Haplotyping via minimum recombinant paradigm

<p>Abstract</p> <p>Background</p> <p>Haplotypes can increase the power of gene detection over genotypes and are essential to estimate linkage disequilibrium.</p> <p>Methods</p> <p>Haplotyping was based on the minimum recombinant paradigm, whereby a phase is obtained only if it uniquely minimises the number of recombinants within a full sib family. Performance of this method was tested across three different data sets, consisting of genotypes and pedigree.</p> <p>Results</p> <p>The percentage of phased alleles ranged from ~80% to ~95%, and the percentage of correct phases reached ~99% in all cases. A measure of uncertainty was obtained via simulations. A partial haplotyping algorithm consisting of four deterministic rules was almost as effective as a full one consisting of six deterministic rules, and took up to 5 times less time to compute.</p> <p>Conclusion</p> <p>Haplotyping via the minimum recombinant paradigm is consistently reliable and computationally efficient. A single simulation is enough to produce a population-wide uncertainty estimate associated with a set of all reconstructed haplotypes.</p

Prediction of IBD based on population history for fine gene mapping

A novel multiple regression method (RM) is developed to predict identity-by-descent probabilities at a locus L (IBDL), among individuals without pedigree, given information on surrounding markers and population history. These IBDL probabilities are a function of the increase in linkage disequilibrium (LD) generated by drift in a homogeneous population over generations. Three parameters are sufficient to describe population history: effective population size (Ne), number of generations since foundation (T), and marker allele frequencies among founders (p). IBDL are used in a simulation study to map a quantitative trait locus (QTL) via variance component estimation. RM is compared to a coalescent method (CM) in terms of power and robustness of QTL detection. Differences between RM and CM are small but significant. For example, RM is more powerful than CM in dioecious populations, but not in monoecious populations. Moreover, RM is more robust than CM when marker phases are unknown or when there is complete LD among founders or Ne is wrong, and less robust when p is wrong. CM utilises all marker haplotype information, whereas RM utilises information contained in each individual marker and all possible marker pairs but not in higher order interactions. RM consists of a family of models encompassing four different population structures, and two ways of using marker information, which contrasts with the single model that must cater for all possible evolutionary scenarios in CM

Effect of family relatedness on characteristics of estimated IBD probabilities in relation to precision of QTL estimates

<p>Abstract</p> <p>Background</p> <p>A random QTL effects model uses a function of probabilities that two alleles in the same or in different animals at a particular genomic position are identical by descent (IBD). Estimates of such IBD probabilities and therefore, modeling and estimating QTL variances, depend on marker polymorphism, strength of linkage and linkage disequilibrium of markers and QTL, and the relatedness of animals in the pedigree. The effect of relatedness of animals in a pedigree on IBD probabilities and their characteristics was examined in a simulation study.</p> <p>Results</p> <p>The study based on nine multi-generational family structures, similar to a pedigree structure of a real dairy population, distinguished by an increased level of inbreeding from zero to 28% across the studied population. Highest inbreeding level in the pedigree, connected with highest relatedness, was accompanied by highest IBD probabilities of two alleles at the same locus, and by lower relative variation coefficients. Profiles of correlation coefficients of IBD probabilities along the marked chromosomal segment with those at the true QTL position were steepest when the inbreeding coefficient in the pedigree was highest. Precision of estimated QTL location increased with increasing inbreeding and pedigree relatedness. A method to assess the optimum level of inbreeding for QTL detection is proposed, depending on population parameters.</p> <p>Conclusions</p> <p>An increased overall relationship in a QTL mapping design has positive effects on precision of QTL position estimates. But the relationship of inbreeding level and the capacity for QTL detection depending on the recombination rate of QTL and adjacent informative marker is not linear.</p

A genome-wide association analysis for porcine serum lipid traits reveals the existence of age-specific genetic determinants

