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:

—-A—————-B—————

Rearranged chromosome:

—-A-B—————

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