Genetic Testing Accuracy Enhanced by Ancestry-Specific Tool

Researchers refine allele frequency estimates in gnomAD using ancestry-based method

Scientists at the Neurological Research Institute at Texas Children’s Hospital and Baylor College of Medicine have introduced a new analytical approach that could improve the interpretation of genetic variation in individuals with complex ancestral backgrounds. The work focuses on allele frequency estimation using a method known as local ancestry inference (LAI) and is now integrated into the Genome Aggregation Database (gnomAD).

The study, published in Nature Communications, demonstrates how LAI can resolve limitations in current genetic databases that often rely on broad population averages. By segmenting the genome according to continental ancestry components, researchers can derive allele frequencies with higher specificity.

Segment-based analysis offers finer resolution

Genetic databases such as gnomAD often categorize individuals into broad groups, including African/African American and Latino/Admixed American. While this classification captures overall genetic diversity, it may obscure the variation within each ancestry segment. To address this, the research team applied LAI, which identifies and partitions genomic regions based on ancestral origin.

Once these regions were defined, the team recalculated the frequency of genetic variants within each segment. The findings revealed substantial differences between aggregate estimates and those derived from ancestry-specific segments. In African/African American and Latino/Admixed American populations, over 80% of genetic sites had higher frequencies in at least one ancestry tract than previously recorded.

Implications for clinical variant classification

This updated method has potential implications for clinical genetics, particularly for variant classification. Current guidelines used by the American College of Medical Genetics and Genomics (ACMG) rely on population frequency thresholds to determine whether a variant is benign. Ancestry-specific recalculations showed that some variants classified as rare at the population level exceed the benign threshold when examined within certain ancestry segments.

By incorporating this approach, clinicians and geneticists may reduce the risk of misclassification, particularly in individuals of admixed ancestry. The availability of ancestry-specific allele frequencies in gnomAD allows for improved diagnostic accuracy without the need for broad or inaccurate population labels.

Public access to updated variant data

The updated allele frequencies are now publicly accessible through gnomAD, enabling broader use by researchers and clinical laboratories. The team emphasizes the importance of accounting for the genetic complexity within admixed populations, particularly as genetic testing becomes more widely adopted across diverse demographic groups.

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