Complete sequence data support lack of balancing selection on PRNP in a natural Chinese population

Zan, Qin; Wen, Bo; He, Yungang; Wang, Yi; Xu, Shuhua; Qian, Ji; Lu, Daru; Jin, Li

doi:10.1007/s10038-006-0383-8

Cited by 3 publications

(3 citation statements)

References 16 publications

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“…The negative Tajima’s D value of −1.44 conflicted with previous reports of this region on chromosome 6 as being under balancing selection and upon inspection, the dissimilar reports were based on small datasets which disregarded low frequency variants [47, 48]. Our complete NGS data showed a dramatic increase in low frequency polymorphisms, thus changing the landscape of evolutionary conclusions.…”

Section: Resultscontrasting

confidence: 69%

A novel application of pattern recognition for accurate SNP and indel discovery from high-throughput data: Targeted resequencing of the glucocorticoid receptor co-chaperone FKBP5 in a Caucasian population

Pelleymounter

Moon

Laederach

et al. 2011

Molecular Genetics and Metabolism

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The detection of single nucleotide polymorphisms (SNPs) and insertion/deletions (indels) with precision from high-throughput data remains a significant bioinformatics challenge. Accurate detection is necessary before next-generation sequencing can routinely be used in the clinic. In research, scientific advances are inhibited by gaps in data, exemplified by the underrepresented discovery of rare variants, variants in non-coding regions and indels. The continued presence of false positives and false negatives prevents full automation and requires additional manual verification steps. Our methodology presents applications of both pattern recognition and sensitivity analysis to eliminate false positives and aid in the detection of SNP/indel loci and genotypes from high-throughput data. We chose FK506-binding protein 51(FKBP5) (6p21.31) for our clinical target because of its role in modulating pharmacological responses to physiological and synthetic glucocorticoids and because of the complexity of the genomic region. We detected genetic variation across a160 kb region encompassing FKBP5. 613 SNPs and 57 indels, including a 3.3 kb deletion were discovered. We validated our method using three independent data sets and, with Sanger sequencing and Affymetrix and Illumina microarrays, achieved 99% concordance. Furthermore we were able to detect 267 novel rare variants and assess linkage disequilibrium. Our results showed both a sensitivity and specificity of 98%, indicating near perfect classification between true and false variants. The process is scalable and amenable to automation, with the downstream filters taking only 1.5 hours to analyze 96 individuals simultaneously. We provide examples of how our level of precision uncovered the interactions of multiple loci, their predicted influences on mRNA stability, perturbations of the hsp90 binding site, and individual variation in FKBP5 expression. Finally we show how our discovery of rare variants may change current conceptions of evolution at this locus.

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Section: Resultscontrasting

confidence: 69%

A novel application of pattern recognition for accurate SNP and indel discovery from high-throughput data: Targeted resequencing of the glucocorticoid receptor co-chaperone FKBP5 in a Caucasian population

Pelleymounter

Moon

Laederach

et al. 2011

Molecular Genetics and Metabolism

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“…A large pool of PRNP mutations have been identified in humans, but all of these are associated with familial prion diseases, or appear to represent harmless polymorphisms. 20 Perhaps there are heretofore undiscovered humans with small chromosomal deletions that encompass the PRNP locus, or even mutations that render humans haploinsufficient or even null for PrP. Such human patients may tell us volumes about the function of PrP C and perhaps that it is dispensable for normal life as is the case for mice 10 and cows.…”

Section: Introductionmentioning

confidence: 99%

The Prion Protein Knockout Mouse

Steele

Lindquist

Aguzzi

2007

Prion

140

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The key pathogenic event in prion disease involves misfolding and aggregation of the cellular prion protein (PrP). Beyond this fundamental observation, the mechanism by which PrP misfolding in neurons leads to injury and death remains enigmatic. Prion toxicity may come about by perverting the normal function of PrP. If so, understanding the normal function of PrP may help to elucidate the molecular mechansim of prion disease. Ablation of the Prnp gene, which encodes PrP, was instrumental for determining that the continuous production of PrP is essential for replicating prion infectivity. Since the structure of PrP has not provided any hints to its possible function, and there is no obvious phenotype in PrP KO mice, studies of PrP function have often relied on intuition and serendipity. Here, we enumerate the multitude of phenotypes described in PrP deficient mice, many of which manifest themselves only upon physiological challenge. We discuss the pleiotropic phenotypes of PrP deficient mice in relation to the possible normal function of PrP. The critical question remains open: which of these phenotypes are primary effects of PrP deletion and what do they tell us about the function of PrP?

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“…It was proposed that balancing selection at M129V had occurred in worldwide populations against Kuru-like epidemics (Hardy et al, 2006;Mead et al, 2003). However, subsequent studies argued that the exclusion of low frequency polymorphisms from data analyses misled the authors to draw a conclusion in the favor of balancing selection (Soldevila et al, 2005(Soldevila et al, , 2006Zan et al, 2006). Heterozygosity at another polymorphic codon where either glutamic acid (E) or lysine (K) is encoded (E219K) is also a protective factor against the development of sCJD in Japanese population (Shibuya et al, 1998a(Shibuya et al, , 1998b.…”

Section: Introductionmentioning

confidence: 96%

Frequency distribution of PRNP polymorphisms in the Pakistani population

Imran

Mahmood

Hussain

et al. 2012

Gene

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Complete sequence data support lack of balancing selection on PRNP in a natural Chinese population

Abstract: The M129V mutation in the human prion protein gene (PRNP) is the primary site linked to susceptibility to prion diseases in humans. The heterozygous state of this allele has been proven to be more resistant to prion-related diseases such as Creutzfeldt-Jakob disease.

Cited by 3 publications

References 16 publications

A novel application of pattern recognition for accurate SNP and indel discovery from high-throughput data: Targeted resequencing of the glucocorticoid receptor co-chaperone FKBP5 in a Caucasian population

A novel application of pattern recognition for accurate SNP and indel discovery from high-throughput data: Targeted resequencing of the glucocorticoid receptor co-chaperone FKBP5 in a Caucasian population

The Prion Protein Knockout Mouse

Frequency distribution of PRNP polymorphisms in the Pakistani population

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