The Wilhelmine W. Key 2002 Invitational Lecture. Phylogeography,haplotype trees,and invasive plant species

The distribution of genetic variants in plant populations is strongly affected both by current patterns of microevolutionary forces, such as gene flow and selection, and by the phylogenetic history of populations and species. Understanding the interplay of shared history and current evolutionary events is particularly confounding in plants due to the reticulating nature of gene exchange between diverging lineages. Certain gene sequences provide historically ordered neutral molecular variation that can be converted to gene genealogies which trace the evolutionary relationships among haplotypes (alleles). Gene genealogies can be used to understand the evolution of specific DNA sequences and relate sequence variation to plant phenotype. For example, in a study of the RPS2 gene in Arabidopsis thaliana, resistant phenotypes clustered in one portion of the gene tree. The field of phylogeography examines the distribution of allele genealogies in an explicit geographical context and, when coupled with a nested clade analysis, can provide insight into historical processes such as range expansion, gene flow, and genetic drift. A phylogeographical approach offers insight into practical issues as well. Here we show how haplotype trees can address the origins of invasive plants, one of the greatest global threats to biodiversity. A study of the geographical diversity of haplotypes in invasive Phragmites populations in the United States indicates that invasiveness is due to the colonization and spread of distinct genotypes from Europe ( Saltonstall 2002). Likewise, a phylogeographical analysis of Tamarix populations indicates that hybridization events between formerly isolated species of Eurasia have produced the most common genotype of the second-worst invasive plant species in the United States.     

The effects of subdivision on the genetic divergence of populations and species

Abstract. An island model of migration is used to study the effects of subdivision within populations and species on sample genealogies and on between-population or between-species measures of genetic variation. The model assumes that the number of demes within each population or species is large. When populations (or species), connected either by gene flow or historical association, are themselves subdivided into demes, changes in the migration rate among demes alter both the structure of genealogies and the time scale of the coalescent process. The time scale of the coalescent is related to the effective size of the population, which depends on the migration rate among demes. When the migration rate among demes within populations is low, isolation (or speciation) events seem more recent and migration rates among populations seem higher because the effective size of each population is increased. This affects the probability of reciprocal monophyly of two samples, the chance that a gene tree of a sample matches the species tree, and relative likelihoods of different types of polymorphic sites. It can also have a profound effect on the estimation of divergence times.     

The imprinted gene DIO3 is a candidate gene for litter size in pigs

Genomic imprinting is an important epigenetic phenomenon, which on the phenotypic level can be detected by the difference between the two heterozygote classes of a gene. Imprinted genes are important in both the development of the placenta and the embryo, and we hypothesized that imprinted genes might be involved in female fertility traits. We therefore performed an association study for imprinted genes related to female fertility traits in two commercial pig populations. For this purpose, 309 SNPs in fifteen evolutionary conserved imprinted regions were genotyped on 689 and 1050 pigs from the two pig populations. A single SNP association study was used to detect additive, dominant and imprinting effects related to four reproduction traits; total number of piglets born, the number of piglets born alive, the total weight of the piglets born and the total weight of the piglets born alive. Several SNPs showed significant (q-value < 0.10) additive and dominant effects and one SNP showed a significant imprinting effect. The SNP with a significant imprinting effect is closely linked to DIO3, a gene involved in thyroid metabolism. The imprinting effect of this SNP explained approximately 1.6% of the phenotypic variance, which corresponded to approximately 15.5% of the additive genetic variance. In the other population, the imprinting effect of this QTL was not significant (q-value > 0.10), but had a similar effect as in the first population. The results of this study indicate a possible association between the imprinted gene DIO3 and female fertility traits in pigs.     

