An evaluation of the replicate pool method: quick estimation of genome-wide linkage peak p -values

The calculation of empirical p -values for genome-wide non-parametric linkage tests continues to present significant computational challenges for many complex disease mapping studies. The gold standard approach is to use gene dropping to simulate null genome scans. Unfortunately, this approach is too computationally expensive for many data sets of interest. An alternative, more efficient method for sampling null genome scans is to pre-calculate pools of family-specific statistics and then resample from these replicate pools to generate “pseudo-replicate” genome scans. In this study, we use simulations to explore properties of the replicate pool p -value estimator [pcirc] RP and show that it provides an excellent approximation to the traditional gene-dropping estimator for significantly less computational effort. While the computational efficiency of the replicate pool estimator is noticeable in almost all data sets, by applying the replicate pool method to several previously characterized data sets we show that savings in computational effort can be especially significant (on the order of 10,000-fold or more) when one or more large families are analyzed. We also estimate replicate pool p -values for the schizophrenia data described by Abecasis et al. and show that [pcirc] RP closely approximates gene-drop p -values for all linkage peaks reported for this study. Lastly, we expand upon Song et al.'s previous work by deriving a conservative estimator of the variance for [pcirc] RP that can easily be computed in practical settings.We have implemented the replicate pool method along with our variance estimator in a new program called Pseudo, which is the first widely available automated implementation of the replicate pool method. Genet . Epidemiol . 30, 2006. © 2006 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50657/1/20147_ftp.pd

Exome Sequencing and Complex Disease: Practical Aspects of Rare Variant Association Studies

Genetic association and linkage studies can provide insights into complex disease biology, guiding the development of new diagnostic and therapeutic strategies. Over the past decade, genetic association studies have largely focused on common, easy to measure genetic variants shared between many individuals. These common variants typically have subtle functional consequence and translating the resulting association signals into biological insights can be challenging. In the last few years, exome sequencing has emerged as a cost-effective strategy for extending these studies to include rare coding variants, which often have more marked functional consequences. Here, we provide practical guidance in the design and analysis of complex trait association studies focused on rare, coding variants

Compreender a Recorrência dos Mixomas Cardíacos. Um Caso Clínico

Recurrence of cardiac myxoma is a rare condition, observed in about 3% of patients in sporadic cases, although it is more frequent in familial ones. Several mechanisms have been proposed to explain such recurrence, and the importance of increased vascularization as a facilitating feature is the subject of debate. The authors report the case of a non-familial right atrial myxoma, unusual for both its histopathology and recurrence

Decreasing population selection rates of resistance mutation K65R over time in HIV-1 patients receiving combination therapy including tenofovir

Objectives The use of tenofovir is highly associated with the emergence of mutation K65R, which confers broad resistance to nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs), especially when tenofovir is combined with other NRTIs also selecting for K65R. Although recent HIV-1 treatment guidelines discouraging these combinations resulted in reduced K65R selection with tenofovir, updated information on the impact of currently recommended regimens on the population selection rate of K65R is presently lacking. Methods In this study, we evaluated changes over time in the selection rate of resistance mutation K65R in a large population of 2736 HIV-1-infected patients failing combination antiretroviral treatment between 2002 and 2010. Results The K65R resistance mutation was detected in 144 patients, a prevalence of 5.3%. A large majority of observed K65R cases were explained by the use of tenofovir, reflecting its wide use in clinical practice. However, changing patterns over time in NRTIs accompanying tenofovir resulted in a persistent decreasing probability of K65R selection by tenofovir-based therapy. The currently recommended NRTI combination tenofovir/emtricitabine was associated with a low probability of K65R emergence. For any given dual NRTI combination including tenofovir, higher selection rates of K65R were consistently observed with a non-nucleoside reverse transcriptase inhibitor than with a protease inhibitor as the third agent. Discussion Our finding of a stable time trend of K65R despite elevated use of tenofovir illustrates increased potency of current HIV-1 therapy including tenofovi

A Genomic Signature and the Identification of New Sporulation Genes

Bacterial endospores are the most resistant cell type known to humans, as they are able to withstand extremes of temperature, pressure, chemical injury, and time. They are also of interest because the endospore is the infective particle in a variety of human and livestock diseases. Endosporulation is characterized by the morphogenesis of an endospore within a mother cell. Based on the genes known to be involved in endosporulation in the model organism Bacillus subtilis, a conserved core of about 100 genes was derived, representing the minimal machinery for endosporulation. The core was used to define a genomic signature of about 50 genes that are able to distinguish endospore-forming organisms, based on complete genome sequences, and we show this 50-gene signature is robust against phylogenetic proximity and other artifacts. This signature includes previously uncharacterized genes that we can now show are important for sporulation in B. subtilis and/or are under developmental control, thus further validating this genomic signature. We also predict that a series of polyextremophylic organisms, as well as several gut bacteria, are able to form endospores, and we identified 3 new loci essential for sporulation in B. subtilis: ytaF, ylmC, and ylzA. In all, the results support the view that endosporulation likely evolved once, at the base of the Firmicutes phylum, and is unrelated to other bacterial cell differentiation programs and that this involved the evolution of new genes and functions, as well as the cooption of ancestral, housekeeping functions.FCT grant: (PEst-OE/EQB/LA0004/2011), FCT Ph.D. fellowship: (SFRH/BPD/36328/2007), FCT postdoc fellowship: (SFRH/BPD/65605/2009), Instituto Gulbenkian de Ciência research fellowship

