Related Experiment Video
Updated: Jul 12, 2026
09:35
Analysis of Somatic Hypermutation in the JH4 intron of Germinal Center B cells from Mouse Peyer's Patches
Published on: April 20, 2021
Strand-biased spreading of mutations during somatic hypermutation
Shyam Unniraman1, David G Schatz
1Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511, USA.
Science (New York, N.Y.)
|September 1, 2007
Summary
Somatic hypermutation (SHM) diversity in antibody genes is initiated by activation-induced deaminase (AID) deaminating cytosines. Mismatch repair machinery targets top-strand uracils, promoting SHM during the antibody response.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Somatic hypermutation (SHM) generates antibody gene diversity.
- Activation-induced deaminase (AID) initiates SHM by deaminating DNA cytosines to uracils.
- The mechanisms linking initial deamination to broader mutations are unclear.
Purpose of the Study:
- To investigate the role of DNA strand asymmetry in AID targeting and mutation outcomes.
- To elucidate the contribution of mismatch repair (MMR) to strand-biased SHM.
Main Methods:
- Utilizing mouse models with and without mismatch repair deficiency.
- Assessing the impact of AID-induced uracils on the top (nontemplate) versus bottom (template) DNA strands.
- Analyzing mutation patterns at A/T residues flanking uracil sites.
Main Results:
- A single uracil on the top DNA strand recruits AID and induces mutations at adjacent A/T residues.
- Uracils on the bottom DNA strand result in minimal mutations.
- This strand asymmetry is abolished in MMR-deficient mice, indicating MMR's role in processing top-strand uracils.
Conclusions:
- The DNA strand influences AID recruitment and subsequent mutation generation during SHM.
- Mismatch repair preferentially targets top-strand uracils, driving mutation accumulation in antibody genes.
- Understanding strand bias in SHM provides insights into immune system diversification and potential errors.
Related Concept Videos
01:20Mismatch Repair
Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
01:36Mismatch Repair
Overview
01:30Spontaneous and Induced Mutations
Spontaneous mutations arise infrequently during DNA replication due to errors in the process. A key factor behind these errors is tautomeric shifts in nitrogenous bases, where bases transition from keto to enol forms or amino to imino forms. This shift can alter base-pairing rules, leading to mutations. Additionally, reactive oxygen species (ROS) arising from aerobic metabolism can damage DNA, resulting in depurination (loss of a purine base) or depyrimidination (loss of a pyrimidine base).
02:53Conservative Site-specific Recombination and Phase Variation
Because the DNA segments are cut and reorganized in a direction-specific manner, site-specific recombination has emerged as an efficient genetic engineering technique. Flippase and Cyclization recombinases or Flp and Cre, respectively, are two members of the tyrosine recombinase family derived from bacteriophages, that are used to mediate site-specific DNA insertions, deletions, and targeted expression of proteins in mammalian cell lines.
The recognition sites for Cre recombinase called LoxP...
The recognition sites for Cre recombinase called LoxP...
02:21Cancers Originate from Somatic Mutations in a Single Cell
Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...
02:21Cancers Originate from Somatic Mutations in a Single Cell
Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...