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Lecture 13

Lecture 13 - Chromosomal Rearrangements

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Biology 2581B
Jim Karagiannis

LECTURE 12: CHROMOSOMAL REARRANGEMENTS Key Concepts 1. Chromosome rearrangements Paradox? • Mouse versus human genome o At the sequence level – many similarities o Same type of genes o Genes with similar sequences • However, when comparing chromosomes o Comparison of staining patterns of chromosomes suggested no conservation o 20 mouse versus 23 human chromosomes • After both genomes were sequenced, each mouse chromosome could be “pieced” together from different human chromosomes • These are called syntenic segments – identity of genes, order of genes, orientation of transcription o Almost the same • When comparing both genomes as a whole o “Break” the mouse genome in 100s of fragments – but they can be aligned with the human genome! o Package size and package content are different, but the overall genome i  the same Unique toAnimals? • All of the different genomes can be aligned with the sequence from rice, for example, but again, the packaging and contents are different • Collinearity – can align all the different genomes, have the same information (just not in the same order) Are Rearrangements always Deleterious? • No, often they are not • Generation of antibodies – based on rearrangements of genomic information • How are 10 different antibodies encoded by only 2-3 x 10 genes? • How is the immune system able to respond to new challenges? • Chromosome 14 and B cell development • Chromosome 14 has different segments (V-segments, D-segments, J- segments) • Recombination aligns these segments close together – this is what increases the number of different antibodies that our bodies can generate • Rearrangements of chromosomes are part of a normal event, as seen here Lack of Diversity • If there is a lack of diversity in making antibodies, it can lead to a shift in the formation of T and B cell clones • Often observed in lymphomas • If recombination is not able to occur, you are disturbing the production of antibodies Deletions • Loss of sequences • Small deletions – affect a single gene • Large deletions – leads to the loss of 10s or 100s of genes • Can be caused by X-ray or other chromosome damaging agents that break the DNA backbone • Typically deleterious, as you are missing genes • Detection of deletions o DNAbreakage may cause deletions – when a chromosome sustains two double-strand breaks, a deletion will result if the chromosomal fragments are not properly religated o One way to detect deletions is by PCR – two PCR primers shown will amplify a larger PCR product from wild-type DNAthan from DNAwith a deletion o Can also be detected through karyotyping  If deletion is large enough, it impedes on the bending pattern  Karyotyping can be used to detect large deletions – look for variations in appearance • Most homozygous deletions are lethal – large deletions result in the loss of several genes, and most of the time, some of these lost genes have important functions • Even most heterozygous deletions are lethal • But there are exceptions o Humans  Wolf–Hirschhorn syndrome • Deletion from the short arm of chromosome 4  Cri du chat syndrome • Deletion from the short arm of chromosome 5 o Typically lead to severe phenotypes o Humans cannot survive if more than 3% of their genome is deleted • Most deletions have an effect: gene dosage • Effect on recombination o No recombination can occur within the deletion loop o The genes in the loop cannot be separated o Deletion loops have an impact on how we calculate recombination distances, as genetic distance between loci on either side will be underestimated Using Deletions to Map Mutations • Famous example: polytene chromosomes in salivary glands of Drosophila o Giant chromosomes o 10 rounds of replication but no mitosis  Each chromosome consists of 2 = 1024 double helices o Extensively used for deletion mapping because you can see chromosomal processes very easily due to their size o Allows you to visualize where a particular deletion is taking place because bending patterns can be compared • White mutation (w), roughest mutation (rst), facet mutation (fa) o All 3 loci are in close proximity on X chromosome, all affect eye morphology o Chromosomes can be examined for deletions to see what is missing to determine mutation o By mapping deletions, you can see where they are in the chromosome and what they are by looking at bending patterns Duplications • Addition of sequences • Tandem – when additional sequences are right next to each other In tandem duplications, the repeated regions lie adjacent to each other in the same or in reverse order. In nontandem duplications, the two copies of the same region are separated. • How
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