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Peischl et al. explore the way evolutionary forces shape genetic variability in expanding human populations. Over a few generations of separate evolution... Humans have colonized the planet through a series of range expansions, which deeply impacted genetic diversity in newly settled areas and potentially increased the frequency of deleterious mutations on expanding wave fronts. To test this prediction, we studied the genomic diversity of French Canadians who colonized Quebec in the 17th century. We used historical information and records from ∼4000 ascending genealogies to select individuals whose ancestors lived mostly on the colonizing wave front and individuals whose ancestors remained in the core of the settlement. Comparison of exomic diversity reveals that: (i) both new and low-frequency variants are significantly more deleterious in front than in core individuals, (ii) equally deleterious mutations are at higher frequencies in front individuals, and (iii) front individuals are two times more likely to be homozygous for rare very deleterious mutations present in Europeans. These differences have emerged in the past six to nine generations and cannot be explained by differential inbreeding, but are consistent with relaxed selection mainly due to higher rates of genetic drift on the wave front. Demographic inference and modeling of the evolution of rare variants suggest lower effective size on the front, and lead to an estimation of selection coefficients that increase with conservation scores. Even though range expansions have had a relatively limited impact on the overall fitness of French Canadians, they could explain the higher prevalence of recessive genetic diseases in recently settled regions of Quebec.

Dans le cadre d’un programme de recherche sur la diversité génétique des populations régionales du Québec, nous avons mesuré la contribution des ancêtres amérindiens au pool génique de 794 participants résidant dans les régions de Montréal, du Saguenay—Lac-Saint-Jean (SLSJ), de la Gaspésie et de la Côte-Nord. Les ancêtres amérindiens ont été identifiés à partir de reconstructions généalogiques (fichier BALSAC) et de données génétiques (ADN mitochondrial) à l’aide d’une approche qui repose sur l’exploitation conjointe de ces deux types de données. Les résultats indiquent que plus de la moitié des participants ont au moins un ancêtre amérindien dans leur généalogie. Ceci veut dire que la majorité des participants sont porteurs de gènes reçus de fondateurs amérindiens. Cependant la contribution génétique totale de ces ancêtres aux quatre groupes régionaux demeure faible. En effet, elle est de moins de 1 % au SLSJ et à Montréal alors qu’elle dépasse à peine 1 % sur la Côte-Nord et en Gaspésie., In the context of a research programme on the genetic diversity of regional populations in Quebec, we measured the contribution of Amerindian ancestors to the gene pool of 794 participants living in the Montreal, Saguenay-Lac-St-Jean (SLSJ), Gaspe Peninsula and North Shore regions. Amerindian ancestors were identified through genealogical reconstructions (BALSAC database) and genetic data (mitochondrial DNA) using an approach relying on the joint exploitation of the two types of data. Results show that more than half of the participants have at least one Amerindian ancestor in their genealogy. This means that a majority of participants carry genes received from Amerindian founders. However the total genetic contribution of these ancestors to the four regional groups is low, reaching less than 1 % in SLSJ and Montreal and slightly more than 1 % on the North Shore and in the Gaspe Peninsula.

Humans have colonized the planet through a series of range expansions, which deeply impacted genetic diversity in newly settled areas and potentially increased the frequency of deleterious mutations on expanding wave fronts. To test this prediction, we studied the genomic diversity of French Canadians who colonized Quebec in the 17th century. We used historical information and records from ∼4000 ascending genealogies to select individuals whose ancestors lived mostly on the colonizing wave front and individuals whose ancestors remained in the core of the settlement. Comparison of exomic diversity reveals that i) both new and low frequency variants are significantly more deleterious in front than in core individuals, ii) equally deleterious mutations are at higher frequencies in front individuals, and iii) front individuals are two times more likely to be homozygous for rare very deleterious mutations present in Europeans. These differences have emerged in the past 6-9 generations and cannot be explained by differential inbreeding, but are consistent with relaxed selection on the wave front. Modeling the evolution of rare variants allowed us to estimate their associated selection coefficients as well as front and core effective sizes. Even though range expansions had a limited impact on the overall fitness of French Canadians, they could explain the higher prevalence of recessive genetic diseases in recently settled regions. Since we show that modern human populations are experiencing differential strength of purifying selection, similar processes might have happened throughout human history, contributing to a higher mutation load in populations that have undergone spatial expansions.