METAL: fast and efficient meta-analysis of genomewide association scans

Summary: METAL provides a computationally efficient tool for meta-analysis of genome-wide association scans, which is a commonly used approach for improving power complex traits gene mapping studies. METAL provides a rich scripting interface and implements efficient memory management to allow analyses of very large data sets and to support a variety of input file formats

The Ribatejano pig: Rebirth of a local population? First results on growth, and carcass parameters

In order to assess the productive performance of the Ribatejano (RI) pig, resulting from a cross between Alentejano (AL) and Bísaro (BI) breeds, castrated male pigs AL, BI, ALxBI and BIxAL were studied within the framework of the TREASURE project. Ten pigs from each genotype, raised in traditional free-range system and fed commercial diets ad libitum, were slaughtered at ~65 kg live weight (LW). Data obtained show that BI, ALxBI and BIxAL attained slaughter weight faster (P<0.001) than AL pigs. Overall, carcass length (P<0.001), carcass yield (P=0.06), and lean cuts weight (P<0.01) were higher in BI than AL pigs, with intermediate values for both crosses. Conversely, fat cuts weight, ZP fat depth (P<0.01) and average backfat thickness (P<0.001) were higher in AL than in BI, and ALxBI and BIxAL pigs. At 65kg LW, RI crosses presented intermediate characteristics between fatter (AL) and leaner (BI) genotypes. This cross could therefore be an alternative to the use of other (modern) breeds for crossing, helping to increase the revenue of autochthonous pig producers, and also maintain or increase the pure breed populations, contributing to animal biodiversity

Relative impact of indels versus SNPs on complex disease

It is unclear whether insertions and deletions (indels) are more likely to influence complex traits than abundant single‐nucleotide polymorphisms (SNPs). We sought to understand which category of variation is more likely to impact health. Using the SardiNIA study as an exemplar, we characterized 478,876 common indels and 8,246,244 common SNPs in up to 5,949 well‐phenotyped individuals from an isolated valley in Sardinia. We assessed association between 120 traits, resulting in 89 nonoverlapping‐associated loci.We evaluated whether indels were enriched among credible sets of potential causal variants. These credible sets included 1,319 SNPs and 88 indels. We did not find indels to be significantly enriched. Indels were the most likely causal variant in seven loci, including one locus associated with monocyte count where an indel with causality and mechanism previously demonstrated (rs200748895:TGCTG/T) had a 0.999 posterior probability. Overall, our results show a very modest and nonsignificant enrichment for common indels in associated loci.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147866/1/gepi22175_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147866/2/gepi22175-sup-0001-Gagliano-Supplementary.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147866/3/gepi22175.pd

Comparing variant calling algorithms for target-exon sequencing in a large sample

Abstract Background Sequencing studies of exonic regions aim to identify rare variants contributing to complex traits. With high coverage and large sample size, these studies tend to apply simple variant calling algorithms. However, coverage is often heterogeneous; sites with insufficient coverage may benefit from sophisticated calling algorithms used in low-coverage sequencing studies. We evaluate the potential benefits of different calling strategies by performing a comparative analysis of variant calling methods on exonic data from 202 genes sequenced at 24x in 7,842 individuals. We call variants using individual-based, population-based and linkage disequilibrium (LD)-aware methods with stringent quality control. We measure genotype accuracy by the concordance with on-target GWAS genotypes and between 80 pairs of sequencing replicates. We validate selected singleton variants using capillary sequencing. Results Using these calling methods, we detected over 27,500 variants at the targeted exons; >57% were singletons. The singletons identified by individual-based analyses were of the highest quality. However, individual-based analyses generated more missing genotypes (4.72%) than population-based (0.47%) and LD-aware (0.17%) analyses. Moreover, individual-based genotypes were the least concordant with array-based genotypes and replicates. Population-based genotypes were less concordant than genotypes from LD-aware analyses with extended haplotypes. We reanalyzed the same dataset with a second set of callers and showed again that the individual-based caller identified more high-quality singletons than the population-based caller. We also replicated this result in a second dataset of 57 genes sequenced at 127.5x in 3,124 individuals. Conclusions We recommend population-based analyses for high quality variant calls with few missing genotypes. With extended haplotypes, LD-aware methods generate the most accurate and complete genotypes. In addition, individual-based analyses should complement the above methods to obtain the most singleton variants.http://deepblue.lib.umich.edu/bitstream/2027.42/110906/1/12859_2015_Article_489.pd