Chromosome Rearrangements

Chromosome Rearrangements

• Professor: Ina Anreiter

• Date: October 22, 2024

Lecture Overview

• Topics Covered:

  • Chromosome Rearrangements

  • Somatic Recombination

    • V(D)J recombination in the adaptive immune system

  • Cancer

  • Learning, memory, and Alzheimer Disease

• Textbook Chapters:

  • Chapter 14

  • Chapter 5.6 and 14.1

Types of Mutations

• Categories:

  • Mutations

    • Substitutions

    • Deletions

    • Insertions

    • Chromosomal rearrangements

Types of Chromosomal Rearrangements

• Main Types:

  • Rearrangements

    • Deletions

    • Inversions

    • Reciprocal and translocations

    • Insertions

• Occurrence:

  • Rearrangements can happen on one chromosome or between two chromosomes.

Mechanisms of Chromosomal Rearrangements

• Causes:

  • Double stranded breaks followed by non-homologous end joining

  • Illegitimate crossing over

Deletions

• Definition:

  • Loss of a segment of a chromosome

Phenotypic and Genetic Effects of Deletions

• Homozygosity:

  • Often lethal or harmful depending on size and affected genes

• Deletion Heterozygotes:

  • Possible mutant phenotype due to gene dosage effects (i.e., haploinsufficiency)

  • Increased risk of phenotype due to recessive mutant alleles

• Example:

  • Greig Syndrome

Using Deletions in Gene Location

• Method:

  • Examine the phenotype of a heterozygote for a recessive allele and deletion.

  • If the phenotype is mutant, the mutant gene lies inside the deleted region; if wild-type, it lies outside.

Gene Mapping with Deletions

• Example:

  • Demonstrated in Drosophila melanogaster using various deletion genotypes to identify a gene’s location.

Duplications

• Definition:

  • Duplication of a segment of the chromosome

Types of Duplications

• Categories:

  • Tandem Duplications:

    • Duplicated segments are adjacent and in the same order

  • Nontandem Duplications:

    • Requires more DNA breaks, dispersed duplicates.

Phenotypic and Genetic Effects of Duplications

• Triplosensitivity:

  • Too many copies can be harmful like too few.

• Examples:

  • Trisomy conditions (e.g., Down syndrome, Edwards syndrome)

  • MECP2 duplication syndrome and Potocki-Lupski syndrome.

Inversions

• Definition:

  • A segment of DNA is flipped 180° in orientation

Types of Inversions

• Categories:

  • Pericentric Inversion:

    • Centromere is within the inverted segment

  • Paracentric Inversion:

    • Centromere is not within the inverted segment

Phenotypic and Genetic Effects of Inversions

• Breakpoints can disrupt genes, potentially leading to various health effects.

• Fertility Impact:

  • Inversions can reduce fertility due to unviable gametes.

Translocations

• Definition:

  • A segment of a chromosome is transferred to a nonhomologous chromosome.

Phenotypic and Genetic Effects of Translocations

• Breaks within genes can disrupt function, associated with several cancers.

• Examples:

  • Philadelphia chromosome, XX male syndrome.

Robertsonian Translocations

• Arise from breaks at or near centromeres of acrocentric chromosomes, potentially leading to Down syndrome.

Aberrant Crossing-Over

• Can cause all types of chromosomal rearrangement through repeated sequences or transposable elements (TEs).

Transposable Elements (TEs)

• Definition:

  • Segments of DNA that can move within a genome.

• Discovery:

  • Barbara McClintock's work on maize.

Types of TEs

• Categories:

  • Retrotransposons (LTR, non-LTR)

  • DNA transposons

Mechanisms of TE Movement

• Includes transcription, reverse transcription, and integration into target genomic DNA.

Impact of TEs

• TEs can disrupt gene function, altering phenotypes and contributing to chromosomal rearrangements.

Genetic Variation from Rearrangements

• Chromosome rearrangements can lead to new gene expression patterns and gene fusion.

Chromosomal Change and Speciation

• Significant role of chromosome rearrangements in the evolution and adaptation of species.

Somatic Recombination

• Can occur outside of meiotic processes, linked to DNA repair and tumorigenesis.

V(D)J Recombination

• Essential for generating antibody diversity in adaptive immunity.

• Starts with recombination activating genes (RAG) which introduce breaks in DNA.

Alzheimer Disease Connection

• Research indicates somatic recombination may contribute to genomic variants associated with Alzheimer's Disease.

Review and Practice

• Recommended exercises from Chapter 14 to solidify understanding.