A series of mutations of tuberculosis, present in the 1990s among elderly persons in the Province of Quebec (Canada), is interpreted as the outcome of a suite of three episodes of high mobility. The most recent is the rapid urbanization of the 1950s. In the 1840s exceptional mobility was a feature of frontier settlement and exploitation of timber. Unusual mobility in the 1750s and 1760s was associated with wartime conditions of the British conquest of Quebec and re-settlement of Acadian refugees. The scenario was developed from cartographic analysis (using geographic information systems), genealogies of the human hosts, and molecular genetics of the bacterium.

The predominance of the T14484C mutation in French Canadians with Leber hereditary optic neuropathy is due to a founder effect. By use of genealogical reconstructions of maternal lineages, a woman married in Quebec City in 1669 is identified as the shared female ancestor for 11 of 13 affected individuals, who were previously not known to be related. These individuals carry identical mitochondrial haplogroups. The current geographic distribution of French Canadian cases overlaps with that of the founder's female descendants in 1800. This is the first example of genealogical reconstruction to identify the introduction of a mitochondrial mutation by a woman in a founder population.

Objectives: To investigate genetic homogeneity in a set of hypertensive families and in subsets chosen for high and low prevalence of obesity; and to compare fasting insulin and lipids, ion transport, and water homeostasis in the obese and lean families. Research Methods and Procedures: The study was carried out in a relative population isolate of the Saguenay/Lac St. Jean region in Canada. Genetic homogeneity was evaluated with the mean coeffigcients of kinship (φ) and inbreeding (F) computed with ascending genealogies. Serum insulin and lipids were measured after overnight fasting. Total body water was estimated with bioelectrical impedance. Sodium-lithium countertransport and sodium-potassium co-transport were determined in freshly isolated erythrocytes. Results: F and φ were increased in hypertensive families compared with families selected at random. F and φ were further increased within the subsets of obese and lean families. In addition, fasting insulin, total body water, sodium-lithium countertransport, and sodium-potassium co-transport were higher in the obese than in the lean families. The two subsets of families did not differ by fasting lipids. Discussion: In the Saguenay/Lac St. Jean population, the degree of genetic homogeneity was increased in families selected for hypertension, and it was further increased in subsets of hypertensive families with high and low prevalence of obesity. This suggests that hypertension in lean and obese individuals may represent, at least in part, separate genetic entities. Some of the extra genes shared in common within the subsets may contribute to their differences in body weight, insulin sensitivity, ion transport, and water homeostasis.

Since their origin, human populations have colonized the whole planet, but the demographic processes governing range expansions are mostly unknown. We analyzed the genealogy of more than one million individuals resulting from a range expansion in Quebec between 1686 and 1960 and reconstructed the spatial dynamics of the expansion. We find that a majority of the present Saguenay Lac-Saint-Jean population can be traced back to ancestors having lived directly on or close to the wave front. Ancestors located on the front contributed significantly more to the current gene pool than those from the range core, likely due to a 20% larger effective fertility of women on the wave front. This fitness component is heritable on the wave front and not in the core, implying that this life-history trait evolves during range expansions.

International audience; The pacemaking activity of specialized tissues in the heart and gut results in lifelong rhythmic contractions. Here we describe a new syndrome characterized by Chronic Atrial and Intestinal Dysrhythmia, termed CAID syndrome, in 16 French Canadians and 1 Swede. We show that a single shared homozygous founder mutation in SGOL1, a component of the cohesin complex, causes CAID syndrome. Cultured dermal fibroblasts from affected individuals showed accelerated cell cycle progression, a higher rate of senescence and enhanced activation of TGF-b signaling. Karyotypes showed the typical railroad appearance of a centromeric cohesion defect. Tissues derived from affected individuals displayed pathological changes in both the enteric nervous system and smooth muscle. Morpholino-induced knockdown of sgol1 in zebrafish recapitulated the abnormalities seen in humans with CAID syndrome. Our findings identify CAID syndrome as a novel generalized dysrhythmia, suggesting a new role for SGOL1 and the cohesin complex in mediating the integrity of human cardiac and gut rhythm.

