2.6) Understanding Genetic Variation

You are truly unique. But how unique? How much of your DNA is the same as your neighbors? As humans, our DNA is 99.8% the same! This is what makes us human. Our individuality lies in the remaining 0.2%. It is that 0.2% that results in all of the uniqueness between people.

In fact, we share a lot of DNA with other species.  Did you know that your DNA is also 98.5% the same as chimpanzees, 75% the same as a mouse, and 42% the same as a goldfish? The concept of uniqueness is important because even though we have considerable DNA in common with many other species, those small important differences make us genetically unique. (It is worth noting that as more research is being done, these numbers have been changing.)

Figure 2-12 Human DNA is about 98.5% the same as a chimpanzee, 75% the same as a mouse and 42% the same as a goldfish.

Genetic variations and health

To make new cells, an existing cell divides in two, copying the identical genetic material and DNA so the new cells will each have a complete copy of genetic instructions. Cells sometimes make mistakes during the copying process – kind of like typos. These typos lead to variations in the DNA sequence.

A gene mutation is a permanent alteration in the DNA sequence that makes up a gene, such that the sequence differs from what is found in most people. Mutations range in size; they can affect anywhere from a single DNA building block (base pair) to a large segment of a chromosome that includes multiple genes. Over the course of your lifetime you will acquire mutations. As your cells replicate, mistakes are sometimes made.

Cancerous Cells. Did you know?

For cancer to occur, many deleterious mutations have to accumulate in a single cell. The abnormal behaviors demonstrated by cancer cells are the result of a series of mutations in key regulatory genes. The cells become progressively more abnormal as more genes become damaged. Often, the genes that are in control of DNA repair become damaged first, rendering the cells susceptible to increasing levels of genetic mayhem. This is the reason that the risk of getting cancer increases with age. Hereditary mutations that affect a cell’s ability to detect these mutations can increase your risk of developing cancer.

Genes such as TNFA have been studied extensively in relation to cancer. Depending on how it is functioning, it can have an impact on tumor activity and progression or regression (Ghosh, 2020). 

This gene is reported on in the DNA + Health report in the Inflammation test as it can influence the inflammatory process.

Disease-causing gene mutations are uncommon because they decrease an organism’s probability of surviving to reproduce. Due to this natural selection, when they occur they are most often not passed down to future generations. For example, a mutation that makes you blind would be considered a disease-causing mutation. Genetic changes that do not cause disease are more likely to be passed down. These types of changes are more likely to be passed down through generations because they are not deleterious to your survival. 

A genetic variation that changes eye color from brown to green is considered a normal genetic variation. Genetic variations that occur in more than 1 percent of the population are called polymorphisms. Polymorphisms are common enough to be considered a normal variation in the DNA. Polymorphisms are responsible for many of the normal differences between people such as eye color, hair color, and blood type. Although many polymorphisms have no negative effects on a person’s health, some of these variations may influence the risk of developing certain disorders.

Mutation: A permanent alteration in the DNA sequence that makes up a gene, such that the sequence differs from what is found in most people. Changing the structure or function of a gene in a way that can potentially be transmitted to future offspring.

Polymorphism: Genetic alterations that occur in more than 1 percent of the population are called polymorphisms. Polymorphisms are common enough to be considered a normal variation in the DNA and can be passed on to future generations. 

Mutations can be classified as hereditary or acquired

Hereditary mutations are inherited from your parents and are present throughout your life in virtually every cell in the body. These mutations are also called germline mutations because they are present in the parent’s egg or sperm cells, which are also called germ cells. When an egg and a sperm cell unite, the resulting fertilized egg cell receives DNA from both parents. If this DNA has a mutation, the child that grows from the fertilized egg will have the mutation in each of his or her cells.

In contrast, acquired mutations occur at some time during your life and are present only in certain cells, not in every cell in the body. These changes can be caused by environmental factors such as ultraviolet radiation from the sun or can occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation.

Hereditary mutation: Inherited from your parents and are present throughout your life in virtually every cell in the body.