Background: The genetic determinism of blood lipid concentrations, the main risk factor for atherosclerosis, is practically unknown in species other than human and mouse. Even in model organisms, little is known about how the genetic determinants of lipid traits are modulated by age-specific factors. To gain new insights into this issue, we have carried out a genome-wide association study (GWAS) for cholesterol (CHOL), triglyceride (TRIG) and low (LDL) and high (HDL) density lipoprotein concentrations measured in Duroc pigs at two time points (45 and 190 days). Results: Analysis of data with mixed-model methods (EMMAX, GEMMA, GenABEL) and PLINK showed a low positional concordance between trait-associated regions (TARs) for serum lipids at 45 and 190 days. Besides, the proportion of phenotypic variance explained by SNPs at these two time points was also substantially different. The four analyses consistently detected two regions on SSC3 (124 Mb, CHOL and LDL at 190 days) and SSC6 (135 Mb, CHOL and TRIG at 190 days) with highly significant effects on the porcine blood lipid profile. Moreover, we have found that SNP variation within SSC3, SSC6, SSC10, SSC13 and SSC16 TARs is associated with the expression of several genes mapping to other chromosomes and related to lipid metabolism. Conclusions: Our data demonstrate that the effects of genomic determinants influencing lipid concentrations in pigs, as well as the amount of phenotypic variance they explain, are influenced by age-related factors.This work has been funded by grants AGL2007-66707-C02 and AGL2010-22208-C02 (Ministerio de Ciencia e Innovación) and CSD 2007-00036 (Ministerio de Ciencia e Innovación, Consolider Ingenio 2010 Program)

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Candidate gene analysis for quantitative traits using the transmission disequilibrium test: the example of the melanocortin 4-receptor in pigs.

Population-wide associations between loci due to linkage disequilibrium can be used to map quantitative trait loci (QTL) with high resolution. However, spurious associations between markers and QTL can also arise as a consequence of population stratification. Statistical methods that cannot differentiate between loci associations due to linkage disequilibria from those caused in other ways can render false-positive results. The transmission-disequilibrium test (TDT) is a robust test for detecting QTL. The TDT exploits within-family associations that are not affected by population stratification. However, some TDTs are formulated in a rigid form, with reduced potential applications. In this study we generalize TDT using mixed linear models to allow greater statistical flexibility. Allelic effects are estimated with two independent parameters: one exploiting the robust within-family information and the other the potentially biased between-family information. A significant difference between these two parameters can be used as evidence for spurious association. This methodology was then used to test the effects of the fourth melanocortin receptor (MC4R) on production traits in the pig. The new analyses supported the previously reported results; i.e., the studied polymorphism is either causal or in very strong linkage disequilibrium with the causal mutation, and provided no evidence for spurious association

Genomic architecture of heritability and genetic correlations for intramuscular and back fat contents in Duroc pigs

Genetic parameters such as heritability and correlations of fat traits in a Duroc population were dissected using molecular markers. The heritabilities of intramuscular fat in 2 muscles, the gluteus medius and LM, and back fat were 0.54, 0.48, and 0.23, respectively. The genetic correlations were well estimated with standardized SNP effects, being 0.65 between intramuscular fat traits and ∼0.37 between any intramuscular fat trait and back fat. Genetic correlations were overestimated when ignoring molecular information. Twelve chromosomes showed additive genetic variance for intramuscular fat compared with 8 for back fat. Population structure was accommodated using 4 different models. The number of significant, P < 5 × 10-5 (suggestive, P < 2 × 10-3), SNP varied across models and ranged from 0 to 4 (2 to 261) for intramuscular fat in the gluteus medius, from 0 to 57 (9 to 564) for intramuscular fat in the LM, and from 3 to 4 (22 to 168) for back fat. Several SNP showed significant deviations from an additive mode of action. Only 2 SNP significantly affected 2 traits simultaneously.This study was funded by grant AGL2010-22208-C02-01 (Ministerio de Ciencia e Innovación, Spain).Peer reviewe

Mapping of multiple quantitative trait loci affecting bovine spongiform encephalopathy.

A whole-genome scan was conducted to map quantitative trait loci (QTL) for BSE resistance or susceptibility. Cows from four half-sib families were included and 173 microsatellite markers were used to construct a 2835-cM (Kosambi) linkage map covering 29 autosomes and the pseudoautosomal region of the sex chromosome. Interval mapping by linear regression was applied and extended to a multiple-QTL analysis approach that used identified QTL on other chromosomes as cofactors to increase mapping power. In the multiple-QTL analysis, two genome-wide significant QTL (BTA17 and X/Y(ps)) and four genome-wide suggestive QTL (BTA1, 6, 13, and 19) were revealed. The QTL identified here using linkage analysis do not overlap with regions previously identified using TDT analysis. One factor that may explain the disparity between the results is that a more extensive data set was used in the present study. Furthermore, methodological differences between TDT and linkage analyses may affect the power of these approaches