Lymphocyte-defined loci in cattle.

Using the results of all paired one-way mixed lymphocyte culture tests on families of half-sibs, we have established that the lymphocyte-defined system in cattle contains a minimum of two loci. The methodology presented is applicable to studies of the lymphocyte-defined systems of other species.

Estimates of inbreeding in a natural population: a comparison of sampling properties.

The average inbreeding coefficient f of a population can be estimated in several different ways based solely on the genotypic frequencies at a single locus. The means and variances of four different estimates have been compared. While the four estimates are equivalent when there are two alleles, the best estimates when there are three or more alleles are based upon total heterozygosity (Formula: see text) where x and y are the expected and observed number of heterozygotes) and the proportion of alleles that are homozygous (Formula: see text) where k = the number of alleles, aii = the number of AiAi homozygotes, and 2aij = the number of AiAj heterozygotes). Both are minimally based estimates of f and have identical sampling variances when all alleles are equally frequent. However, when alleles have different frequencies, the choice between these two estimates depends on the gene frequencies and the true inbreeding coefficient of a population; f2 is the best estimate when the true average inbreeding coefficient is suspected to be low or f = 0, while f1 is best in populations with large average inbreeding coefficients. Approximate sampling variances of these two estimates are given for any f and any number of alleles with arbitrary gene frequencies; these approximations are accurate for samples as small as n = 100. The chi-square and maximum likelihood estimates of f are not as good for realistic sample sizes.

The frequency of consanguineous matings due to multiple use of donors in artificial insemination.

The amount of inadvertent inbreeding as a result of donor anonymity in artificial insemination has been estimated. A child from a first-cousin mating or closer is expected approximately once every 41/2 years in the United States as a result of artificial insemination by donor. Since a child with unknown paternity seems less likely to mate with paternal relatives than is a child with known paternity, artificial insemination by donor may actually reduce the average inbreeding of the population. Nevertheless, to reduce recessive diseases, inbreeding should be kept to a minimum by limiting the number of children produced by a single donor. Formulas are presented for local risks of inbreeding based on the number of children per donor.

A note of relative risks.

In the study of disease correlations with specific antigens, the current expression for "relative risks" is computationally convenient. However, a more exact expression has been devised which is also more easily interpretable as the relative probability of contracting a disease for individuals carrying a specific antigen as compared to the probability for those not carrying that antigen.

HLA antigens and susceptibility to juvenile diabetes: do additive relative risks imply genetic heterogeneity?

The relative risk of B8/B15 heterozygotes for juvenile-onset diabetes is higher than the risk for people having B8 or B15 alone. This has been cited as evidence for genetic heterogeneity in juvenile diabetes. However, the observed relative risks are compatible with a single susceptibility allele. If disease susceptibility is recessive, for example, then an individual with two disease associated antigens is more likely to be susceptible than an individual with only one associated antigen. The relative risk for an HLA heterozygote should be intermediate between that of the respective homozygotes, so that an interaction effect of two alleles can only be supported if the heterozygote risk is significantly greater than both homozygote risks. The estimated relative risks for B8 and B15 homozygotes, based on data from four different populations, is approximately equal to the risk for B8/B15 heterozygotes. Moreover, disease manifestations which are differentially associated with B8 and B15, such as antibody production to exogenous insulin, may be due to linkage disequilibrium between HLA and other loci which are not directly related to susceptibility of juvenile diabetes. Therefore, while the susceptibility to juvenile diabetes may have several genetic forms, there is no support for distinct B8-associated and B15-associated forms of susceptibility.

A new algorithm for clustering lymphocyte typing sera.

An algorithm is presented for clustering antisera by computer. It has two novel features: the leading serum to which all other sera in the cluster are compared is chosen as the most centrally located serum in the cluster; the similarity between two sera is defined from the 2 X 2 table of serum reactions as s = 2a/(2a + b + c). This similarity index is a better measure of the similarity between two sera than conventional measures of similarity such as the correlation coefficient. Finally, the identification of cluster and serum subsets provides a more complete analysis of cross-reactivity and multispecificity, and suggests which absorptions might yield monospecific typing sera. A computer program which performs this serum cluster analysis is available upon request.