Acquired mutation: Occur at some time during your life and are present only in certain cells, not in every cell in the body.

Big idea! Genetic testing for hereditary polymorphisms

In genetic testing for diet, fitness and health we examine hereditary mutations, specifically polymorphisms. They are present throughout your life in virtually every cell in the body and they occur in more than 1 percent of the population. They are common enough to be considered a normal variation in the DNA.

Figure 2-13 Ultraviolet (UV) photons can harm DNA molecules.

Complex or multifactorial traits are…complex!

Most traits are complex, they are a result of the combination of many genes as well as changes in gene expression and environmental factors. 

Researchers are learning that nearly all conditions and diseases have a genetic component. Some disorders, such as sickle cell disease and cystic fibrosis, are caused by mutations in a single gene. The causes of most other disorders, however, are much more complex. Common medical problems such as heart disease, diabetes, and obesity do not have a single genetic cause—they are associated with the effects of multiple genes in combination with lifestyle and environmental factors. Conditions caused by many contributing factors are called complex or multifactorial disorders.

Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person’s risk of inheriting or passing on these disorders. Researchers look for major contributing genes for many common complex disorders and traits.

Different traits have different heritability

Different traits have different heritability. Heritability is the proportion of an observed variation in a particular trait (e.g. smoking) that can be attributed to inherited genetic factors (e.g. addictive tendencies) in contrast to environmental ones (e.g. exposure to cigarettes). Or, the extent to which genetic differences contribute to differences in the observed behaviour.

One way to determine the contribution of genetics and environment to a trait is to study identical twins (same inherited genetic structure) that have been reared apart (different environment). For example, this is the case with identical twins that have been separated and raised in two different cultures. If twin one was raised in Japan and twin two was raised in America, each twin will likely speak the language and eat the cuisine of the culture they were raised in. 

  • Although they are genetically identical, they may not grow up speaking the same language. Twin one would likely speak Japanese, whereas twin two would likely speak English. Language is a trait with low heritability.
  • Because they are genetically identical, they may have some shared risk for obesity, but their overall weight will also be determined by diet and exercise. There may be some weight difference between twin one and twin two based on lifestyle. Weight is a trait with medium heritability.
  • Because they are genetically identical, both twins are expected to have the same eye color. Eye color is a trait with high heritability.

Increased genetic risk, getting away with a warning!

Increased genetic risk or predisposition is an increased likelihood of developing a particular condition or outcome based on a person’s genetic makeup. Increased risk results from genetic variations that are inherited from a parent. These genetic changes can contribute to the development of a condition but do not directly cause it. Some people with a predisposing genetic variation for a disease may never get the disease while others will, even within the same family. 

Genetic variations can have large or small effects on the likelihood of developing a particular disease. For example, certain mutations in the BRCA1 or BRCA2 genes may increase your risk of developing breast cancer and ovarian cancer. Variations in other genes, such as BARD1 and BRIP1, can also increase breast cancer risk, but the contribution of these genetic changes to a person’s overall risk appears to be much smaller.

Current research is focused on identifying genetic changes that have a small effect on disease risk but are common in the general population. Each of these variations only slightly increases a person’s risk. Genetic variations, each with a small effect, may underlie susceptibility to common diseases, including cancer, obesity, diabetes, heart disease, and mental illness. 

In people with a genetic predisposition, the risk of disease can depend on multiple factors in addition to identified genetic changes. These include other genetic factors that are not tested for or are not yet understood as well as lifestyle and other environmental factors. You have the power to read your DNA, identify potential points of genetic risk, and change your destiny.

Although your genetic makeup cannot be altered, using lifestyle and environmental modifications (such as having more frequent health screenings and maintaining a healthy body weight) you may be able to reduce your overall risk. The conditions are complex or multifactorial. The genetic risks we are looking at are warnings from your DNA map and not life sentences!

