Founder effect and genetic disease in Sottunga, Finland

Pedigree data are analyzed in order to determine the factors responsible for the high frequencies of certain genetic disorders in an isolated Swedish-speaking population of Finland's A land archipelago. The founders of Sottunga are identified, and the genetic contributions of each founder to descending birth cohorts are estimated. Founders born before 1700 have far more descendants in the contemporary gene pool than do more recent founders. However, because of migration and depopulation since 1900, the expected genetic contributions of the early founders to the present-day population are similar to those of later founders. A descendant in the contemporary population has a 2% chance of having inherited a particular gene from the founder who makes the largest single contribution to the gene pool. This corresponds approximately to a 2% probability of inheriting an autosomal dominant disease gene from this founder. Given an average inbreeding coefficient of 0.0016, the probability of inheriting two recessive disease genes from this founder is 0.000032. The incidence of autosomal dominant von Willebrand disease in Sottunga is greater than 10% while that of autosomal recessive tapetoretinal disease is 1.5%. We conclude, therefore, that the high frequencies of these diseases are not due to the disproportionate genetic contribution of one or a few particular founders. It is more likely that these disease genes occurred in high frequency in the initial population or were introduced repeatedly through time.     

Partitioning heterozygosity in subdivided populations: Some misuses of Nei's decomposition and an alternative probabilistic approach

Nei's decomposition of total expected heterozygosity in subdivided populations into within‐ and between‐subpopulation components, H_S and D_ST, respectively, is a classical tool in the conservation and management of genetic resources. Reviewing why this is not a decomposition into independent terms of within‐ and between‐subpopulation gene diversity, we illustrate how this approach can be misleading because it overemphasizes the within‐subpopulation component compared to Jost's nonadditive decomposition based on gene diversity indices. Using probabilistic partitioning of the total expected heterozygosity into independent within‐ and between‐subpopulation contributions, we show that the contribution of the within‐subpopulation expected heterozygosity to the total expected heterozygosity is not H_S, as suggested by Nei's decomposition, but H_S/s, with s being the number of subpopulations. Finally, we compare three possible approaches of decomposing total heterozygosity in subdivided populations (i.e., Nei's decomposition, Jost's approach, and probabilistic partitioning) with regard to independence between terms and sensitivity to unequal subpopulation sizes. For the conservation and management of genetic resources, we recommend using probabilistic partitioning and Jost's differentiation parameter rather than Nei's decomposition.     

Variability of the genetic contribution of Quebec population founders associated to some deleterious genes.

Relatively high frequencies of some rare inherited disorders can be found in the Saguenay Region (Quebec). To understand this phenomenon, a research project on the 17th-century founder effect that led to the formation of French Canadians' gene pool is being carried out. The focus of this study is on founders who contributed to the Saguenay gene pool and who are related to contemporary probands suffering from any one of five hereditary diseases: cystic fibrosis, tyrosinemia, hemochromatosis, Charlevoix-Saguenay spastic ataxia, and sensorimotor polyneuropathia with or without agenesis of the corpus callosum. A control group has been added for comparison purposes. Altogether, 545 ascending genealogies have been reconstructed, using the Interuniversity Institute for Population Research's RETRO database, leading to > 2,500 founders. The genetic contribution of each founder to each group has been measured. Results show that (1) nearly 80% of the individuals' gene pool come from founders who settled in Nouvelle-France in the 17th century, whatever the group; (2) 15% of the founders explain 90% of the total genetic contribution of the founders, but this pattern varies from one group to another; (3) there is no subgroup of founders more related to any given group of individuals.     

Clarification of genetic terms and their use in the management of captive populations

Some of the concepts, terms, and methods used in the genetic management of captive populations have not been defined precisely in the scientific literature and consequently have been misunderstood and misused. The definitions and interrelationships among gene diversity, effective population size, founder genome equivalents, inbreeding, allelic diversity, mean kinship, and kinship value are presented here. It is important to understand what populations and generations are used as the baselines against which losses of genetic variation are measured. Gene diversity and founder genome equivalents are defined relative to a source population from which founders of the captive population were randomly sampled. Inbreeding and allelic diversity are assessed relative to the founders. The potential gene diversity that would result from an equalization of frequencies of founder alleles retained in the population can never be achieved because, among other limitations, the random process of gene transmission will prevent equalization of allele frequencies even if animals are bred optimally. The gene diversity achievable with the population can be determined by iterative production of hypothetical offspring from the pairs with lowest mean kinship. The long-term objective for offspring production from each animal is also thereby generated. Mean kinships should be recalculated with each real or hypothetical birth and death, because offspring objectives based on current mean kinships might correlate poorly with the optimal long-term offspring objectives. © 1995 Wiley-Liss, Inc.     