Current practice of artificial insemination by donor in the United States.

Of 711 physicians likely to perform artificial insemination by donor surveyed to determine their current practices, 471 responded, of whom 379 reported that they performed this procedure. They accounted for approximately 3576 births by this means in 1977. In addition to treating infertility, 26 per cent of these physicians used the procedure to prevent transmission of a genetic disease, and 10 per cent used if for single women. Donors of semen were primarily from universities, were only superficially screened for genetic diseases, and were then matched phenotypically to the recipient's husband. Most recipients were inseminated twice per cycle. Only 17 per cent of physicians used the same donor for a given recipient, and 32 per cent used multiple donors within a single cycle. Only 37 per cent kept records on children, and only 30 per cent on donors. The identity of donors usually was carefully guarded to ensure privacy and to avoid legal complications.

PIP: In December 1977 a questionnaire was sent to 711 physicians likely to perform artificial insemination by donor. 379 of the 471 who responded indicated that they performed this procedure, accounting for approximately 3576 births by this means in 1977. In addition to treating infertility, 26% of these physicians used the procedure to prevent transmission of a genetic disease. 10% of the physicians used the procedure for single women. Donors of semen were primarily from universities, were only superficially screened for genetic diseases, and were then matched phenotypically to the recipient's husband. 61.4% of the doctors inseminated women twice per cycle; others did so either once (17%) or 3 times (20.5%). Only 17% of physicians used the same donor for a given recipient, and 32% used multiple donors within a single cycle. Only 37% kept records on children, and only 30% on donors. The identity of donors usually was carefully guarded to ensure privacy and to avoid legal complications. On the basis of the results of this survey, the following issues concerning artificial insemination by donor appear most important: 1) the screening of donors for genetic diseases is inadequate; 2) current practices reflect little concern for the possibility of consanguineous matings or other effects of multiple donor use; 3) present records on artificial insemination are woefully deficient; and 4) information concerning artificial insemination is scanty.

Transitivity of response in the mixed lymphocyte culture test.

We present a model of mixed lymphocyte culture (MLC) response which assumes one specificity per locus. It also assumes that an animal A will fail to stimulate animal B if, and only if, the set of specificities possessed by A is a subset of the set of specificities in B. The last assumption implies that non-stimulation is transitive; that is, if A does not stimulate B, and B does not stimulate C, then A will not stimulate C. The inclusion of antigenic sets can be used to partially order the animals in a hierarchy. Partial ordering can detect multiple lymphocyte-defined (LD) loci with relative ease; it indicates the number of antigens present in particular individuals; and it detects exceptions to the rule of transitivity which may expose immune response genes, minor loci, or other mechanisms that affect MLC response. This analytical procedure is most useful when testing half-sib families or hybrids sharing a common parental strain. We have applied this procedure to the MLC in cattle half-sib families and found that the data strongly support the existence of at least four LD loci.

The bovine major histocompatibility complex (BoLa): close linkage of the genes controlling serologically defined antigens and mixed lymphocyte reactivity.

Detection of linkage between genetic loci in cattle has been hampered by the lack of large full -sib families. A unique source of full-sib families is now available from embryo transplantation. Lymphocytes from six full-sib families, ranging in size from three to seven siblings, were tested for serologically defined BoLA antigens (BoLA-A). In addition, mixed lymphocyte reactivity (MLR) was tested between all paired combinations of cells within each family to distinguish BoLA-D specificities. Serologically identical siblings within each family were reciprocally nonreactive in MLR, and vice versa; thus, no recombinants were detected between the BoLA-A and the BoLA-D loci. Classical genetic linkage analysis revealed that these loci are significantly closer than 11.9 centimorgans.