What is genetic mosaicism?
In this post we will discuss what might seem like an obscure topic but is a very real-life issue: being composed of more than one genome. Or in other words, situations where an individual carries two different types of genetic information in the cells of their body. This is especially significant for those who are interested in prenatal DNA testing.
How can you get more than one type of genetic information in your body?
In order for a person to end up with more than one type of genetic information through out the body, it means that a mutation in their DNA had to occur and that this specific mutation ended up being propagated through many of the cells making up the body. The earlier this mutation event occurs, the more likely it will be present in more cells in the future adult body, although this can take place at any point in life. Although timing is not the only criteria. Another influencing factor would be which cell type the DNA mutation occurs in. So you can appreciate that if such event takes place in an embryo, meaning very early in the human development, it can be propagated to a very large segment of cells in the grown-up body.
This is not a trivial issue. We discussed this before - how mosaicism affects the prenatal tests. Non-invasive prenatal screening (NIPS but more popularly referred to as NIPT with “T” for testing) analyzes baby derived DNA floating in the maternal blood to determine chromosomal abnormalities. However, the baby DNA is not actually from the fetus which has no contact with maternal blood, but rather from the placenta which does contact maternal blood. Both the fetus and the placenta originate from the same fertilized egg and therefore the circulating placental DNA is often just referred to as circulating fetal DNA. However, at times the placenta can show a different chromosome number than the fetus, due to some mutation event. This is referred to as placental mosaicism, and such a circumstance would lead to false positive finding. It is for this reason that NIPS is not a diagnostic test but only a screening assay and always has to be confirmed with a diagnostic test.
Discovery of mosaicism in such circumstances is still important because mosaicism can result in a miscarriage, birth defects or developmental delay, and hence can still inform about pregnancy outcomes. It is for this reason that we wanted to generate this article.
Another example that we mentioned in the past was the unusual case of Polish-American female Olympic champion, Stanislawa Walasiewicz (in the US known as Stella Walsh) whom we spotlighted in one of our yearly recounts of most shared genetic stories of 2019. Walasiewicz, was made up of two types of genomes, one that contained XY sex chromosomes (typically only observed in males with females being XX and these sex chromosome pairings are responsible for imparting biological gender), and another that contained only one X chromosome (thus one chromosome was missing). The condition of missing one X sex chromosome is referred to as Turner syndrome, but it still results in a female biological gender but it also can potentially lead to medical and developmental issues. Walasiewicz struggled her entire life with attacks on her gender definition because she did not fit the typical female body type. In her case, it is very possible that the embryo was conceived to be XY male but very early in the development a mistake happened where one of the cells did not inherit Y chromosome, leading to mosaic presentation.
While this might not have applied to Stanilslawa (who, according to autopsy had no functioning female reproductive organs), mosaicism in adults is also important for reproductive implications because depending which body parts are affected by mosaicism, a seemingly normal parent might lead to the appearance of disease in children if the sperm or eggs produced by the parent are actually affected by mosaicism. Unlike two unsuspecting carriers of genetic mutations accidentally combining their mutations in their offspring (which could easily be tested for with one overall DNA testing), the condition of mosaicism might not be as easily detected and could require more than one tissue type to be genetically tested to be identified.
By the way, there is another, separate way that a person could end up with more than one type of genetic material coursing through their body - this is referred to as chimerism. Mosaicism refers specifically to having two different types of genetic information with the second type of genetic information derived from mutation of the original. With chimerism you could be made up of more than one type of genetic information if a person is a fusion of two completely different genomes. This is very rare event and happens when two zygotes accidentally fuse together (or basically two separate fertilized eggs with independent genomes fuse together). We also talked about this in the most shared genetic stories of 2016. We bring it up now to make a clear distinction from mosaicism.
What kind of DNA mutations lead to mosaicism?
While a DNA mutation might not sound like much, this can range from a single DNA nucleotide base change (the simplest of changes to the DNA code) to alterations involving large stretches of DNA code (these are referred to as structural variants), or to even entire chromosomes (your massive DNA genome is divided into 46 segments called chromosomes). Any of these events can be detrimental to health outcomes, even survival, but the rule of thumb is that mutations affecting larger segments of DNA run an increased risk of more adverse outcomes.
As you might imagine, mosaicism can have very broad clinical presentations depending on how much of the body is affected, the type of mutation involved, and thus could be challenging to diagnose.
Sometimes, the disorder present in a person can only exist because it is in a mosaic state, where a portion of the body’s cells are normal and a portion are affected. The reason why the condition is never seen to be present in all the cells is because the mutation event in such a scenario would actually be lethal to survival. One such example is the Proteus syndrome, or the condition that is believed to have affected Joseph Merrick, widely known as the Elephant Man.
How common is mosaicism?
Mosaicism is likely to be extremely common, more the norm than not, but the vast majority of mosaic events are likely going to be benign in nature and hence not ever on a clinical radar. It is the pathogenic mosaicism (those that impact your health) that are of importance to focus on. It is known to lead to skin disorders, cancer, neuro-developmental disorders and a variety of growth disorders to name a few. Many of us are likely experiencing consequences of some mosaicism without ever knowing it (just think how few people out there still know anything about their genomes).
