Understanding Genetics
Understanding Genetics
What Are Chromosomes?
It is not difficult to understand what a chromosome is. You can see them (in pictures taken with a powerful microscope). They look like tiny worms with stripes. But what you can not see is their precious cargo—our genes. For this reason, many people have trouble picturing what a gene is. To understand why chromosome differences can cause problems, we need to understand what genes are and what they do.
Genes
A gene is a segment of DNA that has a special meaning. The meaning is encoded in the order or sequence of the bases A, C, G, and T. The genetic triplet code refers to the fact that every set of three bases represents a building block for a protein. These building blocks are called amino acids. Most genes are simply instructions to tell the cell how to make a specific protein. Other genes play a role in directing the cell to make or stop making particular proteins.
To make a human being, it takes approximately 22 000 genes. Each cell in our body must hold all those genes, so they are wound up tightly into chromosomes. These packages can loosen and tighten according to the needs of the cell. For example, if a cell needs to divide (which is how they reproduce themselves so that we can grow), the chromosomes relax and allow their DNA to be copied, base-by-base, into an exact replica. When the cell splits in two, the copied chromosomes can move into the new cell that is formed. This process is called mitosis.
Mitosis
Another very important situation in which our cells need to copy our genetic information and divide is when we make our gametes. The term gametes refers to either a woman’s eggs or a man’s sperm cells. They are special because they only carry half of the genes found in the rest of our cells. The process by which gametes form is called meiosis, which is very similar to mitosis, except at this end of it, we have only half the number of chromosomes in each cell. This only happens in the gonads (testes for men, ovaries for women).
To hold all our 22 000 genes, we need to have 23 pairs of chromosomes in each cell. Why do they come in pairs? Because we inherit one of each pair from our mother and the other from our father. Likewise, our genes come in pairs. So, we have 46 chromosomes in all, in almost every cell in our body. The exception, of course, is in our gametes.
How and Why Do Chromosome Differences Happen?
To understand how chromosome differences happen, we need to know how babies are made at the cellular level. It all begins with the gametes—the egg and sperm. These cells are special because, unlike the rest of the cells in our body, they contain only 23 chromosomes each—that is, only one of each pair. The reason for this is simple. When the sperm fertilizes the egg, the result is a zygote, a cell that now has a full set of 46 chromosomes. This zygote can then begin the process of copying its chromosomes so it can divide into two cells, then four, then sixteen, and so on. Soon, you have an embryo (which just looks like a cluster of cells growing in the wall of the uterus), which grows into a fetus and placenta. A fetus begins to look like a human baby by the second trimester of pregnancy.
Chromosome differences usually (but not always) happen before fertilization. They occur when the egg or sperm forms in the mother’s ovaries or the father’s testes. We do not know, in most cases, exactly why they happen. The process of making copies of chromosomes and genes is not perfect; errors can occur spontaneously and naturally. We will get into the specific types of errors in the next section. The important things to remember are:
- Chromosome differences can happen to anyone: male or female, rich or poor, young or older, healthy or sick.
- Errors in copying chromosomes are natural and common.
- There is nothing you did to cause this to happen.
- There is nothing you could have done to prevent this from happening.
Errors that cause chromosome differences in the egg can happen before you are even born! That is right—females are born with all the eggs they will ever have already in their ovaries. Each month during a woman’s menstrual cycle, one of her ovaries releases a single egg, and you cannot control which egg is released. Some types of chromosome differences in the egg are more likely to happen with age—for example, trisomy 21 (Down syndrome).
Errors that cause chromosome differences in sperm frequently happen, as new sperm are always being produced in the testes once males reach puberty. Usually, sperm with chromosome differences are not as fast or strong as those with normal chromosomes, so when hundreds of thousands of sperm are competing to fertilize one egg, the best one usually gets there first! But this is not always the case, and we do not really understand why.
Chromosome differences can also occur after fertilization, but this is much less common. We will discuss this in the section about chromosomal mosaicism.