Inference for nonlinear epidemiological models using genealogies and time series

Phylodynamics - the field aiming to quantitatively integrate the ecological and evolutionary dynamics of rapidly evolving populations like those of RNA viruses - increasingly relies upon coalescent approaches to infer past population dynamics from reconstructed genealogies. As sequence data have become more abundant, these approaches are beginning to be used on populations undergoing rapid and rather complex dynamics. In such cases, the simple demographic models that current phylodynamic methods employ can be limiting. First, these models are not ideal for yielding biological insight into the processes that drive the dynamics of the populations of interest. Second, these models differ in form from mechanistic and often stochastic population dynamic models that are currently widely used when fitting models to time series data. As such, their use does not allow for both genealogical data and time series data to be considered in tandem when conducting inference. Here, we present a flexible statistical framework for phylodynamic inference that goes beyond these current limitations. The framework we present employs a recently developed method known as particle MCMC to fit stochastic, nonlinear mechanistic models for complex population dynamics to gene genealogies and time series data in a Bayesian framework. We demonstrate our approach using a nonlinear Susceptible-Infected-Recovered (SIR) model for the transmission dynamics of an infectious disease and show through simulations that it provides accurate estimates of past disease dynamics and key epidemiological parameters from genealogies with or without accompanying time series data.     

Inferring Population Histories for Ancient Genomes Using Genome-Wide Genealogies

Ancient genomes anchor genealogies in directly observed historical genetic variation and contextualize ancestral lineages with archaeological insights into their geography and cultural associations. However, the majority of ancient genomes are of lower coverage and cannot be directly built into genealogies. Here, we present a fast and scalable method, Colate, the first approach for inferring ancestral relationships through time between low-coverage genomes without requiring phasing or imputation. Our approach leverages sharing patterns of mutations dated using a genealogy to infer coalescence rates. For deeply sequenced ancient genomes, we additionally introduce an extension of the Relate algorithm for joint inference of genealogies incorporating such genomes. Application to 278 present-day and 430 ancient DNA samples of >0.5x mean coverage allows us to identify dynamic population structure and directional gene flow between early farmer and European hunter-gatherer groups. We further show that the previously reported, but still unexplained, increase in the TCC/TTC mutation rate, which is strongest in West Eurasia today, was already present at similar strength and widespread in the Late Glacial Period ~10k−15k years ago, but is not observed in samples >30k years old. It is strongest in Neolithic farmers, and highly correlated with recent coalescence rates between other genomes and a 10,000-year-old Anatolian hunter-gatherer. This suggests gene-flow among ancient peoples postdating the last glacial maximum as widespread and localizes the driver of this mutational signal in both time and geography in that region. Our approach should be widely applicable in future for addressing other evolutionary questions, and in other species.     

Hybrid zone origins, species boundaries, and the evolution of wing-pattern diversity in a polytypic species complex of North American admiral butterflies (Nymphalidae: Limenitis)

Hybrid zones present opportunities to study the effects of gene flow, selection, and recombination in natural populations and, thus, provide insights into the genetic and phenotypic changes that occur early in speciation. Here we investigate a hybrid zone between mimetic (Limenitis arthemis astyanax) and nonmimetic (Limenitis arthemis arthemis) populations of admiral butterflies using DNA sequence variation from mtDNA and seven nuclear gene loci. We find three distinct mitochondrial clades within this complex, and observe a strong overall concordance between wing-pattern phenotypes and mitochondrial variation. Nuclear gene genealogies, in contrast, revealed no evidence of exclusivity for either wing-pattern phenotype, suggesting incomplete barriers to gene exchange and/or insufficient time for lineage sorting. Coalescent simulations indicate that gene flow between these two subspecies is highly asymmetric, with the majority of migration occurring from mimetic into nonmimetic populations. Selective sweeps of alleles responsible for mimetic phenotypes may have occurred more than once when mimetic and nonmimetic Limenitis occurred together in the presence of the model (Battus philenor).     