METAPOP—A software for the management and analysis of subdivided populations in conservation programs

We introduce a computer program for the dynamic and flexible management of conserved subdivided populations. Using molecular marker data or pedigree information, the software determines the optimal contributions (i.e., number of offspring) of each individual, the number of migrants, and the particular subpopulations involved in the exchange of individuals in order to maintain the largest level of gene diversity in the whole population with a desired control in the rate of inbreeding. Restrictions can be introduced for the total number of migrants, and the mating of particular pairs and their contribution. A full genetic diversity analysis of the population is carried out. The optimal contribution from each subpopulation to a pool of maximal gene diversity is also provided by the program.     

Interrelations between effective population size and other pedigree tools for the management of conserved populations

Genetic parameters widely used to monitor genetic variation in conservation programmes, such as effective number of founders, founder genome equivalents and effective population size, are interrelated in terms of coancestries and variances of contributions from ancestors to descendants. A new parameter, the effective number of non-founders, is introduced to describe the relation between effective number of founders and founder genome equivalents. Practical recommendations for the maintenance of genetic variation in small captive populations are discussed. To maintain genetic diversity, minimum coancestry among individuals should be sought. This minimizes the variances of contributions from ancestors to descendants in all previous generations. The method of choice of parents and the system of mating should be independent of each other because a clear-cut recommendation cannot be given on the latter.     

Analysis of founder representation in pedigrees: Founder equivalents and founder genome equivalents

The concepts of “founder equivalent” and “founder genome equivalent” are introduced to facilitate analysis of the founding stocks of captive or other populations for which pedigrees are available. The founder equivalents of a population are the number of equally contributing founders that would be expected to produce the same genetic diversity as in the population under study. Unequal genetic contributions by founders decrease the founder equivalents, portend greater inbreeding in future generations than would be necessary, and reflect a greater loss of the genetic diversity initially present in the founders. The number of founder genome equivalents of a population is that number of equally contributing founders with no random loss of founder alleles in descendants that would be expected to produce the same genetic diversity as in the population under study. The number of founder genome equivalents is approximately that number of wild-caught animals that would be needed to obtain the same amount of genetic diversity as is in the descendant captive population. Founder equivalents and founder genome equivalents allow comparison of the genetic merits of adding new wild-caught stock vs. further equalizing founder representations in a captive population.     

Selective recovery of founder genetic diversity in aquacultural broodstocks and captive, endangered fish populations

Hatchery broodstocks used for genetic conservation or aquaculture may represent their ancestral gene pools rather poorly. This is especially likely when the fish that found a broodstock are close relatives of each other. We re-analysed microsatellite data from a breeding experiment on red sea bream to demonstrate how lost genetic variation might be recovered when gene frequencies have been distorted by consanguineous founders in a hatchery. A minimal-kinship criterion based on a relatedness estimator was used to select subsets of breeders which represented the maximum number of founder lineages (i.e., carried the fewest identical copies of ancestral genes). UPGMA clustering of Nei's genetic distances grouped these selected subsets with the parental gene pool, rather than with the entire, highly drifted offspring generation. The selected subsets also captured much of the expected heterozygosity and allelic diversity of the parental gene pool. Independent pedigree data on the same fish showed that the selected subsets had more contributing parents and more founder equivalents than random subsets of the same size. The estimated mean coancestry was lower in the selected subsets, meaning that inbreeding in subsequent generations would be lower if they were used as breeders. The procedure appears suitable for reducing the genetic distortion due to consanguineous and over-represented founders of a hatchery gene pool.     

