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From what I understand, an individual can hold up to two HLA-DRB345 alleles (but can be less) that can each be HLA-DRB3, HLA-DRB4 or HLA-DRB5.

However, since HLA-DQB1 and HLA-DQB2 are entirely different genes and we have two alleles for each of those two genes necessarily, I'm struggling to understand if HLA-DRB3/4/5 are three different genes or three different "version" of the same gene.

Similarly:

  • Are HLA-DRB3/4/5 located at the same place on the chromosome?
  • What about the people that have neither HLA-DRB3 nor HLA-DRB4 nor HLA-DRB5? Is there no genetic code at the place where other people have it?
  • Why is there only DRB3 on the "maps" of chromosomes like this one (http://www.biorigami.com/wp-content/uploads/2014/11/MHC1.png) and never the three of them (I wanted to know what "orders" they were in).

Finally, wikipedia states: DRB1 is expressed at a level five times higher than its paralogues DRB3, DRB4 and DRB5 but doesn't provide a source. Would someone know about a scientific article or an entry proving this?

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The reference to DRB3, DRB4, and DRB5 as paralogues of DRB1 indicates that these are different genes. However, as paralogues they share essentially the same structure, having presumably originated from a gene duplication at some point in the past.

From Wikipedia:

DRB1 is present in all individuals. Allelic variants of DRB1 are linked with either none or one of the genes DRB3, DRB4 and DRB5.

Particular alleles ("versions") of DRB1 are linked with one of the other DRB genes, or none of them. Linked genes are often located near each other on a chromosome, such that recombination rarely breaks the linkage between them. DRB1 and the other DRB genes are found on human chromosome 6 within several kilobases of each other. (Unfortunately, that link will only be valid for 90 days; a screenshot is below.)

Screenshot from the NCBI Genome Data Viewer, zoomed in on human chromosome 6 from about 3700–3820 kilobases on scaffold NT_167248.2. HLA-DRB3 is shown from about 3715–3729 kilobases and HLA-DRB1 is shown from about 3779–3792kilobases

So, for this region of chromosome 6, some alleles carry a particular version of DRB1 and a copy of one of the other paralogues, and other alleles for this region carry a different version of DRB1 without another paralogue. Since we all carry two copies of chromosome 6 we all carry two copies of DRB1, plus 0, 1, or 2 copies selected from the other paralogues.

Are HLA-DRB3/4/5 located at the same place on the chromosome?

They are located nearby DRB1, and each of them are "upstream" by about the same distance.

What about the people that have neither HLA-DRB3 nor HLA-DRB4 nor HLA-DRB5? Is there no genetic code at the place where other people have it?

Correct, they carry a deletion relative to chomosomes with one of the paralogues.

Why is there only DRB3 on the "maps" of chromosomes and never the three of them?

DRB3, DRB4, and DRB5 do not occur together on a chromosome. They are essentially different alleles, except they're alleles of a chromosomal region and not of just a gene.

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  • $\begingroup$ Thank you so much, I have two follow up questions though: 1/ about your link, why can we only see DRB3? Is it because the person which was sequenced only has DRB3? When I search for DRB4 I see the same (DRB4 and DRB1 but neither DRB3 nor DRB5) i.imgur.com/XoIRVjf.png? 2/ when you say "Correct, they carry a deletion relative to chomosomes with one of the paralogues.", does that mean that some people have literally thousands of nucleotides less than others? I thought the deletions were always very small like 1 or 2 nucleotides, but I guess I was mistaken. $\endgroup$ Aug 4, 2023 at 9:46
  • $\begingroup$ Also, the "3800K", etc .. of HLA-DRB1 don't map between my screenshot and yours, is this because alleles are not always at the same "place" depending on the individual sequenced? $\endgroup$ Aug 4, 2023 at 9:48
  • $\begingroup$ You can only see DRB3 because the chromosome shown (NT_167248.2) only carries DRB1 and DRB3, the one you show (NM_021983.5) only carries DRB1 and DRB4. As far as I can tell DRB3/4/5 don't occur together on the same chromosome, they just happen to be in the roughly the same place relative to DRB1. My hypothesis is that something like DRB1 existed prior to the other DRBs, but at one point got duplicated so there were two DRB1s adjacent to each other. This pair persisted in the population and the new DRB eventually differentiated somewhat from DRB1 becoming, say, DRB3. $\endgroup$ Aug 4, 2023 at 15:17
  • $\begingroup$ [hypothesis continued] At a later time or in another part of the population a similar duplication occurred, but now the new DRB differentiated in a different way to become maybe DRB4. Since the new DRB3 and DRB4 appeared independently, they're not together on a chromosome. For that to happen there would first need to be someone carrying both DRB3 and DRB4, and then recombination would have to occur in just the right way for their offspring to get a chromosome with DRB1, DRB3, and DRB4. $\endgroup$ Aug 4, 2023 at 15:24
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    $\begingroup$ Yes, or at least a large chunk of a chromosome. $\endgroup$ Aug 8, 2023 at 18:05

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