Ancestral Stories of Ghanaian Bimoba Reflect Millennia-Old Genetic Lineages

Oral history and oral genealogies are mechanisms of collective memory and a main cultural heritage of many populations without a writing system. In the effort to analytically address the correspondence between genetic data and historical genealogies, anthropologists hypothesised that genealogies evolve through time, ultimately containing three parts: literal – where the most recent ancestry is truthfully represented; intended – where ancestry is inferred and reflects political relations among groups; and mythical – that does not represent current social reality. While numerous studies discuss oral genealogies, to our knowledge no genetic studies have been able to investigate to what extent genetic relatedness corresponds to the literal and intended parts of oral genealogies. We report on the correspondence between genetic data and oral genealogies among Bimoba males in a single village in North-Eastern Ghana. We compared the pairwise mismatch distribution of Y chromosome short tandem repeat (Y-STR) haplotypes among all lineages present in this village to the self-reported (oral) relatedness. We found that Bimoba are able to correctly identify unrelated individuals in 92% of the cases. In contrast, they are able to correctly identify related individuals only in 38% of the cases, which can be explained by three processes: (1) the compression of genealogies, leading to increasing inaccuracy with increasing genealogical distance, (2) inclusions into the lineage from intended relations such as clan co-option or adoptions, and (3) false paternities, which in this study were found to have a minor effect on the correspondence between genetic data and oral genealogies. In addition, we observed that 70% of unrelated pairs have from six to eight Y-STR differences, a diversification peak which we attribute to an ancient West African expansion dating around 9454 years ago. We conclude that, despite all caveats, oral genealogies are reflecting ancient lineages more accurately than previously thought.     

Purifying Selection Causes Widespread Distortions of Genealogical Structure on the Human X Chromosome

The extent to which selective forces shape patterns of genetic and genealogical variation is unknown in many species. Recent theoretical models have suggested that even relatively weak purifying selection may produce significant distortions in gene genealogies, but few studies have sought to quantify this effect in humans. Here, we employ a reconstruction method based on the ancestral recombination graph to infer genealogies across the length of the human X chromosome and to examine time to most recent common ancestor (TMRCA) and measures of tree imbalance at both broad and very fine scales. In agreement with theory, TMRCA is significantly reduced and genealogies are significantly more imbalanced in coding regions and introns when compared to intergenic regions, and these effects are increased in areas of greater evolutionary constraint. These distortions are present at multiple scales, and chromosomal regions as broad as 5 Mb show a significant negative correlation in TMRCA with exon density. We also show that areas of recent TMRCA are significantly associated with the disease-causing potential of site as measured by the MutationTaster prediction algorithm. Together, these findings suggest that purifying selection has significantly distorted human genealogical structure on both broad and fine scales and that few chromosomal regions escape selection-induced distortions.     

Intra-deme molecular diversity in spatially expanding populations

We report here a simulation study examining the effect of a recent spatial expansion on the pattern of molecular diversity within a deme. We first simulate a range expansion in a virtual world consisting in a two-dimensional array of demes exchanging a given proportion of migrants (m) with their neighbors. The recorded demographic and migration histories are then used under a coalescent approach to generate the genetic diversity in a sample of genes. We find that the shape of the gene genealogies and the overall pattern of diversity within demes depend not only on the age of the expansion but also on the level of gene flow between neighboring demes, as measured by the product Nm, where N is the size of a deme. For small Nm values (< approximately 20 migrants sent outwards per generation), a substantial proportion of coalescent events occur early in the genealogy, whereas with larger levels of gene flow, most coalescent events occur around the time of the onset of the spatial expansion. Gene genealogies are star shaped, and mismatch distributions are unimodal after a range expansion for large Nm values. In contrast, gene genealogies present a mixture of both very short and very long branch lengths, and mismatch distributions are multimodal for small Nm values. It follows that statistics used in tests of selective neutrality like Tajima's D statistic or Fu's F(S) statistic will show very significant negative values after a spatial expansion only in demes with high Nm values. In the context of human evolution, this difference could explain very simply the fact that analyses of samples of mitochondrial DNA sequences reveal multimodal mismatch distributions in hunter-gatherers and unimodal distributions in post-Neolithic populations. Indeed, the current simulations show that a recent increase in deme size (resulting in a larger Nm value) is sufficient to prevent recent coalescent events and thus lead to unimodal mismatch distributions, even if deme sizes (and therefore Nm values) were previously much smaller. The fact that molecular diversity within deme is so dependent on recent levels of gene flow suggests that it should be possible to estimate Nm values from samples drawn from a single deme.     

