An Sci 362 1st Edition Lecture 23Outline of Last Lecture I. ReadingII. Whole Genome Association StudyIII. Linkage Disequilibrium AnalysisIV. WTCCCa. Objectivesb. Populationc. Control Groupsd. Crohn’s DiseaseV. LessonsOutline of Current Lecture I. What are structural variantsII. Significance of structural variants vs. other polymorphismsIII. How are structural variants detectedIV. How do structural variants cause aberrant phenotypesCurrent LectureWhat are Structural Variants?- What is the cause of structural variation?o Structural features of the genome such as sequence motif and arrangement may predispose- Three mechanisms proposed:o Non-allelic homologous recombination (NAHR)o Non-homologous end-joining (NHEJ)o Fork Stalling and Template Switching (FoSTeS)- Non-allelic homologous recombination (NAHR)o Causes recurrent genomic rearrangements (ie. many rearrangements in similar location when comparing across individuals)o Occurs between two low copy repeats (LCRs; also called segmental duplications)o LCRs are blocks of DNA from ~10,000 – 400,000 bp with >96% sequence similarity (with segments within of 300-500 bp having 100% similarity)o Length related to proximity Closer proximity => smaller block- LCRs can mis-align during meiosis or mitosisThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.o If LCRs are on same chromosome and in same orientation, duplication or deletion resultso If LCRs are on same chromosome and in different orientation, inversion resultso LCRs are on different chromosomes, translocations can result- Non-homologous end-joining (NHEJ)o NHEJ is a mechanism for repair of double strand breaks in DNA 1. Detection of DSB 2. Molecular bridging of broken DNA ends 3. Modification of the ends to make them compatible and ligatable 4. The final ligation- Fork Stalling and Template Switching (FoSTeS) mechanismo Occurs during DNA replicationSignificance of Structural Variants- Structural variants ≥50 bp in size affect ~0.5% of the genome in an individual on average- Number of bases altered by structural variation in an individual exceeds that due to SNPsHow Are Structural Variants Detected?- Array hybridization- Quantitative analysis of high density SNP data- Optical mapping- Next-gen sequencingNext-gen Sequencing- Typical next generation sequencingo Tens of millions of readso Read lengths are short (100-150 bp)o Sequence data is accurateo https://www.youtube.com/watch?v=77r5p8IBwJko https://www.youtube.com/watch?v=womKfikWlxM- Single molecule sequencingo Tens of thousands of readso Read lengths are long (~8,000 bp)o Sequence data is less accurateo
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