The impact of assumptions about founder relationships on the effectiveness of captive breeding strategies

Many breeding programs managed by zoos and aquariums employ strategies that minimize mean kinship as a way of retaining genetic diversity (MK strategies). MK strategies depend on accurate and complete pedigrees, but population founders are generally assumed to be unrelated and not inbred. This assumption was historically necessitated by the unavailability of data on founder relationships, but with DNA techniques it is sometimes now possible to estimate those relationships. We used computer simulations to investigate the impact of founder assumptions on the effectiveness of MK strategies. Individuals with known pedigrees were managed in groups of 10, 30, and 100 founders at two different rates of reproduction and two different degrees of founder relationship. The impact of assuming founders were unrelated was quantified by calculating the differences in gene diversity and inbreeding that were observed between simulations that used known relationships and simulations that assumed founders were unrelated. Results indicated that utilizing known relationships retained 0–2% more gene diversity over ten generations than assuming founders were unrelated, with specific results dependent on the conditions of a given scenario. Similar results were observed for inbreeding, with long-term levels of inbreeding being 0–2% lower when relationships were known. There were higher benefits to knowing founder relationships as reproductive rate increased, as well as when full-siblings were included in small groups of founders. Overall, however, long-term benefits gained from knowing founder relationships were generally small. Therefore, MK strategies probably often produce near optimal results when standard founder assumptions are made.     

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.     

Genetic diversity of laboratory gray short-tailed opossums (Monodelphis domestica): effect of newly introduced wild-caught animals.

The colony of gray, short-tailed opossums (Monodelphis domestica) at the Southwest Foundation for Biomedical Research, the primary supplier of this species for research purposes, was founded with nine animals trapped in 1978 in the state of Pernambuco, Brazil. Since 1984, 14 newly acquired founders from the state of Paraiba, Brazil have contributed to the gene pool of the colony. The animals from Paraiba and their descendants are significantly larger than the founders from Pernambuco and their descendants. The two groups also differ significantly in several measurements of morphologic traits. The changes in proportional contribution of each founder to the colony, and changes in inbreeding coefficients during the colony's history, are evaluated. Using previously established markers and three newly identified markers (ACP2, APRT, and DIA1), we show that the Paraiba-derived animals differ significantly from the original founders in allele frequencies and heterozygosity. The genetic diversity of the colony has been substantially increased by acquisition of the new founders from Paraiba. The colony is highly polymorphic, with 22.2% of loci surveyed by protein electrophoresis being variable. We conclude that the genetic differences between populations and among projects within the colony should be considered in future colony management procedures and in selection of experimental subjects.     

Genetic diversity,population structure and subdivision of local Balkan pig breeds in Austria,Croatia, Serbia and Bosnia-Herzegovina and its practical value in conservation programs

Background

At present the Croatian Turopolje pig population comprises about 157 breeding animals. In Austria, 324 Turopolje pigs originating from six Croatian founder animals are registered. Multiple bottlenecks have occurred in this population, one major one rather recently and several more older and moderate ones. In addition, it has been subdivided into three subpopulations, one in Austria and two in Croatia, with restricted gene flow. These specificities explain the delicate situation of this endangered Croatian lard-type pig breed.

Methods

In order to identify candidate breeding animals or gene pools for future conservation breeding programs, we studied the genetic diversity and population structure of this breed using microsatellite data from 197 individuals belonging to five different breeds.

Results

The genetic diversity of the Turopolje pig is dramatically low with observed heterozygosities values ranging from 0.38 to 0.57. Split into three populations since 1994, two genetic clusters could be identified: one highly conserved Croatian gene pool in Turopoljski Lug and the"Posavina" gene pool mainly present in the Austrian population. The second Croatian subpopulation in Lonjsko Polje in the Posavina region shows a constant gene flow from the Turopoljski Lug animals.

Conclusions

One practical conclusion is that it is necessary to develop a "Posavina" boar line to preserve the "Posavina" gene pool and constitute a corresponding population in Croatia. Animals of the highly inbred herd in Turopoljski Lug should not be crossed with animals of other populations since they represent a specific phenotype-genotype combination. However to increase the genetic diversity of this herd, a program to optimize its sex ratio should be carried out, as was done in the Austrian population where the level of heterozygosity has remained moderate despite its heavy bottleneck in 1994.     

