Sickle cell anemia IS inherited in an autosomal recessive pattern, but sickle cell trait IS NOT inherited in an autosomal recessive pattern?

Question

It's all about the alleles of the hemoglobin beta gene. Sickle cell anemia is inherited in an autosomal recessive pattern, which means that both copies of the gene in each cell have mutations. Those who are heterozygous for the sickle cell allele produce both normal and abnormal hemoglobin so the inheritance pattern of the trait is considered to be codominant . Two different types of relationship between the same alleles. Why?

I think it is because in the sickle cell anemia the important thing is: To determine whether the individual is 'HEALTHY' or 'SICK'. But in the sickle cell trait we go deeper and are concerned with the presence of 'NORMAL' or 'SICKLE' RBCs inside the body. Did I get it right?

• HbAHbA: Healthy (only normal RBCs can be seen)

• HbAHbS: Healthy (Both normal and sickle RBCs can be seen)

• HbSHbS: Sick (Only sickle RBCs can be seen)

As you can see here, the inheritance pattern for anemia is an autosomal recessive pattern, but for the trait the pattern is codominance. The question is: Why are there two different types of relationship between the same alleles?

Consider this question:

What is the type of relationship between the normal and mutant alleles (which causes sickle cell anemia) of the hemoglobin beta gene? Autosomal recessive pattern or codominance?

Can one choose one of the options? I think this question is vague. Because if the sickle cell anemia was mentioned, the answer would be autosomal recessive pattern. But if the sickle cell trait (the presence or absence of sickle RBCs) was mentioned, the answer would be codominance. Isn't it so?

Edit

With thanks to Bryan Krause, I searched a little more and saw this in Wikipedia just now.

The sickle cell trait can be used to demonstrate the concepts of co-dominance and incomplete dominance. An individual with the sickle cell trait shows incomplete dominance when the shape of the red blood cell is considered. This is because the sickling happens only at low oxygen concentrations. With regards to the actual concentration of hemoglobin in the circulating cells, the alleles demonstrate co-dominance as both 'normal' and mutant forms co-exist in the bloodstream. Thus it is an ambiguous condition showing both incomplete dominance and co-dominance.[citation needed]

Before this, I believed that only two phenotypes can be seen in HbAHbS individuals: Normal RBC and Sickle-shaped RBC

But now I doubt it. Is there one more phenotype? A red blood cell that is not normal nor sickle-shaped but rather something in between? A red blood cell that is sickled incompletely? Is this phenotype really observed, studied or defined scientifically?

Answer 1

These phenotypic dominance terms you learn in school - autosomal recessive/dominant, co-dominance, incomplete dominance... these are all just descriptive terms based on phenotype that become somewhat irrelevant and outdated once you have a better molecular understanding of what exactly goes on with different alleles of a gene. If none of them apply well, that's fine, because the real world doesn't follow these basic rules.

For sickle cell anemia, the serious form of the illness, the inheritance is more or less autosomal recessive, as you say. Those with two abnormal copies of the HBB gene have symptoms; those with one copy are generally symptom-free.

However, at a cellular level, it turns out that both normal and abnormal versions of hemoglobin exist. If we define co-dominance as "contributions of both alleles are visible in the phenotype", then at an intracellular level, the phenotype is co-dominant. That said, these terms are typically used at the organismal level. After all, patterns of dominance in Mendelian inheritance far pre-date any understanding at the molecular level of these things. It's very typical for traits considered to be recessive at an organismal level to show measurable differences at a molecular level in heterozygotes, yet these differences are compensated for (such as via feedback loops in gene expression) such that the phenotype isn't observed.

If we look carefully, though, even at the whole-organism level, sickle-cell carriers (heterozygotes) don't have exactly the same phenotype as those who are homozygous for the normal HBB allele. Heterozygotes are considered as having the sickle-cell trait. They're somewhat less sensitive to malaria, but there are also some associations with cardiovascular comorbidities and signs of sickle-cell disease in adverse conditions such as dehydration, especially at high exertion in athletes. Incomplete dominance describes a heterozygous phenotype "distinct from and often intermediate to the phenotypes of the homozygous genotypes". Note in this definition the word distinct and the qualifier often intermediate. There is no stipulation that the heterozygous phenotype needs to be precisely in between the homozygous phenotypes, or even that it has to be between them at all rather than somehow orthogonal, it merely must be distinct. This seems to me like the best description for sickle-cell inheritance overall, though it may be harder to follow in a pedigree as the heterozygous phenotype may not be obvious enough to recognize in every carrier.

If you have to pick one for a multiple choice question, incomplete dominance is the most comprehensive answer, but all three of these are potential answers if you constrain the parameters of the problem. It's far less important to be able to assign these particular labels, though, than it is to understand what actually happens with a sickle cell allele.

Some more quotes from Wikipedia:

The sickle cell trait can be used to demonstrate the concepts of co-dominance and incomplete dominance. An individual with the sickle cell trait shows incomplete dominance when the shape of the red blood cell is considered. This is because the sickling happens only at low oxygen concentrations. With regards to the actual concentration of hemoglobin in the circulating cells, the alleles demonstrate co-dominance as both 'normal' and mutant forms co-exist in the bloodstream

I disagree a bit with the next sentence in Wikipedia, though:

Thus it is an ambiguous condition showing both incomplete dominance and co-dominance

I don't think it's particularly ambiguous, it's just necessary to either define what level of analysis you're making the statement about or to recognize that none of these terms are entirely sufficient to describe the complexity that exists in biology.