Genomic and genealogical investigation of the French Canadian founder population structure

Characterizing the genetic structure of worldwide populations is important for understanding human history and is essential to the design and analysis of genetic epidemiological studies. In this study, we examined genetic structure and distant relatedness and their effect on the extent of linkage disequilibrium (LD) and homozygosity in the founder population of Quebec (Canada). In the French Canadian founder population, such analysis can be performed using both genomic and genealogical data. We investigated genetic differences, extent of LD, and homozygosity in 140 individuals from seven sub-populations of Quebec characterized by different demographic histories reflecting complex founder events. Genetic findings from genome-wide single nucleotide polymorphism data were correlated with genealogical information on each of these sub-populations. Our genomic data showed significant population structure and relatedness present in the contemporary Quebec population, also reflected in LD and homozygosity levels. Our extended genealogical data corroborated these findings and indicated that this structure is consistent with the settlement patterns involving several founder events. This provides an independent and complementary validation of genomic-based studies of population structure. Combined genomic and genealogical data in the Quebec founder population provide insights into the effects of the interplay of two important sources of bias in genetic epidemiological studies, unrecognized genetic structure and cryptic relatedness.     

Origin and spread of the 1278insTATC mutation causing Tay-Sachs disease in Ashkenazi Jews: genetic drift as a robust and parsimonious hypothesis

The 1278insTATC is the most prevalent -hexosaminidase A (HEXA) gene mutation causing Tay-Sachs disease (TSD), one of the four lysosomal storage diseases (LSDs) occurring at elevated frequencies among Ashkenazi Jews (AJs). To investigate the genetic history of this mutation in the AJ population, a conserved haplotype (D15S981:175–D15S131:240–D15S1050:284–D15S197:144–D15S188:418) was identified in 1278insTATC chromosomes from 55 unrelated AJ individuals (15 homozygotes and 40 heterozygotes for the TSD mutation), suggesting the occurrence of a common founder. When two methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the insertion was found to be 40±12 generations (95% confidence interval: 30–50 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 8th–9th century. This corresponds with the demographic expansion of AJs in central Europe, following the founding of the Ashkenaz settlement in the early Middle Ages. The results are consistent with the geographic distribution of the main TSD mutation, 1278insTATC being more common in central Europe, and with the coalescent times of mutations causing two other LSDs, Gaucher disease and mucolipidosis type IV. Evidence for the absence of a determinant positive selection (heterozygote advantage) over the mutation is provided by a comparison between the estimated age of 1278insTATC and the probability of the current AJ frequency of the mutant allele as a function of its age, calculated by use of a branching-process model. Therefore, the founder effect in a rapidly expanding population arising from a bottleneck provides a robust parsimonious hypothesis explaining the spread of 1278insTATC-linked TSD in AJ individuals.Electronic database information: URLs for the data in this article are as follows: , ,     

Effects of a range expansion on adaptive and neutral genetic diversity in dispersal limited Hazel grouse (<Emphasis Type="Italic">Bonasa bonasia</Emphasis>) in the French Alps

Biogeographic range expansions, when related to dispersal limitation, may have counter intuitive effects on genetic diversity. At range margins the relative roles of demographic changes, connectivity and genetic diversity need to be integrated for a successful assessment of population viability. Historically the Hazel grouse (Bonasa bonasia) in France was found in the north of the French Alps and also in a disjunct population in the nearby Jura Mountains. The species has recently undergone a range expansion in a north to south axis in the Alps. Local population size estimates and migration patterns during expansion have previously been studied. In this study, we performed genotyping at neutral (microsatellite) and adaptive (MHC) genetic markers in Hazel grouse. We compared diversity and differentiation (F_ST and D_EST) at three sampling localities along the expansion axis in the French Alps and Jura, as well as at two sampling localities in Sweden, where the population has had a long-term continuous and stable distribution. Strong serial founder effects were found between the French localities, resulting in stronger isolation further south, with a relatively high neutral differentiation (pair-wise F_ST = 0.117). However, the loss of adaptive diversity MHC was slight. No adaptive differentiation (MHC D_EST = ?0.015) was observed, thus, the French localities can be considered uniform units with regard to MHC diversity, a criterion to treat populations in these localities as a management unit.     

