In this lesson, we're going to talk a little bit about recessive genetic conditions and some of their more common characteristics. We'll use Tay-Sachs disease as an example throughout this lesson. You may recall that Tay-Sachs disease is a rare genetic disorder in humans that causes progressive neurological deterioration starting at only three to six months of age.
Unfortunately, there is no known cure or effective treatment for Tay-Sachs disease, and most children who suffer from the disease die by the age of four. When it comes to inheritance, Tay-Sachs disease is an autosomal recessive disorder, which you may remember is a genetic disorder that is caused by a gene on an autosome and is only seen in individuals with two copies of the affected allele.
Now you may be wondering, why is it that children with Tay-Sachs disease are so severely affected, and yet carriers who have one copy of a Tay-Sachs allele show no signs of the disease whatsoever? The answer to this question lies in the biochemistry of the disease.
Tay-Sachs disease can actually be caused by a few different mutations of the HEXA gene, each of which leads to the expression of a completely dysfunctional enzyme with no activity. When an individual has two copies of a Tay-Sachs allele, they have no functional beta-hexosaminidase A activity. As a result, GM2 ganglioside quickly builds up in the neurons and Tay-Sachs disease occurs.
However, functional beta-hexosaminidase A is a very efficient enzyme. It's so efficient that even if a person has only one copy of the HEXA gene and makes only half the normal amount of functional enzyme, it's more than enough to clear the excess GM2 ganglioside from their neurons. In carriers, half of the normal amount of functional enzyme is sufficient for normal function.
This phenomenon is called haplosufficiency. Haplosufficiency occurs in situations where a single copy of a functional gene is enough to maintain normal function. Heterozygote carriers of recessive alleles usually exhibit haplosufficiency, which is the main reason why they remain unaffected even though their cells are making some dysfunctional proteins.
Now let's talk a little bit about inheritance patterns. We know that Tay-Sachs disease is recessive because the HEXA gene is haplosufficient. But what about lethal conditions caused by genes that are haploinsufficient, meaning that a single copy of a functional gene is not enough to maintain normal function? A disease caused by a haploinsufficient gene would have a dominant inheritance pattern. If a dominant condition is lethal before sexual maturity, it would not allow the causative gene to survive beyond the lifetime of the person it was originally expressed in.
Now, just to be clear, I am definitely not saying that the Tay-Sachs allele somehow evolved to become recessive so that it could survive. Alleles cannot evolve to become recessive! That is not the way that genes and alleles work. Alleles cannot change themselves or take any other actions to try to survive.
Instead, what I am saying is that alleles that cause early-onset lethal conditions will only become established if their inheritance allows them to be passed along to individuals without always killing them. In other words: lethal alleles will only survive if they aren't always lethal or if they kill after an individual has already reproduced.
Early-onset lethal autosomal dominant alleles certainly arise by mutation from time to time, but these alleles kill the first person that expresses them, so they don't get passed on, and they don't become established. Therefore, they are not usually recognized as a genetic condition.
Autosomal recessive alleles are very different. Because it takes two copies, one from the mother and one from the father, a new autosomal recessive allele can survive by chance for many generations. During this time, the allele can be passed on to more people each generation with no adverse effect before a person finally receives two copies of the allele and exhibits the recessive phenotype.
Even if the consequences of the recessive phenotype are as severe as prenatal death, the allele will only rarely result in harm to the individual. This is because the recessive allele will usually be present with a dominant wild-type allele. Therefore, even a lethal recessive allele can usually survive as a minor allele in the gene pool. The lower the frequency of the allele, the less likely it is to result in a recessive homozygous individual who won't survive. As a result, these alleles tend to survive at very low frequencies within the gene pool.
Let's review. The causative gene for Tay-Sachs disease is the HEXA gene. This gene encodes the beta-hexosaminidase A enzyme, which is responsible for the normal degradation of GM2 ganglioside. The HEXA gene is haplosufficient, which means that a single copy of the functional gene is enough to maintain normal function. However, if both copies of the gene encode dysfunctional enzyme, GM2 ganglioside cannot be degraded in neurons and the excess buildup of GM2 ganglioside eventually kills the neurons, causing Tay-Sachs disease.
Some genes are haploinsufficient, meaning that a single copy of a functional gene is not enough to maintain normal function. Disorders caused by haploinsufficient genes usually have a dominant inheritance pattern. In human genetics, there are lots of examples of early-onset lethal recessive conditions, but early-onset lethal dominant conditions cannot become established because the causative allele will kill the individual before it can be passed on to the next generation.
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