Actually, the most common mosaicism is loss of Y sex chromosome in males, with even up to 20% of older men exhibiting loss of Y chromosome in some of their blood cells! The reason why this is significant is because loss of Y chromosome was linked with increased risk of mortality from any cause for affected men, but especially cancer. When analyzing the biggest risk factors for cancer mortality in men, loss of Y chromosome turned out to be the biggest predisposing risk factor! I bet you men out there did not even know that! To compare, in second place was also genetic content change, but this time not affecting Y chromosome, but rather any other chromosomes but sex chromosomes (non- sex chromosome are called autosomes). It was accidental duplication of genetic content in autosomes (so certain stretch of DNA is present in more than one copy. This is referred as copy number variation and we covered it previously in another blog post dedicated to cancer). Smoking came only in third place! Hypertension was in fourth place. But loss of Y sex chromosomes had by far the largest impact.
Loss of genetic material is still very underappreciated cancer contributing factor. Loss of Y chromosome was so significant in its impact on male lifespan, that such individuals experienced lifespan shorter by more than 5.5 years! Authors proposed that this finding could explain why men are more frequently affected by cancer compared to women.
When it comes to the placenta, which is important for pregnant women considering non-invasive prenatal testing/screening, older studies indicated that up to 2% of the time placenta can differ in its genetic composition from the fetus. However, the bulk of that is referred to as pseudo-mosaicism (affecting less than 2% of cells) and about 0.8% is actually mosaicism. This is also through the assessment of chorionic villi of the placenta. In such instances, the NIPT test result would be positive, suggesting that a fetus is affected when it actually would not be (a false positive result). It is for this reason that a diagnostic testing would have to be performed; in this case the best test is amniocentesis. This test requires a collection of amniotic fluid surrounding the fetus which will have free floating fetus cells in it, and hence allows for the direct genetic investigation of the fetus. However, the amniocentesis or chorionic villi diagnostic test has a small risk of pregnancy loss. It is a necessary test to confirm NIPT results in case of mosaicism, but it is not a test to be taken lightly.
NIPT has a false positive rate of around 0.13%. If you are wondering why the difference between what is found with NIPT versus chorionic villi results, both of which assess the placenta after all, it could be that for NIPT to detect mosaic results, enough cells have to be affected. Below that certain threshold of affected cells, NIPT will simply not detect it because NIPT already works on the fringes of insanely small amounts of biological material being analyzed. Thus chorionic villi test should detect more placental mosaics than NIPT.
By the way, in very rare events, the fetus can also be affected with mosaicism while the placenta is not. This would lead to false negative result with NIPT, where NIPT assay would inform that fetus is fine when it is not. Amniocentesis testing reports mosaicism in 0.1-0.3% of the cases. NIPT assay has been estimated to have a false negative result rate of 0.26%.
Thus to summarise, most mosaic cases uncovered through placenta testing will be confined to a placenta while most of mosaic cases uncovered through amniocentesis will be confined to the fetus.
Placental mosaicism will usually still cause some abnormalities in the developing fetus. One reason is that the genetic abnormality in the placenta will lead to some placental dysfunction which in turn will impact proper development of the fetus.
In more rare circumstances, if the zygote (ball of cells stemming from the fertilized egg which will lead to both the fetus and placenta development) has an abnormal count of chromosomes (one too many, or a trisomy, such as for example Down syndrome), some of the cells can attempt to rescue the situation by ensuring that daughter cells will have a correct number of chromosomes. But these daughter cells while ending up having correct number of chromosomes, they could end up actually inheriting same two chromosomes from a single parent rather than chromosomes from each of the two parents. Meaning that in the rescue process of removing the extra chromosome, the chromosome from the other parent was removed, with a daughter cell retaining two same chromosomes from a same parent. This is referred to as uniparental disomy and can lead to fetus abnormalities. This is because while we retain a set of chromosomes from each parent, sometimes, genetic information from only one parental chromosome is used, while the other parent’s chromosome genetic information is silenced from being used. This means that genetic information from only specific parent is allowed to be used. This is called imprinting. If that imprinting process does not take place, this can lead to problems. Therefore if your cells end up with two chromosomes from same parents, and imprinting was to take place, this process might be completely prevented by having two identical chromosomes from a same parent.
How is mosaicism distributed in the body?
Recently an interesting article came out proposing a new type of classification of different types of mosaicism (which spurred the creation of this article). We will not go into all the complexities of different classifications here. The one classification that we did want to briefly touch upon is body distribution. The pattern of distribution can be confined to very specific points of the body, which is the most common type of mosaicism, and this often includes tumour development, or those skin anomalies you see confined to a specific location. You could also have multiple such single points randomly distributed throughout the body. The counterpart to that would be mosaicism that is segmental with specific distribution pattern and clearly defined demarcation. These can lead to some unique patterns depending on the point of occurrence in the development but they are not clearly understood yet. Skin lesions for example can take the form of large squares, or when multiple lesions are present, they can resemble a checkerboard, blocks, or flag-like arrangements, and are observed in many skin disorders. We wanted to bring it up because it is not uncommon but often unknown to people how it might happen.
We hope this provides great overview of mosaicism especially for those women considering NIPT testing during their pregnancy. NIPT is not a trivial test and good understanding of potential outcomes is important. Mosaicism is not a common confounding factor during NIPT but a very important reason why all positive NIPT results need to be retested. Merogenomics is a big proponent of full NIPT (where all chromosomes are assessed for potential genetic content alterations) and is even bigger proponent of good background and education. This now includes dedicated post to genetic mosaicism.
In the meantime, happy DNA testing!