International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

A3. A 945 kb Sequence Analysis of the Distal End of Mouse Major Histocompatibility Complex (Mhc) and Comparison to HLA

Toyoyuki Takada, Attila Kumánovics1, Claire Amadou, Elsy P. Jones1, Masayasu Yoshino, Maria Athanasiou2, Glen A. Evans2, Kirsten Fischer Lindahl
Howard Hughes Medical Institute, 1Center for Immunology, and 2McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050

The distal half of the mouse Mhc on Chr 17, from H2-D to H2-M2 (D17Mit24), contains about 100 genes, including more than 60 Mhc class I genes, which are traditionally grouped into the H2-Q, -T, and -M regions. We have built a BAC contig and determined the genomic sequence of nine overlapping clones that span 945,130 bp from the H2-M region of strain 129/Sv (H2bc). The comparison with the orthologous region of the human Mhc shows that most of the non-class I genes are conserved while the class I genes are paralogous. This difference is believed to be due to species-specific expansion of class I sequences within a framework of conserved genes.

Gene content: class I expansions vs framework

A mouse-specific class I expansion spans 600 kb between a newly identified zinc finger gene (Zfp), which separates H2-T from H2-M, and Zfp173. It contains 17 H2-M class Ib genes or pseudogenes falling into two subfamilies by sequence similarity: the "M1 family" with nine members surrounded by the "M10 family" with eight members. The corresponding human region contains only one class I gene fragment, HLA-92.

A framework zone of conserved genes includes six zinc finger genes (Zfp173, the hematopoietic differentiation factor gene: Herf1, and four new and potentially expressed genes) and the testis-expressed Tctex4, -5 and -6 genes.

The second class I expansion telomeric to Tctex4 is 30 kb wide and contains the three class I genes H2-M4, -M5, and -M6. The corresponding class I region in man has expanded to 380 kb, and includes the three class I genes HLA-A, -G and -F surrounded by ten pseudogenes and gene fragments.

The most telomeric 80-kb region in our contig is also conserved between man and mouse. This region includes Zfp57 (a Krüppel-like zinc-finger gene), the myelin-oligodendrocyte glycoprotein gene (Mog), and the beta-receptor for gamma-amino-butyric acid (Gababr1).

In the analysed region, all the non-class I genes are conserved between man and mouse. However, a detailed sequence comparison revealed unexpected differences in some of the zinc finger genes, leading to species-specific loss of individual domains in the predicted proteins.

Genomic environment

The first class I expansion has a low (42%) G+C content combined with a high (30%) L1 repeat content. The region telomeric to Zfp173 has an average of one gene every 15 kb, a higher (45%) G+C content combined with a high (16%) percentage of SINE repeats in contrast to the "low G+C-high L1" region centromeric to Zfp173.

Sequencing of the proximal part of the mouse Mhc class I region is in progress. Preliminary data show that the H2-Q and H2-T class I gene expansions are not correlated with the composition of genome wide repeats (LINE, SINE, etc.); their specific involvement in all class I duplications is therefore unlikely.

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