The split of the Arara population: comparison of genetic drift and founder effect

The total genetic diversity of the Amerindian population is as high as that observed for other continental human populations because a large contribution from variation among tribes makes up for the low variation within tribes. This is attributed mainly to genetic drift acting on small isolated populations. However, a small founder population with a low genetic diversity is another factor that may contribute to the low intratribal diversity. Small founder populations seem to be a frequent event in the formation of new tribes among the Amerindians, but this event is usually not well recorded. In this paper, we analyze the genetic diversity of the Arara of Laranjal village and the Arara of Iriri village, with respect to seven tandem repeat autosomic segments (D1S80, ApoB, D4S43, vW1, vW2, F13A1 and D12S67), two Y-chromosome-specific polymorphisms (DYS19 and DYS199), and mitochondrial DNA (mtDNA) markers (restriction fragment length polymorphisms and sequencing of a segment of the D loop region). The occurrence of a single Y chromosome and mtDNA haplotype, and only 1-4 alleles of the autosomic loci investigated, corroborates historic and demographic records that the Arara of Iriri were founded by a single couple of siblings who came from the Arara of Laranjal, the largest group. Notwithstanding this fact, the genetic distance and the molecular variance between the two Arara villages were greater than those observed between them and other Amazonian tribes, suggesting that the microevolutionary process among Brazilian Amerindians may be misinterpreted if historic demographic data are not considered.     

Recent origin and spread of a common Lithuanian mutation, G197del LDLR, causing familial hypercholesterolemia: positive selection is not always necessary to account for disease incidence among Ashkenazi Jews

G197del is the most prevalent LDL receptor (LDLR) mutation causing familial hypercholesterolemia (FH) in Ashkenazi Jew (AJ) individuals. The purpose of this study was to determine the origin, age, and population distribution of G197del, as well as to explore environmental and genetic effects on disease expression. Index cases from Israel (n=46), South Africa (n=24), Russia (n=7), The Netherlands (n=1), and the United States (n=1) were enlisted. All trace their ancestry to Lithuania. A highly conserved haplotype (D19S221:104-D19S865:208-D19S413:74) was identified in G197del chromosomes, suggesting the occurrence of a common founder. When two methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the deletion was found to be 20 +/- 7 generations (the 95% confidence interval is 15-26 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 14th century. This corresponds with the founding of the Jewish community of Lithuania (1338 a.d.), as well as with the great demographic expansion of AJ individuals in eastern Europe, which followed this settlement. The penetrance of mutation-linked severe hypercholesterolemia is high (94% of heterozygotes have a baseline concentration of LDL cholesterol (LDL-C) that is >160 mg/dl), and no significant differences in the mean baseline lipid level of G197del carriers from different countries were found. Polymorphisms of apolipoprotein E and of scavenger-receptor class B type I were observed to have minor effects on the plasma lipid profile. With respect to determinative genetic influences on the biochemical phenotype, there is no evidence that could support the possibility of a selective evolutionary metabolic advantage. Therefore, the founder effect in a rapidly expanding population from a limited number of families remains a simple, parsimonious hypothesis explaining the spread of G197del-LDLR-linked FH in AJ individuals.     

A rapid population expansion retains genetic diversity within European rabbits in Australia

The well documented historical translocations of the European rabbit (Oryctolagus cuniculus) offer an excellent framework to test the genetic effects of reductions in effective population size. It has been proposed that rabbits went through an initial bottleneck at the time of their establishment in Australia, as well as multiple founder events during the rabbit's colonization process. To test these hypotheses, genetic variation at seven microsatellite loci was measured in 252 wild rabbits from five populations across Australia. These populations were compared to each other and to data from Europe. No evidence of a genetic bottleneck was observed with the movement of 13 rabbits from Europe to Australia when compared to French data. Within Australia the distribution of genetic diversity did not reflect the suggested pattern of sequential founder effects. In fact, the current pattern of genetic variation in Australia is most likely a result of multiple factors including mutation, genetic drift and geographical differentiation. The absence of reduced genetic diversity is almost certainly a result of the rabbit's rapid population expansion at the time of establishment in Australia. These results highlight the importance of population growth following a demographic bottleneck, which largely determines the severity of genetic loss.     