Fertility on the US-Mexico border

Using Bongaarts' model, the relative importance of the proximate determinants of fertility is explored in five populations on the US-Mexico border. For the groups closest to natural fertility (the two Mexican groups), lactation, use of contraception, and marriage all were moderately important in terms of their direct effect on fertility. For the group with lowest fertility (Anglo-American), contraceptive use was an important factor inhibiting fertility; marriage was important but not nearly as important as contraceptive use. For the two US Mexican-American groups, contraceptive use was an important intermediate variable, not as important as for Anglo-Americans, but more important than it was for the two populations in Mexico. The proportion married was a moderately important factor for the Mexican-American groups. For these five populations the principal differences in fertility rates result from substantial differences in the use of effective contraception. Bongaarts' model proved very useful as an analytical framework in this study.     

Matrilineal fertility inheritance detected in hunter-gatherer populations using the imbalance of gene genealogies

Fertility inheritance, a phenomenon in which an individual's number of offspring is positively correlated with his or her number of siblings, is a cultural process that can have a strong impact on genetic diversity. Until now, fertility inheritance has been detected primarily using genealogical databases. In this study, we develop a new method to infer fertility inheritance from genetic data in human populations. The method is based on the reconstruction of the gene genealogy of a sample of sequences from a given population and on the computation of the degree of imbalance in this genealogy. We show indeed that this level of imbalance increases with the level of fertility inheritance, and that other phenomena such as hidden population structure are unlikely to generate a signal of imbalance in the genealogy that would be confounded with fertility inheritance. By applying our method to mtDNA samples from 37 human populations, we show that matrilineal fertility inheritance is more frequent in hunter-gatherer populations than in food-producer populations. One possible explanation for this result is that in hunter-gatherer populations, individuals belonging to large kin networks may benefit from stronger social support and may be more likely to have a large number of offspring.     

The complex analytical landscape of gene flow inference

Gene flow estimation is essential for characterizing local adaptation, speciation potential and connectivity among threatened populations. New model-based population genetic methods can resolve complex demographic histories, but many studies in fields such as landscape genetics continue to rely on simple rules of thumb focused on gene flow to explain patterns of spatial differentiation. Here, we show how methods that use gene genealogies can reveal cryptic demographic histories and provide better estimates of gene flow with other parameters that contribute to genetic variation across landscapes and seascapes. We advocate for the expanded use and development of methods that consider spatial differentiation as the product of multiple forces interacting over time, and caution against a routine reliance on post-hoc gene flow interpretations.     

Matrilineal Fertility Inheritance Detected in Hunter–Gatherer Populations Using the Imbalance of Gene Genealogies

Fertility inheritance, a phenomenon in which an individual's number of offspring is positively correlated with his or her number of siblings, is a cultural process that can have a strong impact on genetic diversity. Until now, fertility inheritance has been detected primarily using genealogical databases. In this study, we develop a new method to infer fertility inheritance from genetic data in human populations. The method is based on the reconstruction of the gene genealogy of a sample of sequences from a given population and on the computation of the degree of imbalance in this genealogy. We show indeed that this level of imbalance increases with the level of fertility inheritance, and that other phenomena such as hidden population structure are unlikely to generate a signal of imbalance in the genealogy that would be confounded with fertility inheritance. By applying our method to mtDNA samples from 37 human populations, we show that matrilineal fertility inheritance is more frequent in hunter–gatherer populations than in food-producer populations. One possible explanation for this result is that in hunter–gatherer populations, individuals belonging to large kin networks may benefit from stronger social support and may be more likely to have a large number of offspring.     

Does organismal pedigree impact the magnitude of topological congruence among gene trees for unlinked loci?