SummaryWe have previously reported that the 3363 inserted (Ins) C mutation in exon 6 of the protein C gene was present in four unrelated French patients and in four French Canadian families with type I protein C deficiency as well as in a large Vermont protein C deficient kindred of French Canadian origin. The present study was designed to investigate the likelihood of the existence of a founder effect for this mutation in protein C deficient individuals of French origin living in France, Québec and Vermont. In order to demonstrate a possible founder effect for the 3363 InsC mutation, we have previously constructed a high-resolution genetic map to locate several highly polymorphic markers close to the protein C locus. Thereafter, the markers D2S347, D2S2339, D2S383, D2S2271 and D2S2215 were genotyped in 117 heterozygotes from France (n = 7), Québec (n = 36) or Vermont (n = 74). The allelic frequency distribution of these five markers was also determined in fifty control French Canadian subjects and thirty-two unaffected members of the Vermont kindred with normal protein C levels and compared with their frequency in our cohort of heterozygotes. Our data suggest that patients from Québec and Vermont carry a common haplotype at the protein C locus. Moreover, in order to study the evolutionary history of the 3363 InsC mutation, we traced back the ascending genealogy of one proband in each of the families with this mutation. These results showed that the 3363 InsC mutation was most probably introduced in North America by a couple of French settlers who established themselves in 1669 on Isle d‘Orleans located near Québec City. All heterozygotes for the 3363 InsC mutation living in North America are related to these founders within 10 generations. Thus, these families afford a unique opportunity to evaluate the role of the protein C system in thrombophilia due to the high degree of linkage disequilibrium at the protein C gene, which in essence holds that variable more constant than in a more heterogeneous population.

Hypertension is a complex disease in which environment and heredity interact. It is a polygenic trait that can be studied by investigating its intermediate phenotypes. We have selected the population from the Saguenay-Lac St. Jean region because it is a relative genetic isolate. We have found that the prevalence of hypertension at every age level was greater than in a control Canadian population. A sib pair analysis was used to measure familial correlation and heritability of more than 200 phenotypes among which were renal functions, anthropometric measures and cardiac morphology and reactivity. Very strong familial correlations were estimated for several cardiovascular phenotypes. During a pharmacological infusion of norepinephrine, we observed that systolic blood pressure was increased as expected but that the heritable component of this phenotype increased from null at baseline to close to 70%. Preliminary total genome scans completed on the DNA of the participants have selected several regions linked to these phenotypes. This type of study opens the door to pharmacogenetic studies in which sib pairs are analyzed for their concordant or discordant response to a medication.

For years, studies of founder populations and genetic isolates represented the mainstream of genetic mapping in the effort to target genetic defects causing Mendelian disorders. The genetic homogeneity of such populations as well as relatively homogeneous environmental exposures were also seen as primary advantages in studies of genetic susceptibility loci that underlie complex diseases. European colonization of the St-Lawrence Valley by a small number of settlers, mainly from France, resulted in a founder effect reflected by the appearance of a number of population-specific disease-causing mutations in Quebec. The purported genetic homogeneity of this population was recently challenged by genealogical and genetic analyses. We studied one of the contributing factors to genetic heterogeneity, early Native American admixture that was never investigated in this population before. Consistent admixture estimates, in the order of one per cent, were obtained from genome-wide autosomal data using the ADMIXTURE and HAPMIX software, as well as with the fastIBD software evaluating the degree of the identity-by-descent between Quebec individuals and Native American populations. These genomic results correlated well with the genealogical estimates. Correlations are imperfect most likely because of incomplete records of Native founders' origin in genealogical data. Although the overall degree of admixture is modest, it contributed to the enrichment of the population diversity and to its demographic stratification. Because admixture greatly varies among regions of Quebec and among individuals, it could have significantly affected the homogeneity of the population, which is of importance in mapping studies, especially when rare genetic susceptibility variants are in play.

Data from uniparentally inherited genetic systems were used to trace evolution of human populations. Reconstruction of the past primarily relies on variation in present-day populations, limiting historical inference to lineages that are found among living subjects. Our analysis of four population groups in the Gaspé Peninsula, demonstrates how this may occasionally lead to erroneous interpretations. Mitochondrial DNA analysis of Gaspesians revealed an important admixture with Native Americans. The most likely scenario links this admixture to French-Canadians from the St. Lawrence Valley who moved to Gaspesia in the 19th century. However, in contrast to genetic data, analysis of genealogical record shows that Native American maternal lineages were brought to Gaspesia in the 18th century by Acadians who settled on the south-western coast of the peninsula. Intriguingly, within three generations, virtually all Métis Acadian families separated from their nonadmixed relatives and moved eastward mixing in with other Gaspesian groups, in which Native American maternal lines are present in relatively high frequencies. Over time, the carriers of these lines eventually lost memory of their mixed Amerindian-Acadian origin. Our results show that a reliable reconstruction of population history requires cross-verification of different data sources for consistency, thus favouring multidisciplinary approaches.

