Changing “the Average Human has 46 Chromosomes” to “ALL Humans”
You might have stumbled across the fact that most humans have 46 chromosomes. Key word: most.
Well what about the minority of humans that don’t?
Almost all diseases are hereditary or the result of a genetic abnormality. What if we could abolish the very possibility of developing a chromosome-related disorder? Gene editing opens a completely different ballgame for disease prevention. Advancements in this area will hit the ball of disease out of the park.
Let’s zone in on one particular genetic abnormality, aneuploidies.
Breaking Down the “Loids”
First of all, there are diploids. This term refers to the 46 chromosomes an average human has. It is a cell or organism that has paired chromosomes, one set of 23 from each parent. Human haploid is the term for those individual sets of 23 chromosomes.
Chromosomal abnormalities occur when there is more or less than two complete sets of the human haploid genome.
Here are a few examples:
- Triploidy: 3 human haploid sets (69 chromosomes).
- Tetraploidy: 4 human haploid sets (92 chromosomes).
Keep in mind these are extremely rare.
An aneuploidy [an·yuh·ploy·dee] is a little more complicated but short definition: a cell where the chromosome number is not an exact multiple of the haploid chromosome, therefore there are no “sets.”
Development of Aneuploidies
The development of an aneuploidy is by no means random, there is a genetic procedure behind it.
An aneuploidy usually arises because a gamete is formed containing more or fewer chromosomes than the normal complement. This gamete results from phenomenon called non-disjunction where replicated chromosomes do not separate properly at cell division.
Non-disjunction can occur at meiosis I during the anaphase. This means at least one pair of homologous chromosomes did not separate during cell division. The end result is two cells that have an extra copy of one chromosome and two cells that are missing that chromosome.
In humans, n + 1 designates a cell with 23 chromosomes plus an extra copy of one for a total of 24 chromosomes. Then of course, n — 1 designates a cell missing a chromosome for a total of only 22 chromosomes in humans.
This phenomenon can also occur at meiosis II during anaphase II. Instead of homologous chromosomes not separating, in meiosis II at least one pair of sister chromatids did not separate.
In this case, two cells will have the normal haploid number of chromosomes, one cell will have an extra chromosome (n + 1) and one will be missing a chromosome (n — 1).
Homologous Chromosomes vs. Sister Chromatids
Think of them as fraternal and identical twins. Homologous chromosomes, the “fraternal twins,” consists of two non-identical copies of a chromosome, one from each parent. On the other hand, sister chromatids, the “identical twins,” are genetically the same and are identical copies of one another, specifically created for cell division.
Now that you have gained an understanding of the biology, I have something to tell you…
This is serious.
Contributing Factors
Aneuploidies do not develop at random times to random people majority of the time. Non disjunction generally occurs due to age as the risk of delivering a trisomic fetus increases from 1.9% in women aged 25–29 years to over 19% in women aged over 39 years.
There is also evidence that folic acid deficiency, smoking, obesity and low-dose irradiation with radioactive contaminants increases the risk of non-disjunction.
Severity
Most aneuploidies are lethal.
Trisomy 13 (Patau Syndrome) and trisomy 18 (Edward’s Syndrome) have severe phenotypic consequences, which are rarely compatible with long-term survival. The survival time for patients with trisomy 13 is between 7-10 days and it is reported that 86%-91% of live-born patients with Patau syndrome do not survive beyond 1 year of life. Additionally, only about 12% of babies born with trisomy 18 survive the first year of life.
A more common aneuploidy is trisomy 21, down syndrome. Trisomy 21 is not as lethal as trisomy 13 and 18 however the frequency is concerning as 1 in only 800 babies develop down syndrome. The average lifespan isn’t great either as it is around 47 years.
You’re right, this is serious. But can we cure aneuploidies?
Two words: Gene Editing.
Aneuploidy disorders have been considered to be incurable. However, recent studies using genetic engineering have revealed the possibility of performing aneuploidy therapy in cultured cells. A key therapy I will be diving into is the elimination of an entire chromosome using 2 methods.
Cre/loxP System
As the name suggests, the Cre-Lox system relies on two components to function: a Cre recombinase, and its recognition site, loxP. A single loxP site contains two 13-bp inverted repeats flanking an asymmetric 8-bp core sequence recognized by Cre recombinase.
The implementation of the inverted loxP into the chromosomes are performed by standard gene targeting using the CRISPR/Cas9 nickase system. Chromosomes with inverted loxP sites can be converted to unstable dicentric and acentric chromosomes, which will then be excluded during cell division. This process leads to promoting elimination of the target chromosome with the inverted loxP sites.
Here is a very simplified explanation!
Think of it as picking out vegetables from your salad. The sauce gets all over the the onions and pickles and doesn’t taste good so you exclude them. The inverted loxP poses as the sauce that makes the onions and pickles taste bad. Instead of vegetables changed to taste bad, chromosomes are changed to be unstable dicentric and acentric chromosomes. This leaves you to easily target the lettuce and eat it, “eliminating the chromosome.”
The Cre/loxP System has been tested and proven successful on mice, so there is possibility for treatment in humans.
CRISPR/Cas9 System
The general idea for the usage of CRISPR/Cas9 in aneuploidy treatment is to introduce various DNA cleavages for target chromosome elimination.
The CRISPR/Cas9 system targets the unique repeat sequences in DNA, which introduces multiple DNA double-strand breaks into the target chromosome in order to delete the chromosome in its entirety.
In this example, XY mouse zygotes are injected with Cas9 mRNA and sgRNA to the repeat sequence on the X chromosome for the generation of XO chromosome mice in vivo. On the other hand, Down Syndrome induced pluripotent stem cells transfected with CRISPR/Cas9 expression transmit to multiple splits into the extra copy of chromosome 21 in vitro. (The extra copy of chromosome 21 is the root cause of Down Syndrome).
That may be a lot to understand. In simple terms, what the CRISPR/Cas9 system does is introduce breaks in the DNA’s unique repeat sequences using various guide RNAs. Then, the cells split into the extra chromosome 21 which is the cause of Down Syndrome, eventually deleting the chromosome.
Again, this method has only been executed on mice. Fortunately, scientists experienced positive results leading to hope for treatment in humans.
It Can Happen
Curing aneuploidies is definitely not a pipe dream.
With proven results in mice, scientists will soon be testing these methods on humans. These approaches so far must be accompanied by a risk of random alterations to the genome. However recently, as an alternative approach that eliminates this risk, it has been reported that iPSC reprogramming can correct structural and numerical chromosomal abnormalities.
New systems and research are being discovered every minute. It is only a matter of time before aneuploidy treatment becomes widespread in humans.
Further Reading:
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