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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 45 of the ancestry informative SNPs available in the HGDP Panel. Only European and Middle-Eastern populations from HGDP Panel are considered. (a) The top two Principal Components (PC1 and PC2) of the PCA represent 7.57 and 3.71% of the genetic variance. Each plot represents one individual: case, or control from Chtimi sample or from the HGDP European and Middle-Eastern populations. (b) PC1 distances calculated between each variant carrier and each control from HGDP European and Middle-Eastern populations or Chtimi sample.
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fig3: Determination of the geographic origin of the Chtimi sample and variant carriers based on 45 of the ancestry informative SNPs available in the HGDP Panel. Only European and Middle-Eastern populations from HGDP Panel are considered. (a) The top two Principal Components (PC1 and PC2) of the PCA represent 7.57 and 3.71% of the genetic variance. Each plot represents one individual: case, or control from Chtimi sample or from the HGDP European and Middle-Eastern populations. (b) PC1 distances calculated between each variant carrier and each control from HGDP European and Middle-Eastern populations or Chtimi sample.

Mentions: To gain further insights into the origin of the variant and particularly to determine whether it most likely originated in the North or South of Europe, we performed some additional analyses with the reference panels restricted to their European or Middle-East populations. In the HGDP panel, we selected populations from the Middle-East and Europe in order to estimate the part of Mediterranean origin in the Chtimi sample and variant carriers and to put the Chtimi sample and variant carriers on a North/South gradient. In this panel, the same 45 ancestry informative markers as the ones used in the worldwide analysis were available. We performed a PCA (Figure 3a), and it appeared that the Chtimi sample and variant carriers were closer to the European populations than to the Middle-Eastern ones (P-value of Mann–Whitney's test=5.70 × 10−12 for PC1 distances). A distance on PC1 was computed between each variant carrier and each control from HGDP populations or from Chtimi sample (Figure 3b); these distances were smaller when considering the European and Chtimi samples than when considering Middle-Eastern populations, indicating a more likely European than Middle-Eastern origin of variant carriers. To infer a more precise European origin, we considered two populations from HapMap3 panel: CEU from Northern Europe and TSI from Tuscan, Southern Europe, and their genotypes at 62 of the ancestry-informative SNPs. We also realized a PCA: the PC1 only explained 3.84% of the variance but the Chtimi sample and variant carriers clustered with CEU individuals in a distinct group from TSI individuals. Indeed, for PC1 distances, Chtimi controls and variant carriers were closer to the HapMap3 CEU than to the HapMap3 TSI (P-value of Mann–Whitney's test=1.15 × 10−5), indicating a more likely Northern than Southern origin in Europe, which was confirmed on the HGDP panel restricted to European population. Indeed, when classifying the European populations from HGDP into three groups: North (represented by the Orcadian population), Central (French Basque, French, North Italian and Tuscan populations) and South Europe (Sardinian population), we found that the Chtimi sample clustered with Northern and Central Europeans and the cases mainly with the Northern Europeans Supplementary Data S6. These different results argued in favor of the hypothesis that the studied variant was native to Northern Europe and was not introduced by recent migrations from other regions of the world.


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 45 of the ancestry informative SNPs available in the HGDP Panel. Only European and Middle-Eastern populations from HGDP Panel are considered. (a) The top two Principal Components (PC1 and PC2) of the PCA represent 7.57 and 3.71% of the genetic variance. Each plot represents one individual: case, or control from Chtimi sample or from the HGDP European and Middle-Eastern populations. (b) PC1 distances calculated between each variant carrier and each control from HGDP European and Middle-Eastern populations or Chtimi sample.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Determination of the geographic origin of the Chtimi sample and variant carriers based on 45 of the ancestry informative SNPs available in the HGDP Panel. Only European and Middle-Eastern populations from HGDP Panel are considered. (a) The top two Principal Components (PC1 and PC2) of the PCA represent 7.57 and 3.71% of the genetic variance. Each plot represents one individual: case, or control from Chtimi sample or from the HGDP European and Middle-Eastern populations. (b) PC1 distances calculated between each variant carrier and each control from HGDP European and Middle-Eastern populations or Chtimi sample.
Mentions: To gain further insights into the origin of the variant and particularly to determine whether it most likely originated in the North or South of Europe, we performed some additional analyses with the reference panels restricted to their European or Middle-East populations. In the HGDP panel, we selected populations from the Middle-East and Europe in order to estimate the part of Mediterranean origin in the Chtimi sample and variant carriers and to put the Chtimi sample and variant carriers on a North/South gradient. In this panel, the same 45 ancestry informative markers as the ones used in the worldwide analysis were available. We performed a PCA (Figure 3a), and it appeared that the Chtimi sample and variant carriers were closer to the European populations than to the Middle-Eastern ones (P-value of Mann–Whitney's test=5.70 × 10−12 for PC1 distances). A distance on PC1 was computed between each variant carrier and each control from HGDP populations or from Chtimi sample (Figure 3b); these distances were smaller when considering the European and Chtimi samples than when considering Middle-Eastern populations, indicating a more likely European than Middle-Eastern origin of variant carriers. To infer a more precise European origin, we considered two populations from HapMap3 panel: CEU from Northern Europe and TSI from Tuscan, Southern Europe, and their genotypes at 62 of the ancestry-informative SNPs. We also realized a PCA: the PC1 only explained 3.84% of the variance but the Chtimi sample and variant carriers clustered with CEU individuals in a distinct group from TSI individuals. Indeed, for PC1 distances, Chtimi controls and variant carriers were closer to the HapMap3 CEU than to the HapMap3 TSI (P-value of Mann–Whitney's test=1.15 × 10−5), indicating a more likely Northern than Southern origin in Europe, which was confirmed on the HGDP panel restricted to European population. Indeed, when classifying the European populations from HGDP into three groups: North (represented by the Orcadian population), Central (French Basque, French, North Italian and Tuscan populations) and South Europe (Sardinian population), we found that the Chtimi sample clustered with Northern and Central Europeans and the cases mainly with the Northern Europeans Supplementary Data S6. These different results argued in favor of the hypothesis that the studied variant was native to Northern Europe and was not introduced by recent migrations from other regions of the world.

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