ABSTRACT
Over the past decade, genomic data have contributed to several insights on global human population histories. These studies have been met both with interest and critically, particularly by populations with oral histories that are records of their past and often reference their origins. While several studies have reported concordance between oral and genetic histories, there is potential for tension that may stem from genetic histories being prioritized or used to confirm community-based knowledge and ethnography, especially if they differ. To investigate the interplay between oral and genetic histories, we focused on the southwestern region of India and analyzed whole-genome sequence data from 156 individuals identifying as Bunt, Kodava, Nair, and Kapla. We supplemented limited anthropological records on these populations with oral history accounts from community members and historical literature, focusing on references to non-local origins such as the ancient Scythians in the case of Bunt, Kodava, and Nair, members of Alexander the Great's army for the Kodava, and an African-related source for Kapla. We found these populations to be genetically most similar to other Indian populations, with the Kapla more similar to South Indian tribal populations that maximize a genetic ancestry related to Ancient Ancestral South Indians. We did not find evidence of additional genetic sources in the study populations than those known to have contributed to many other present-day South Asian populations. Our results demonstrate that oral and genetic histories may not always provide consistent accounts of population origins and motivate further community-engaged, multi-disciplinary investigations of non-local origin stories in these communities.
ABSTRACT
Alzheimer's disease (AD) is the most prevalent cause of dementia1. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aß) is a promising therapeutic strategy2,3. Meningeal lymphatic drainage has an important role in the accumulation of Aß in the brain4, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aß passive immunotherapy by exacerbating the deposition of Aß, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aß by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.
