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Population stratification can confound genetic association studies and often persists despite adjustment using principal components of common variants. Demographic history and rare variants can also contribute to this confounding. But to what extent does demographic history impact fine structure and can be detected in human populations? To address this question, we analysed the Saguenay–Lac-Saint-Jean region of Quebec, a recent founder population long assumed to be homogeneous. Integrating genotype data with genealogical records, we show a strong concordance between realised (genetic) and expected (genealogical) kinship. Using a time-efficient algorithm capable of computing billions of pairwise kinship coefficients for all individuals married in the region between 1931 and 1960, we reveal fine structure at the municipal level, including an east–west genetic gradient shaped by differential founders’ contribution, migration patterns and socioeconomic factors. These findings challenge the assumption of regional homogeneity and suggest that similar recent structure likely exists in other populations worldwide. These signals may be obscured by coarse, ancient structure under standard stratification corrections used in genome-wide association studies and polygenic risk score analyses which can lead to biases and false associations when realised allele frequencies correlate with phenotypic variation. Population stratification can bias genetic studies, yet fine recent structure is often overlooked. Here, the authors integrate genotypes and genealogies from Saguenay-Lac‑Saint‑Jean, revealing municipal‑level structure shaped by founders, migration and socioeconomic history.

In response to the current challenge in genetic studies to make new associations, we advocate for a shift toward leveraging population fine-scale structure. Our exploration brings to light distinct fine-structure within populations having undergone a founder effect such as the Ashkenazi Jews and the population of the Quebec’ province. We leverage the fine-scale population structure to explore its impact on the frequency of rare variants. Notably, we observed an 8-fold increase in frequency for a variant associated with the Usher syndrome in one Quebec subpopulation. Our study underscores that smaller cohorts with greater genetic similarity demonstrate an important increase in rare variant frequencies, offering a promising avenue for new genetic variants’ discovery.

Coalescent simulations are widely used to examine the effects of evolution and demographic history on the genetic makeup of populations. Thanks to recent progress in algorithms and data structures, simulators such as the widely-used msprime now provide genome-wide simulations for millions of individuals. However, this software relies on classic coalescent theory and its assumptions that sample sizes are small and that the region being simulated is short. Here we show that coalescent simulations of long regions of the genome exhibit large biases in identity-by-descent (IBD), long-range linkage disequilibrium (LD), and ancestry patterns, particularly when the sample size is large. We present a Wright-Fisher extension to msprime, and show that it produces more realistic distributions of IBD, LD, and ancestry proportions, while also addressing more subtle biases of the coalescent. Further, these extensions are more computationally efficient than state-of-the-art coalescent simulations when simulating long regions, including whole-genome data. For shorter regions, efficiency can be maintained via a hybrid model which simulates the recent past under the Wright-Fisher model and uses coalescent simulations in the distant past.

The discovery of new variants has leveled off in recent years in epilepsy studies, despite the use of very large cohorts. Consequently, most of the heritability is still unexplained. Rare non-coding variants have been largely ignored in studies on epilepsy, although non-coding single nucleotide variants can have a significant impact on gene expression. We had access to whole genome sequencing (WGS) from 247 epilepsy patients and 377 controls. To assess the functional impact of non-coding variants, ExPecto, a deep learning algorithm was used to predict expression change in brain tissues. We compared the burden of rare non-coding deleterious variants between cases and controls. Rare non-coding highly deleterious variants were significantly enriched in Genetic Generalized Epilepsy (GGE), but not in Non-Acquired Focal Epilepsy (NAFE) or all epilepsy cases when compared with controls. In this study we showed that rare non-coding deleterious variants are associated with epilepsy, specifically with GGE. Larger WGS epilepsy cohort will be needed to investigate those effects at a greater resolution. Nevertheless, we demonstrated the importance of studying non-coding regions in epilepsy, a disease where new discoveries are scarce.

Rare genetic diseases impact many people worldwide and are challenging to diagnose. In this study, we introduce a novel regional population cohort approach to identify pathogenic variants causing Mendelian diseases that occur more frequently within specific populations and are of clinical interest for carrier testing. We utilized a cohort from Quebec, including the Saguenay–Lac-Saint-Jean region, which is known for its founder effect followed by a rapid expansion and higher frequency of certain pathogenic variants. By analyzing both their frequency and origin through shared identical-by-descent segments, we identified founder variants. We calculated and compared their frequency in individuals originating from the Saguenay–Lac-Saint-Jean and from other urban Quebec regions. We validated 38 previously reported variants as being more common due to the founder effect and population expansion. Additionally, we identified 42 unreported founder variants in Quebec or Saguenay–Lac-Saint-Jean, some with carrier rates estimates as high as 1/22. We also observed a greater deleterious mutational load for the studied variants in individuals from the Saguenay–Lac-Saint-Jean compared to other urban Quebec regions. These findings were brought to the clinic, where 12 pathogenic variants were detected in diagnosed patients. Five variants found in this study are responsible for very severe diseases and could be considered for inclusion in a carrier test for the Saguenay–Lac-Saint-Jean population. This study highlights the potential underestimation of rare disease prevalence and presents a population-based approach that could aid clinicians in their diagnostic efforts and patients’ management.

