PRIMUS: Rapid Reconstruction of Pedigrees from Genome-wide Estimates of Identity by Descent

Staples, Jeffrey; Qiao, Dandi; Cho, Michael H.; Silverman, Edwin K.; Nickerson, Deborah A.; Below, Jennifer E.

doi:10.1016/j.ajhg.2014.10.005

Cited by 151 publications

(170 citation statements)

References 54 publications

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“…On the basis of the genome-wide Affymetrix 6.0 SNP genotype data, we used Primus 61,62 to select 626 individuals from the discovery sample using a kinship threshold (0.039) halfway between the values expected for first and second cousins, so that first cousins and more closely related relatives were excluded. These ‘unrelated’ individuals were then haplotyped using SHAPEIT 49–53 and were annotated with ancestral allele information using the selectionTools pipeline 63 .…”

Section: Methodsmentioning

confidence: 99%

A thrifty variant in CREBRF strongly influences body mass index in Samoans

et al. 2016

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Samoans are a unique founder population with a high prevalence of obesity1–3, making them well suited for identifying new genetic contributors to obesity4. We conducted a genome-wide association study (GWAS) in 3,072 Samoans, discovered a variant, rs12513649, strongly associated with body mass index (BMI) (P = 5.3 × 10−14), and replicated the association in 2,102 additional Samoans (P = 1.2 × 10−9). Targeted sequencing identified a strongly associated missense variant, rs373863828 (p.Arg457Gln), in CREBRF (meta P = 1.4 × 10−20). Although this variant is extremely rare in other populations, it is common in Samoans (frequency of 0.259), with an effect size much larger than that of any other known common BMI risk variant (1.36–1.45 kg/m2 per copy of the risk-associated allele). In comparison to wild-type CREBRF, the Arg457Gln variant when overexpressed selectively decreased energy use and increased fat storage in an adipocyte cell model. These data, in combination with evidence of positive selection of the allele encoding p.Arg457Gln, support a ‘thrifty’ variant hypothesis as a factor in human obesity.

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Section: Methodsmentioning

confidence: 99%

A thrifty variant in CREBRF strongly influences body mass index in Samoans

et al. 2016

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“…We next used the PRIMUS suite of analytical tools to evaluate and perform quality controls on this initial data (Staples et al 2013(Staples et al , 2014. The algorithms in PRIMUS that estimate allele sharing were used to infer genealogical relatedness among all pairs.…”

Section: Evaluation Of Initial Data Set Using Primusmentioning

confidence: 99%

The population genomics of rhesus macaques (Macaca mulatta) based on whole-genome sequences

et al. 2016

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Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate in biomedical research, have the largest natural geographic distribution of any nonhuman primate, and have been the focus of much evolutionary and behavioral investigation. Consequently, rhesus macaques are one of the most thoroughly studied nonhuman primate species. However, little is known about genome-wide genetic variation in this species. A detailed understanding of extant genomic variation among rhesus macaques has implications for the use of this species as a model for studies of human health and disease, as well as for evolutionary population genomics. Whole-genome sequencing analysis of 133 rhesus macaques revealed more than 43.7 million single-nucleotide variants, including thousands predicted to alter protein sequences, transcript splicing, and transcription factor binding sites. Rhesus macaques exhibit 2.5-fold higher overall nucleotide diversity and slightly elevated putative functional variation compared with humans. This functional variation in macaques provides opportunities for analyses of coding and noncoding variation, and its cellular consequences. Despite modestly higher levels of nonsynonymous variation in the macaques, the estimated distribution of fitness effects and the ratio of nonsynonymous to synonymous variants suggest that purifying selection has had stronger effects in rhesus macaques than in humans. Demographic reconstructions indicate this species has experienced a consistently large but fluctuating population size. Overall, the results presented here provide new insights into the population genomics of nonhuman primates and expand genomic information directly relevant to primate models of human disease.

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“…Therefore, ensuring that the genetic relationships among the DNA samples match the reported pedigree structure is critical for accurate family-based genetic analysis. 5 Detecting cryptic relationships can be important as well. 6 Genetic relationships identified in population studies can be leveraged for improved haplotype phase inference, detection of population structure, genotype imputation, and study designs such as identical-by-descent (IBD) mapping and tests to detect multiple rare and common variants that contribute to disease.…”

Section: Introductionmentioning

confidence: 99%

“…5 However, genetic datasets often contain relationships that are more distant than third degree, resulting in sparsely connected pedigrees that are unsuitable for reconstruction. Algorithms that consider IBD segment data, such as ERSA (estimation of recent shared ancestry), 16,17 can accurately predict pairwise relationships up to ninth-degree relatives (e.g., fourth cousins), but do not reconstruct pedigrees, nor can they utilize information from known or observed pedigree structures in the data.…”

Section: Introductionmentioning

confidence: 99%

“…Algorithms that consider IBD segment data, such as ERSA (estimation of recent shared ancestry), 16,17 can accurately predict pairwise relationships up to ninth-degree relatives (e.g., fourth cousins), but do not reconstruct pedigrees, nor can they utilize information from known or observed pedigree structures in the data. Here, we introduce PADRE (pedigree-aware distant-relationship estimation), which leverages the pedigree reconstruction of known or cryptic first-to third-degree relatives by PRIMUS (pedigree reconstruction and identification of a maximum unrelated set) 5 along with the accurate distant relationship predictions by ERSA. 17 PADRE, which has been implemented as an extension of PRIMUS and ERSA, uses ERSA-generated relationship likelihoods to identify the highest composite likelihood connection between family networks reconstructed by PRIMUS ( Figure S1), significantly improving the accuracy of the predictions and expanding the range of relationships that can be predicted.…”

Section: Introductionmentioning

confidence: 99%

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PADRE: Pedigree-Aware Distant-Relationship Estimation

Staples

Witherspoon

Jorde

et al. 2016

The American Journal of Human Genetics

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Accurate estimation of shared ancestry is an important component of many genetic studies; current prediction tools accurately estimate pairwise genetic relationships up to the ninth degree. Pedigree-aware distant-relationship estimation (PADRE) combines relationship likelihoods generated by estimation of recent shared ancestry (ERSA) with likelihoods from family networks reconstructed by pedigree reconstruction and identification of a maximum unrelated set (PRIMUS), improving the power to detect distant relationships between pedigrees. Using PADRE, we estimated relationships from simulated pedigrees and three extended pedigrees, correctly predicting 20% more fourth- through ninth-degree simulated relationships than when using ERSA alone. By leveraging pedigree information, PADRE can even identify genealogical relationships between individuals who are genetically unrelated. For example, although 95% of 13(th)-degree relatives are genetically unrelated, in simulations, PADRE correctly predicted 50% of 13(th)-degree relationships to within one degree of relatedness. The improvement in prediction accuracy was consistent between simulated and actual pedigrees. We also applied PADRE to the HapMap3 CEU samples and report new cryptic relationships and validation of previously described relationships between families. PADRE greatly expands the range of relationships that can be estimated by using genetic data in pedigrees.

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PRIMUS: Rapid Reconstruction of Pedigrees from Genome-wide Estimates of Identity by Descent

Cited by 151 publications

References 54 publications

A thrifty variant in CREBRF strongly influences body mass index in Samoans

A thrifty variant in CREBRF strongly influences body mass index in Samoans

The population genomics of rhesus macaques (Macaca mulatta) based on whole-genome sequences

PADRE: Pedigree-Aware Distant-Relationship Estimation

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