Limited Reintroduction Does Not Always Lead to Rapid Loss of Genetic Diversity: An Example from the American Chestnut (Castanea dentata; Fagaceae)

In restoring species, reasons for introducing limited numbers of individuals at different locations include costs of introduction and maintenance, limited founder supply, and risk “bet hedging.” However, populations initiated from few founders may experience increased genetic drift, inbreeding, and diversity loss. We examined the genetic diversity of an isolated stand of more than 5,000 American chestnut trees relative to that of the 9 surviving stand founders (out of 10 total) planted in the 1880s. We used minisatellite DNA probes to reveal 84 genetic markers (circa 24 loci) among the nine founders, and their genetic diversity was compared with three separate plots of descendant trees, as well as with two natural stands. The descendants were circa 7.3% more heterozygous than the founders (mean estimated H= 0.556 vs. 0.518, respectively; p < 0.0001). Genetic differentiation was not pronounced (F_ST < 0.031), and no markers, including those at low frequency among the founders, were lost in the descendants. The founders and natural transects were not significantly different in H or similarity (mean proportion of bands shared). Special planting or mating protocols for establishment of a vigorous American chestnut population from a low number of founders may not be required to avoid strong effects of genetic drift and inbreeding. These results demonstrate that loss of genetic diversity following reintroduction of a limited number of founders is not always inevitable, such as this case where the species is highly outcrossing, expression of heterozygous advantage may occur, the original founders remain as gene contributors over generations, and the establishing population expands constantly and rapidly.     

Fragmentation of the Québec population genetic pool (Canada): evidence from the genetic contribution of founders per region in the 17th and 18th centuries

The 6 million French-Canadians of Québec derive from a relatively small number of founders. Consequently, some hereditary diseases, which may or may not present a worldwide distribution, have been detected in high frequency in this population. Several studies, however, indicate a nonuniform distribution of these diseases through the population, suggesting that the French-Canadian founder effect has been geographically stratified. Here we explore this stratification by using a demographic database, the Population Register of Early Québec, that contains almost all birth, marriage, and death certificates (>712,000) recorded in parish registers between 1608-1800. In this database, every genealogical link has been traced back to the founders of the population, so that we can compute the genetic contribution of founder per region, and then account for the early events that have shaped the distribution of diseases. Ten regions, comprising varying numbers of parishes, have been selected. We first describe each region in terms of homogeneity and concentration of its gene pool. For this purpose, a new concept is introduced, the founders' uniform contribution number (FUN), i.e., the number of founders a population would have if all its founders had an equal contribution. Second, we estimate genetic similarity between regions on the basis of differential genetic contribution. To classify the regions, we use principal component and cluster analysis. Our results show a tripartite clustering of the population, and invite us to reconsider the results obtained from biomolecular and clinical studies, which show a bipartite clustering.     

Genetic characterization of specific pathogen‐free rhesus macaque (Macaca mulatta) populations at the California National Primate Research Center (CNPRC)

A study based on 14 STRs was conducted to understand intergenerational genetic changes that have occurred within the California National Primate Research Center's (CNPRC) regular specific pathogen‐free (SPF) and super‐SPF captive rhesus macaque populations relative to their conventional founders. Intergenerational genetic drift has caused age cohorts of each study population, especially within the conventional population, to become increasingly differentiated from each other and from their founders. Although there is still only minimal stratification between the conventional population and either of the two SPF populations, separate derivation of the regular and super‐SPF animals from their conventional founders has caused the two SPF populations to remain marginally different from each other. The regular SPF and, especially, the super‐SPF populations have been influenced by the effects of differential ancestry, sampling, and lost rare alleles, causing a substantial degree of genetic divergence between these subpopulations. The country of origin of founders is the principal determinant of the MHC haplotype composition of the SPF stocks at the CNPRC. Selection of SPF colony breeders bearing desired genotypes of Mamu‐A^*01 or ‐B^*01 has not affected the overall genetic heterogeneity of the conventional and the SPF research stocks. Because misclassifying the ancestry of research stocks can undermine experimental outcomes by excluding animals with regional‐specific genotypes or phenotypes of importance, understanding founder/descendent genetic relationships is crucial for investigating candidate genes with distinct geographic origins. Together with demographic management, population genetic assessments of SPF colonies can curtail excessive phenotypic variation among the study stocks and facilitate successful production goals. Am. J. Primatol. 72:587–599, 2010. © 2010 Wiley‐Liss, Inc.     