A genomewide linkage-disequilibrium scan localizes the Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency to 2p16

Leigh syndrome (LS) affects 1/40,000 newborn infants in the worldwide population and is characterized by the presence of developmental delay and lactic acidosis and by a mean life expectancy variously estimated at 3-5 years. Saguenay-Lac-Saint-Jean (SLSJ) cytochrome oxidase (COX) deficiency (LS French-Canadian type [LSFC] [MIM 220111]), an autosomal recessive form of congenital lactic acidosis, presents with developmental delay and hypotonia. It is an LS variant that is found in a geographically isolated region of Quebec and that occurs in 1/2,178 live births. Patients with LSFC show a phenotype similar to that of patients with LS, but the two groups differ in clinical presentation. We studied DNA samples from 14 patients with LSFC and from their parents, representing a total of 13 families. Because of founder effects in the SLSJ region, considerable linkage disequilibrium (LD) was expected to surround the LSFC mutation. We therefore performed a genomewide screen for LD, using 290 autosomal microsatellite markers. A single marker, D2S1356, located on 2p16, showed significant (P < 10(-5)) genomewide LD. Using high-resolution genetic mapping with additional markers and four additional families with LSFC, we were able to identify a common ancestral haplotype and to limit the critical region to approximately 2 cM between D2S119 and D2S2174. COX7AR, a gene encoding a COX7a-related protein, had previously been mapped to this region. We determined the genomic structure and resequenced this gene in patients with LSFC and in controls but found no functional mutations. Although the LSFC gene remains to be elucidated, the present study demonstrates the feasibility of using a genomewide LD strategy to localize the critical region for a rare genetic disease in a founder population.     

Whole-Exome Sequencing Reveals a Rapid Change in the Frequency of Rare Functional Variants in a Founding Population of Humans

Whole-exome or gene targeted resequencing in hundreds to thousands of individuals has shown that the majority of genetic variants are at low frequency in human populations. Rare variants are enriched for functional mutations and are expected to explain an important fraction of the genetic etiology of human disease, therefore having a potential medical interest. In this work, we analyze the whole-exome sequences of French-Canadian individuals, a founder population with a unique demographic history that includes an original population bottleneck less than 20 generations ago, followed by a demographic explosion, and the whole exomes of French individuals sampled from France. We show that in less than 20 generations of genetic isolation from the French population, the genetic pool of French-Canadians shows reduced levels of diversity, higher homozygosity, and an excess of rare variants with low variant sharing with Europeans. Furthermore, the French-Canadian population contains a larger proportion of putatively damaging functional variants, which could partially explain the increased incidence of genetic disease in the province. Our results highlight the impact of population demography on genetic fitness and the contribution of rare variants to the human genetic variation landscape, emphasizing the need for deep cataloguing of genetic variants by resequencing worldwide human populations in order to truly assess disease risk.     

The Usher syndrome in the Lebanese population and further refinement of the USH2A candidate region

Usher syndrome (USH) is an autosomal-recessive disease characterized by neurosensory deafness and progressive retinitis pigmentosa. So far, three clinical types of Usher syndrome have been defined, and are caused by defects at more than eight loci. We report the linkage analysis of seven Lebanese families with Usher syndrome, two with type I (USH1) and five with type II (USH2). We demonstrate that one family is linked to the USH1C locus, a rare form of USH1 only reported in the French Acadian population. Linkage analysis of the five USH2 families with recently mapped loci allowed us to reduce the USH2A candidate region to a very small interval flanked by D1S2646/D1S2629 and D1S2827. Furthermore, haplotype comparison between the different families suggests a founder effect for the USH2A mutation among the different Lebanese ethnic groups, while a genetic heterogeneity is noted for Usher syndrome type I. Received: 9 January 1998 / Accepted: 23 March 1998     

Evidence of rapid change in genetic structure and diversity during range expansion in a recovering large terrestrial carnivore

