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Confirmation of a founder effect in a Northern European population of a new β-globin variant: HBB:c.23_26dup (codons 8/9 (+AGAA)).

Marchi N, Pissard S, Cliquennois M, Vasseur C, Le Metayer N, Mereau C, Jouet JP, Georgel AF, Genin E, Rose C - Eur. J. Hum. Genet. (2014)

Bottom Line: More than 200 known different variants can lead to the disease and are mainly found in populations that have been exposed to malaria parasites.Using these EAIMs and comparing with population reference panels, we demonstrated that the variant carriers were very similar to the controls and were closer to North European populations than to South European or Middle-East populations.Rare β-thalassemia variants have already been described in patients sampled in non-endemic regions, but it is the first proof of a founder effect in Northern Europe.

View Article: PubMed Central - PubMed

Affiliation: 1] Inserm UMR-946, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie, Université Paris Diderot, Centre d'Etude du Polymorphisme Humain, Paris, France [2] Eco-Anthropologie et Ethnobiologie, UMR 7206 CNRS, MNHN, Université Paris Diderot, Sorbonne Paris Cite, France [3] Ecole Normale Supérieure de Lyon, Master BioSciences, Lyon, France.

ABSTRACT
β-Thalassemia is a genetic disease caused by a defect in the production of the β-like globin chain. More than 200 known different variants can lead to the disease and are mainly found in populations that have been exposed to malaria parasites. We recently described a duplication of four nucleotides in the first exon of β-globin gene in several families of patients living in Nord-Pas-de-Calais (France). Using the genotypes at 12 microsatellite markers surrounding the β-globin gene of four unrelated variant carriers plus an additional one recently discovered, we found that they shared a common haplotype indicating a founder effect that was estimated to have taken place 225 years ago (nine generations). In order to determine whether this variant arose in this region of Northern Europe or was introduced by migrants from regions of the world where thalassemia is endemic, we genotyped the first 4 unrelated variant carriers and 32 controls from Nord-Pas-de-Calais for 97 European ancestry informative markers (EAIMs). Using these EAIMs and comparing with population reference panels, we demonstrated that the variant carriers were very similar to the controls and were closer to North European populations than to South European or Middle-East populations. Rare β-thalassemia variants have already been described in patients sampled in non-endemic regions, but it is the first proof of a founder effect in Northern Europe.

No MeSH data available.


Related in: MedlinePlus

Determination of the geographic origin of the Chtimi sample and variant carriers based on 54 of the ancestry informative SNPs available in the HapMap3 panel. (a) The top two Principal Components (PC1 and PC2) of the PCA represent 12.84 and 9.82% of the genetic variance. Each plot represents one individual: case, control from the Chtimi sample, or from the HapMap3 panel. (b) Ancestry estimation for the Chtimi sample and variant carriers using ADMIXTURE with three possible ancestry clusters: Africa, Asia, and Europe. Each column represents one individual.
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fig2: Determination of the geographic origin of the Chtimi sample and variant carriers based on 54 of the ancestry informative SNPs available in the HapMap3 panel. (a) The top two Principal Components (PC1 and PC2) of the PCA represent 12.84 and 9.82% of the genetic variance. Each plot represents one individual: case, control from the Chtimi sample, or from the HapMap3 panel. (b) Ancestry estimation for the Chtimi sample and variant carriers using ADMIXTURE with three possible ancestry clusters: Africa, Asia, and Europe. Each column represents one individual.

Mentions: The Chtimi sample and variant carriers were compared with the different populations of the HapMap3 panel based on the genotypes for the 54 SNPs that were available in both panels Supplementary Data S1. The PCA plot (Figure 2a) showed that the Chtimi sample and variant carriers clustered with the Europeans, and this was confirmed by the ancestry estimation using ADMIXTURE as the Chtimi sample and variant carriers have mainly only a European origin (Figure 2b). Two of the four variant carriers have an estimated posterior probability of European origin of 100%. The remaining two have low posterior probabilities of non-European ancestry, but these levels are not higher than the ones estimated for the Chtimi controls who are known to have their grandparents born in the Nord-Pas-de-Calais region. It could indicate either that the two patients are admixed and have some of parts of their genome of Asian ancestry or it could be due to uncertainties in the measures of posterior probability. The second explanation is more likely than the first one as we have run ADMIXTURE on a limited number of markers. If more markers spanning the whole genome were available, the estimates might have been more precise, and interestingly, it might have been possible to determine whether the studied variant falls in the inferred European or non-European part of the genome of these patients. However, given the fact that a founder effect was evidenced for the variant, with all the carriers having inherited the variant from a common ancestor, it is difficult to envisage a scenario where the variant could be in the non-European part of the genome of two out the four variant carriers.