Finally, some chromosome differences are inherited. This can mean that the parent has a chromosome difference in every cell of their body, and therefore in some of their germ cells (egg or sperm). We will get into this more in-depth in the next section.
What Kinds of Chromosome Differences Are There?
There are almost as many types of chromosome differences as there are people who have them! The next few pages will describe each of the most common types of chromosome differences, but many more complex rearrangements exist. We can roughly divide chromosome differences into numerical (also known as aneuploidy) and structural. A numerical difference means that there are more than, or fewer than, 46 chromosomes present. Here are some examples:
- Trisomy – Trisomy literally means three chromosomes. Having three copies of an entire chromosome is usually lethal—that is, the fetus usually miscarries before birth. There are a few exceptions to this—most notable is Trisomy 21, which causes Down syndrome. For reasons we do not fully understand, babies with trisomy for chromosome 18 or 13 can also survive to birth and even longer.
- Monosomy – Monosomy means one chromosome. Missing an entire chromosome is more typically devastating to the developing fetus than having an extra chromosome—in fact, a monosomic embryo is unlikely to lead to a recognized pregnancy because it will die before the pregnancy gets too far along—the only exception to this in Monosomy X—also known as Turner syndrome.
- Tetrasomy – Tetrasomy means four chromosomes, but having four copies of an entire chromosome is unheard of in living humans (except for the X and Y chromosomes). However, you may have a scenario in which there are four copies of a segment of a chromosome. This is the case in Cat Eye syndrome (CES), in which there are four copies of a segment of chromosome 22, and in Pallister-Killian syndrome (PKS), in which there are four copies of a segment of chromosome 12. This is technically a partial tetrasomy since the whole chromosome is not involved.
- Triploidy – this means that there is a whole set of extra chromosomes present, for a total of 69. Triploidy is quite rare and is seen mainly in fetuses that have miscarried or were stillborn.
- Extra structurally abnormal chromosomes (ESACs) – This term describes very small chromosomes such as marker chromosomes and ring chromosomes. Under the microscope, they look very different from the rest of the chromosomes. Often, they consist of “junk” DNA—that is, no genes are present. Occasionally an extra small chromosome contains genes, and if there are already two copies of these genes present on the regular chromosomes, then the individual is said to be trisomic for these particular genes. Depending on what chromosome these extra genes derived from, there may be effects on growth, health or development, or no effect at all.
Structural chromosome differences can be classified as follows:
Deletion – A deletion occurs when a segment of a chromosome is missing. A deletion can be any size, from very large (so it can be seen by a laboratory technician who is analyzing chromosomes under the microscope), to very small and invisible even under the most powerful microscope. A deletion can wipe out hundreds of genes, or just a tiny piece of a single gene, or only a segment of DNA that does not contain any genes. It can be at the very end of a chromosome (called a terminal deletion), or it can take out a piece in the middle of the chromosome (called an interstitial deletion). We used to think that deletions always lead to health and development problems, but now that we have the power to detect much smaller deletions, we know that not all deletions cause issues. It really depends on how many genes, and which ones, have been deleted.
Duplication – A duplication is essentially the opposite of a deletion. Instead of missing a chromosome segment, the duplicated segment is present in three copies instead of the usual two. The duplicated segment may be very large and contain hundreds of genes, or it can be very small and only contain one, a few, or only a piece of a gene, or no genes at all. The duplicated segment may lie directly next to the segment it originated from (this is called in tandem), or it may be in a different location on the same chromosome, or even on a different chromosome. Having extra copies of genes may have no or minimal effect on the developing baby, or could cause severe problems—again, depending on the size and location (and genes involved) in the duplication.
