Rare variation facilitates inferences of fine-scale population structure in humans

NHLBI GO Exome Sequencing Project, ESP Population Genetics and Statistical Analysis Working Group

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Understanding the genetic structure of human populations has important implications for the design and interpretation of disease mapping studies and reconstructing human evolutionary history. To date, inferences of human population structure have primarily been made with common variants. However, recent large-scale resequencing studies have shown an abundance of rare variation in humans, which may be particularly useful for making inferences of fine-scale population structure. To this end, we used an information theory framework and extensive coalescent simulations to rigorously quantify the informativeness of rare and common variation to detect signatures of fine-scale population structure. We show that rare variation affords unique insights into patterns of recent population structure. Furthermore, to empirically assess our theoretical findings, we analyzed high-coverage exome sequences in 6,515 European and African American individuals. As predicted, rare variants are more informative than common polymorphisms in revealing a distinct cluster of European-American individuals, and subsequent analyses demonstrate that these individuals are likely of Ashkenazi Jewish ancestry. Our results provide new insights into the population structure using rare variation, which will be an important factor to account for in rare variant association studies.

Original languageEnglish (US)
Pages (from-to)653-660
Number of pages8
JournalMolecular biology and evolution
Issue number3
StatePublished - Mar 2015

All Science Journal Classification (ASJC) codes

  • Genetics
  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology


  • Exome sequencing
  • Information theory
  • Recent demography


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