How many IGH genes are there? Confused about nomenclature.

Question

[simplitia]

Hi, I'm very confused about the IGH gene. So on NCBI it looks to be a single IGH@ gene or locus. however

the region seems to cover many other IGH genes IGHD1, G1, exc... this is how it looks like, browser

Why I'm interested is because of gene fusions where the 3' gene is written as IGH. However, this is ambiguous because this region seems to cover many variants. My questions are the following.

1. is IGH a single gene or locus containing many small variants. Or if this a gene that gets post prossessed post joining different segments? 1b. do these IGH "variant" contain exons/intron boundaries.
2. On the CCDS website I cannot seem to be be able to locate any IGH genes at all. What I want is to have the coordinates and sequences for each variant.
3. Is there a place I can get the the sequences for each segment and coordinate, best if I can find it on CCDS.

thanks in advance.

Answer 1

[Jeremy]

1.The IGH locus contains many V, D, and J gene segments, as well as constant region genes. The exact number of V, D, and J genes will depend on the species. For example, cows have 12 V, 16 D, and 4 J regions at the IGH locus. Canonical antibodies are composed of two heavy chains (HC) and two light chains (LC). B cells make antibodies. During B cell development, a V, a D, and a J gene combine to form the variable region of the HC. The variable region is joined to a constant region to make a full length HC. See the Wikipedia link below for a description of V(D)J recombination:

V(D)J recombination

1b. Yes, there are introns and exons in IGH.

2 and 3. You can find sequences and coordinates of IGH genes for human, mouse, pig, teleostei, chondrichthyes, camel, llama, alpaca, caiman, sheep, frog, rat, nonhuman primates, rabbit, platypus, bovine, chicken, dog, Atlantic salmon, rainbow trout, horse, and ring-tailed lemur in the IMGT gene tables:

IMGT Repertoires

Note: antibodies also contain signal sequences (called L-part on IMGT) that direct the antibody to be displayed on the plasma membrane.

[simplitia]

thanks. I'm still a bit confused -- please let me know if I'm understanding this correctly.

The IGH locus contains many V, D, and J gene segments, as well as constant region genes

1. so each "gene segment" is a gene? If so why not just call it gene, why a segment? I keep seeing this word and this is one of my confusion.

2. I went to the url you sent IMGT, I'm interested in humans, https://www.imgt.org/IMGTrepertoire/index.php?section=LocusGenes&repertoire=GeneOrder&species=human&group=IGH so based on this table it looks like there are at least. 214 - 217 IGH genes? Am I reading this correctly?

3. Also can help me decipher this? What does it mean when a gene is label as IGHV3-66 vs IGHV3-65?

I couldn't find the sequences on IMGT but luckily it looks like biomart enesembl has the sequences.

[Jeremy]

You're welcome!

1.I think they call them segments because they are spliced together to form a whole antibody. You're right: each one is a gene. At the same time, V, D, J, and constant region genes form the segments of an entire antibody.

2.Only functional genes are used to make antibodies. If you look in the "Fct" column on IMGT, you will see that genes are annotated as either F, P, or ORF. F means functional, which are the genes that are used to make antibodies. P stands for pseudogenes, which are not used. ORF stands for open reading frame; however the genes marked ORF in IMGT are non-functional, despite having an open reading frame. So for counting genes, you will most likely be interested in those that have a unique "IMGT gene name" and are labeled F in the "Fct" column. By my count, this means 57 IGHV, 23 IGHD, and 6 IGHJ genes for humans. And then there are also the HC constant region genes (IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM), which can be found under IGHC on IMGT.

3.IGHV3-66 and IGHV3-65 are two VH genes in the IGHV3 family. This means that they have similar amino acid sequences. You might have also noticed that there are different alleles in the "IMGT allele name" column (e.g. IGHV1-2[star]01, IGHV1-2[star]02, etc.). These refer to different nucleotide sequences that have been observed for the same amino acid sequence.

You can find all sequences by clicking on the link in the "Accession numbers" column.

[simplitia]

this is great thank you so much - this is very comprehensive.

1. I don't see the fct column or acccession you are talking about for humans in the link I had above. Can you send me the direct link to this table?

2. And then there are also the HC constant region genes (IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM), which can be found under IGHC

   can you elaborate on this. What does it mean by constant vs the other IGH genes? thanks again. A

[Jeremy]

1.In the IMGT link I gave above, you'll want to scroll down to #7 (Gene tables), and then click on human under IGHV, IGHD, IGHJ, or IGHC. Then you should see everything that I mentioned.

2.The variable region of an antibody (which is made up of V, D, and J genes) can be very different between different antibodies. For example, an antibody that binds Covid-19 could have a totally different variable region compared to an antibody that binds a bacterium. For humans, 57 X 23 X 6 = 7866 possible HC combinations. However, diversity in the variable region is actually much greater due to somatic hypermutation, as well as insertions and deletions. On the other hand, human antibodies have only 9 different constant region genes, which I listed in my previous comment. These sequences don't change between antibodies. IgM is the same regardless of the variable region sequence and what the antibody binds to. Rather than binding to antigen, the constant regions direct a function to occur. IgA, IgD, IgE, IgG, and IgM are termed the five antibody isotypes. Here is a link giving a little background on each isotype:

Antibody Isotypes

[simplitia]

this is really awesome and I learned a lot from your comments. Thank you for your time.