The crucial role of genome-wide genetic variation in conservation.

The unprecedented rate of extinction calls for efficient use of genetics to help conserve biodiversity. Several recent genomic and simulation-based studies have argued that the field of conservation biology has placed too much focus on conserving genome-wide genetic variation, and that the field should instead focus on managing the subset of functional genetic variation that is thought to affect fitness. Here, we critically evaluate the feasibility and likely benefits of this approach in conservation. We find that population genetics theory and empirical results show that conserving genome-wide genetic variation is generally the best approach to prevent inbreeding depression and loss of adaptive potential from driving populations toward extinction. Focusing conservation efforts on presumably functional genetic variation will only be feasible occasionally, often misleading, and counterproductive when prioritized over genome-wide genetic variation. Given the increasing rate of habitat loss and other environmental changes, failure to recognize the detrimental effects of lost genome-wide genetic variation on long-term population viability will only worsen the biodiversity crisis.

Galapagos Islands Endemic Vertebrates: A Population Genetics Perspective.

The organisms of the Galapagos Islands played a central role in the development of the theory of evolution by Charles Darwin. Examination of the population genetics factors of many of these organisms with modern molecular methods has expanded our understanding of their evolution. Here, I provide a perspective on how selection, gene flow, genetic drift, mutation, and inbreeding have contributed to the evolution of 6 iconic Galapagos species: flightless cormorant, pink iguana, marine iguana, Galapagos hawk, giant tortoises, and Darwin's finches. Because of the inherent biological differences among these species that have colonized the Galapagos, different population genetic factors appear to be more or less important in these different species. For example, the Galapagos provided novel environments in which strong selection took place and the Darwin's finches diversified to produce new species and the cormorant adapted to the nutrient-rich western shores of the Galapagos by losing its ability to fly and genomic data have now identified candidate genes. In both the pink iguana, which exists in one small population, and the Galapagos hawk, which has small population sizes, genetic drift has been potentially quite important. There appears to be very limited interisland gene flow in the flightless cormorant and the Galapagos hawk. On the other hand, both the marine iguana and some of the Darwin's finches appear to have significant interisland gene flow. Hybridization between species and subspecies has also introduced new adaptive variation, and in some cases, hybridization might have resulted in despeciation. Overall, new population genetics and genomics research has provided additional insight into the evolution of vertebrate species in the Galapagos.

Negative-Assortative Mating in the White-Throated Sparrow.

Nonrandom mating based on phenotype has been observed in a number of organisms, but a very high proportion of these examples are of assortative mating. The strongest example of negative-assortative mating is for white-striped versus tan-striped crown in the white-throated sparrow, where about 98% of the observed pairings (mated pairs or social pairs) are between mates with different phenotypes and the correlation between mating types is -0.964. Although nonrandom mating has been explored theoretically for decades, these models have generally not focused on specific well-documented examples. Here we have developed a model to investigate the dynamics and equilibrium of this iconic example. The observed pattern of mating appears to be the result of 96% negative-assortative mating and a 17% advantage of W (white) male × T (tan) female matings compared to the reciprocal T male × W female matings. The equilibrium heterozygosity given these values is 0.500, very close to the 0.501 observed in our large sample of pairings, and this heterozygosity has been maintained for the 29 years from 1988 to 2016. In addition, the equilibrium frequency of 2m inversion determining the white-striped phenotype has been maintained at a frequency very close to its equilibrium frequency of 0.25. Overall, this model demonstrates how evolutionary genetic models can be used to understand negative-assortative mating.

Genomic Variation of Inbreeding and Ancestry in the Remaining Two Isle Royale Wolves.

Inbreeding, relatedness, and ancestry have traditionally been estimated with pedigree information, however, molecular genomic data can provide more detailed examination of these properties. For example, pedigree information provides estimation of the expected value of these measures but molecular genomic data can estimate the realized values of these measures in individuals. Here, we generate the theoretical distribution of inbreeding, relatedness, and ancestry for the individuals in the pedigree of the Isle Royale wolves, the first examination of such variation in a wild population with a known pedigree. We use the 38 autosomes of the dog genome and their estimated map lengths in our genomic analysis. Although it is known that the remaining wolves are highly inbred, closely related, and descend from only 3 ancestors, our analyses suggest that there is significant variation in the realized inbreeding and relatedness around pedigree expectations. For example, the expected inbreeding in a hypothetical offspring from the 2 remaining wolves is 0.438 but the realized 95% genomic confidence interval is from 0.311 to 0.565. For individual chromosomes, a substantial proportion of the whole chromosomes are completely identical by descent. This examination provides a background to use when analyzing molecular genomic data for individual levels of inbreeding, relatedness, and ancestry. The level of variation in these measures is a function of the time to the common ancestor(s), the number of chromosomes, and the rate of recombination. In the Isle Royale wolf population, the few generations to a common ancestor results in the high variance in genomic inbreeding.

Ancestry dynamics in a South American population: The impact of gene flow and preferential mating.