Summary Data from uniparentally inherited genetic systems were used to trace evolution of human populations. Reconstruction of the past primarily relies on variation in present-day populations, limiting historical inference to lineages that are found among living subjects. Our analysis of four population groups in the Gaspe Peninsula, demonstrates how this may occasionally lead to erroneous interpretations. Mitochondrial DNA analysis of Gaspesians revealed an important admixture with Native Americans. The most likely scenario links this admixture to French-Canadians from the St. Lawrence Valley who moved to Gaspesia in the 19th century. However, in contrast to genetic data, analysis of genealogical record shows that Native American maternal lineages were brought to Gaspesia in the 18th century by Acadians who settled on the south-western coast of the peninsula. Intriguingly, within three generations, virtually all Metis Acadian families separated from their nonadmixed relatives and moved eastward mixing in with other Gaspesian groups, in which Native American maternal lines are present in relatively high frequencies. Over time, the carriers of these lines eventually lost memory of their mixed Amerindian-Acadian origin. Our results show that a reliable reconstruction of population history requires cross-verification of different data sources for consistency, thus favouring multidisciplinary approaches.

For a strain of Mycobacterium tuberculosis mono-resistant to pyrazinamide (PZA), we report the geographic distribution within Quebec of the 77 cases diagnosed during 1990-2000. Known as the Quebec mutation (or the pncA deletion), the strain is rare in urban areas and showed an unexpected concentration in Mauricie, one of the 16 health districts of the province, with a cluster of 10 cases situated in a rural area of 35-km radius. The cases occurred among people >50 (98%), of French Canadian origins (90%), and are understood to have arisen by reactivation. The rarity in Montreal and smaller cities is explained by the youthfulness of massive postwar migrations. To reach back into the history of settlement, we examined genealogies: 92,429 ancestral marriages for 32 of the 77 PZA-resistant isolates and 226,535 for a set of 85 controls with isolates of more diverse mycobacterial strains. Genealogical analysis showed no salient common ancestor for the cases, and kinship among them was no greater than observed in control samples from the same regions. But it identified an unsuspected geographical region as the site of ancestral concentrations prior to 1840, for both resistant strains and controls. The following scenario is proposed for the resistant strain: endemic in a specific geographical region by 1800, it dispersed with families moving into regions opened to settlement in the 1840s and 1850s, among them Mauricie, where dispersion was intensified by seasonal mobility of labour in logging, milling and marketing timber. In high-incidence areas, it is difficult to distinguish cases of reactivation from recent infections, but the low-incidence context allows us to observe a 200-year trajectory of a distinctive drug-resistant strain of M. tuberculosis.

Essential hypertension is a heterogeneous disorder that is thought to develop because of several overlapping subsets of underlying mechanisms. One such causal pathway may involve pathophysiological alterations induced by obesity. In the present study, we examined whether investigating clinically defined subtypes of hypertension, such as obesity-associated hypertension, facilitates the search for its genes. Fifty-five extended families were selected on the basis of having ≥2 siblings affected by hypertension from a geographically remote French-Canadian population. Fifteen of these families showed a high prevalence (≥70%) of obesity. Genome-wide scan using qualitative multipoint linkage analysis (GeneHunter 2.1; marker density