Another type of balanced translocation is called a Robertsonian translocation. Again, a person can have this chromosome difference and never know it—about 1 in every 1000 people do. It occurs when two chromosomes (usually one of these: 13, 14, 15, 21 and 22) “stick together” end-to-end to make one long chromosome. A person with a Robertsonian translocation, therefore, has only 45 chromosomes instead of the usual 46—but because all of their genes are present in the right number of copies, there are no effects on health. However, as with reciprocal translocations, this can cause trouble when the person makes eggs or sperm because the chromosome pairs do not separate properly. If the egg or sperm gets too many or too few chromosomes, the resulting embryo will have an unbalanced chromosome complement.
Inversion – This is when a segment of a chromosome is “flipped.” All the genes are present in the right number of copies but now are in a different order. There are two types of inversions: pericentric (which means that the centre part of the chromosome, the centromere, is part of the flipped segment) and paracentric (the centromere is not involved in the inversion). A person carrying an inversion on one of their chromosomes may experience fertility problems. A pericentric inversion can lead to the formation of genetically unbalanced eggs and sperm, and therefore increases the chance of having a child with a deletion or duplication.
Ring chromosomes – Chromosomes are linear—that is, they have two ends (called telomeres). Rarely, the ends of a chromosome stick together and form a ring structure. Sometimes, there is some genetic material missing from the ends of the chromosome (causing deletion of genetic material). Or, the ring chromosome may be supernumerary – which means it is an “extra” small chromosome (causing duplication of genetic material). As mentioned above, deletions and duplications of genetic material can result in medical and developmental problems.
Translocation – this means a piece of a chromosome has broken off from its original location and stuck itself onto another chromosome. A reciprocal translocation means that two chromosomes have traded pieces. If no genetic material was lost or gained from either chromosome during this process, the translocation is balanced. However, if there was a deletion (loss) or duplication (gain) of genetic material during this process, the translocation is unbalanced. An unbalanced translocation can also occur when a parent has a balanced translocation (and as many as 1 in 625 of us have this, and most do not know it). In the process of making eggs or sperm, only one of the translocated chromosomes gets passed on, which results in a deletion of genetic material from one chromosome and a duplication on the other. The effects on the growth, health and development of the child born with a deletion/duplication from an unbalanced translocation depend on which chromosomes are involved and how large the deleted and duplicated segments are.
Mosaicism
A mosaic is something that is made up of a combination of different things. Chromosomal mosaicism means that there are two or more different types of cells in a person’s body. There may be one type with normal chromosomes, and one type with abnormal chromosomes. Or, there could be multiple types with only abnormal chromosomes.
Here is an example. Most people with Down syndrome have trisomy 21—that is, they have 47 chromosomes in total because they have a whole extra chromosome 21 (a total of three copies). Most of the time, it would not matter how many cells you look at from a person with Down syndrome—every single cell will have 47 chromosomes, with an extra 21. However, it is possible to have Trisomy 21 mosaicism, which means that, if you look at 100 cells from that same person, a certain proportion will have 47 chromosomes, and the rest will have normal chromosomes. Often, but not always, a person with Trisomy 21 mosaicism has “a little less Down syndrome” than a person with full (or non-mosaic) Trisomy 21. They still have Down syndrome, but may look a little less like they do, or act a little less like they do. It is impossible to predict because the normal and abnormal cells are mixed up together in every body part. Looking at the chromosomes in blood cells does not necessarily mean you will find the same thing in chromosomes in the skin cells or brain cells.
Mosaicism occurs when a chromosome error happens after fertilization. The zygote starts with a normal set of chromosomes, but an error occurs during mitosis (cell division) in one of those early cells (remember, the embryo begins as one cell and divides to make 2, then 4, then 8, and so on). Once the error occurs, every cell afterward will have the same error. The cells with normal chromosomes will also continue to divide.