Founder events influenced the genetic diversity within the province of Quebec, increasing the frequency of certain rare pathogenic variants in regional populations. Some regions, such as Beauce, remain understudied despite evidence of a regional founder effect. Leveraging extensive genealogical data, we observe a specific regional structure emerging in Beauce following the initial settlement. It is characterised by a gradual increase in inbreeding and kinship coefficients and a low diversity of ancestors. Taking advantage of the region’s genetic distinctiveness, we describe 36 rare pathogenic variants with higher carrier rates in Beauce than in urban regions, likely due to the regional founder effect. This provides the first in-depth study of Beauce’s genetic and genealogical landscape, revealing a distinct structure and suggesting that other overlooked regions, in Quebec and elsewhere, could benefit from fine-scale population structure studies to improve the understanding and management of rare diseases. Fine-scale population analysis combining deep genealogical data and whole-genome sequencing reveals a regional founder effect in Beauce (Quebec, Canada) leading to an increase in frequency for 36 rare pathogenic variants.

According to evolutionary theory, mitochondria could be poisoned gifts that mothers transmit to their sons. This is because mutations harmful to males are expected to accumulate in the mitochondrial genome, the so-called ‘mother’s curse’. However, the contribution of the mother’s curse to the mutation load in nature remains largely unknown and hard to predict, because compensatory mechanisms could impede the spread of deleterious mitochondria. Here we provide evidence for the mother’s curse in action over 290 years in a human population. We studied a mutation causing Leber’s hereditary optical neuropathy, a disease with male-biased prevalence and which has long been suspected to be maintained in populations by the mother’s curse. Male carriers showed a low fitness relative to non-carriers and to females, mostly explained by their high rate of infant mortality. Despite poor male fitness, selection analysis predicted a slight (albeit non-significant) increase in frequency, which sharply contrasts with the 35.5% per-generation decrease predicted if mitochondrial DNA transmission had been through males instead of females. Our results are therefore even suggestive of positive selection through the female line that may exacerbate effects of the mother’s curse. This study supports a contribution of the mother’s curse to the reduction of male lifespan, uncovering a large fitness effect associated with a single mitochondrial variant. In evolutionary biology, ‘mother’s curse’ refers to the possibility of passing on harmful mutations through mitochondria. Here evidence is presented for the mother’s curse in action over 290 years in a human population.

Objective Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug‐resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. Methods We performed exome sequencing of 1,128 individuals with non‐familial non‐acquired focal epilepsy (NAFE) (762 non‐responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non‐responders, 185 responders). We performed gene‐based and gene‐set‐based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. Results We found no gene or gene set that reached genome‐wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non‐familial NAFE and in association with drug‐resistant NAFE. Interpretation Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non‐familial NAFE and imply their involvement in drug‐resistant epilepsy. Future large‐scale genetic research studies are needed to substantiate these findings.

Objective Microdeletions are associated with different forms of epilepsy but show incomplete penetrance, which is not well understood. We aimed to assess whether unmasked variants or double CNVs could explain incomplete penetrance. Methods We analyzed copy number variants (CNVs) in 603 patients with four different subgroups of epilepsy and 945 controls. CNVs were called from genotypes and validated on whole‐genome (WGS) or whole‐exome sequences (WES). CNV burden difference between patients and controls was obtained by fitting a logistic regression. CNV burden was assessed for small and large (>1 Mb) deletions and duplications and for deletions overlapping different gene sets. Results Large deletions were enriched in genetic generalized epilepsies (GGE) compared to controls. We also found enrichment of deletions in epilepsy genes and hotspots for GGE. We did not find truncating or functional variants that could have been unmasked by the deletions. We observed a double CNV hit in two patients. One patient also carried a de novo deletion in the 22q11.2 hotspot. Interpretation We could corroborate previous findings of an enrichment of large microdeletions and deletions in epilepsy genes in GGE. We could also replicate that microdeletions show incomplete penetrance. However, we could not validate the hypothesis of unmasked variants nor the hypothesis of double CNVs to explain the incomplete penetrance. We found a de novo CNV on 22q11.2 that could be of interest. We also observed GGE families carrying a deletion on 15q13.3 hotspot that could be investigated in the Quebec founder population.

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.