Admixture Has Shaped Romani Genetic Diversity in Clinically Relevant Variants

Area of Science:

• Population Genetics
• Human Genomics
• Medical Genetics

Background:

• Clinically relevant mutation studies exhibit a significant Eurocentric bias.
• The Romani population, originating from South Asia with West Eurasian gene flow, is underrepresented in genetic research, primarily studied for founder mutations in Mendelian disorders.
• Understanding genetic variation in diverse populations is crucial for accurate disease risk assessment and personalized medicine.

Purpose of the Study:

• To analyze exome and genome-wide data from healthy Spanish Roma individuals to investigate complex traits and diseases.
• To apply a novel framework focusing on both increased and decreased allele frequencies, considering local ancestry.
• To characterize clinically relevant genetic variation in the Romani population beyond founder mutations.

Main Methods:

• Analysis of exome sequences and genome-wide array data from 89 healthy Spanish Roma individuals.
• Application of a framework that considers local ancestry and allele frequency distributions (both increased and decreased).
• Comparison of variant frequencies between Romani and non-Romani European populations.

Main Results:

• Identified enrichment of Online Mendelian Inheritance in Man (OMIM) traits linked to genes with deleterious variants showing altered frequencies in Romani or non-Romani individuals (e.g., obesity enriched in Roma with South Asian ancestry link; non-insulin dependent diabetes enriched in non-Roma).
• Observed significant differences in pathogenic variant frequencies, with some low-frequency variants in non-Roma being virtually absent in the Roma.
• Detected frequency changes in drug-response variants, with many increased in Roma associated with metabolic and cardiovascular drugs.

Conclusions:

• Clinically relevant genetic variation in the Romani population is not solely defined by founder mutations; significant frequency differences exist compared to non-Roma.
• Admixture events have resulted in clinically damaging variants traceable to both European and South Asian ancestries.
• Genetic susceptibility and drug response variations differ across ancestries, underscoring the need to move beyond Eurocentric genetic studies.