Hybridization and Stratification of Nuclear Genetic Variation in Macaca mulatta and M. fascicularis

We used genotypes for 13 short tandem repeats (STRs) to assess the genetic diversity within and differentiation among populations of rhesus macaques (Macaca mulatta) from mainland Asia and long-tailed macaques (M. fascicularis) from mainland and insular Southeast Asia. The subjects were either recently captured in the wild or derived from wild-caught founders maintained in captivity for biomedical research. A large number of alleles are shared between the 2 macaque species but a significant genetic division between them persists. The distinction is more clear-cut among populations that are not, or are unlikely to have recently been, geographically contiguous. Our results suggest there has been significant interspecific nuclear gene flow between rhesus macaques and long-tailed macaques on the mainland. Comparisons of mainland and island populations of long-tailed macaques reflect marked genetic subdivisions due to barriers to migration. Geographic isolation has restricted gene flow, allowing island populations to become subdivided and genetically differentiated. Indonesian long-tailed macaques show evidence of long-term separation and genetic isolation from the mainland populations, whereas long-tailed macaques from the Philippines and Mauritius both display evidence of founder effects and subsequent isolation, with the impact from genetic drift being more profound in the latter.     

Gene survival in the Asian wild horse (Equus przewalskii): I. Dependence of gene survival in the calgary breeding group pedigree

The joint probability distribution of the number of distinct (not identical by descent) genes from each founder of the Equus przewalskii population that survive in the five horses of the Calgary Zoological Gardens breeding group has been calculated. The dependence structure of this distribution is investigated, and informative marginal distributions are given, among them the distributions of the genetic contributions of each founder to the Calgary horses and the distribution of wild-type genes in these horses. The dependence pattern is found to be complex; there is no substitute for exact calculation of the full joint probability distribution of numbers of surviving genes. Probabilities of gene survival give a more complete summary of the genetic structure of a set of individuals than is provided by more routine measures such as heterozygosity or founder contributions. The feasibility of computing these probabilities for small groups of current individuals descended from few founders via long and complex pedigrees, provides a new approach to assessing such groups, and could be used also in selecting animals to form the founder stock of propagules for future reintroduction programs.     

Assimilation of new founders into existing captive populations

When new founders are added to an existing captive population, it is useful to establish a target number of offspring from each of these new founders that will maximize the amount of gene diversity retained in the captive population. This article presents a method for calculating an optimal number of offspring that should be produced from each new founder by considering the retention of founder genomes from dead and non-reproductive founders. © 1994 Wiley-Liss, Inc.     

The cryptic genetic structure of the North American captive gorilla population

Western lowland gorillas (Gorilla gorilla gorilla) were imported from across their geographical range to North American zoos from the late 1800s through 1974. The majority of these gorillas were imported with little or no information regarding their original provenance and no information on their genetic relatedness. Here, we analyze 32 microsatellite loci in 144 individuals using a Bayesian clustering method to delineate clusters of individuals among a sample of founders of the captive North American zoo gorilla collection. We infer that the majority of North American zoo founders sampled are distributed into two distinct clusters, and that some individuals are of admixed ancestry. This new information regarding the existence of ancestral genetic population structure in the North American zoo population lays the groundwork for enhanced efforts to conserve the evolutionary units of the western lowland gorilla gene pool. Our data also show that the genetic diversity estimates in the founder population were comparable to those in wild gorilla populations (Mondika and Cross River), and that pairwise relatedness among the founders is no different from that expected for a random mating population. However, the relatively high level of relatedness (R = 0.54) we discovered in a pair of known breeding pairs reveals the need for incorporating genetic relatedness estimates in the captive management of western lowland gorillas.     

Inbreeding trends and genetic diversity in purebred sheep populations

Monitoring the rate of change in inbreeding and genetic diversity within a population is important to guide breeding programmes. Such interest stems from the impact of loss in genetic diversity on sustainable genetic gain but also the impact on performance (i.e. inbreeding depression). The objective of the present study was to evaluate trends in inbreeding and genetic diversity in 43 066 Belclare, 120 753 Charollais, 22 652 Galway, 78 925 Suffolk, 187 395 Texel, and 19 821 Vendeen purebred sheep. The effective population size for each of the six breeds was between 116.0 (Belclare population) and 314.8 (Charollais population). The Charollais population was the most genetically diverse with the greatest number of effective founders, effective ancestors, and effective founder genomes; conversely, the Belclare was the least genetically diverse population with the fewest number of effective founders, effective ancestors, and effective founder genomes for each of the six breeds investigated. Overall, the effective population sizes and the total genetic diversity within each of the six breeds were above the minimum thresholds generally considered to be required for the long-term viability of a population.