Submitted by Few_Abrocoma1475 t3_11cehnu in askscience

My professor mentioned that the immunoglobulin genes can be on different chromosomes so I was just wondering if this ever results in the combining of chromosomes during somatic recombination.

Google doesn't seam to know the answer so hopefully a reddit expert can help.



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iayork t1_ja3b6ep wrote

This is a great question.

B and T lymphocytes are unique in vertebrates because they’re designed to physically chop out and re-link chunks of their chromosomes, as part of the development of antibodies and T cell receptors (V(D)J recombination in Wikipedia). A super simplified sketch

Original chromosome:


Rearranged chromosome:


This is driven by Recombination-activating genes, which look for specific DNA sequences (“A” and “B” in my ludicrously simplified sketch above), cut the chromosome at those signals, and re-attach the broken ends.

So far, so good. But evolution is stupid, and this process happens simultaneously on multiple chromosomes, because antibodies and TcR have multiple chains and those chains are encoded on different chromosomes.

So what’s supposed to happen is:

Antibody heavy chain, chromosome 1: —-A—————-B————— > —-A-B—————

Antibody light chain, chromosome 2: —-a—————-b————— > —-a-b—————

The question is, Why doesn’t RAG hop across the chromosomes and do this:

—-A—————-B————— \ —-A-b—————

—-a—————-b————— / —-a-B—————

Or some other weird combinations that would lead to splicing, chopping, and/or discarding chromosomes?

The answer is (1) RAG needs to see a particular chromosome loop structure that’s formed when the single chromosome is being spliced (Chromosomal Loop Domains Direct the Recombination of Antigen Receptor Genes, but (2) RAG fucks up all the time and that’s one reason lymphomas are such a common tumor (though chromosomal translocations are not the only reason for this).

> Memory B cells acquired, on average, 18 off-target mutations genome-wide for every on-target IGHV mutation during the germinal centre reaction. Structural variation was 16-fold higher in lymphocytes than in stem cells, with around 15% of deletions being attributable to off-target recombinase-activating gene activity

Diverse mutational landscapes in human lymphocytes

> Canonical chromosomal translocations juxtaposing antigen receptor genes and oncogenes are a hallmark of many lymphoid malignancies. These translocations frequently form through the joining of DNA ends from double-strand breaks (DSBs) generated by the recombinase activating gene (RAG)-1 and -2 proteins at lymphocyte antigen receptor loci and breakpoint targets near oncogenes.

Aberrantly resolved RAG-mediated DNA breaks in Atm-deficient lymphocytes target chromosomal breakpoints in cis

> inappropriate RAG activity throughout the genome has been implicated in a large variety of human and mouse lymphomas. Mechanisms by which RAG can provoke or perpetuate lymphoma include deregulation of certain genes by translocation to antigen receptor regulatory regions, the formation of chimeric oncogenes, inactivation of tumor suppressor or micro-RNA loci, or activation of oncogenes.

Recombination Activating Genes (RAG) in Lymphoma Development


Few_Abrocoma1475 OP t1_ja3rhzz wrote

This is an incredible response, I really appreciate it.


cstmoore t1_ja3ttlc wrote

I agree, but I take issue with the use of the word "designed."


iayork t1_ja3u6xi wrote

You’ll find that actual evolutionary biologists use “designed” all the time. If your main exposure to evolution is via media popularizers, you might avoid the word, but scientists are adult enough to understand its use.


cstmoore t1_ja3z77m wrote

Feynman might disagree. Just because the word is used conventionally doesn't mean it's accurate. Its continued use gives it an undeserved legitimacy that helps to perpetuate the inaccuracy.


d0uble_h3lix t1_ja2v8xo wrote

Yes. Any two simultaneous double-stranded breaks have the potential to be stitched together during repair, although translocation events are going to be much much less frequent than the correct recombination (and observed even less frequently than that due to spontaneous death or targeted removal of cells where this occurs). But it is not impossible for the cell to survive and even propagate after such an event.

Here’s a paper discussing the topic:


Bad_DNA t1_ja2vjse wrote

Are we talking homo sapien? Yes. The number of chromosomes and number of genes (or recombined genes) aren't directly related. By definition, a species will have the same number of chromosomes, 'though gametes obviously have one of a pair and somatic lines both pairs, with the exception of cells that dispense with the nucleus like RBCs and platelets.

If your prof is discussing transposons or miosis (as opposed to mitosis), you might want to ask them for clarification.


Bax_Cadarn t1_ja3pefu wrote

Annoying nitpick of the day: platelets aren't even cells like RBCs are (who actually have a nucleus during their griwth which they then discard), but parts of cytoplasm of a megacariocyte.


Bad_DNA t1_ja3yoi3 wrote

No annoying at all -- completely accurate. Platelets being the 'bits and pieces' part of the clotting :)