Recovery of natural populations occurs often with simultaneous or subsequent range expansions. According to population genetic theory, genetic structuring emerges at the expansion front together with decreasing genetic diversity, owing to multiple founder events. Thereupon, as the expansion proceeds and connectivity among populations is established, homogenization and a resurgence of genetic diversity are to be expected. Few studies have used a fine temporal scale combined with genetic sampling to track range expansions as they proceed in wild animal populations. As a natural experiment, the historical eradication of large terrestrial carnivores followed by their recovery and recolonization may facilitate empirical tests of these ideas. Here, using brown bear (Ursus arctos) as model species, we tested predictions from genetic theory of range expansion. Individuals from all over Finland were genotyped for every year between 1996 and 2010 using 12 validated autosomal microsatellite markers. A latitudinal shift of about 110 km was observed in the distribution and delineation of genetic clusters during this period. As the range expansion proceeded, we found, as theory predicts, that the degree of genetic structure decreased, and that both genetic variation and admixture increased. The genetic consequences of range expansions may first be detected after multiple generations, but we found major changes in genetic composition after just 1.5 generations, accompanied by population growth and increased migration. These rapid genetic changes suggest an ongoing concerted action of geographical and demographic expansion combined with substantial immigration of bears from Russia during the recovery of brown bears within the large ecosystem of northern Europe.     

Genetic Diversity in Introduced Populations with an Allee Effect

A phenomenon that strongly influences the demography of small introduced populations and thereby potentially their genetic diversity is the demographic Allee effect, a reduction in population growth rates at small population sizes. We take a stochastic modeling approach to investigate levels of genetic diversity in populations that successfully overcame either a strong Allee effect, in which populations smaller than a certain critical size are expected to decline, or a weak Allee effect, in which the population growth rate is reduced at small sizes but not negative. Our results indicate that compared to successful populations without an Allee effect, successful populations with a strong Allee effect tend to (1) derive from larger founder population sizes and thus have a higher initial amount of genetic variation, (2) spend fewer generations at small population sizes where genetic drift is particularly strong, and (3) spend more time around the critical population size and thus experience more genetic drift there. In the case of multiple introduction events, there is an additional increase in diversity because Allee-effect populations tend to derive from a larger number of introduction events than other populations. Altogether, a strong Allee effect can either increase or decrease genetic diversity, depending on the average founder population size. By contrast, a weak Allee effect tends to decrease genetic diversity across the entire range of founder population sizes. Finally, we show that it is possible in principle to infer critical population sizes from genetic data, although this would require information from many independently introduced populations.     

An island within an island: genetic differentiation of Anopheles gambiae in São Tomé, West Africa, and its relevance to malaria vector control

Islands are choice settings for experimental studies of vector control strategies based on transgenic insects. Before considering this approach, knowledge of the population structure of the vector is essential. Genetic variation at 12 microsatellite loci was therefore studied in samples of the malaria vector Anopheles gambiae s.s., collected from six localities of S?o Tomé island (West Africa). The objectives were (i) to assess the demographic stability and effective population size of A. gambiae from these sites, (ii) to determine population differentiation and (iii) to relate the observed patterns of population structure with geographic, ecological and historical aspects of the vector on the island. Significant population differentiation, revealed by FST and RST statistics, was found between the southernmost site, Porto Alegre, and northern localities. The observed patterns of population substructure are probably a result of restrictions to gene flow in the less inhabited, more densely forested and mountainous south. In all localities surveyed, A. gambiae appeared to be experiencing a demographic expansion, consistent with a relatively recent (ca. 500 years) founder effect. The results are discussed with respect to current and future prospects of malaria vector control.     

Genetic liability to schizophrenia in Oceanic Palau: a search in the affected and maternal generation

While liability to schizophrenia (Scz) is due to genetic and environmental factors, specific factors are largely unknown. We postulate a two-hit model for Scz, in which initial liability is generated during fetal brain development: this “hit” is precipitated by environmental stressors biologically interacting with maternal genetic vulnerability to the stress. Additional liability to Scz is generated by individual genetic vulnerability. To evaluate these putative levels of vulnerability, we search in the genome of both affected individuals and their mothers for variation that differs, statistically, from that in the general population. For parental analyses, mothers were treated as “affected,” rather than their offspring, and the fathers were treated as “controls”. We used a sample from the Palauan population: 175 individuals diagnosed with Scz, broadly defined; 87 mothers and 45 fathers of affected individuals. Pedigree and diagnostic data were available on 2,953 living and deceased subjects. DNA from 553 individuals was genotyped for short tandem repeats (STR) spaced approximately every 10 cM across the genome. We tested for association between affection status and STR alleles; such an approach was reasonable, despite the widely spaced markers, because this population has far-ranging linkage disequilibrium (LD). Results for the truly affected individuals were modest, whereas results from the maternal generation were promising. For a recessive model and a test for excess allele matching across mothers, significant findings occurred for D20S481, D10S1221, D6S1021, D13S317, and D18S976. Regions in which at least two adjacent markers produced substantial association statistics include 2p12-11.2, 2q24.1-32.1, 6q12-14.1, 10q23.2-24.21, 12q23.2-24.21 and 17q23.2-23.3.     

