  Whole-genome sequencing in an isolated population with few founders directly
ascertains variants from the population bottleneck that may be rare elsewhere.
In such populations, shared haplotypes allow imputation of variants in
unsequenced samples without resorting to statistical methods, as in studies of
outbred cohorts. We focus on an isolated population cohort from the Pacific
Island of Kosrae, Micronesia, where we previously collected SNP array and rich
phenotype data for the majority of the population. We report identification of
long regions with haplotypes co-inherited between pairs of individuals and
methodology to leverage such shared genetic content for imputation. Our
estimates show that sequencing as few as 40 personal genomes allows for
imputation in up to 60% of the 3,000-person cohort at the average locus. We
ascertained a pilot data-set of whole-genome sequences from seven Kosraean
individuals, with average 5X coverage. This dataset identified 5,735,306 unique
sites of which 1,212,831 were previously unknown. Additionally, these Kosraen
variants are unusually enriched for alleles that are rare in other populations
when compared to geographic neighbors. We were able to use the presence of
shared haplotypes between the seven individuals to estimate imputation accuracy
of known and novel variants and achieved levels of 99.6% and 97.3%,
respectively. This study presents the first whole-genome analysis of a
homogenous isolate population with emphasis on rare variant inference.
