## **Core Concept**
Sickle cell anemia is a genetic disorder caused by a specific mutation in the HBB gene that codes for the beta-globin subunit of hemoglobin. This mutation leads to the production of abnormal hemoglobin, known as sickle hemoglobin or hemoglobin S. The disorder is characterized by the sickling of red blood cells under certain conditions, which can cause a variety of health problems.

## **Why the Correct Answer is Right**
The correct answer involves a change from glutamic acid (which is negatively charged) to valine (which is nonpolar) at the sixth position of the beta-globin chain. This substitution is due to a point mutation in the HBB gene where adenine (A) is replaced by thymine (T) in the DNA sequence, leading to a change from GAG (glutamic acid) to GTG (valine) in the codon. This change results in hemoglobin S (HbS), which has a tendency to polymerize under low oxygen conditions, causing red blood cells to assume a sickle shape.

## **Why Each Wrong Option is Incorrect**
- **Option A:** This option does not accurately describe the amino acid substitution seen in sickle cell anemia.
- **Option B:** This option suggests a different substitution that is not associated with sickle cell anemia.
- **Option D:** This option also does not accurately describe the amino acid substitution seen in sickle cell anemia.

## **Clinical Pearl / High-Yield Fact**
A key clinical pearl is that sickle cell anemia is most prevalent in areas where malaria has been or still is a significant problem, suggesting a selective advantage for carriers of the sickle cell trait (HbAS) against malaria. However, individuals with sickle cell anemia (HbSS) suffer from significant morbidity and mortality due to complications of the disease.

## **Correct Answer:** . Glutamic acid to Valine.