Avesthagen releases “The First complete Zoroastrian-Parsi Mitochondria Reference Genome: Implications of mitochondrial signatures in an endogamous, non-smoking population” – The study unravels mitochondrial signatures linked to persian origin, longevity and associated health conditions
Avesthagen Limited, with support from the Foundation for a Smoke Free World, New York, USA is developing a systems biology-based approach for the early predictive diagnosis of tobacco related cancers such as lung, head and neck, esophagus, stomach, colon, prostate and bladder cancers to achieve cessation of smoking.
Since 2008, The Avestagenome Project® has been collecting a biobank of Zoroastrian Parsi blood samples and extensive patient data from over 4,500 members of this community.
Recognizing the importance of the Parsi cohort and the unique system’s approach to research, the US-based, ‘Foundation for a Smoke-Free World’, whose mission is to end smoking within this generation, awarded Avesthagen “Cancer risk in smoking subjects assessed by next generation sequencing profile of circulating free DNA and RNA” to prioritize research into lung and tobaccorelated cancers.
In order to gain a clearer understanding of the historically recorded migration of the Zoroastrian-Parsis, decipher their phylogenetic relationships and understand disease association to their individual mitochondrial genomes, Avesthagen generated the first complete de novo Zoroastrian-Parsi Mitochondrial Reference Genome, AGENOME-ZPMS-HV2a-1. Phylogenetic analysis of additional 100 Parsi mitochondrial genome sequences, showed their distribution into 7 major haplogroups and 25 sub-haplogroups and a largely Persian origin for the Zoroastrian-Parsi community. Individual reference genomes for each major haplogroup were used to assemble the Zoroastrian-Parsi Mitochondrial Consensus Genome (AGENOME-ZPMCG V1.0) for the first time in the world.
The study identified 420 mitochondrial variants in the Zoroastrian-Parsi genomes. Bioinformatic analysis of these variants showed a presence of longevity as a trait and associated conditions like cancers such as colon, prostate, neurodegenerative conditions like Parkinsons, rare diseases like Lebers Hereditary Optic Neuropathy and asthenozoospermia, a fertility disorder. Furthermore, the study uncovered 12 unique variants, previously unreported for other populations which are under further investigation.
The research, in specific found a lack of association with Lung cancers and low frequency of DNA mutational signatures associated with Tobacco smoking carcinogen induced cancers in the Parsi community, attesting to unique non-smoking social practices practiced in the community, whose origins go back a millennia.
The research work now released on bioRxiv converges, ancient history, human migration, endogamous population genetics, social behavior and customs that express in genetic signatures of wellness and health.
Dr.Villoo Morawala-Patell, Founder and CMD, Avesthagen Limited and The Avestagenome Project® says “We believe in bringing science to life by drawing it out of the confines of the laboratory and setting it free to work in the real, everyday world”. Both, Avesthagen Limited and The Avestagenome Project® was built on the bedrock of understanding and extrapolating diversity, from environment to human communities; The Parsi-Zoroastrian community renowned for its philanthropy will be contributing through The Avestagenome Project® to global health through a deeper understanding of genetics, disease and environment.
The present-day Zoroastrian-Parsis have roots in ancient pastoralist migrations from circumpolar regions1 leading to their settlement on the Eurasian Steppes2 and later, as Indo Iranians in the Fertile Crescent3. From then, the Achaemenids (550 – 331 BC), and later the Sassanids (224 BC – 642 AD) established the mighty Persian Empires2. The Arab invasion of Persia in 642 AD necessitated the migration of Zoroastrians from Pars to India where they settled as Parsis and practiced their faith, Zoroastrianism. Endogamy became a dogma, and the community has maintained the practice since their arrival in India. Fire is the medium of worship4 as it is considered pure and sacrosanct; Social ostracism practiced against smokers resulted in a non-smoking community, thus forming a unique basis for our study.
In order to gain a clearer understanding of the historically recorded migration of the Zoroastrian-Parsis, decipher their phylogenetic relationships and understand disease association to their individual mitochondrial genomes, we generated the first complete de novo Zoroastrian-Parsi Mitochondrial Reference Genome, AGENOME-ZPMS-HV2a-1. Phylogenetic analysis of additional 100 Parsi mitochondrial genome sequences, showed their distribution into 7 major haplogroups and 25 sub-haplogroups and a largely Persian origin for the Parsi community. We have generated individual reference genomes for each major haplogroup and assembled the Zoroastrian Parsi Mitochondrial Consensus Genome (AGENOME-ZPMCG V1.0) for the first time in the world.
We report 420 variants, specifically 12 unique mitochondrial variants in the 100 mitochondrial genome sequences compared with the revised Cambridge Reference Sequence (rCRS) standard.
Disease association mapping showed 217 unique variants linked to longevity and 41 longevity associated disease phenotypes across most haplogroups. Our results indicate none of the variants are linked to lung cancer. Mutational signatures, C>A, G>T transitions36, linked to tobacco carcinogens were found at extremely low frequencies in the Zoroastrian-Parsi cohort.
Our analysis of gene-coding, tRNA and the D-Loop regions revealed haplogroup specific disease associations for Parkinson’s, Alzheimer’s, Cancers, and Rare diseases.
These disease signatures investigated in the backdrop of generations of endogamy, in the rapidly declining, endangered Zoroastrian-Parsi community of India, provides exceptional universal opportunity to understand and mitigate disease.
The full text of the paper can be read in the downloadable PDF here.