Big idea! In genetic testing for diet, fitness and health we are testing for complex traits

Genetic testing for diet, fitness and health looks at complex traits. The traits are a result of the combination of many genes as well as changes in gene expression and environmental factors like diet, fitness and health. Your results for each complex trait report on many genetic variations. They are polygenic, related to or determined by many genes. They are also determined by your environment. By making changes to your lifestyle and habits, your environmental factors, you can affect these traits. Together your genes, gene expression and environmental factors will determine your ultimate health and wellness.

Get away with a warning!

Environmental Risk + Genetic Risk = Total Risk

Get genetic testing, find out where you have increased genetic risk, heed the warning! Use the tools available to you to decrease your environmental risk in order to manage your total risk.

For example:

Genetic Risk for Heart Disease + Obesity = Danger

Genetic Risk for Heart Disease + Healthy Weight = Warning

Detecting genetic variations, single nucleotide polymorphisms

Given genetic variations create our differences, it is helpful to understand common types of genetic variations. These include single nucleotide polymorphisms (SNPs), insertions and deletions, frame shifts, copy number variations and variable number tandem repeats to name a few! 

The most common type of polymorphism is the SNP. SNPs account for 90% of all sequence variants (Collins, 1998). This is the variation generally reported on in lifestyle DNA testing. SNPs are useful and widely used markers in genetic studies. 

SNP variants are designated by numbers beginning with “rs”, for example rs1815739, and cataloged in the public NCBI dbSNP database https://www.ncbi.nlm.nih.gov/snp/.

Single nucleotide polymorphism (SNP): A variation in a single nucleotide (for instance, having a cytosine, or C, where there’s normally an adenine, or A).

SNP is pronounced “snip”.

Your DNA has variations called SNPs. A SNP is a DNA sequence variation that is common in the population. As with other polymorphisms, SNPs are present in 1% or more of the population. Each SNP represents a difference in a single DNA nucleotide building block. For example, a SNP may replace the nucleotide cytosine (C) with the nucleotide thymine (T) in a certain stretch of DNA. A SNP can affect the normal structure and functioning of a gene.

Many SNPs have no effect on health or development. Some of these genetic differences, however, have proven to be very important in the study of human health. Researchers have found SNPs that predict an individual’s response to certain drugs, susceptibility to environmental factors such as toxins, and risk of developing particular diseases or intolerances. SNPs can also be used to track the inheritance of diseases within families. 

SNPs occur normally throughout a person’s DNA. Scientists have found more than 324 million SNPs in populations around the world as of 2017 (NCBI, 2017). SNPs are estimated to occur once in every 100-300 nucleotides on average and are a major source of differences between people (Ke et al., 2008). 

Given we have 3 billion nucleotides in our DNA strand, this means that you have roughly 10-30 million SNPs in your DNA. Most commonly, these variations are found in the DNA between genes. They can act as biological markers, helping researchers to locate genes that are associated with a disease, condition, or trait. When SNPs occur within a gene or in a regulatory region near a gene, they may play a more direct role in disease by affecting the gene’s function.

SNPs are like typos. The typos can change the meaning a little or a lot. 

In the sentence: The cat ran after the mouse.

If the ‘e’ in ‘the’ changes to a ‘c’, we can still understand the sentence. 

“Thc cat ran after the mouse,” The variation has minimal effect.  

If the ‘c’ in ‘cat’ changes to an ‘r’, the meaning of the sentence changes. 

“The rat ran after the mouse.” The variation has greater effect. 

If the ‘e’ between ‘the’ and ‘cat’ is deleted. 

The sentence becomes; “Thc atr ana ftert hem ouse” – the variation has had significant effect and the gene is unlikely to perform the function it is intended to do.

Inherited genetic diseases

Most inherited genetic diseases are recessive, which means that a person must inherit two copies of the mutated gene, one from their mother and another from their father to inherit the disease. While we would expect for natural selection to remove these errors from our population, instead some of them have been passed down to become relatively common. The reasons that these disease-causing mutations have persisted are interesting to scientists. 

