How Genes Work and Some Other Concepts in Genetics
In this month’s post, I thought I’d compile some brief explanations of concepts related to DNA and genetics that I get asked about a lot. I’ve written about some of this previously in various installments, but I thought I’d use this space to provide an updated review. Genetics can sometimes be complicated, and like all complicated concepts associated with commercialized products and services, those promoting them (DNA Labs included), often have to over-simplify topics in order to deliver a clear and concise message. This has become especially true in today’s world of social media posts that only focus on headlines and Tweets that are limited to 140 characters. While still oversimplifying in this short newsletter article, I hope to shed some light on some common and some lesser-known concepts in genetics.
DNA and Genetic Variation:
DNA is a long string-like molecule that is made up of Guanine, Adenine, Thymine and Cytosine, which are represented by the letters G, A, T and C. These letters are the basis of the genetic code, and in each of our cells, we have 6 billion of them, 3 billion we inherit from mom and 3 billion from dad. You may have seen a DNA sequence represented like this: ATGCGCGGTCCAATCATTG
The genetic code is like a blueprint that is a string of DNA that makes up genes that encode all of the proteins that do different things in our body.
When in most people there is usually a “G” in a certain position but is sometimes changed to a “T” in other people, this is called a genetic variant. We refer to the more common one as “typical” and the less common one, “atypical”.
Everyone has millions of genetic variants that make us unique, and some of the variants just so happen to impact the function of the proteins that they encode.
The Central Dogma:
DNA → RNA → Protein
Our DNA is found in almost all cells – it uses a genetic code that contains instructions for your cells to create proteins. Proteins are the enzymes, receptors, transporters, hormones, etc., which perform essential functions throughout the body and make us who we are. Before the information contained in our DNA is translated into a protein, there is an intermediate step whereby DNA is transcribed into RNA, and the RNA is then translated into proteins. The relationship between DNA, RNA and proteins is referred to as the central dogma of molecular biology, whereby genes are encoded in DNA, transcribed into RNA messages, and finally translated to create the protein encoded by that gene. We have a massive amount of DNA in our cells. The entire complement of DNA is called the genome, and is made up of nucleotides, represented by the letters A, T, C and G. We have 6 billion(!) of these letters in our genome.
Cookbook → Photocopy → Meal
As an analogy, your DNA is like a cookbook, whereby each page of the book contains a recipe – i.e., just as each gene in your genome contains instructions to create a protein, each recipe in your cookbook contains instructions to create a meal. Now imagine whenever you have to make a meal, you have to photocopy (or transcribe) the recipe of interest onto another piece of paper. This photocopy is like your RNA, and is translated to create the meal, or protein. Now to take it one step further, imagine that you have one little change in the recipe compared to one of your friends. For example, your friend’s recipe might call for 2 teaspoons of sugar, whereas your recipe would be identical, except instead of 2 teaspoons, your recipe calls for 3. You can see how a little change like this in your DNA can result in a change to the meal. This is similar to how genetic variations work in that a little change in the DNA could potentially result in a physical change to the protein, and these changes could potentially influence how we develop, how we function, and how we interact with the environment.
Simple “Mendelian” genetics:
Back in the mid to late 1800s, Gregor Mendel, an Austrian monk, introduced a new theory of inheritance based on discrete “units of inheritance”, which we now know are “genes”, that are passed down from parent to offspring, whereby each parent contributes one version (“allele”) of the gene, resulting in the offspring having two copies (together known as the “genotype”). Mendel’s theory of inheritance came about after noticing that certain traits (“phenotypes”) in his pea plants (e.g., stem length, pea shape, flower colours, etc.), were being passed on from generation to generation in predictable ways. He also noticed that certain traits were passed on in either a dominant or recessive manner. An offspring that receives at least one dominant allele will show the dominant trait, whereas an offspring must receive two recessive alleles (one from each parent), in order to show the recessive trait. If the two alleles are the same, this is referred to as homozygous, and someone can be homozygous for the dominant allele OR homozygous for the recessive allele. If the two alleles are different, then this is referred to as heterozygous. If someone is heterozygous for a given gene, they would show the dominant phenotype. Some examples of traits that follow this single gene Mendelian pattern of inheritance include physical traits such as having a widow’s peak (a V-shaped hairline), or hitchhiker’s thumb (thumb curves backward). Hemochromatosis (leading cause of iron overload), is another example of a Mendelian trait. The risk allele is recessive, so both parents would need to pass on a recessive allele in order for their child to inherit the disease. Our LoveMyHealth™ test will let you know if you have a risk of iron overload yourself, or if you are a carrier of the recessive allele and thus risk passing it on to your child.
