Philip W. Hedrick

A STANDARDIZED GENETIC DIFFERENTIATION MEASURE

Interpretation of genetic differentiation values is often problematic because of their dependence on the level of genetic variation. For example, the maximum level of GST is less than the average within population homozygosity so that for highly variable loci, even when no alleles are shared between subpopulations, GST may be low. To remedy this difficulty, a standardized measure of genetic differentiation is introduced here, one which has the same range, 0–1, for all levels of genetic variation. With this measure, the magnitude is the proportion of the maximum differentiation possible for the level of subpopulation homozygosity observed. This is particularly important for situations in which the mutation rate is of the same magnitude or higher than the rate of gene flow. The standardized measure allows comparison between loci with different levels of genetic variation, such as allozymes and microsatellite loci, or mtDNA and Y-chromosome genes, and for genetic differentiation for organisms with different effective population sizes.

PERSPECTIVE : HIGHLY VARIABLE LOCI AND THEIR INTERPRETATION IN EVOLUTION AND CONSERVATION

Although highly variable loci, such as microsatellite loci, are revolutionizing both evolutionary and conservation biology, data from these loci need to be carefully evaluated. First, because these loci often have very high within‐population heterozygosity, the magnitude of differentiation measures may be quite small. For example, maximum GST values for populations with no common alleles at highly variable loci may be small and are at maximum less than the average within‐population homozygosity. As a result, measures that are variation independent are recommended for highly variable loci. Second, bottlenecks or a reduction in population size can generate large genetic distances in a short time for these loci. In this case, the genetic distance may be corrected for low variation in a population and tests to detect bottlenecks are advised. Third, statistically significant differences may not reflect biologically meaningful differences both because the patterns of adaptive loci may not be correlated with highly variable loci and statistical power with these markers is so high. As an example of this latter effect, the statistical power to detect a one‐generation bottleneck of different sizes for different numbers of highly variable loci is discussed. All of these concerns need to be incorporated in the utilization and interpretation of patterns of highly variable loci for both evolutionary and conservation biology.

Conservation genetics: where are we now?

Genetic studies in endangered species have become widespread in the past decade, and with new information from various genome projects, new applications and insights are forthcoming. Generally, neutral variants are used for conservation applications, and when combined with highly variable loci and/or many more markers, these approaches should become much more informative. Conservation genetics is also concerned with detrimental and adaptive variation, which are more difficult to identify and characterize; however, the ability to predict the extent of such variation might become more successful and applied in future conservation efforts. Neutral variants might be used to identify adaptive variants, but the overlay of different mutational processes and selective regimes suggests that extreme caution should be used in making such identifications.

PERSPECTIVE: DETECTING ADAPTIVE MOLECULAR POLYMORPHISM: LESSONS FROM THE MHC

Abstract. In the 1960s, when population geneticists first began to collect data on the amount of genetic variation in natural populations, balancing selection was invoked as a possible explanation for how such high levels of molecular variation are maintained. However, the predictions of the neutral theory of molecular evolution have since become the standard by which cases of balancing selection may be inferred. Here we review the evidence for balancing selection acting on the major histocompatibility complex (MHC) of vertebrates, a genetic system that defies many of the predictions of neutrality. We apply many widely used tests of neutrality to MHC data as a benchmark for assessing the power of these tests. These tests can be categorized as detecting selection in the current generation, over the history of populations, or over the histories of species. We find that selection is not detectable in MHC datasets in every generation, population, or every evolutionary lineage. This suggests either that selection on the MHC is heterogeneous or that many of the current neutrality tests lack sufficient power to detect the selection consistently. Additionally, we identify a potential inference problem associated with several tests of neutrality. We demonstrate that the signals of selection may be generated in a relatively short period of microevolutionary time, yet these signals may take exceptionally long periods of time to be erased in the absence of selection. This is especially true for the neutrality test based on the ratio of nonsynonymous to synonymous substitutions. Inference of the nature of the selection events that create such signals should be approached with caution. However, a combination of tests on different time scales may overcome such problems.

Evolution and ecology of MHC molecules: from genomics to sexual selection

In the past few years the DNA sequence database for molecules of the MHC (major histocompatibility complex) has expanded greatly, yielding a more complete picture of the long-term rates and patterns of evolution of the MHC in vertebrates. Sharing of MHC allelic lineages between long-diverged species (trans-species evolution) has been detected virtually wherever it is sought, but new analyses of linked neutral regions and the complexities of sequence convergence and microrecombination in the peptide binding region challenge traditional phylogenetic analyses. Methods for estimating the intensity of selection on MHC genes suggest that viability is important, but recent studies in natural populations of mammals give inconsistent results concerning mate choice. The complex and interacting roles of microrecombination, parasite-mediated selection and mating preferences for maintaining the extraordinary levels of MHC polymorphism observed are still difficult to evaluate.

