Gaucher Disease: The Origins of the Ashkenazi Jewish N370S and 84GG Acid β-Glucosidase Mutations

Abstract

Type 1 Gaucher disease (GD), a non-neuronopathic lysosomal storage disorder, results from the deficient activity of acid beta-glucosidase (GBA). Type 1 disease is panethnic but is more prevalent in individuals of Ashkenazi Jewish (AJ) descent. Of the causative GBA mutations, N370S is particularly frequent in the AJ population, (q approximately .03), whereas the 84GG insertion (q approximately .003) occurs exclusively in the Ashkenazim. To investigate the genetic history of these mutations in the AJ population, short tandem repeat (STR) markers were used to map a 9.3-cM region containing the GBA locus and to genotype 261 AJ N370S chromosomes, 60 European non-Jewish N370S chromosomes, and 62 AJ 84GG chromosomes. A highly conserved haplotype at four markers flanking GBA (PKLR, D1S1595, D1S2721, and D1S2777) was observed on both the AJ chromosomes and the non-Jewish N370S chromosomes, suggesting the occurrence of a founder common to both populations. Of note, the presence of different divergent haplotypes suggested the occurrence of de novo, recurrent N370S mutations. In contrast, a different conserved haplotype at these markers was identified on the 84GG chromosomes, which was unique to the AJ population. On the basis of the linkage disequilibrium (LD) delta values, the non-Jewish European N370S chromosomes had greater haplotype diversity and less LD at the markers flanking the conserved haplotype than did the AJ N370S chromosomes. This finding is consistent with the presence of the N370S mutation in the non-Jewish European population prior to the founding of the AJ population. Coalescence analyses for the N370S and 84GG mutations estimated similar coalescence times, of 48 and 55.5 generations ago, respectively. The results of these studies are consistent with a significant bottleneck occurring in the AJ population during the first millennium, when the population became established in Europe.

An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy

“…The AJ population was initially selected for the haplotype studies because previous founder mutations have been identified in shared haplotype blocks, which has facilitated gene discovery for recessive disorders prevalent among AJ individuals. 19,20,27 The feasibility of this approach is further supported by a recent study of an SMN1 deletion founder allele in the US Hutterite population that identified a shared haplotype and a single origin for mutations in the population, with an estimated SMA carrier frequency of one in eight. 28 To search for potential founder alleles, microsatellite analyses were performed with markers flanking the SMN1 locus, and…”

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

“…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 …”

Recent and ongoing selection in the human genome

“…One exception might be diseases with late onset under the assumption that older individuals do not contribute to the fitness of their offspring. Examples of negative selection acting on disease-causing mutations include mutations in GBA causing Gaucher disease 77 , mutations in nucleotide-binding oligomerization-domaincontaining 2 gene (NOD2; also known as CARD15) causing Crohn disease 78 , mutations in CMH1, CMH2, CMH3, and CMH4 causing familial hypertrophic cardiomyopathy 79 , and a host of other genetic disorders that are caused by de novo mutations or segregating recessive mutations. If negative selection alone is operating, the disease mutations are expected to segregate at low frequencies, and to be predominantly recessive.…”

“…Another possible explanation for the segregation of disease alleles at moderate or high frequencies is that genetic drift has acted on mutations that have only moderate fitness effects, possibly exacerbated by bottlenecks in the population size, as suggested for Gaucher disease in Askhenazi Jews 77 . Yet another explanation is that there might have been a recent change in the direction of selection.…”