Complex multigenic/polygenic traits:
While there are a lot of traits based on single genes that are inherited in this Mendelian pattern, most traits are actually a result of the contribution of multiple genes and of course, environmental factors (e.g., diet, temperature, lifestyle, etc.), may also play a role. Some examples of physical traits that are a result of multiple genes include eye colour, hair colour, height, etc.
Penetrance and Expressivity:
Penetrance is defined as the percentage of people with the genetic mutation who actually show signs of the disease or phenotype; i.e., penetrance explains whether the disease shows up. For example, with Huntington’s disease (which is inherited in a dominant manner), there is complete penetrance, which means that all people carrying the mutation (the “bad” version of the gene) will unfortunately get the disease. The BRCA1 and BRCA2 genes, which are well known genes associated with breast and ovarian cancer, show incomplete penetrance, whereby not everyone that carries the risk alleles will go on to develop the disease. Expressivity explains the extent to which a given genotype is expressed at the phenotypic level; i.e., expressivity explains how a disease shows up. In Marfan syndrome for example, the same mutations occur in the FBN1 gene in different patients, however the characteristics of the syndrome widely vary among them.
Nature vs. Nurture and Epigenetics:
Epigenetics is the study of how external factors (such as lifestyle, diet, environment, stress, trauma, etc.) can influence the way our genes work. Unlike genetic variants, such as Single Nucleotide Polymorphisms (SNPs), epigenetic variants do not change the A’s, T’s, C’s and G’s of the DNA sequence, but can influence how your body expresses certain genes. Interestingly, epigenetic changes can be reversible (all the more reason to live a healthy lifestyle), and can be passed on from generation to generation. At the molecular level, biologists look at epigenetic changes to DNA via processes such as methylation or histone acetylation. In response to certain external factors, these molecular changes to DNA (for example the addition of methyl groups to the DNA backbone), can change how accessible the associated genes are by literally opening up and unwinding a tangled DNA strand, and thus can influence how those genes are turned on and off.
Autosomes, Sex-linked Genes, and Copy Number Variations:
As mentioned above, we carry two copies of every gene, one from mom and one from dad, and they can be the same (homozygous) or different (heterozygous). While this is the rule, there are some exceptions. Our DNA is packaged in our cells in structures called chromosomes. We have 23 pairs of chromosomes; 22 of them are not sex-linked, or “autosomal”, and these are numbered based on their size, whereby chromosome 1 is the biggest, and chromosome 22 is the smallest of the autosomal chromosomes. The last pair of chromosomes is sex-linked, whereby females carry two (relatively large) X chromosomes, and males have one (relatively large) X and one (relatively small) Y chromosome. So females have two copies of every gene on the X chromosome, while males would only have one. Interestingly, throughout evolution, different animals have come up with different ways to equalize the expression of genes across different biological sexes through a process called dosage compensation. Some organisms compensate by increasing the expression of X-linked genes in males, while other organisms, including humans, actually turn off one of the two X-chromosomes in females. Another exception to the ‘two copies of every gene’ rule is seen as certain genes are commonly found to be duplicated or deleted, which would lead to a Copy Number Variation, or CNV. One example is the duplication of the gene CYP2D6, which is involved in drug metabolism, and tested as part of our MatchMyMeds™ drug compatibility test. Some people carry 3 or more copies of this gene and therefore have higher than normal levels of gene expression and in turn, would have higher levels of CYP2D6 enzyme activity in their cells. These people are known as ultrarapid metabolizers, and may, for example, be at risk of unwanted side effects. Some genes are commonly found to be missing or deleted; so instead of the normal 2 copies, they would have 1 or zero copies of a gene, and would therefore be at risk of having low or no expression of that gene. Examples of genes that are commonly found to be missing are the Glutathione-S-Transferase enzymes, GSTM1 and GSTT1, which are covered as part of our LoveMyHealth™-PRO panel. Those with less than 2 copies of either of these genes have a reduced ability to clear toxins from their system via the glutathione pathway and are thus at increased risk for diseases related to oxidative stress including cardiovascular disease, endometriosis, and some cancers.
While this article is still an oversimplification of the complexities we have in our genes, I hope this brief summary sheds some light and helps create a better understanding of these concepts in genetics.
Dr. Aaron Goldman, PhD
Chief Science Officer