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Testis-organizing H-Y antigen as a discrete protein; Its MHC restricted immune recognition and the genomic environment in which H-Y gene operates

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Summary

Human H-Y antigen in solution demonstrates the high affinity, low capacity binding affinity to its specific receptor exclusively residing on the plasma membrane of gonadal somatic elements, and this interaction induced precocious testicular differentiation in XX embryonic indifferent gonads. This H-Y polypeptide is hydrophobic and made of 160 or so amino acid residues to which no more than 5 glucosamine residues are attached. Surprising similarities to interferons are noted with interest.

The male determing part of the mouse Y chromosome DNA was recently identified by Singh et al. (in press) on sex reversed XX,Sxr/-male mice. We found this part to contain a 30 KBP long stretch in which neither a single Hae III restriction site GGCC nor a single Alu I restriction site AGCT resides. By contrast, the coding sequence for H-Y antigen should contain one ot two Hae III sites and three or four Alu I sites per 0.5 KBP. Thus, the Y-linked male determining gene is believed to represent a regulatory element rather than the H-Y antigen structural gene.

We are thus forced to consider genetic regulatory mechanisms as they operate in mammals. In this respect, it is of utmost importance to realize the oft neglected peculiarity of the mammalian genome in which genes (coding sequences) are out-numbered nearly 50-to-1 by senseless junk or selfish DNA sequences. Even in the euchromatic region of chromosomes, the average distance between neighboring genes was estimated as 35 KBP. Being junk, these long stretches of intergenic spacers can not rely upon natural selection to eliminate deleterious consequences of randomly drifting mutational base changes; i.e., inadvertent generation of RNA polymerase II promotor sites as well as nonsense coding sequences in the midst of spacers. Intergenic spacers avoid these deleterious consequences by apparently starting as repeats of a specific short base sequence, such as the primordial sequence of 20 BP: (AGCTG) (AGCTG) (AGCTG) (GGGTG). Thus, repeated sequences within intergenic spacers do not appear to be concerned with regulation of genes downstream. On the other hand, the primordial sequence above is particularly vulnerable to frequent and inadvertent generation of the RNA polymerase III promotor sequence AGCAGGGT. Consequently, short RNAs are often transcribed from intergenic spacers. The regulatory significance of such short RNA is also doubtful.

Evolutionary reasons as to why the immune system chooses to recognize not H-Y antigen per se but (H-Y + altered self MHC) antigen complexes are also discussed. Mistaken identification of certain other antigens as H-Y is inherent in this associative recognition.

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  1. Division of Biology, City of Hope Research Institute, 91010, Duarte, CA, USA

    Susumu Ohno, Jörg T. Epplen & Shizuyo Sutou

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  1. Susumu Ohno
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Ohno, S., Epplen, J.T. & Sutou, S. Testis-organizing H-Y antigen as a discrete protein; Its MHC restricted immune recognition and the genomic environment in which H-Y gene operates. Hum Genet 58, 37–45 (1981). https://doi.org/10.1007/BF00284147

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