Chromosome Differences versus Chromosome Disorders
Anyone can have a chromosome difference. Many of us do and do not even know it. But not nearly as many of us have chromosome disorders. So, what is the difference? The Mirriam-Webster dictionary defines a disorder as “an abnormal physical or mental condition.” While we do not like referring to people as normal or abnormal, it is hard to come up with a more precise definition. Let us assume “abnormal” refers to anything that comes to medical attention: an illness or physiological difference (such as pneumonia or constipation), a physical difference (such as a cleft lip), or a difference in mental or behavioural functioning (such as an intellectual disability or autism spectrum disorder). With this definition of abnormal, we can define a chromosome disorder as any chromosome difference that causes abnormalities in health, physical form or ability, or mental functioning.
Here is an example. Stephanie has a chromosome difference—she has a balanced translocation between two of her chromosomes 11 and 22 (it is balanced because she does not have any genetic information missing or extra). Other than having recurrent miscarriages before she got pregnant with her daughter Maia, having this chromosome difference has not affected her health, physical ability, or intelligence. She does not have a chromosome disorder.
Stephanie’s daughter Maia has both a chromosome difference and a chromosome disorder. Her chromosome difference is not the same as her mother’s. Maia has an extra chromosome, so she has a total of 47. This extra chromosome (called a derivative chromosome) consists of a piece of chromosome 22 and a piece of chromosome 11. This extra chromosome was present in the egg that Stephanie produced right before she got pregnant with Maia. Having an extra chromosome has caused Maia’s mental and physical development to be abnormal.
Maia’s chromosome disorder happens to have a name—Emanuel syndrome. So, what is a syndrome, exactly? By definition, a syndrome is “a group of signs and symptoms that occur together.” A syndrome does not have to be caused by a chromosome difference. For example, AIDS is acquired immune deficiency syndrome, which is caused by infection by human immunodeficiency virus (HIV). We do not always know the exact cause of a syndrome—for example, SIDS (sudden infant death syndrome) is given as the cause of death of an infant who was otherwise healthy, who dies for no apparent reason. Historically, labelling a group of patients with a “syndrome” based on their common features was useful for research because studying these patients sometimes helps medical scientists to discover the underlying cause. Before we knew about chromosomes, we knew about Down syndrome, because people with Down syndrome have many similarities to each other. It was only later that we figured out that it is caused by trisomy 21.
Here are a few of the more common examples of syndromes caused by chromosome differences. They are all considered to be chromosome disorders, too. The ones mentioned here are named after the doctor(s) who first described them in the medical literature. This practice is less common now; as new syndromes are identified, they tend to be named after the main features of the condition (like Velocardiofacial syndrome) or after the underlying genetic or chromosomal abnormality (like 22q11.2 deletion syndrome).
- Down syndrome – this is caused by having an extra chromosome 21. Therefore, it is also known as Trisomy 21.
- Turner syndrome – this is caused by having only one sex chromosome, instead of two; therefore, it is sometimes called Monosomy X. Individuals with Turner syndrome are female, but they tend to be shorter than average, and they are infertile due to the underdevelopment of their internal reproductive organs. They also may have certain physical features in common, such as a broad or webbed neck, a rounded chest wall and deep-set finger and toenails.
- Prader-Willi syndrome (PWS) – individuals with PWS can have a deletion on chromosome 15, which originated in the sperm of their father, or they can have two copies of chromosome 15 from their father and none from their mother (this is called uniparental disomy). Characteristic features of this syndrome include hypotonia and poor feeding during infancy, followed by excessive hunger and food-seeking, leading to obesity during childhood, as well as intellectual disability.
- Angelman syndrome (AS) – Interestingly, AS can be caused by a deletion of the identical region of chromosome 15 as in PWS, but rather than originating in the sperm of the father, the deletion originates in the egg from the mother. Individuals with AS have a completely different syndrome from those with PWS. They are more severely intellectually disabled, and they tend to have small heads (microcephaly) and ataxia (problems maintaining balance).
There are hundreds of other less common chromosome disorders, and some of them are extremely rare. Some are even unique to a single individual.
Written by Dr. Melissa Carter.
Excerpt from Raising the Goddess of Spring: A guide for parents raising children with rare chromosome disorders Available on Amazon.
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