Evidence for prehistoric origins of the G2019S mutation in the North African Berber population

Haj, Rafiqua Ben El; Salmi, Ayyoub; Regragui, W.; Moussa, Ahmed; Bouslam, Naïma; Tibar, Houyam; Benomar, Ali; Yahyaoui, M.; Bouhouche, Ahmed

doi:10.1371/journal.pone.0181335

Cited by 15 publications

(17 citation statements)

References 58 publications

(75 reference statements)

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“…Another well-known example is the Parkinson’s disease-associated p.G2019S LRRK2 mutation, which is known to be present on different haplotypes suggesting different founders. One of them was estimated to have occurred 159 generations ago in a Berber founder [20]. The identification of recurrent mutations in autosomal-dominant genes in the absence of a founder effect or evidence for multiple founders points to the regular occurrence of DNMs in these genes.…”

Section: Indirect Argumentsmentioning

confidence: 99%

The role of de novo mutations in adult-onset neurodegenerative disorders

Nicolas

Veltman

2018

Acta Neuropathol

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The genetic underpinnings of the most common adult-onset neurodegenerative disorders (AOND) are complex in majority of the cases. In some families, however, the disease can be inherited in a Mendelian fashion as an autosomal-dominant trait. Next to that, patients carrying mutations in the same disease genes have been reported despite a negative family history. Although challenging to demonstrate due to the late onset of the disease in most cases, the occurrence of de novo mutations can explain this sporadic presentation, as demonstrated for severe neurodevelopmental disorders. Exome or genome sequencing of patient-parent trios allows a hypothesis-free study of the role of de novo mutations in AOND and the discovery of novel disease genes. Another hypothesis that may explain a proportion of sporadic AOND cases is the occurrence of a de novo mutation after the fertilization of the oocyte (post-zygotic mutation) or even as a late-somatic mutation, restricted to the brain. Such somatic mutation hypothesis, that can be tested with the use of novel sequencing technologies, is fully compatible with the seeding and spreading mechanisms of the pathological proteins identified in most of these disorders. We review here the current knowledge and future perspectives on de novo mutations in known and novel candidate genes identified in the most common AONDs such as Alzheimer's disease, Parkinson's disease, the frontotemporal lobar degeneration spectrum and Prion disorders. Also, we review the first lessons learned from recent genomic studies of control and diseased brains and the challenges which remain to be addressed.

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Section: Indirect Argumentsmentioning

confidence: 99%

The role of de novo mutations in adult-onset neurodegenerative disorders

Nicolas

Veltman

2018

Acta Neuropathol

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“…The variant is common in North-Africans, and it was found in about 20% and 40% of Parkinson’s disease cases in AJ and North-Africans, respectively. The variant was previously dated to a few thousands of years ago [69, 70]. The remaining variants were recessive.…”

Section: Resultsmentioning

confidence: 99%

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

Waldman

Backenroth

Harney

et al. 2022

Preprint

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We report genome-wide data for 33 Ashkenazi Jews (AJ), dated to the 14th century, following a salvage excavation at the medieval Jewish cemetery of Erfurt, Germany. The Erfurt individuals are genetically similar to modern AJ and have substantial Southern European ancestry, but they show more variability in Eastern European-related ancestry than modern AJ. A third of the Erfurt individuals carried the same nearly-AJ-specific mitochondrial haplogroup and eight carried pathogenic variants known to affect AJ today. These observations, together with high levels of runs of homozygosity, suggest that the Erfurt community had already experienced the major reduction in size that affected modern AJ. However, the Erfurt bottleneck was more severe, implying substructure in medieval AJ. Together, our results suggest that the AJ founder event and the acquisition of the main sources of ancestry pre-dated the 14th century and highlight late medieval genetic heterogeneity no longer present in modern AJ.

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“…This would explain the new observations . Furthermore, PD‐linked mutations have been around since prehistoric times and may therefore have had a selective advantage for young people encountering situations demanding rapid responses, for example, escape or hunting activities.…”

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confidence: 79%