gene diversity MHC

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Victor Barac

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Immunoglobulin Gene Diversity MHC vs Ig / T-cell receptor diversity – MHC diversity is in the population  lots in pop’l, individual only expresses 6  Determined by co-dominant expression of alleles – TCR / Ig diversity is in each individual  somatic recombination  Produced by recombination in each T or B cell o Each T cell leaving thymus has a different binding capability o Recombination is not in germline cells 13  Produces a repertoire of 10 antibody specificities Immunoglobulin gene organization – Gene segments encoding variable and constant regions are separate  C  codes for constant domain of heavy chain  Variable (V) segments are upstream – each Ig domain is 100 aas given by seq’s 300 bp long o Human ≈ 40 diff domains for Igκ ... 30 for Ig ... 40 for IgH – Each V domain is preceded by a leader sequence  Codes short hydrophobic segment if it is to be presented on cell surface  Not transcribed if Ig is to be secreted – Separated by introns (:) of up to 2000 bps – V domains differ in sequence, but this doesn’t really have to do w/ fxn (evolutionary origin)  Come in families at least 80% similar (they just kind of look like each other) J and D segments  help generate specificities – V segments alone are too few to create 10 specifications – In the introns between V and C are joining (J) segments  30-50 bp long  Igκ 5, Ig 4  1 for each C domain – Heavy chain also has diversity (D) segments between V and J  IgH 6 J and 25 D  D segments code for carboxyl terminus of V domain incl. CDR3  allows for 2º structure o CDR3 is a 10 aa long binding site  makes most variable part  Can mess w/ this the most b/c you can Δ nucs at ends  diff proteins How does recombination occur? – Controlled by products of 2 recombinase activating genes  RAG-1 + RAG-2  Recognize recombination signal seq’s (RSS) w/in intron o Brings domains together and makes sure you’re following joining rules o RSSs are highly conserved  Ensures that V, D, and J are joined in the right place and in the right order o Can only join like  V to D to J – 2 variants of RSS  1, and 1 w/ 12 random nucs  RSS w/ 23 random nucs in btwn  corresponds to 2 turns of DNA  RSS w/ 12 random nucs in btwn  corresponds to 1 turn of DNA o  when lining up DNA, nonamer + heptomer will still be on same side of molecule o  can chop up DNA and put it back together w/out ruining structure Rules of recombination – Recombination only occurs between segments on the same chromosome – A 12 bp RSS must combine with a 23 bp RSS .. usually – Can only join a V ↔ J ( or κ chain) or V ↔ D ↔ J Modes of recombination – Looping out: DNA btwn segments to be joined loops out  Brings 2 RSSs close together  Loop is removed + degraded
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