Biozzi Mice

Gino Doria, Laboratory of Immunology, AMB-BIO-MED, ENEA, Rome, Italy

Biozzi mice are lines of mice genetically selected for high (H) or low (L) antibody responsiveness. From the initial study in 1968 by Biozzi and his group, five different selections, referred to as selections I, II, III, IV and V, were carried out by Biozzi and colleagues.

The character selected was the maximal or minimal antibody response at a given time after an optimal dose of the various antigens used in the different selections. The antibody response was measured by direct or passive agglutination. In every population the frequency of the log2 of the agglutinin titer (the highest doubling serum dilution giving a positive agglutination) was normally distributed.

Except for selection II, two non-cross-reactive antigens were alternated in consecutive generations in order to avoid the specific interference of maternal antibodies passively transmitted to the progeny. In selection I the antigen used was sheep red blood cells (SRBC) for the first six generations; subsequently SRBC and pigeon erythrocytes were alternated at each generation. In all generations of selection II, mice were immunized with SRBC but the period between weaning and immunization was prolonged to allow elimination of the maternal antibodies. Selections III and IV were carried out for responses to flagellar and somatic antigens, respectively, of two non-cross-reactive Salmonellae (S. typbimurium and S. oranienburg) given alternately. The antigens used for selection V were bovine serum albumin and rabbit gammaglobulin, alternately.

High and low antibody responder lines were produced by bidirectional selective breeding. Starting from a foundation population (FO) of outbred albino mice displaying great variability in antibody response, the two-way selective breeding was performed for maximal or minimal antibody response and repeated in each consecutive generation. Assortative mating of the highest responder mice produced the H line, while that of the lowest responder mice produced the L line. In each line several pairs were culled at each generation and were issued from different families to delay the increase in consanguinity. The two lines diverged progressively until the maximal interline separation was reached at a given generation (selection limit).

According to the principles of quantitative genetics as applied in these studies, at the selection limit the two lines are considered homozygous for all independent loci controlling the antibody response, owing to the progressive accumulation of high-effect alleles in the H line and low-effect alleles in the L line.

The total response (TR) to selection is the interline difference at the selection limit, while the response (R) to selection is the difference between the mean values of two successive generations of each line. The selection differential (S) is the difference between the mean of the selected parents and that of the total population out of which they have been culled. The mean realized heritability (h1) is calculated by the linear regression coefficient of cumulated R versus cumulated S over the generations between FO and the selection limit, and is equal to R/S.

Once the selection limit was attained, the following interline hybrids were derived from H and L parents: (H x L) = Fl; (F1 x Fl) = F2; (F1 x H) = BcH; (F1 xL) = BcL. Using mean values (x) and variances (V) of the character measured in these mouse populations, relevant genetic parameters were estimated. The total additive effect (a) of all the homozygous loci in H and L lines at the selection limit in the absence of dominance is given by a = 3 (xH - xL).

The global dominance deviation (d) in F1 hybrids is given by d = xFl - i (xH + xL).

The dominance effect is d/a.

The environmental variance (VE) is the mean phenotypic variance of the genetically homogeneous populations: H and L lines at the selection limit and their F'l hybrids. Therefore,

The phenotypic variance of the genetically heterogeneous populations, FO, F2, BcH and BcL, is contributed by both genetic and environmental factors. The variance of F2 hybrids is

where VA is the additive variance and VD the dominance variance. The summed variance of the two backcrosses {VBcH + VBcL) is

Since

Knowing VA, the number (n) of independent loci controlling the character is calculated as a2

Since the h1 value results from the additive effect of homozygous loci occupied by either high- or low-effect alleles, the heritability of the character can also be measured in the progeny of interline crosses (F2 or backcrosses) by the ratio of the additive variance to the total phenotypic variance, as follows:

Comparison of the immunogenetic parameters in the five selections (Table 1) revealed a remarkable

Table 1 Genetic parameters of the five selections

Selection

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