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Biomedical subjects

P W Hedrick

Publications and source records attributed to P W Hedrick.

At least 19 recordsLinked to original sources
PubMed1994

Rare alleles, MHC and captive breeding.

In recent years, more detailed genetic information has become available for individuals of endangered species in captive breeding programs. There have been suggestions that this information be used to identify rare alleles, particularly those at the MHC, that can be subsequently selected for captive breeding programs. First, we summarize the current information on the MHC relevant to conservation genetics, so that such a possible breeding program is seen in a proper perspective. For example, very few specific alleles at the MHC have been identified as selectively advantageous, even though there has been substantial effort to find such alleles in humans and a few other organisms. Further, many of the balancing selection models suggested for MHC variation are based on heterozygotes in general having a higher fitness than homozygotes and not on specific selectively advantageous alleles. Because there is no detailed data on MHC variability in captive populations, we used transferrin data in Przewalski's horses to evaluate a breeding program to select for rare alleles. In this species, one individual, 1060, has been identified to have the transferrin allele J. We determine the effect on founder contribution of multiply mating 1060 to increase the number of copies of this allele. Since there were 485 individuals in the population at this time, this extra mating had little detrimental effect on the distribution of founder contributions and the number of founder equivalents. We then selected 65, an ancestor of 1060, which had a high likelihood of being the individual that passed on the J allele in the lineage of 1060. We examined the effect of increasing the number of copies of alleles of 65 at a time when the population had only 22 other individuals. In this case, even though the founder contributions were changed more, there was also little effect on the founder contributions and the number of founder equivalents. Overall, it appears that selection that results in a limited change in the number of copies of rare alleles may not always have an overall detrimental effect. However, because other pedigrees may have very different properties, it is essential to perform a detailed pedigree analysis of any such selective breeding program to determine its effect before such a selection program is implemented.

Alleles↗
PubMed1994

Purging inbreeding depression and the probability of extinction: full-sib mating.

Inbreeding depression has been a topic of interest in recent years from a number of perspectives, particularly in the captive breeding of endangered species. Generally, the goal of captive breeding is to avoid the detrimental effects of inbreeding depression and to retain genetic variation for future adaptation. However, an important component of another suggested approach to captive breeding is to purge rapidly the population of its genetic load so that its long-term fitness is not compromised. I have examined the effectiveness of purging the genetic load by documenting both the reduction in inbreeding depression and the increase of the probability of extinction when there is continuous full-sib mating. When the genetic load is the result of lethals, the inbreeding depression is quickly purged without a high probability of extinction, except when the total genetic load is high. On the other hand, if the load is due to detrimentals of relatively small effect, the genetic load becomes fixed, the mean fitness is reduced, and the probability of extinction may be greatly increased. In other words, the success of such a programme to purge genetic load without an increase in the probability of extinction is highly dependent upon the genetic basis of inbreeding depression, information that is not readily available for most species.

Adaptation, Physiological↗
PubMed1992

Female choice and variation in the major histocompatibility complex.

The cause of the high genetic variability in the major histocompatibility complex (MHC) is not entirely clear. Recently, two reports suggest that female mice prefer to mate with males different from them at the MHC. A model of female choice appropriate for those observations is developed here. Female choice can in fact reduce the observed proportions of homozygotes, maintain genetic polymorphism, influence mating-type frequencies and generate gametic disequilibrium.

Animals↗
PubMed1991

Heterozygosity at individual amino acid sites: extremely high levels for HLA-A and -B genes.

The amino acid heterozygosities per site for HLA-A and -B loci are determined to be extremely high by combining population serotypic frequencies with amino acid sequences. For the 54 amino acid sites thought to have functional importance, the average heterozygosity per site is 0.301. Sixteen positions have heterozygosities greater than 0.5 at one or both loci and the frequencies of amino acids at a given position are very even, resulting in nearly the maximum heterozygosity possible. Furthermore, the high heterozygosity is concentrated in the peptide-interacting sites, whereas the sites that interact with the T-cell receptor have lower heterozygosity. Overall, these results indicate the importance of some form of balancing selection operating at HLA loci, maybe even at the individual amino acid level.

Alleles↗
PubMed1990

Genotypic-specific habitat selection: a new model and its application.

A new model of genotypic-specific habitat selection is proposed in which habitats are given a biologically meaningful way with differences in the frequency of various niches. Conditions for polymorphism are quite robust even for small viability differences. A method to estimate habitat selection parameters from information on habitat preference is given. Even when habitat preference is not great, it may have a large effect on maintaining polymorphism.

Animals↗
PubMed1990

Evolution at HLA: possible explanations for the deficiency of homozygotes in two populations.

There is substantial evidence that some form of balancing selection is important for loci in the HLA region. Two classic studies found a large deficiency of homozygotes for these loci. Four possible proposed selective explanations were proposed: (1) heterozygous advantage; (2) linked lethal; (3) maternal-fetal interaction, and (4) resistance to infectious disease. These hypotheses as well as another explanation, different male and female gametic frequencies, have been examined here to try and evaluate their potential impact on genotypic frequencies. For any of these selective mechanisms to alone account for the observed homozygous deficiency, selection and/or others factors would have to be extremely strong. The linked lethal selection model and the hypothesis based on different male and female gametic frequencies appear to be unlikely explanations for these observations. Other factors that may influence genotypic frequencies are also discussed.

Female↗
PubMed1988

Inference of recombinational hotspots using gametic disequilibrium values.

Gametic disequilibrium between RFLP sites have been used to infer recombinational hotspots. However, some measures of gametic disequilibrium, such as the correlation coefficient, are quite dependent upon allelic frequencies. The normalized disequilibrium measure of Lewontin, on the other hand, is independent of allelic frequencies. Data from the beta-globin gene cluster are used as an illustration of such potential misinterpretations and the use of these measures.