Laure Conan a publie trois romans historiques - A l'oeuvre et a l'epreuve (1891), Z 'Oublie (1900) et La Seve immortelle (1925) - qui ont etonne les critiques : la propension de l'auteur pour les analyses psychologiques les ont amenes a considerer ces recits a la lumiere de son premier roman, Angeline de Montbrun (1881-1882). Nous proposons pour notre part d'analyser le discours historien de ces trois romans en nous referant aux preceptes de la philosophie theologique de l'histoire institues par saint Augustin dans La Cite de Dieu. Nous esperons ainsi degager le sens chretien que Laure Conan donne a l'aventure de la Nouvelle-France, et ce, en considerant l'analogie augustinienne entre l'histoire de la societe et l'histoire individuelle. Notre premier chapitre est une analyse du sens imagine par Laure Conan a propos de l'histoire de la societe canadienne-francaise. Tout comme saint Augustin qui explique l'histoire de la chretiente depuis une societe originelle ideale, la romanciere suggere que l'histoire de la communaute canadienne-francaise est fondee sur un unique projet : la reproduction des pratiques ancestrales de societes chretiennes modeles (l'Eglise primitive, les Croises, les pionniers Francais en Amerique). Le projet est toutefois mis en opposition a toute autre societe qui s'inscrit en rupture avec ce passe originel (la laicisation de la societe francaise, le protestantisme anglais, le paganisme autochtone). Ainsi, il ressort que, depuis 1'evangelisation des Jesuites en Huronie, jusqu'a l'occupation anglaise et la fin du regime francais, la societe canadienne-francaise est demeuree unie, immobile. Consequemment, elle realiserait la volonte de Dieu. Nous proposons dans le chapitre deux de reprendre les preceptes historiens expliquant l'avenement de la societe chretienne de Nouvelle-France afin d'expliquer le sens que donne Laure Conan a l'histoire de ses heros. Il ressort que, des l'instant ou ceux-ci consentent a sacrifier leur nature humaine afin de demeurer fideles a leur engagement de baptises, ces heros assurent la perennite d'une âme chretienne canadianisee. Le chapitre trois nous est l'occasion d'approfondir un aspect de l'âme : son aptitude memorielle. La religion judeo-chretienne institue la foi et les ecritures comme des demarches memorielles fondamentales dans la pratique religieuse. De meme, les heros conaniens, qui cheminent pour la conversion de leur âme, trouvent dans la memoire de la chretiente les arguments qui les confirment dans leur choix. Les femmes, en tant que gardiennes de la foi, et l'ecriture rythment ainsi les etapes de la conversion de l'âme du heros et de l'heroine. Seculaires, les preceptes de la philosophie theologique de l'histoire institues par saint Augustin (origine ideale, temps degenerescent, eternite de l'âme chretienne, autorite de la memoire) fondent le discours historien de Laure Conan sur la societe de la Nouvelle-France et sur ses heros. Toutefois, elle prend ses distances des ecrits du theologien sur deux points. D'une part, la nature humaine qui, selon saint Augustin, participe a la demarche religieuse du chretien si elle emane d'une volonte vertueuse, n'est, pour Laure Conan, qu'un leurre dont les chretiens doivent se mefier. D'autre part, la romanciere magnifie le role de l'ecriture - de toute ecriture en fait, si celle-ci revele une âme chretienne - au point d'en faire le principal sensible grâce auquel le heros franchit les etapes qui lui permettent d'approcher Dieu.

La genealogie de trente proposants atteints de la mutation dite canadienne-francaise (deletion de 10Kb) de l'hypercholesterolemie familiale a ete reconstruite. Les proposants, leurs parents et leurs grands-parents montrent une concentration geographique croissante dans les regions de la Cote-du-Sud et du Bas-Saint-Laurent. Les parents presumes porteurs de la mutation sont plus apparentes entre eux que les parents presumes sains. Vingt-quatre ancetres communs a toutes les genealogies ont ete identifies. Parmi ceux-ci, six souches familiales differentes sont communes a toutes les genealogies des parents presumes porteurs et viennent principalement des provinces de l'ouest de la France. Ces ancetres ont donc pu avoir introduit la mutation au Quebec.

Equilibrium charge-state distributions have been measured for argon ions in thin carbon foils between 2 and 20 MeV. Equilibration takes place in foils at least as thin as 5 ..mu..g/cm/sup 2/. Our measurements link up smoothly with other work at lower and at higher energies. Several models have been applied to postdict the data. It was found that while the mean charge can be quite accurately determined from empirical models, such as the Gaussian one, or even from extrapolation on Z, serious discrepancies arise with respect to the distribution widths. As a result, charge fractions which are off the peaks of the distributions can be in error by factors of 2 or more, rendering their measurement essential for the purposes of the present study. Evidence of ionic LM shell structure has also been observed in this work.

The Saguenay-Lac St-Jean population of Quebec is relatively isolated and has genealogical records dating to the 17th-century French founders. In 120 extended families with at least one sib pair affected with early-onset hypertension and/or dyslipidemia, we analyzed the genetic determinants of hypertension and related cardiovascular and metabolic conditions. Variance-components linkage analysis revealed 46 loci after 100,000 permutations. The most prominent clusters of overlapping quantitative-trait loci were on chromosomes 1 and 3, a finding supported by principal-components and bivariate analyses. These genetic determinants were further tested by classifying families by use of LOD score density analysis for each measured phenotype at every 5 cM. Our study showed the founder effect over several generations and classes of living individuals. This quantitative genealogical approach supports the notion of the ancestral causality of traits uniquely present and inherited in distinct family classes. With the founder effect, traits determined within population subsets are measurably and quantitatively transmitted through generational lineage, with a precise component contributing to phenotypic variance. These methods should accelerate the uncovering of causal haplotypes in complex diseases such as hypertension and metabolic syndrome.