One of the fundamental assumptions in the multi-locus approach to phylogeographic studies is that unlinked loci have independent genealogies. For this reason, congruence among gene trees from unlinked loci is normally interpreted as support for the existence of external forces that may have concordantly shaped the topology of multiple gene trees. However, it is also important to address and quantify the possibility that gene trees within a given species are all inherently constrained to some degree by their shared organismal pedigree, and thus in this strict sense are not entirely independent. Here we demonstrate by computer simulations that gene trees from a shared pedigree tend to display higher topological concordance than do gene trees from independent pedigrees with the same demographic parameters, but we also show that these constraining effects are normally minor in comparison to the much higher degree of topological concordance that can routinely emerge from external phylogeographic shaping forces. The topology-constraining effect of a shared pedigree decreases as effective population size increases, and becomes almost negligible in a random mating population of more than 1,000 individuals. Moreover, statistical detection of the pedigree effect requires a relatively large number of unlinked loci that far exceed what is typically used in current phylogeographic studies. Thus, with the possible exception of extremely small populations, multiple unlinked genes within a pedigree can indeed be assumed, for most practical purposes, to have independent genealogical histories.     

Mitochondrial and nuclear genetic contribution of female founders to a contemporary population in northeast Quebec.

A common challenge in population genetics is to reconstruct the evolutionary history of populations on the basis of current allele frequencies. Through pedigree analysis, we have the opportunity to study the genetic contribution of founders to the contemporary population. This contribution over many generations accounts for the probable introduction, survival, and extinction of genes in the population. I use this method to follow nuclear and mitochondrial genes in the Saguenay population of northeast Quebec by tracing back ascending genealogies of 160,315 individuals born between 1950 and 1971 by using the BALSAC database. This study leads us to conclude that even in a growing population, the loss rate of mtDNA is high. The survival of mtDNA in the population is independent of the time of introduction in the population. The number of copies of a particular mtDNA gene in the contemporary population is higher for genes introduced earlier, but the correlation between these two variables is low (the relation is not linear). Compared to nuclear contribution, mitochondrial contribution is higher, but the loss rate of nuclear DNA is lower. The differential contribution (the fact that few founders contribute a lot) is the same proportion for nuclear and mtDNA, but only 592 female founders contribute 50% of the mtDNA gene pool of the contemporary cohort, compared to 994 for nuclear DNA. Since we have no molecular data on founders' haplotypes, these results cannot give us the diversity level in the population. However, this study enables us to compare the evolutionary fates of nuclear and mitochondrial genes in this expanding population.     

Spatial subdivision of populations and estimates of genetic variation

Measures of variation in space are strongly affected by correlations between subdivisions used for sampling. Here we consider variation in gene frequencies across populations. Usually the variance of gene frequencies is standardized by dividing it by the mean gene frequency times one minus the mean (FST). Under the model of isolation by distance (usually called the "stepping stone" model), at the stationary state the correlation between the gene frequencies of two populations falls exponentially with the geographic distance between them. Using this model, we derive formulas for variances of blocks of populations of different sizes in one- and two-dimensional space and suggest that the theoretical results may be useful for understanding real observations, some examples of which are presented. We demonstrate how FST increases with the degree of subdivision among populations. We also show the effect of gaps between the sampled populations. Our results are valid, however, for traits other than gene frequencies, as long as their correlation with geographic distance falls exponentially. In the extension to 2-dimensional spaces, we present in closed form the distributions of distances between nodes of a lattice or of two lattices. These distributions might have applications in ecology.     