Demographic history and genetic diversity in West Indian Coereba flaveola populations

The bananaquit (Coereba flaveola) has been well studied throughout the Caribbean region from a phylogenetic perspective. However, data concerning the population genetics and long-term demography of this bird species are lacking. In this study, we focused on three populations within the Lesser Antilles and one on Puerto Rico and assessed genetic and demographic processes, using five nuclear and two mitochondrial markers. We found that genetic diversity of bananaquits on Puerto Rico exceeds that on the smaller islands (Dominica, Guadeloupe and Grenada); this might reflect either successive founder events from Puerto Rico to Grenada, or more rapid drift in smaller populations subsequent to colonization. Population growth rate estimates showed no evidence of rapid expansion and migration was indicated only between populations from the closest islands of Dominica and Guadeloupe. Overall, our results suggest that a "demographic fission" model, considering only mutation and drift, but without migration, can be applied to these bananaquit populations in the West Indies.     

Recent Demographic History and Present Fine-Scale Structure in the Northwest Atlantic Leatherback (Dermochelys coriacea) Turtle Population

The leatherback turtle Dermochelys coriacea is the most widely distributed sea turtle species in the world. It exhibits complex life traits: female homing and migration, migrations of juveniles and males that remain poorly known, and a strong climatic influence on resources, breeding success and sex-ratio. It is consequently challenging to understand population dynamics. Leatherbacks are critically endangered, yet the group from the Northwest Atlantic is currently considered to be under lower risk than other populations while hosting some of the largest rookeries. Here, we investigated the genetic diversity and the demographic history of contrasted rookeries from this group, namely two large nesting populations in French Guiana, and a smaller one in the French West Indies. We used 10 microsatellite loci, of which four are newly isolated, and mitochondrial DNA sequences of the control region and cytochrome b. Both mitochondrial and nuclear markers revealed that the Northwest Atlantic stock of leatherbacks derives from a single ancestral origin, but show current genetic structuration at the scale of nesting sites, with the maintenance of migrants amongst rookeries. Low nuclear genetic diversities are related to founder effects that followed consequent bottlenecks during the late Pleistocene/Holocene. Most probably in response to climatic oscillations, with a possible influence of early human hunting, female effective population sizes collapsed from 2 million to 200. Evidence of founder effects and high numbers of migrants make it possible to reconsider the population dynamics of the species, formerly considered as a metapopulation model: we propose a more relaxed island model, which we expect to be a key element in the currently observed recovering of populations. Although these Northwest Atlantic rookeries should be considered as a single evolutionary unit, we stress that local conservation efforts remain necessary since each nesting site hosts part of the genetic diversity and species history.     

Colonization models and initial genetic diversity in the Americas

The mode and tempo of colonization of the Americas established the initial pattern of continental genetic diversity. Despite a long history of study, the process of settlement remains controversial in terms of date, rate, and pattern. While there is agreement that Asia was the source population, several different models have been proposed for the colonization process. A classic model postulates a rapid spread of population ("blitzkrieg") from a small band of hunters entering through the corridor between the continental ice sheets circa 11,000 years B.P. Colonization occurred as a wave of expansion across the land masses of North and South America. An alternative model envisions the original colonists initially limiting settlement to the coastline, using boats, and entering the Americas at an earlier date, circa 13,500 B.P. Range expansion along this linear habitat from North to South America could be rapid without requiring population saturation of entire continental regions. These models have markedly different implications for genetic variation among Native Americans. The blitzkrieg colonization process would have generated multiple founder effects leading to extreme loss of genetic variation. Computer simulation of this model shows nearly complete fixation in 30 generations. Simulation of the coastal model, on the other hand, requires less extreme demographic assumptions and maintains substantial genetic variability after 100 generations. Although with the coastal model continental interiors are occupied less rapidly than with the blitzkrieg model, the coastal model allows earlier entry and rapid expansion to the southern limits of the hemisphere.     