Alleles↗
PubMed1988

HLA-sharing, recurrent spontaneous abortion, and the genetic hypothesis.

A number of studies indicates that there is a high sharing of HLA antigens in couples having recurrent spontaneous abortions. The genetic hypothesis to explain this phenomenon suggests that this fetal loss results from homozygosity of recessive lethal or deleterious alleles in gametic disequilibrium with HLA antigens. Theory predicting the lethality rate is derived when antigens are shared at one, two or three loci, given that the disequilibrium is absolute. In addition, the effects of partial disequilibrium, inbreeding, and segregation distortion on the lethal proportion are examined.

Abortion, Habitual↗
PubMed1988

Maternal-fetal interactions and the maintenance of HLA polymorphism.

There is some empirical evidence that a fetus with an HLA antigen not present in its mother has a higher survival than a fetus sharing antigens with its mother. We have developed both single locus and two-locus theoretical models to examine this mode of selection. First, this immunologically based model appears to have the potential to maintain many alleles at a single locus and to result in an excess of heterozygotes when selection is strong. Second, substantial gametic disequilibrium is maintained between alleles at two loci for this selection mode when recombination is that observed between HLA loci A, B, and DR. Overall, it appears that this mode of selection has the potential to strongly affect genetic variation in the HLA region.

Alleles↗
PubMed1987

Estimation of the rate of partial inbreeding.

Estimates are given for the rate of partial inbreeding when a maternal homozygous genotype and her progeny are known. Also considered are estimates for X-linked genes (or haplo-diploid organisms), situations in which there is more than one type of inbreeding, inbreeding in previous generations, variation in male allelic frequencies, and null alleles. These procedures could be used in animals as well as plants although the size of the progeny array must be fairly large.

Animals↗
PubMed1987

Gametic disequilibrium measures: proceed with caution.

Five different measures of gametic disequilibrium in current use and a new one based on R. C. Lewontin's D', are examined and compared. All of them, except the measure based on Lewontin's D', are highly dependent upon allelic frequencies, including four measures that are normalized in some manner. In addition, the measures suggested by A. H. D. Brown, M. F. Feldman and E. Nevo, and T. Ohta can have negative values when there is maximum disequilibrium and have rates of decay in infinite populations that are a function of the initial gametic array. The variances were large for all the measures in samples taken from populations at equilibrium under neutrality, with the measure based on D' having the lowest variance. In these samples, three of the measures were highly correlated, D2, D (equal to the correlation coefficient when there are two alleles at each locus) and the measure X(2) of Brown et al. Using frequency-dependent measures may result in mistaken conclusions, a fact illustrated by discussion of studies inferring recombinational hot spots and the effects of population bottlenecks from disequilibrium values.

Alleles↗
PubMed1986

A two-locus neutrality test: applications to humans, E. coli and lodgepole pine.

The expected disequilibrium between two loci with k alleles at one locus and l alleles at the other is given for a sample of size n drawn from a population under neutrality equilibrium. Three different measures of disequilibrium with 95% intervals are tabulated for combinations of n, k, l and 4Nc, where N is the effective population size and c is the amount of recombination between the loci. The extent and pattern of disequilibrium are strongly dependent upon 4Nc and are somewhat dependent on n, k and l. The 95% intervals are large, particularly for low numbers of alleles and low values of 4Nc. As examples, observed disequilibrium from histocompatibility loci in humans (HLA) and electrophoretic data in E. coli and lodgepole pine were compared to these theoretical values. Using information about recombination rates, the HLA data showed more disequilibrium than neutrality expectations, whereas electrophoretic data from E. coli and lodgepole pine had somewhat less disequilibrium than neutrality expectations.

Alleles↗
PubMed1986

Charge changes in protein evolution.

The number of charge changes relative to total amino acid replacements for each of seven protein sequences (cytochrome c, hemoglobin alpha, hemoglobin beta, myoglobin, insulin, and fibrinopeptides A and B) has been studied. This number was compared with the expected value obtained under the assumption of random nucleotide substitution. The results obtained indicate that four proteins--hemoglobin alpha, hemoglobin beta, myoglobin, and insulin--are accumulating charge changes at rates slower than those predicted by a model of random substitution. Cytochrome c and fibrinopeptides A and B are accumulating charge changes at rates similar to those predicted by a random model.

Animals↗
PubMed1986

Average inbreeding or equilibrium inbreeding?

The equilibrium inbreeding is always higher than the average inbreeding. For human populations with high inbreeding levels, the inbreeding equilibrium is more than 25% higher than the average inbreeding. Assuming no initial inbreeding in the population, the equilibrium inbreeding value is closely approached in 10 generations or less. A secondary effect of this higher inbreeding level is that the equilibrium frequency of recessive detrimental alleles is somewhat lower than expected using average inbreeding.

Consanguinity↗
PubMed1985

Analysis of negative and multiple HLA antigen disease associations.

The nature and extent of negative and multiple HLA antigen disease associations are investigated theoretically under two models. The first model assumes that an HLA antigen is involved directly in predisposing individuals to disease. The second model assumes that the association of a particular HLA antigen(s) with a disease is the result of linkage disequilibrium between the allele determining the antigen and alleles at a nearby locus which confers susceptibility to disease. We determined whether observed decreases in antigen frequencies among a patient group are simply the inevitable result of the fact that if one or more alleles at a locus is increased in frequency, then others must be decreased. Under the antigen predisposing model exact predictions concerning allele and antigen class frequencies at the predisposing locus, and the non-predisposing loci, are given. The predictions are examined using HLA-DR data for multiple sclerosis.

Alleles↗