Confirmation of a founder effect in a Northern European population of a new β-globin variant: HBB:c.23_26dup (codons 8/9 (+AGAA)).

Marchi N, Pissard S, Cliquennois M, Vasseur C, Le Metayer N, Mereau C, Jouet JP, Georgel AF, Genin E, Rose C - Eur. J. Hum. Genet. (2014)

Determination of the geographic origin of the Chtimi sample and variant carriers based on 54 of the ancestry informative SNPs available in the HapMap3 panel. (a) The top two Principal Components (PC1 and PC2) of the PCA represent 12.84 and 9.82% of the genetic variance. Each plot represents one individual: case, control from the Chtimi sample, or from the HapMap3 panel. (b) Ancestry estimation for the Chtimi sample and variant carriers using ADMIXTURE with three possible ancestry clusters: Africa, Asia, and Europe. Each column represents one individual.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4538212&req=5

fig2: Determination of the geographic origin of the Chtimi sample and variant carriers based on 54 of the ancestry informative SNPs available in the HapMap3 panel. (a) The top two Principal Components (PC1 and PC2) of the PCA represent 12.84 and 9.82% of the genetic variance. Each plot represents one individual: case, control from the Chtimi sample, or from the HapMap3 panel. (b) Ancestry estimation for the Chtimi sample and variant carriers using ADMIXTURE with three possible ancestry clusters: Africa, Asia, and Europe. Each column represents one individual.
Mentions: The Chtimi sample and variant carriers were compared with the different populations of the HapMap3 panel based on the genotypes for the 54 SNPs that were available in both panels Supplementary Data S1. The PCA plot (Figure 2a) showed that the Chtimi sample and variant carriers clustered with the Europeans, and this was confirmed by the ancestry estimation using ADMIXTURE as the Chtimi sample and variant carriers have mainly only a European origin (Figure 2b). Two of the four variant carriers have an estimated posterior probability of European origin of 100%. The remaining two have low posterior probabilities of non-European ancestry, but these levels are not higher than the ones estimated for the Chtimi controls who are known to have their grandparents born in the Nord-Pas-de-Calais region. It could indicate either that the two patients are admixed and have some of parts of their genome of Asian ancestry or it could be due to uncertainties in the measures of posterior probability. The second explanation is more likely than the first one as we have run ADMIXTURE on a limited number of markers. If more markers spanning the whole genome were available, the estimates might have been more precise, and interestingly, it might have been possible to determine whether the studied variant falls in the inferred European or non-European part of the genome of these patients. However, given the fact that a founder effect was evidenced for the variant, with all the carriers having inherited the variant from a common ancestor, it is difficult to envisage a scenario where the variant could be in the non-European part of the genome of two out the four variant carriers.

Bottom Line: More than 200 known different variants can lead to the disease and are mainly found in populations that have been exposed to malaria parasites.Using these EAIMs and comparing with population reference panels, we demonstrated that the variant carriers were very similar to the controls and were closer to North European populations than to South European or Middle-East populations.Rare β-thalassemia variants have already been described in patients sampled in non-endemic regions, but it is the first proof of a founder effect in Northern Europe.

View Article: PubMed Central - PubMed

Affiliation: 1] Inserm UMR-946, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie, Université Paris Diderot, Centre d'Etude du Polymorphisme Humain, Paris, France [2] Eco-Anthropologie et Ethnobiologie, UMR 7206 CNRS, MNHN, Université Paris Diderot, Sorbonne Paris Cite, France [3] Ecole Normale Supérieure de Lyon, Master BioSciences, Lyon, France.

ABSTRACT
β-Thalassemia is a genetic disease caused by a defect in the production of the β-like globin chain. More than 200 known different variants can lead to the disease and are mainly found in populations that have been exposed to malaria parasites. We recently described a duplication of four nucleotides in the first exon of β-globin gene in several families of patients living in Nord-Pas-de-Calais (France). Using the genotypes at 12 microsatellite markers surrounding the β-globin gene of four unrelated variant carriers plus an additional one recently discovered, we found that they shared a common haplotype indicating a founder effect that was estimated to have taken place 225 years ago (nine generations). In order to determine whether this variant arose in this region of Northern Europe or was introduced by migrants from regions of the world where thalassemia is endemic, we genotyped the first 4 unrelated variant carriers and 32 controls from Nord-Pas-de-Calais for 97 European ancestry informative markers (EAIMs). Using these EAIMs and comparing with population reference panels, we demonstrated that the variant carriers were very similar to the controls and were closer to North European populations than to South European or Middle-East populations. Rare β-thalassemia variants have already been described in patients sampled in non-endemic regions, but it is the first proof of a founder effect in Northern Europe.

No MeSH data available.


Related in: MedlinePlus