Founder effects and genetic variability in Quebec

Knowledge of the genetic population structure lies at the heart of mapping studies aiming genes responsible for Mendelian and complex traits. The Quebec population, which is of mostly French descent, is considered an excellent model for such genetic epidemiological endeavours because it is a young founder population. Yet, the assessment of the founder effect has relied mostly on the observed distribution of monogenic diseases and on the analysis of the underlying mutations with investigations focusing on the Saguenay region. To eliminate this clinical bias and to obtain a more complete image of the genetic diversity, different regional populations of Quebec were investigated by analysing neutral markers that represent maternal, paternal and X chromosome lineages. Results indicate that Quebec does not appear more homogeneous nor significantly different from European populations. However, a series of regional founder effects, particularly visible at the level of rare variants, are observed. These effects can be explained by the successive migrations of descendants of the first immigrants from the initial sites of settlement towards the outer regions. Depending on the number of founders and their diversity, as well as on the degree of isolation and the magnitude of the interbreeding with the neighbouring or local populations, such as Amerindians or later migrants, the consequences of these regional founder effects are more or less detectable in the contemporary population.     

Linkage disequilibrium in the domesticated pig

This study investigated the extent of linkage disequilibrium (LD) in two genomic regions (on chromosomes 4 and 7) in five populations of domesticated pigs. LD was measured with D' and tested for significance with the Fisher exact test. Effects of genetic (linkage) distance, chromosome, population, and their interactions on D' were tested both through a linear model analysis of covariance and by a theoretical nonlinear model. The overall result was that (1) the distance explained most of the variability of D', (2) the effect of chromosome was significant, and (3) the effect of population was significant. The significance of the chromosome effect may have resulted from selection and the significance of the population effect illustrates the effects of population structures and effective population sizes on LD. These results suggest that mapping methods based on LD may be valuable even with only moderately dense marker spacing in pigs.     

The genetic signature of rapid range expansion by flying squirrels in response to contemporary climate warming

Climate is an important factor limiting species distributions. Historic climate‐change related range movements have modified the genetic diversity of species by the merging and splitting of gene pools and by the effects associated with recurrent founder events. These effects are often inferred, either from retrospective analyses of current genetic patterns or from simulations. Rarely has it been possible for the population genetic effects of range expansion to be examined with contemporaneous demographic data. We characterized the genetic signature of rapid range expansion by southern flying squirrels (Glaucomys volans) and compared these results to a stationary population of the closely related northern flying squirrel (Glaucomys sabrinus) in Ontario, Canada. Samples were taken during an approximately 200 km range expansion by G. volans (1994–2003) and genotyped at 6 (G. sabrinus) and 8 (G. volans) microsatellite loci. For G. volans, but not G. sabrinus, we found evidence of a latitudinal gradient in allele frequencies and a decrease in allelic richness along the axis of expansion. We found no evidence of isolation‐by‐distance in either species or of genetic bottlenecks in the area of G. volans expansion. These results suggest that serial founder events can cause an immediate reduction in genetic diversity following rapid range expansion with high levels of gene flow giving rise to heterogeneity within what would classically be termed panmixia. Given the pace of anthropogenic climate change, and the increasing incidence of range movements in response, this may be an important, immediate consequence of climate change.     

The gene responsible for a severe form of peripheral neuropathy and agenesis of the corpus callosum maps to chromosome 15q.

Peripheral neuropathy with or without agenesis of the corpus callosum (ACCPN) is a devastating neurodegenerative disorder that is transmitted as an autosomal recessive trait. Genealogical studies in a large number of affected French Canadian individuals suggest that ACCPN results from a single founder mutation. A genomewide search using 120 microsatellite DNA markers in 14 French Canadian families allowed the mapping of the ACCPN gene to a 5-cM region on chromosome 15q13-q15 that is flanked by markers D15S1040 and D15S118. A maximum two-point LOD score of 11.1 was obtained with the marker D15S971 at a recombination fraction of 0. Haplotype analysis and linkage disequilibrium support a founder effect. These findings are the first step in the identification of the gene responsible for ACCPN, which may shed some light on the numerous conditions associated with the progressive peripheral neuropathy or agenesis of the corpus callosum.