OBJECTIVES: European ancestry in many populations in Latin America at autosomal loci is often higher than that from X-linked loci indicating more European male ancestry and more Amerindian female ancestry. Generally, this has been attributed to more European male gene flow but could also result from an advantage to European mating or reproductive success. METHODS: Population genetic models were developed to investigate the dynamics of gene flow and mating or reproductive success. Using estimates of autosomal and X-chromosome European ancestry, the amount of male gene flow or mating or reproductive advantage for Europeans, or those with European ancestry, was estimated. RESULTS: In a population from Antioquia, Colombia with an estimated 79% European autosomal ancestry and an estimated 69% European X-chromosome ancestry, about 15% male gene flow from Europe or about 20% mating or reproductive advantage of Europeans over Amerindians resulted in these levels of European ancestry in the contemporary population. Combinations of gene flow and mating advantage were nearly additive in their impact. CONCLUSIONS: Gene flow, mating advantage, or a combination of both factors, are consistent with observed levels of European ancestry in a Latin American population. This approach provides a general methodology to determine the levels of gene flow and mating differences that can explain the observed contemporary differences in ancestry from autosomes and X-chromosomes.

Examining the cause of high inbreeding depression: analysis of whole-genome sequence data in 28 selfed progeny of Eucalyptus grandis.

The genome-wide heterozygosity at 9590 genes, all heterozygous in a single Eucalyptus grandis parent tree, was examined in a group of 28 S1 offspring. Heterozygosity ranged from 52-79%, averaging 65.5%, much higher than the 50% expected under random segregation, supporting the occurrence of strong (47%) selection against homozygosity. The expected pattern of heterozygosity from theoretical calculations and simulations for recessive detrimentals (pseudo-overdominance) and intrinsic heterozygote advantage was examined and compared with that observed. The observed patterns are consistent with at least several detrimental loci with large effects on both parental chromosomes of the 11 pairs. It is likely that 100 or more genes, many with substantial effects on viability, are contributing to this inbreeding depression. Although our genome-wide analysis of nearly 10 000 genes strongly suggested that pseudo-overdominance was responsible for the observed high inbreeding depression, heterozygote advantage could not be excluded. Finding inconvertible evidence of the cause of inbreeding depression still presents a difficult challenge. This study is the first theoretical examination of the genomic effect of inbreeding in a forest tree and provides an approach to analyze these data to determine the extent and cause of inbreeding depression across other plant genomes.

New reservoirs of HLA alleles: pools of rare variants enhance immune defense.

Highly polymorphic exons of the major histocompatibility complex (MHC, or HLA in humans) encode critical amino acids that bind foreign peptides. Recognition of the peptide-MHC complexes by T cells initiates the adaptive immune response. The particular structure of these exons facilitates gene conversion(GC) events, leading to the generation of new alleles. Estimates for allele creation and loss indicate that more than 10000 such alleles are circulating at low frequencies in human populations. Empirical sampling has affirmed this expectation. This suggests that the MHC loci have a system for moving valuable and often complex variants into adaptive service. Here, we argue that HLA loci carry many new mutant alleles prepared to assume epidemiologically meaningful roles when called on by selection provoked by exposure to new and evolving pathogens. Because new mutant alleles appear in a population at the lowest possible frequency (i.e., a single copy), they have typically been thought of as having little consequence. However, this large population of rare yet potentially valuable new alleles may contribute to pathogen defense.

Heterozygote advantage: the effect of artificial selection in livestock and pets.

There are a number of mutants in livestock and pets that have a heterozygote advantage because of artificial selection for these mutants in heterozygotes and strong detrimental effects from natural selection in homozygotes. In livestock, these mutants include ones that influence milk yield in dairy cattle, fecundity in sheep, litter size in pigs, muscling in beef cattle, color in horses, lean meat content in pigs, and comb morphology in chickens. In pets, these mutants include ones that influence tail length in cats and hairlessness, muscling, color, or ridgeback hair in dogs. A large variety of mutants are responsible, including small or large deletions or insertions and single base-pair nonsynonymous changes. Many of the mutants cause loss of function for the genes involved, a change that results in the pleiotropic effects of a desired phenotype in heterozygotes and low fitness or an undesirable phenotype in mutant homozygotes. I examine how selection changes the frequency of these mutants and provide an approach to estimate the amount of artificial selection that is necessary to maintain these mutants at the high frequencies often observed. The amount of artificial selection ranges from low selection favoring heterozygotes for double muscling in whippet dogs to very strong selection favoring the "flash" (part white, part solid) heterozygote in boxer dogs and the rose comb in chickens. In several examples (rose comb in Wyandotte chickens and the hair ridge in Rhodesian ridgeback dogs), there is actually stronger selection for the mutant than against it, making the frequency of the mutant greater than 50%.

Measuring relatedness between inbred individuals.