For some diseases like Sickle Cell Anemia, the answer is clear. The DNA mutation that causes Sickle Cell Anemia has become common in our population due to an adaptive advantage in malaria-stricken populations. Cystic fibrosis, another genetic mutation, seems to have spread in Europe during the Bronze Age. Although Cystic fibrosis remains common, no adaptive advantage to carrying Cystic fibrosis has been identified as of yet.

Example:  DNA errors – Sickle Cell Anemia

Sickle Cell Anemia is an inherited blood disorder where red blood cells become sickle/crescent shaped. The sickle cell genetic variation is believed to have arisen in geographic areas, where there are higher fetal hemoglobin levels and individuals tend to have milder disease. 

In parts of the world where malaria is prevalent there is an adaptive advantage to be a carrier of Sickle Cell Anemia. A carrier has one defective and one normal gene. The malaria parasite has a complex lifecycle and spends part of it in red blood cells. In a Sickle Cell Anemia carrier, the malaria parasite causes the red blood cells with defective hemoglobin to rupture prematurely, and the malaria parasite is unable to reproduce. 

Carriers of Sickle Cell Anemia are still able to contract malaria, but their symptoms are generally less severe. Therefore, in areas where malaria is a problem, people’s chances of survival actually increase if they carry a single copy of the Sickle Cell gene. This has led to the prevalence of the Sickle Cell Anemia disease, especially among malaria-stricken populations.

Kato, G., Piel, F., Reid, C. et al. Sickle cell disease. Nat Rev Dis Primers 4, 18010 (2018).

Laland, K. N, Odling-Smee, J, & Feldman, M. W. (2001). Cultural niche construction and human evolution. Journal of Evolutionary Biology, 14(1), 22-33.

Example:  DNA errors – Cystic fibrosis

Cystic fibrosis is a genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung and sinus infections. 

Evidence suggests that this genetic variation arose in the early Bronze Age and spread from West to Southeast Europe. A population known as the Bell Beaker folk are believed to be the population responsible for the early spread of Cystic fibrosis. They appeared around 4000 B.C. and were distinguished by their ceramic beakers, for pioneering copper and bronze north of the Alps and for their great mobility. They manufactured and traded metal goods, especially weapons.

This network of elite tribes spread their culture and their genes from west to east into regions that correspond closely to the present-day European Union, where the highest incidence of Cystic fibrosis is found.

The genetic variation that causes Cystic fibrosis is most common in individuals with Northern European ancestry. In the Caucasian population 1 in 29 individuals carries this genetic variation and approximately 1 out of every 3,000 live births is affected.

Kerem, B, Rommens, J, Buchanan, J, Markiewicz, D, Cox, T, Chakravarti, A, . . . Tsui, L. (1989). Identification of the cystic fibrosis gene: Genetic analysis. Science (American Association for the Advancement of Science), 245(4922), 1073-1080.

Dawson, K.P, & Frossard, P.M. (2000). A hypothesis regarding the origin and spread of the cystic fibrosis mutation ΔF508. QJM: Monthly Journal of the Association of Physicians, 93(5), 313-315.

Farrell, Philip, Férec, Claude, Macek, Milan, Frischer, Thomas, Renner, Sabine, Riss, Katharina, . . . Génin, Emmanuelle. (2018). Estimating the age of p.(Phe508del) with family studies of geographically distinct European populations and the early spread of cystic fibrosis. European Journal of Human Genetics: EJHG, 26(12), 1832-1839.

Genetic variation is necessary!

Genetic variation is necessary. It helps populations change over time to survive and thrive. Variations that help an organism survive and reproduce are passed on to the next generation. Variations that hinder survival and reproduction are eliminated from the population. This process of natural selection can lead to significant changes in the appearance, behavior, or physiology of individuals in a population, in just a few generations. Genetic variation permits flexibility and survival of a population in the face of changing environmental circumstances.

For example, our ancestors faced different challenges as foraging hunter-gatherers than we do now. As a species we have evolved to meet the demands of the current environment. What makes you truly unique is the genetic variability that exists within your DNA.