Sickle Cell Anaemia: Glu to Val Substitution (NEET)
Biology · Principles of Inheritance and Variation · NEET
Sickle cell anaemia is an autosomal recessive disorder. One tiny change in the beta globin gene (codon GAG changes to GUG) swaps glutamic acid (Glu) for valine (Val) at the 6th position of the beta globin chain. This makes the haemoglobin clump together when oxygen is low, so red blood cells change from a round disc into a sickle (banana) shape. Memory hook: "6th spot, GAG to GUG, Glu becomes Val" — the number 6 links to Glu-to-Val.
A single base change (GAG to GUG) at the 6th codon of the beta globin gene swaps Glu for Val. The mutant HbS polymerises under low oxygen, turning the round red blood cell into a sickle shape.
Your doubts, answered
Which amino acid is replaced by which in sickle cell anaemia?
Glutamic acid (Glu) at the 6th position of the beta globin chain is replaced by Valine (Val). The order to remember is Glu OUT, Val IN. A common NEET trap says valine replaces lysine — that is WRONG. It is glutamic acid, not lysine.
What is the codon change GAG to GUG and where does it happen?
The change is a single base substitution at the 6th codon of the beta globin gene. The normal codon GAG (codes for Glu) becomes GUG (codes for Val). So at the mRNA level, the middle A is replaced by U. Only one base changes, which is why it is called a point mutation (single base substitution).
Is sickle cell anaemia dominant or recessive?
It is an autosomal recessive trait. This means the disease only shows when both alleles are the mutant type. It is NOT sex-linked and NOT dominant. The gene is on chromosome 11 (autosome), which is why it is called 'autosome-linked'.
Why does only HbSHbS show the disease and not HbAHbS?
The trait is controlled by one pair of alleles: HbA (normal) and HbS (mutant). There are three genotypes: HbAHbA (normal), HbAHbS (carrier, looks healthy), and HbSHbS (diseased). Only the homozygous HbSHbS person shows sickle cell disease. The heterozygous HbAHbS person is a carrier — they appear normal but can pass the mutant gene to children (50% chance).
Is sickle cell anaemia a point mutation or a frameshift mutation?
It is a point mutation, specifically a substitution. Only ONE base is swapped (GAG to GUG). No base is added or deleted, so the reading frame does not shift. Frameshift mutations happen only with insertion or deletion of bases.
Why does the red blood cell change shape?
With valine in place, the mutant haemoglobin (HbS) undergoes polymerisation (the molecules stick together in chains) under low oxygen tension. This pulls the red blood cell from its normal biconcave disc shape into a long, sickle-like (curved) shape. The sickled cells block small blood vessels and break easily, causing anaemia.
⚠️ The NEET trap ✗ In sickle cell anaemia, valine replaces lysine at the sixth position of the beta globin chain. ✓ Valine replaces GLUTAMIC ACID (Glu), not lysine, at the 6th position of the beta globin chain. The codon changes from GAG to GUG. 🧠 NEET 2023 used the 'lysine' trap. Remember: Glu OUT, Val IN. The two Gs in GAG and GUG stay; only the middle base changes A to U.
Real NEET questions
NEET 2023 Phase 2
In which disorder does change of a single base pair in the gene for beta globin chain result in change of glutamic acid to valine?
A · Haemophilia
B · Phenylketonuria
C · Thalassemia
D · Sickle cell anaemia ✓
Solution: Sickle cell anaemia results from a single base substitution (point mutation) in the beta globin gene: codon GAG changes to GUG, so glutamic acid (Glu) is replaced by valine (Val) at the 6th position of the beta globin chain. The other disorders do not involve this Glu-to-Val change.
NEET 2021
In a cross between a male and female, both heterozygous for the sickle cell anaemia gene, what percentage of the progeny will be diseased?
A · 25% ✓
B · 100%
C · 50%
D · 75%
Solution: Sickle cell anaemia is autosomal recessive; only the homozygous HbSHbS individual shows disease. A cross HbAHbS x HbAHbS gives a 1:2:1 ratio: 1 HbAHbA : 2 HbAHbS : 1 HbSHbS. Only 1/4 = 25% (the HbSHbS progeny) are diseased.
Solution: Sickle cell anaemia is an autosomal (autosome-linked) recessive trait affecting the beta globin chain, whose HBB gene lies on chromosome 11. The others are wrong: thalassemia is autosomal recessive (not X-linked), haemophilia is X-linked recessive (not Y-linked), and phenylketonuria is autosomal recessive (not dominant).
Solved Principles of Inheritance and Variation NEET PYQs
Try the real previous-year questions from this chapter — each with the answer and a full solution.
A point mutation, specifically a single base substitution. The codon GAG changes to GUG at the 6th codon of the beta globin gene. It is not a frameshift because no base is added or deleted.
On which chromosome is the sickle cell gene located?
The beta globin gene (HBB) is on chromosome 11, which is an autosome. This is why sickle cell anaemia is called an autosome-linked recessive trait.
What is the difference between HbA and HbS?
HbA is the normal allele that makes normal haemoglobin. HbS is the mutant allele carrying the Glu-to-Val change. HbAHbA is normal, HbAHbS is a healthy-looking carrier, and HbSHbS is the diseased person.
Why do sickled cells cause anaemia?
The mutant HbS polymerises (clumps) under low oxygen, bending the red blood cell into a sickle shape. These cells break easily (rapid destruction) and get stuck in small vessels, so oxygen delivery drops and the person becomes anaemic.
Is sickle cell anaemia a Mendelian disorder?
Yes. It is caused by a change in a single gene and follows a clear pattern of inheritance (autosomal recessive), so it is a Mendelian disorder — unlike Down's syndrome, which is a chromosomal disorder caused by aneuploidy.