Linkage disequilibrium under recurrent bottlenecks

To model deviations from selectively neutral genetic variation caused by different forms of selection, it is necessary to first understand patterns of neutral variation. Best understood is neutral genetic variation at a single locus. But, as is well known, additional insights can be gained by investigating multiple loci. The resulting patterns reflect the degree of association (linkage) between loci and provide information about the underlying multilocus gene genealogies. The statistical properties of two-locus gene genealogies have been intensively studied for populations of constant size, as well as for simple demographic histories such as exponential population growth and single bottlenecks. By contrast, the combined effect of recombination and sustained demographic fluctuations is poorly understood. Addressing this issue, we study a two-locus Wright-Fisher model of a population subject to recurrent bottlenecks. We derive coalescent approximations for the covariance of the times to the most recent common ancestor at two loci in samples of two chromosomes. This covariance reflects the degree of association and thus linkage disequilibrium between these loci. We find, first, that an effective population-size approximation describes the numerically observed association between two loci provided that recombination occurs either much faster or much more slowly than the population-size fluctuations. Second, when recombination occurs frequently between but rarely within bottlenecks, we observe that the association of gene histories becomes independent of physical distance over a certain range of distances. Third, we show that in this case, a commonly used measure of linkage disequilibrium, σ(2)(d) (closely related to r(2)), fails to capture the long-range association between two loci. The reason is that constituent terms, each reflecting the long-range association, cancel. Fourth, we analyze a limiting case in which the long-range association can be described in terms of a Xi coalescent allowing for simultaneous multiple mergers of ancestral lines.     

Methodology of reconstruction and preliminary analysis of 1533 genealogies of parma valley population (centuries XVI–XX)

The reconstruction of the genealogies and the detailed knowledge of the biological and kinship relationship linking the past and the present members of a population and their succession in time, can be a precious source of information for those who want to reconstruct and analyze biological and cultural mechanisms by which human populations evolve and adapt to environmental changes.The methods used for the reconstruction of the genealogies are described and an analysis of the results obtained is presented in order to test the validity of the techniques employed on the basis of the reliability of the results.Finally, a discussion of some possible lines of research derived from analysis of the data are presented, given that the use of genealogies, far from being restricted to the genealogies themselves, can offer a valid contribution to the analysis of the structure and evolution of human populations.     

Admixed ancestry and stratification of Quebec regional populations

Population stratification results from unequal, nonrandom genetic contribution of ancestors and should be reflected in the underlying genealogies. In Quebec, the distribution of Mendelian diseases points to local founder effects suggesting stratification of the contemporary French Canadian gene pool. Here we characterize the population structure through the analysis of the genetic contribution of 7,798 immigrant founders identified in the genealogies of 2,221 subjects partitioned in eight regions. In all but one region, about 90% of gene pools were contributed by early French founders. In the eastern region where this contribution was 76%, we observed higher contributions of Acadians, British and American Loyalists. To detect population stratification from genealogical data, we propose an approach based on principal component analysis (PCA) of immigrant founders' genetic contributions. This analysis was compared with a multidimensional scaling of pairwise kinship coefficients. Both methods showed evidence of a distinct identity of the northeastern and eastern regions and stratification of the regional populations correlated with geographical location along the St-Lawrence River. In addition, we observed a West-East decreasing gradient of diversity. Analysis of PC-correlated founders illustrates the differential impact of early versus latter founders consistent with specific regional genetic patterns. These results highlight the importance of considering the geographic origin of samples in the design of genetic epidemiology studies conducted in Quebec. Moreover, our results demonstrate that the study of deep ascending genealogies can accurately reveal population structure.     

Population structure in the American oyster as inferred by nuclear gene genealogies

Multiple haplotypes from each of three nuclear loci were isolated and sequenced from geographic populations of the American oyster, Crassostrea virginica. In tests of alternative phylogeographic hypotheses for this species, nuclear gene genealogies constructed for these haplotypes were compared to one another, to a mitochondrial gene tree, and to patterns of allele frequency variation in nuclear restriction site polymorphisms (RFLPs) and allozymes. Oyster populations from the Atlantic versus the Gulf of Mexico are not reciprocally monophyletic in any of the nuclear gene trees, despite considerable genetic variation and despite large allele frequency differences previously reported in several other genetic assays. If these populations were separated vicariantly in the past, either insufficient time has elapsed for neutral lineage sorting to have achieved monophyly at most nuclear loci, or balancing selection may have inhibited lineage extinction, or secondary gene flow may have moved haplotypes between regions. These and other possibilities are examined in light of available genetic evidence, and it is concluded that no simple explanation can account for the great variety of population genetic patterns across loci displayed by American oysters. Regardless of the source of this heterogeneity, this study provides an empirical demonstration that different sequences of DNA within the same organismal pedigree can have quite different phylogeographic histories.