Dataset Information

Estimating KIR Haplotype Frequencies on a Cohort of 10,000 Individuals: A Comprehensive Study on Population Variations, Typing Resolutions, and Reference Haplotypes.

ABSTRACT: The killer cell immunoglobulin-like receptors (KIR) mediate human natural killer (NK) cell cytotoxicity via activating or inhibiting signals. Although informative and functional haplotype patterns have been reported, most genotyping has been performed at resolutions that are structurally ambiguous. In order to leverage structural information given low-resolution genotypes, we performed experiments to quantify the effects of population variations, reference haplotypes, and genotyping resolutions on population-level haplotype frequency estimations as well as predictions of individual haplotypes. We genotyped 10,157 unrelated individuals in 5 populations (518 African American[AFA], 258 Asian or Pacific Islander[API], 8,245 European[EUR], 1,073 Hispanic[HIS], and 63 Native American[NAM]) for KIR gene presence/absence (PA), and additionally half of the AFA samples for KIR gene copy number variation (CNV). A custom EM algorithm was used to estimate haplotype frequencies for each population by interpretation in the context of three sets of reference haplotypes. The algorithm also assigns each individual the haplotype pairs of maximum likelihood. Generally, our haplotype frequency estimates agree with similar previous publications to within <5% difference for all haplotypes. The exception is that estimates for NAM from the U.S. showed higher frequency association of cB02 with tA01 (+14%) instead of tB01 (-8.5%) compared to a previous study of NAM from south of the U.S. The higher-resolution CNV genotyping on the AFA samples allowed unambiguous haplotype-pair assignments for the majority of individuals, resulting in a 22% higher median typing resolution score (TRS), which measures likelihood of self-match in the context of population-specific haplo- and geno-types. The use of TRS to quantify reduced ambiguity with CNV data clearly revealed the few individuals with ambiguous genotypes as outliers. It is observed that typing resolution and reference haplotype set influence haplotype frequency estimates. For example, PA resolution may be used with reference haplotype sets up to the point where certain haplotypes are gene-content subsets of others. At that point, CNV must be used for all genes.

SUBMITTER: Vierra-Green C

PROVIDER: S-EPMC5056762 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Estimating KIR Haplotype Frequencies on a Cohort of 10,000 Individuals: A Comprehensive Study on Population Variations, Typing Resolutions, and Reference Haplotypes.

Vierra-Green Cynthia C Roe David D Jayaraman Jyothi J Trowsdale John J Traherne James J Kuang Rui R Spellman Stephen S Maiers Martin M

PloS one 20161010 10

The killer cell immunoglobulin-like receptors (KIR) mediate human natural killer (NK) cell cytotoxicity via activating or inhibiting signals. Although informative and functional haplotype patterns have been reported, most genotyping has been performed at resolutions that are structurally ambiguous. In order to leverage structural information given low-resolution genotypes, we performed experiments to quantify the effects of population variations, reference haplotypes, and genotyping resolutions ...[more]

PMID: 27723813

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Project description:MotivationHuman ancient DNA (aDNA) studies have surged in recent years, revolutionizing the study of the human past. Typically, aDNA is preserved poorly, making such data prone to contamination from other human DNA. Therefore, it is important to rule out substantial contamination before proceeding to downstream analysis. As most aDNA samples can only be sequenced to low coverages (<1× average depth), computational methods that can robustly estimate contamination in the low coverage regime are needed. However, the ultra low-coverage regime (0.1× and below) remains a challenging task for existing approaches.ResultsWe present a new method to estimate contamination in aDNA for male modern humans. It utilizes a Li&Stephens haplotype copying model for haploid X chromosomes, with mismatches modeled as errors or contamination. We assessed this new approach, hapCon, on simulated and down-sampled empirical aDNA data. Our experiments demonstrate that hapCon outperforms a commonly used tool for estimating male X contamination (ANGSD), with substantially lower variance and narrower confidence intervals, especially in the low coverage regime. We found that hapCon provides useful contamination estimates for coverages as low as 0.1× for SNP capture data (1240k) and 0.02× for whole genome sequencing data, substantially extending the coverage limit of previous male X chromosome-based contamination estimation methods. Our experiments demonstrate that hapCon has little bias for contamination up to 25-30% as long as the contaminating source is specified within continental genetic variation, and that its application range extends to human aDNA as old as ∼45 000 and various global ancestries.Availability and implementationWe make hapCon available as part of a python package (hapROH), which is available at the Python Package Index (https://pypi.org/project/hapROH) and can be installed via pip. The documentation provides example use cases as blueprints for custom applications (https://haproh.readthedocs.io/en/latest/hapCon.html). The program can analyze either BAM files or pileup files produced with samtools. An implementation of our software (hapCon) using Python and C is deposited at https://github.com/hyl317/hapROH.Supplementary informationSupplementary data are available at Bioinformatics online.

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Dataset Information

Estimating KIR Haplotype Frequencies on a Cohort of 10,000 Individuals: A Comprehensive Study on Population Variations, Typing Resolutions, and Reference Haplotypes.

Publications

Estimating KIR Haplotype Frequencies on a Cohort of 10,000 Individuals: A Comprehensive Study on Population Variations, Typing Resolutions, and Reference Haplotypes.

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