Rare variant enriched identity-by-descent enables the detection of distant relatedness and older divergence between populations

Abstract

MotivationThe global human population has experienced an explosive growth from a few million to roughly 7 billion people in the last 10,000 years. Accompanying this growth has been the accumulation of rare variants that can inform our understanding of human evolutionary history. Common variants have primarily been used to infer the structure of the human population and relatedness between two individuals. However, with the increasing abundance of rare variants observed in large-scale projects, such as Trans-Omics for Precision Medicine (TOPMed), the use of rare variants to decipher cryptic relatedness and fine-scale population structure can be beneficial to the study of population demographics and association studies. Identity-by-descent (IBD) is an important framework used for identifying these relationships. IBD segments are broken down by recombination over time, such that longer shared haplotypes give strong evidence of recent relatedness while shorter shared haplotypes are indicative of more distant relationships. Current methods to identify IBD accurately detect only long segments (> 2cM) found in related individuals. AlgorithmWe describe a metric that leverages rare-variants shared between individuals to improve the detection of short IBD segments. We computed IBD segments using existing methods implemented in Refined IBD where we enrich the signal using our metric that facilitates the detection of short IBD segments (<2cM) by explicitly incorporating rare variants. ResultsTo test our new metric, we simulated datasets involving populations with varying divergent time-scales. We show that rare-variant IBD identifies shorter segments with greater confidence and enables the detection of older divergence between populations. As an example, we applied our metric to the Old-Order Amish cohort with known genealogies dating 14 generations back to validate its ability to detect genetic relatedness between distant relatives. This analysis shows that our method increases the accuracy of identifying shorter segments that in turn capture distant relationships. ConclusionsWe describe a method to enrich the detection of short IBD segments using rare-variant sharing within IBD segments. Leveraging rare-variant sharing improves the information content of short IBD segments better than common variants alone. We validated the method in both simulated and empirical datasets. This method can benefit association analyses, IBD mapping analyses, and demographic inferences.