Medical genetics / edited by Victor A. McKusick and Robert Claiborne.

Date:
[1973]
Catalogue details

Licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

Credit: Medical genetics / edited by Victor A. McKusick and Robert Claiborne. Source: Wellcome Collection.

    202/328 (page 180)
    McDEVITT parently related genes in the chromo¬ some region have served to focus at¬ tention on the question: What is going on in the rest of the chromo¬ some region? A short distance to the right of the D locus, there is a gene designated as Tla (thymus leukocyte antigen), which controls a series of cell surface antigens expressed only on thymo¬ cytes. On the left side of the chromo¬ somal region there is another identi¬ fied gene unrelated to histocompatibil¬ ity; it codes for short tail (T). Per¬ haps most important in our context is the gene discovered by Shreffler that codes for the serum alpha globulin known as serum substance — the Ss gene. By a series of crosses between strains with low levels of serum sub¬ stance (Ss') and those with high lev¬ els (Ss''), it was found that the Ss gene sits on the chromosome virtually equidistant from the К and D loci. Practically, now, one has a three-point map of the H-2 region in the mouse, К to the left, D to the right, and Ss in the middle. Having such a clearly defined way to delineate the chromo¬ some region and its two halves has proved a great convenience in efforts to locate the various Ir genes. The reason that our knowledge of the H-2 region has been of such im¬ portance to the localization of Ir genes is, of course, the linkage between the two systems. This was discovered al¬ most by accident. It will be recalled that in order to obtain direct evidence for the relationship between Ir genes and immunocompetent cells, we un¬ dertook cell transfer studies aimed at transferring responsiveness from re¬ sponder to nonresponder animals. To do this it was necessary to circumvent histocompatibility barriers.We looked for strains that would be difi'erent in response level to the test antigens but of the same H-2 type. (Some 25 H-2 types have been identified and these are designated H-2'', H-2'', etc.) In this way it was hoped that frustration of the experiments by graft-vs-host and host-vs-graft reactions could be avoided. Our original aim was to trans¬ fer tissues from C57 mice, which are H-2'' and responders, into с в a mice, which are H-2'' and nonresponders. These efforts were frustrated by histoincompatibility. Therefore, we searched for inbred strains that were genetically similar to C57 but 90 80 70 C3H 60 £ 50 40 30 20 10 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Days After First Injection Sham Thymectomized Total Antibody |-*-| Sham Thymectomized 7S Antibody The effects of thymectomy and sham thymectomy are recorded for nonresponder mice (above) and for responders (facing page). Thymectomy is combined with lethal irradi¬ ation to eliminate residual T cells. In effect, the nonresponder patterns are unaffected carried the H-2'' type of the с в л mice. Fortunately, such mice were readily available almost off the shelf because Snell and his students over a number of years had undertaken to produce a series of inbred strains that were genetically identical except for the chromosome carrying the H-2 complex of genes. Such lines of mice, which differ only for a single trans¬ plantation antigen and therefore re¬ ject tissue grafts, are called coisogenic resistant or congenie mice. We pur¬ chased several congenie lines in order to make the appropriate cell transfers. We tested them wdth (T,G)-A-L and its related antigens simply to make sure that their response was consistent vidth their major genetic background. We were very much sur¬ prised to find that the responses of every congenie line tested correlated identically with those of the donor of its H-2 chromosome, without relation¬ ship to the rest of its genetic back¬ ground. This suggested linkage be¬ tween H-2 and Ir was confirmed by subsequent linkage studies. Establishing the linkage between the Ir and H-2 was a piece of extreme good luck. Out of a vast number of possibilities. Ir was linked with an extremely well-studied chromosome region. We instantly became heirs to more than a half century of knowl¬ edge acquired by the geneticists who had been studying the inheritance of histocompatibility. The Ir—H-2 link¬ age has greatly facilitated not only the identification of some 30 specific Ir genes but also precise mapping of many of them on the chromosome. Such mapping can be done by us¬ ing animals carrying recombinant chromosomes. It will be recalled that the H-2 region has a К locus at one end and a D locus at the other, that the H-2 type is determined by genes associated with each of these loci, and finally that there is a predictable rate of crossing over in which animals will obtain the К locus from one H-2 chromosome and the D locus from another. If animals homozygous for such recombinant chromosomes are used for immunization with (T,G)- A-L, it becomes possible to deter¬ mine whether the Ir gene under study is associated with the К or with the D side of H-2. By using other known points on the chromosome, such as T 180