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

Durst, Ronen; Colombo, Roberto; Shpitzen, Shoshi; Avi, Liat Ben; Friedlander, Yechiel; Wexler, Roni; Raal, Frederick J.; Marais, David; Defesche, Joep C.; Mandelshtam, M. Yu.; Kotze, Maritha J.; Leitersdorf, Eran; Meiner, Vardiella

doi:10.1086/320123

Cited by 45 publications

(37 citation statements)

References 63 publications

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“…Figure 4c contrasts the Ashkenazi Jewish mismatch distribution with that of the Druze, a Near Eastern population with low effective size. 26 The Druze t of 4.6 is similar to that of the Ashkenazi Jews, again suggesting a period of shared growth. However, the Druze show an increase in f 0 , but not f 1 , as do the Ashkenazi Jewish populations.…”

Section: Mismatch Distributionsmentioning

confidence: 80%

“…The higher dispersion of Near Eastern relative to European populations in the plot could be the result of stronger genetic drift in the Bedouins and Druze, two populations with small effective sizes. 26 Although not readily apparent in the MDS plot, AMOVA analysis (results not shown) indicated that Ashkenazi populations as a whole are genetically more similar to Near Eastern non-Jewish populations than to European non-Jewish populations. Table 1 reports HVS-1 haplotype diversity (h) and nucleotide diversity (p) values for our Ashkenazi samples, as well as for 10 European non-Jewish populations from similar geographic regions and five Near Eastern non-Jewish populations.…”

Section: Multidimensional Scaling (Mds) and Genetic Distances Betweenmentioning

confidence: 86%

“…While several authors posited that the high frequency of genetic conditions, such as TaySachs disease, is the result of heterozygote advantage, 5,28 -30 others have argued for an important role of genetic drift. 6,26 For example, Risch et al 6 proposed that founder effects resulting from the dynamics of population growth in the 16 -19th centuries, especially in the northern Jewish Pale of Settlement (Lithuania and Belarus), explain most, if not all of the genetic diseases observed at high frequency in the Ashkenazi population today. This hypothesis was supported by the inference of a recent age of the single founder mutation (B350 years) that causes early-onset idiopathic torsion dystonia.…”

Section: Discussionmentioning

confidence: 99%

“…39 This suggests the possibility that contemporary Ashkenazi mtDNA diversity may derive, in part, from a small and subdivided ancestral mtDNA gene pool, and is consistent with the hypothesis that some high frequency disease alleles originated before the separation of Jewish communities in the Near East. 40,41 Indeed, estimates of the age of mutations causing Ashkenazi genetic diseases range from recent times (ie, during demographic upheavals within Europe in the past 500 years), 6,26,40,42 to times when ancestral Ashkenazi populations were first migrating to and within Europe, 43 to times before Jewish populations migrated out of the Near East. 40,44,45 …”

Section: Discussionmentioning

confidence: 99%

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MtDNA evidence for a genetic bottleneck in the early history of the Ashkenazi Jewish population

et al. 2004

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The relative roles of natural selection and accentuated genetic drift as explanations for the high frequency of more than 20 Ashkenazi Jewish disease alleles remain controversial. To test for the effects of a maternal bottleneck on the Ashkenazi Jewish population, we performed an extensive analysis of mitochondrial DNA (mtDNA) hypervariable segment 1 (HVS-1) sequence and restriction site polymorphisms in 565 Ashkenazi Jews from different parts of Europe. These patterns of variation were compared with those of five Near Eastern (n ¼ 327) and 10 host European (n ¼ 849) non-Jewish populations. Only four mtDNA haplogroups (Hgs) (defined on the basis of diagnostic coding region RFLPs and HVS-1 sequence variants) account for B70% of Ashkenazi mtDNA variation. While several Ashkenazi Jewish mtDNA Hgs appear to derive from the Near East, there is also evidence for a low level of introgression from host European non-Jewish populations. HVS-1 sequence analysis revealed increased frequencies of Ashkenazi Jewish haplotypes that are rare or absent in other populations, and a reduced number of singletons in the Ashkenazi Jewish sample. These diversity patterns provide evidence for a prolonged period of low effective size in the history of the Ashkenazi population. The data best fit a model of an early bottleneck (B100 generations ago), perhaps corresponding to initial migrations of ancestral Ashkenazim in the Near East or to Europe. A genetic bottleneck followed by the recent phenomenon of rapid population growth are likely to have produced the conditions that led to the high frequency of many genetic disease alleles in the Ashkenazi population.

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Section: Mismatch Distributionsmentioning

confidence: 80%

Section: Multidimensional Scaling (Mds) and Genetic Distances Betweenmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

MtDNA evidence for a genetic bottleneck in the early history of the Ashkenazi Jewish population

et al. 2004

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“…La classe et le type de mutations sont reconnus pour avoir une influence sur les phénotypes de THF, leur impact sur le développement de MCA a été largement étudié (45, [55][56][57]. Les 920 mutations du gène du LDLR peuvent être divisées en cinq classes, selon l'effet qu'elles exercent sur l'expression de la protéine (Tableau 3).…”

Section: Les Mutations Dans Le Gène Du Ldlrunclassified

adiponectine, un modulateur du risque de maladie coronarienne athérosclérotique dans l'hypercholestérolémie familiale /

Bouhali¹

2006

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LDL-receptor mutations in Europe

2004

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Familial hypercholesterolemia (FH) is a clinical definition for a remarkable increase of cholesterol serum concentration, presence of xanthomas, and an autosomal dominant trait of either increased serum cholesterol or premature coronary artery disease (CAD). The identification of the low-density lipoprotein (LDL)-receptor (LDLR) as the underlying cause and its genetic characterization in FH patients revealed more insights in the trafficking of LDL, which primarily transports cholesterol to hepatic and peripheral cells. Mutations within LDLR result in hypercholesterolemia and, subsequently, cholesterol deposition in humans to a variable degree. This confirms the pathogenetic role of LDLR and also highlights the existence of additional factors in determining the phenotype. Autosomal dominant FH is caused by LDLR deficiency and defective apolipoprotein B-100 (APOB), respectively. Heterozygosity of the LDLR is relatively common (1:500). Clinical diagnosis is highly important and genetic diagnosis may be helpful, since treatment is usually effective for this otherwise fatal disease. Very recently, mutations in PCSK9 have been also shown to cause autosomal dominant hypercholesterolemia. For autosomal recessive hypercholesterolemia, mutations within the so-called ARH gene encoding a cellular adaptor protein required for LDL transport have been identified. These insights emphasize the crucial importance of LDL metabolism intra- and extracellularly in determining LDL-cholesterol serum concentration. Herein, we focus on the published European LDLR mutation data that reflect its heterogeneity and phenotypic penetrance.

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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

Cited by 45 publications

References 63 publications

MtDNA evidence for a genetic bottleneck in the early history of the Ashkenazi Jewish population

MtDNA evidence for a genetic bottleneck in the early history of the Ashkenazi Jewish population

adiponectine, un modulateur du risque de maladie coronarienne athérosclérotique dans l'hypercholestérolémie familiale /

LDL-receptor mutations in Europe

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