Genetic relatedness between individuals is an important measure in many areas of biology. However, some relatedness measures for use with molecular (allele) data assume that the individuals themselves are not inbred. Here, we present a new measure of relatedness based on the different modes of identity-by-descent for alleles that has an upper bound of 1 even when the individuals being compared are themselves inbred. This new measure is compared to several other measures of relatedness using several simple examples and pedigree data from the wolf population in Isle Royale National Park.

Estimation of Male Gene Flow: Use Caution.

Because male gene flow cannot easily be estimated directly in many organisms, Hedrick et al. (2013) provided an approach to estimate male gene flow given estimates of diploid nuclear and female differentiation. This approach appears to work well when there is lower female than male gene flow. However, in a tiger data set there was less female differentiation observed as estimated by mitochondrial DNA than expected given the observed overall nuclear diploid differentiation. To analyze these data, we suggest an alternative approach which allows incorporation of sex-specific gene flow and sex-specific effective population size. We find that the pattern of differentiation observed in tigers was consistent with a lower male than female effective population size using this alternative approach. Further, this finding is consistent with observed data in tigers where the male effective population size was 33% that of the female effective population size.

Heterozygote Advantage in a Finite Population: Black Color in Wolves.

There is a striking color polymorphism for wolves in the Yellowstone National Park where approximately half the wolves are black. The genetic basis for this polymorphism is known, and fitnesses of the genotypes are estimated. These estimates suggest that there is strong heterozygote advantage but substantial asymmetry in the fitness differences of the 2 homozygotes. Theoretically, such fitnesses in a finite population are thought to reduce genetic variation at least as fast as if there were no selection at all. Because the color polymorphism has remained at about the same frequency for 17 years, about 4 generations, we investigated whether this was consistent with the theoretical predictions. Counter to this general expectation of loss, given the initial frequency of black wolves, the theoretical expectation in this case was found to be that the frequency would only decline slowly over time. For example, if the effective population size is 20, then the expected black allele frequency after 4 generations would be 0.191, somewhat less than the observed value of 0.237. However, nearly 30% of the time the expected frequency is 0.25 or greater, consistent with the contemporary observed frequency. In other words and in contrast to general theoretical predictions, because of the short period of time in evolutionary terms and the relatively weak selection at low frequencies, the observed variation and the predicted theoretical variation are not inconsistent.

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 Darwin's finches, yellow skin in chickens and non-native ancestry in an endangered native salamander, are examined.

Coat colour in mouse populations selected for weight gain: support for hitchhiking, not pleiotropy.

With many molecular markers in many species, research efforts in quantitative genetics have focused on dissecting these traits and understanding the importance of factors such as correlated response due to hitchhiking or pleiotropy. Here, in an examination of long-term selection experiments in mice, the evidence strongly supports the primary importance of hitchhiking on the coat colour loci brown and dilute in mice selected for high weight gain. First, the amount of observed change in coat colour allele frequency could not be explained by genetic drift alone, implying that selection was of high importance. Second, the allele frequency changes included reversals in the direction change, but there were still positive correlations in the early generations with differences in weight gain between the phenotypes. Third, the correlation between the change in allele frequencies and phenotypic difference in weight gain declined over time, consistent with the decay expected from linkage associations. Fourth, the changes at both loci in a short-term selection experiment for low weight gain were in the opposite direction than the changes in the contemporaneous related population selected for high weight gain.

Estimation of male gene flow from measures of nuclear and female genetic differentiation.

An approach is provided to estimate male gene flow and the ratio of male to female gene flow, given that there are estimates of diploid, nuclear gene flow and haploid, female gene flow. This approach can be applied to estimates of differentiation (F ST ) from biparentally and maternally inherited markers, assuming the equilibrium island model and equal effective numbers of males and females. Corrections to formulas used previously for California sea lions (González-Suárez M, Flatz R, Aurioles-Gamboa D, Hedrick PW, Gerber LR. 2009. Isolation by distance among California sea lion populations in Mexico: redefining management stocks. Mol Ecol. 18:1088-1099.) and American bison (Halbert ND, Gogan PJP, Hedrick PW, Wahl L, Derr JN. 2012. Genetic population substructure in bison in Yellowstone National Park. J Hered. 103:360-370.) are given and revised values for those species are calculated. The effect of unequal male and female effective population sizes, nonequilibrium conditions, and approximations of differentiation formulas are briefly discussed.

The far-reaching effects of genetic process in a keystone predator species, grey wolves.

Although detrimental genetic processes are known to adversely affect the viability of populations, little is known about how detrimental genetic processes in a keystone species can affect the functioning of ecosystems. Here, we assessed how changes in the genetic characteristics of a keystone predator, grey wolves, affected the ecosystem of Isle Royale National Park over two decades. Changes in the genetic characteristic of the wolf population associated with a genetic rescue event, followed by high levels of inbreeding, led to a rise and then fall in predation rates on moose, the primary prey of wolves and dominant mammalian herbivore in this system. Those changes in predation rate led to large fluctuations in moose abundance, which in turn affected browse rates on balsam fir, the dominant forage for moose during winter and an important boreal forest species. Thus, forest dynamics can be traced back to changes in the genetic characteristics of a predator population.