisms over billions of years. Current technologies allow scientists to take advantage of the prevalence of mutations. Through access to large quantities of data about mutations and human health, scientist can learn more about disease risk and develop new treatments.
As a scientist, one of my biggest pet peeves is when people say they "have the gene for X." I always respond by saying, "Everyone has the gene for X; it’s whether you have a mutation in that gene." I, however, have been thinking about the differences between genes and mutations since high school. Understanding our genetic information— what makes each individual different and what causes genetic diseases, including cancer— can be confusing to those who have not been immersed in learning about biology for years, especially when we’re talking about something so small it requires the power of the strongest of microscopes to even be seen. The genetic information I’m talking about is DNA, the instruction book of our cells.
Humans, as a species, are defined by the common instruction book we all have, which is called the genome. This book is comprised of DNA, which is split into 23 chromosomes. Each chromosome is a distinct chapter of the book that contains words, called genes, made up of a series of letters (A, T, C, and G). Many of these genes encode (or dictate the building of) proteins. Proteins are the workhorses of the cells. It’s as if DNA is the Ikea instruction manual (with a few more words), and proteins are the resulting furniture.
Every person originates from a single cell containing a set of 23 chromosomes from each of our parents. That single cell divides, creating two cells, which then both divide. As this pattern continues, each cell gives rise to more and more cells, which comprise every part of our body. Each time a cell divides the DNA needs to be copied, maintaining both the words and the order of the words in each chapter.
A protein inside each cell, DNA polymerase, is responsible for copying each letter in the genome every time a cell divides. Similar to the mistakes that are bound to happen when we’re jotting down notes, writing an article (such as this one) or writing a paper for school, DNA polymerase also makes mistakes. Like spellcheck on our computers, DNA polymerase is able to proofread, but also like spellcheck, it doesn’t necessarily find all the mistakes. So every once in a while (every one in 10 billion letters!), an error is written into our DNA. These errors are what we call mutations.
Historically, things we classify as "mutants" have gotten a bad reputation. X-Men, Teenage Mutant Ninja Turtles, and Spider Man (remember that bite from the radioactive spider?) are all characters associated with the word "mutant" who do good things for the world, albeit, a fictional one. Simply put, mutations are changes that can have either a positive or negative impact.
Mutations drive both diversity and evolution. Mutations are part of the reason some people have curly hair and others have straight hair. Or why some people have blue eyes and others have brown. There are about 3 million DNA letters that differ between any two people. So even though we all carry the same instruction book, we each carry different versions of it. Many times mutations occur in innocuous parts of the genome. They might be in a sequence that does not code for any proteins (so-called "junk" DNA). They might even occur in a gene but not change the function of the resulting protein. Mutations can also drive evolution, if the change allows an organism to survive better in its given environment.
In England, for example, during the industrial revolution, the peppered moth evolved from a peppered-pattern coloring to a solid-black bodied coloring. This change in pigmentation stemmed from mutations in the DNA in some moths that gave the black-bodied moths an advantage at survival in the changing environment. While evolution has no goal or reason why a change happens, it is widely thought the black-bodied moths were able to camouflage better against the soot and pollution in the environment than their peppered-patterned counterparts. These moths, as a result, were not targeted by predators and, consequently, able to breed and become more frequent in the population than the peppered-patterned moths. After the industrial revolution, as the soot began to disappear, the pepper-patterned moths had the camouflage advantage and began to repopulate the environment.
On the flip side of mutations allowing moths to better survive in a changing environment, mutations can sometimes cause detriments. Mutations, however, that cause disadvantages for some create advantages for others. The mutations that cause the sickle-cell trait in red blood cells, for example, confer resistance to malaria in some people. The same mutations that cause the sickle-cell trait, on the other hand, prevent red blood cells from receiving adequate amounts of oxygen, which can lead to serious effects for people with these mutations. Cancer, similarly, is caused by genetic mutations but affects genes involved in the growth of cells; if a mutation results in a functional change of the resulting protein, it could lead to uncontrolled growth of cells and the formation of a tumor.
There are two main types of genes and mutations that lead to cancer: tumor suppressors and oncogenes. Both tumor suppressors and oncogenes control the progression through the cell cycle that causes cells to divide, similar to controlling a car through both the gas and brake pedals. When control of cell division is lost, tumors can form, sometimes resulting in cancer. Tumor suppressor genes, such as BRCA1 and BRCA2, create proteins that have the job of preventing cell division and ensuring everything is working properly in the cell. Tumor suppressors act like the braking mechanism of a car, halting the progression of cell division when something goes wrong. Mutations in tumor suppressor genes that cause the resulting proteins to lose their functions can allow cell division to occur despite problems arising in the cell. These mutations are similar to brake-failure, causing a car to continue going despite pressing on the brakes. Cells that fail to halt when there is a problem continue to accumulate problems as they divide.
Oncogenes, on the other hand, normally promote cell growth and division. Oncogenes are regulated to make proteins at certain times during the cell cycle or even in specific cells in our bodies. Mutations in oncogenes may result in a protein being made at the wrong time, or even being made in cells in which it does not normally function. Too much protein function or function at the wrong time can cause cells to divide uncontrollably. The function of an oncogene is similar to the engine of a car: the engine causes the car to drive, however, the driver controls when and where the car goes. A mutation in an oncogene is akin to the gas pedal getting stuck and the car continuing to drive without a foot on the gas. Neither a mutation in a tumor suppressor or an oncogene alone causes cancer. The mis-regulation of cell function that arises from mutations in tumor suppressors or oncogenes, however, can lead to the malfunction of other proteins, which together give rise to cancer.
Mutations in tumor suppressor genes or oncogenes may occur either in a single cell at any point in a person’s life or they may be inherited from generation to generation and exist in every cell of the body. One way these mutations are propagated and increase in frequency within a given population over generations is through inbreeding. The high frequency of three specific mutations, called founder mutations, in the BRCA1 and BRCA2 genes seen in Eastern European Jews, for example, is likely due to breeding within isolated shtetl communities for many generations. The small population size in these communities increased the likelihood that someone who developed a mutation in one of these genes would pass it on to a child. Inbreeding then made it more likely that one or both parents were carriers of the mutation, increasing the chances of their children inheriting the mutation.
Mutations are differences in the spellings of the words that make up our genetic instruction books. They arise naturally and are present when comparing the DNA of any two people. Variation is introduced in every new generation, in many different species, and has allowed the evolution and diversification of all of the organisms on our planet for billions of years. Mutation can certainly bring the bad with the good, by allowing plants, animals, and microbes to survive changing environments while also causing disease. Introducing change into our genomes, however, is a process that is inherent to the persistence of life.
The consequences of mutations are difficult for biologists to predict and study in a laboratory setting. The bioinformatics and genomics revolution over the past two decades has given scientists the power to learn more about the consequence of mutations by analyzing trends in large data sets. New collaborations and initiatives, such as All of Us, aim to gather and share data so researchers have access to large data sets previously unattainable. These new technologies are driving the innovation of tools for every branch of the medical world.
Throughout my series of journal articles, I will explore the current research in the BRCA cancer field, as well as explore the new technology that will lead us toward better means of prediction, detection, and treatment of these cancers. My next article will delve further into the function of the BRCA1 and BRCA2 genes in maintaining the integrity of our DNA. I will discuss how a mutation in one of these genes, can lead to the accumulation of damage in our cells which can drive the formation of cancer. I look forward to taking this journey with all of you.