# Study design and the sampling of deleterious rare variants in biobank-scale datasets

## TL;DR

This paper shows how the geographic diversity of genetic samples affects the discovery of rare harmful genetic variants in large-scale studies.

## Contribution

The paper introduces a stochastic model and empirical validation to show how geographic breadth influences the discovery and frequency of deleterious rare variants.

## Key findings

- Geographically broad samples discover more distinct rare variants compared to narrow samples.
- Broad samples detect variants at lower average frequencies, often as singletons.
- The effects of geographic breadth are stronger with larger sample sizes and stronger selection.

## Abstract

As genetic studies grow, researchers are increasingly seeking to identify rare genetic variants with large impacts on traits. In this paper, we combine theoretical methods and data analysis to show how differences in sampling with respect to geographic location can influence the number and frequency of genetic variants that are found. Our results suggest that geographically broad samples will include more distinct genetic variants, though each variant will be found at a lower frequency, as compared to geographically narrow samples. Our results can help researchers to consider the implications of study design on expected results when constructing new genetic samples.

One key component of study design in population genetics is the “geographic breadth” of a sample (i.e., how broad a region across which individuals are sampled). How the geographic breadth of a sample impacts observations of rare, deleterious variants is unclear, even though such variants are of particular interest for biomedical and evolutionary applications. Here, in order to gain insight into the effects of sample design on ascertained genetic variants, we formulate a stochastic model of dispersal, genetic drift, selection, mutation, and geographically concentrated sampling. We use this model to understand the effects of the geographic breadth of sampling effort on the discovery of negatively selected variants. We find that samples which are more geographically broad will discover a greater number of variants as compared to geographically narrow samples (an effect we label “discovery”); though the variants will be detected at lower average frequency than in narrow samples (e.g., as singletons, an effect we label “dilution”). Importantly, these effects are amplified for larger sample sizes and fitness effects. We validate these results using both population genetic simulations and empirical analyses in the UK Biobank. Our results are particularly important in two contexts: the association of large-effect rare variants with particular phenotypes and the inference of negative selection from allele frequency data. Overall, our findings emphasize the importance of considering geographic breadth when designing and carrying out genetic studies, especially at biobank scale.