* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Immunogenetics 1
Extrachromosomal DNA wikipedia , lookup
Genetic testing wikipedia , lookup
Protein moonlighting wikipedia , lookup
Genomic imprinting wikipedia , lookup
Gene desert wikipedia , lookup
Transposable element wikipedia , lookup
Population genetics wikipedia , lookup
History of RNA biology wikipedia , lookup
Human genome wikipedia , lookup
Genetic code wikipedia , lookup
Minimal genome wikipedia , lookup
Nutriepigenomics wikipedia , lookup
Gene expression programming wikipedia , lookup
Public health genomics wikipedia , lookup
Human genetic variation wikipedia , lookup
Point mutation wikipedia , lookup
Deoxyribozyme wikipedia , lookup
Gene expression profiling wikipedia , lookup
Polycomb Group Proteins and Cancer wikipedia , lookup
Genome evolution wikipedia , lookup
Non-coding DNA wikipedia , lookup
Nucleic acid analogue wikipedia , lookup
Epigenetics of human development wikipedia , lookup
Genome editing wikipedia , lookup
Biology and consumer behaviour wikipedia , lookup
Vectors in gene therapy wikipedia , lookup
Primary transcript wikipedia , lookup
Helitron (biology) wikipedia , lookup
Therapeutic gene modulation wikipedia , lookup
Genetic engineering wikipedia , lookup
Designer baby wikipedia , lookup
Genome (book) wikipedia , lookup
Cre-Lox recombination wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
Microevolution wikipedia , lookup
PART I • Immnoglobulins are proteins • Proteins are specified by genes • There are too few genes to specify all the antibodies. – i. e., ~32,000 genes < 10,000,000,000 Ab’s • How is Ig diversity specified genetically? Ig proteins are specified by genetic “cassettes” • Light chains are specified by “variable” (V), “joining (J), and “constant” (C) gene segments (aka “cassettes”). DNA rearrangement alternative RNA spicing and Ig proteins are specified by genetic “cassettes” • Heavy chains are specified by “variable” (V), “diversity” (D), “joining (J), and “constant” (C) gene segments (aka “cassettes”). DNA rearrangement alternative RNA splicing and Another view…. PART II • Cassettes rearrange… • How does this happen? • How do you get one “V” fusing to one “J” (in a light chain)? • In a heavy chain, a “D” fuses with a “J”; then the fused DJ cassette fuses with a “V” cassette… • The orderliness of this process implies that there are genetic instructions. What are they? Cassettes rearrange… • The heptamer is a palindrome – (i.e., it exhibits two-fold rotational symmetry.) • The nonamer is AT-rich – “Turns” refer to the DNA helix… Cassettes rearrange… One turn – two turn rule… • one turn and two turn are “recombination signal sequences” • one turn only reacts with a two turn • Recombination signal sequences are the substrates of enzymes RAG-1 and RAG-2 (“RAG” = recombination-activating gene) So… cassettes are marked by RSS (i.e., they are substrates for recombination.) Thus, cassettes can be fused. What is the consequence? Look at mouse: A mouse has: 134 VH, 13 DH, 4 JH segments 85 V6, 4 J6 segments and 2 V8, 3 J8 segments Thus, a mouse has: 134 C 13 C 4 = 6968 heavy chains 85 C 4 = 340 kappa chain and 2C 3= 6 lambda chains PART III (the HARD part…) 2.4 C 106 < 1010 So, there must be additional mechanisms of diversity other than “fusing” “cassettes” How does a RAG enzyme work? Junctional flexibility The “hairpin loop” Junctional flexibility, “P” nucleotides, and “N” nucleotides are added to CDR3 Somatic hypermutation One turn – two turn rule… • one turn only reacts with a two turn • crossover between direct repeats (same transcriptional orientation) leads to deletion • crossover between indirect repeats leads to inversion PART IV • How do immunoglobulins assemble? • Some immunoglobulins are in the surface membrane of immature B-cells while other immunoglobulins of the same idiotype are secreted by mature B-cells. What’s the difference? • Similarly, identical variable regions can be shared among different isotypes. How? • B-cells are diploids with two sets of genetic instructions. How does just one set get expressed?