5.

Genetic Recombination

 DNA RECOMBINATION
o exchange of genetic material
o multiple chromosomes
o between different regions of the same chromosome
 HOMOLOGOUS REGIONS
o line up in preparation for exchange
o nonhomologous recombination do exist
 DIPLOID EUKARYOTIC ORGANISMS
o exchange of genetic information between newly duplicated chromosomes
 ROLE OF RECOMBINATION
o first demonstrated through experiments with maize.
 Discovered the evidence for recombination of physically tracking of unusual
knob structure.
 Barbara McClintock
 Harriet Creighton
 Alleles physically linked to knobbed chromosome.
 other alleles were tied to the normal chromosome
 THOSE FOLLOWED THESE ALLELES THROUGH MEIOSIS
o McClintock
o Creighton
 Recombination
o occurs in prokaryotic cells, a
o especially well characterized in E. coli.
o DNA repair
o replication in prokaryotic organisms.
 bacteria
o do not undergo meiosis
 conjugation
o Type of sexual reproduction

Models of Recombination

 GENETIC RECOMBINATION
o highly complex process
o involves the alignment of two homologous DNA 
o precise breakage of each strand
o exchange between the strands
o sealing of the resulting recombined molecules.
 Holliday junction 
o crosses over and invades the other chromosome
  branch migration
o junction travels down the DNA

Recombination Enzymes

 E. coli 
o genes that code for these enzymes
 recA gene 
o encodes a protein 
 three polypeptides form protein complex
o recB
o recC
o recD
 two other genes
o ruvA
o ruvB
 ligase and DNA polymerase
o contribute to recombination
 Rad genes
o sensitive to radiation
o eukaryotic recombination
 Rad51 gene
o homologous to recA
o encodes protein
o highly conserved
 , single-stranded DNA (ssDNA)
o coated with the protein RPA
 replication protein A
o higher affinity for ssDNA than Rad51
 tumor suppressor genes
o BRCA1 
o BRCA2 
 regulating recombination
 Risk for individuals that are heterozygous for BRCA2
o breast and ovarian cancer
o Fanconi's anemia
o a genetic disease  predisposition to cancer,
o other defects.

6. Human Chromosome Translocations and Cancer

 Translocations
o generate novel chromosomes
o place genes in new linkage relationships
o occurred during the course of evolution.
o associated with negative consequences
 aneuploidy
 infertility
 cancer
Translocations Generate Novel Chromosomes

 Translocations
o first detected cytologically
o common in cancer cells
o produce oncogenes
o require double-strand breaks in DNA
 novel chromosomes
o appeared prominently in tumor cells
 Tumor Cells
o "growth-stimulatory chromosomes"
o role in malignancy

Karyotypes Are Used to Classify Translocations

 Translocations
o human chromosomes
o great clinical interest
o linked to a number of disorders
o cytogeneticist examines a karyotype
o change in the length
o banding pattern of a chromosome arm
 Different Disorders
o mental retardation
o infertility
o cancer
 Nonreciprocal translocations
o one-way translocations
o chromosomal segment is transferred
 .Reciprocal translocations
o exchange of segments from two nonhomologous chromosomes
o balanced translocation
 Robertsonian translocations
o acrocentric chromosomes become joined
o Chromosome p arms are lost during Robertsonian translocations
 Familial Down syndrome 
o less common than the form in which patients have 47 chromosomes
o 46 chromosomes
o two normal copies of chromosome 21
o Robertsonian translocation with chromosome 21 material
o inherit the translocation chromosome

Investigators Use Multi-Color FISH to Scan for Translocations

 multi-color fluorescence in situ hybridization (FISH)

o spectral karyotyping
o screen patient samples
o provides a sensitive genome-wide overview
o cancer diagnoses
o hybridized with a mixture of fluorescent DNA probes
o reveal small translocations
Translocation Carriers Face Reproductive Issues

 Balanced translocations
o undetected in individuals
o total amount of genetic material has not been changed
 prophase I
o cross-like structure forms
o allow synapsis 
o crossing over
 anaphase I
o chromosomes can segregate
 gametes
o aneuploidy
o excess of some genes
 alternate segregation 
o euploid gametes
o outnumber euploid gametes

Translocations Can Produce Oncogenes

 translocation
o disruption or misregulation
 molecular rearrangements,
o various cancers
 Clinically Defined Cancers
o Leukemias
o Lymphomas
o Sarcomas
 Burkitt's lymphoma
o chromosomes 8 and 14 in patients
 MYC proto-oncogene
o chromosome 8 under the control of the powerful immunoglobin
o normally signals for cell proliferation
 immunoglobin heavy chain gene
o promoter on chromosome 14
o promoter is normally active.
 chronic myelogenous leukemia (CML).
o initially identified as a minute
o unusually small, chromosome
 BCR (breakpoint cluster region)
o chromosome 22
o coding sequence of the ABL gene on chromosome 9.
 BCR-ABL fusion protein 
o encoded by the chimeric gene
 chimeric gene
o protein tyrosine kinase
o