Genome-wide data from medieval German Jews show that the Ashkenazi founder event pre-dated the 14th century

Waldman, Shamam; Backenroth, Daniel; Harney, Éadaoin; Flohr, Stefan; Neff, Nadia C.; Buckley, Gina; Fridman, Hila; Akbari, Ali; Rohland, Nadin; Mallick, Swapan; Olalde, Ïñigo; Cooper, Leo; Lomes, Ariel; Lipson, Joshua; Nistal, Jorge Cano; Yu, Jin; Barzilai, Nir; Peter, Inga; Atzmon, Gil; Ostrer, Harry; Lencz, Todd; Maruvka, Yosef E.; Lämmerhirt, Maike; Beider, Alexander; Rutgers, Leonard Victor; Renson, Virginie; Prufer, Keith M.; Schiffels, Stephan; Ringbauer, Harald; Sczech, Karin; Carmi, Shai; Reich, David

doi:10.1016/j.cell.2022.11.002

Cited by 17 publications

(16 citation statements)

References 95 publications

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“…A recent genome-wide study of samples from ancient Ashkenazi Jews indicated the highest genomic overlap with Turkish Jews (Sephardi Jews). 77 This presumably indicates a common genetic pool between Sepharadi and Ashkenazi Jews, as previously suggested. 78 The CNV analysis identified different haplotype backgrounds for P-1/P-2 and PS-1.…”

Section: Discussionsupporting

confidence: 66%

A pathogenic variant in the uncharacterized RNF212B gene results in severe aneuploidy male infertility and repeated IVF failure

Gershoni¹,

Braun²,

Hauser³

et al. 2023

Human Genetics and Genomics Advances

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Section: Discussionsupporting

confidence: 66%

A pathogenic variant in the uncharacterized RNF212B gene results in severe aneuploidy male infertility and repeated IVF failure

Gershoni¹,

Braun²,

Hauser³

et al. 2023

Human Genetics and Genomics Advances

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“…However, the simulation tests have always a restricted scope, as the models simulated cannot encompass all the complexities of real genomes. In addition, the empirical estimates are generally done without knowing the real demography of the populations, even though relevant changes in population size can be assumed from different sources of data or contrasted with historical data on some occasions (Waldman et al, 2022). Thus, in this study, we aimed to evaluate the performance of the Santiago et al (2020) method with experimental data from a Drosophila melanogaster population subjected to laboratory controlled drastic changes in size over generations.…”

mentioning

confidence: 99%

An empirical test of the estimation of historical effective population size using Drosophila melanogaster

Novo

Pérez‐Pereira

Santiago

et al. 2023

Molecular Ecology Resources

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The availability of a large number of high‐density markers (SNPs) allows the estimation of historical effective population size (Ne) from linkage disequilibrium between loci. A recent refinement of methods to estimate historical Ne from the recent past has been shown to be rather accurate with simulation data. The method has also been applied to real data for numerous species. However, the simulation data cannot encompass all the complexities of real genomes, and the performance of any estimation method with real data is always uncertain, as the true demography of the populations is not known. Here, we carried out an experimental design with Drosophila melanogaster to test the method with real data following a known demographic history. We used a population maintained in the laboratory with a constant census size of about 2800 individuals and subjected the population to a drastic decline to a size of 100 individuals. After a few generations, the population was expanded back to the previous size and after a few further generations again expanded to twice the initial size. Estimates of historical Ne were obtained with the software GONE both for autosomal and X chromosomes from samples of 17 individuals sequenced for the whole genome. Estimates of the historical effective size were able to infer the patterns of changes that occurred in the populations showing generally good performance of the method. We discuss the limitations of the method and the application of the software carried out so far.

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“…The geographic distribution of present-day LRRK2 G2019S carriers both aligns with the known history surrounding the dispersion of the variant while also revealing novel insights regarding the population structure. 3,45 High carrier rates in North Africa support the concept of an ancient Moroccan Berber founder. The enriched geographic location in Eastern Europe-specifically in the area corresponding to the Pale of Settlement-aligns with the hypothesis of a subsequent flow of the LRRK2 G2019S variant into the Ashkenazi Jewish community, likely predating the 14 th century bottleneck.…”

Section: Discussionmentioning

confidence: 99%

“…The enriched geographic location in Eastern Europe—specifically in the area corresponding to the Pale of Settlement—aligns with the hypothesis of a subsequent flow of the LRRK2 G2019S variant into the Ashkenazi Jewish community, likely predating the 14 th century bottleneck. 3,4,45–47…”

Section: Discussionmentioning

confidence: 99%

Genetic Analysis and Natural History of Parkinson’s Disease Due to the LRRK2 G2019S Variant

Kmiecik,

Micheletti,

Coker

et al. 2023

Preprint

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The LRRK2 G2019S variant is the most common cause of monogenic Parkinson's Disease (PD); however, questions remain regarding the penetrance, clinical phenotype, and natural history of carriers. We performed a 3.5 year prospective longitudinal online study in a large number of 1,286 genotyped LRRK2 G2019S carriers and 109,154 controls, with and without Parkinson's disease (PD) recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every six months, as well as demographics, family histories, and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modeling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G2019S carriers in the 23andMe database and identified regions of the world where carrier frequencies are highest. We observed that despite a one year longer disease duration (p=0.016), LRRK2 G2019S carriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behavior disorder (RBD), and hyposmia (all p-values<0.0002). The cumulative incidence of PD in G2019S carriers by age 60 was 8.66%. G2019S carriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk in G2019S carriers with a PD polygenic risk score in the top 25% versus non-carriers in the bottom 25%. In addition to identifying ancient founding events in people of North African and Ashkenazi descent, our genetic ancestry analyses infer that the G2019S variant was later introduced to Spanish colonial territories in the Americas. Our results suggest LRRK2 G2019S PD appears to be a slowly progressive predominantly motor subtype of PD with a lower prevalence of hyposmia, RBD, and cognitive impairment. This suggests that the current prodromal criteria, which are based on idiopathic PD, may lack sensitivity to detect the early phases of LRRK2 PD in G2019S carriers. We show that polygenic burden may contribute to the development of PD in the LRRK2 G2019S carrier population. Collectively, the results should help support screening programs and candidate enrichment strategies for upcoming trials of LRRK2 inhibitors in early-stage disease.

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Genome-wide data from medieval German Jews show that the Ashkenazi founder event pre-dated the 14th century

Cited by 17 publications

References 95 publications

A pathogenic variant in the uncharacterized RNF212B gene results in severe aneuploidy male infertility and repeated IVF failure

A pathogenic variant in the uncharacterized RNF212B gene results in severe aneuploidy male infertility and repeated IVF failure

An empirical test of the estimation of historical effective population size using Drosophila melanogaster

Genetic Analysis and Natural History of Parkinson’s Disease Due to the LRRK2 G2019S Variant

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