PATHOGEN RESISTANCE AND GENETIC VARIATION AT MHC LOCI

Abstract.— Balancing selection in the form of heterozygote advantage, frequency‐dependent selection, or selection that varies in time and/or space, has been proposed to explain the high variation at major histocompatibility complex (MHC) genes. Here the effect of variation of the presence and absence of pathogens over time on genetic variation at multiallelic loci is examined. In the basic model, resistance to each pathogen is conferred by a given allele, and this allele is assumed to be dominant. Given that s is the selective disadvantage for homozygotes (and heterozygotes) without the resistance allele and the proportion of generations, which a pathogen is present, is e, fitnesses for homozygotes become (1 —s)(n‐1)e and the fitnesses for heterozygotes become (1 —s)(n‐2)e, where n is the number of alleles. In this situation, the conditions for a stable, multiallelic polymorphism are met even though there is no intrinsic heterozygote advantage. The distribution of allele frequencies and consequently heterozygosity are a function of the autocorrelation of the presence of the pathogen in subsequent generations. When there is a positive autocorrelation over generations, the observed heterozygosity is reduced. In addition, the effects of lower levels of selection and dominance and the influence of genetic drift were examined. These effects were compared to the observed heterozygosity for two MHC genes in several South American Indian samples. Overall, resistance conferred by specific alleles to temporally variable pathogens may contribute to the observed polymorphism at MHC genes and other similar host defense loci.

Conservation Genetics: Techniques and Fundamentals

Conservation genetics utilizes the tools and concepts of genetics and applies them to problems in conservation biology. For example, molecular genetic techniques, such as protein electrophoresis, and analysis of mitochondrial DNA and highly variable nuclear genes (including DNA fingerprinting), have been important in documenting the extent and pattern of genetic variation in endangered species. We review these techniques and their advantages and disadvantages, and give examples of their application to endangered species. For captive animal populations, pedigree analysis has become the basic approach to evaluate breeding priority of particular individuals. Several pedigree analysis techniques are commonly used, but peeling and gene dropping give the most information. We compared these techniques and illustrate their value with applications to the Guam Rail, Przewalskis horse, and other endangered captive animals. The rationale for much conservation genetic interpretation is base in evolutionary genetics. We discuss the avoidance of inbreeding depression and the maintenance of genetic variation-both primary conservation genetic goals-from this perspective. In addition, we suggest aspects of these factors that deserve greater attention in their overall application to conservation planning. Finally, we briefly mention three evolutionary topics-the relationship of heterozygosity and fitness, population bottlenecks, and outbreeding depression-that have implications for conservation genetics. Although simple interpretation in these areas is appealing, we feel that because they are only generally understood and often quite controversial, their application to endangered-species management should be carefully evaluated and monitored.

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 continous 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.

Adaptive introgression in animals: examples and comparison to new mutation and standing variation as sources of adaptive variation.

Adaptive genetic variation has been thought to originate primarily from either new mutation or standing variation. Another potential source of adaptive variation is adaptive variants from other (donor) species that are introgressed into the (recipient) species, termed adaptive introgression. Here, the various attributes of these three potential sources of adaptive variation are compared. For example, the rate of adaptive change is generally thought to be faster from standing variation, slower from mutation and potentially intermediate from adaptive introgression. Additionally, the higher initial frequency of adaptive variation from standing variation and lower initial frequency from mutation might result in a higher probability of fixation of the adaptive variants for standing variation. Adaptive variation from introgression might have higher initial frequency than new adaptive mutations but lower than that from standing variation, again making the impact of adaptive introgression variation potentially intermediate. Adaptive introgressive variants might have multiple changes within a gene and affect multiple loci, an advantage also potentially found for adaptive standing variation but not for new adaptive mutants. The processes that might produce a common variant in two taxa, convergence, trans‐species polymorphism from incomplete lineage sorting or from balancing selection and adaptive introgression, are also compared. Finally, potential examples of adaptive introgression in animals, including balancing selection for multiple alleles for major histocompatibility complex (MHC), S and csd genes, pesticide resistance in mice, black colour in wolves and white colour in coyotes, Neanderthal or Denisovan ancestry in humans, mimicry genes in Heliconius butterflies, beak traits in Darwins finches, yellow skin in chickens and non‐native ancestry in an endangered native salamander, are examined.

Multilocus Systems in Evolution

Population studies of genetic variation and microevolution are classically discussed in terms of changes in gene frequencies and the maintenance of polymorphic loci that can be identified by Mendelian analyses. In recent years, however, a great deal of attention has been given to the evolutionary dynamics and polymorphisms of interacting and linked loci (e.g., Clegg et al., 1972; Lewontin, 1974; Karlin, 1976). The special properties of multilocus systems, namely, gene interaction and linkage, were first briefly considered in theory by Fisher (1930) and Wright (1932). Fisher discussed in particular the role of modifiers in the evolution of dominance and clearly recognized the importance of linkage in the evolution of interacting polymorphisms. Wright proposed an intermediate optimum model in which natural selection favors intermediate phenotypes over the extremes for a continuous metric trait and emphasized the role of linkage in the makeup of gametic arrays.