Search bioRxiv⌕ Search

Biology subjects

Gianola, D.

Publications and source records attributed to Gianola, D..

3 recordsLinked to original sources

Learning genetic values of individuals with incomplete pedigree, genomic and phenotypic data

Prediction of outcomes is important in personalized medicine, animal and plant breeding. Typical inputs for building prediction models in agriculture include genealogies, molecular markers and phenotypes. Information is seldom complete, i.e., there may be individuals that lack at least one of such inputs. For instance, all individuals may possess pedigree data but only a fraction is genotyped for molecular markers. A solution for such situation is known as "single-step best linear unbiased prediction" (SS-BLUP). A more general scenario is one where, in addition to the setting of SS-BLUP, there are subjects with genomic data but lacking genealogy, with or without phenotypes. Our study presents a novel "single-step" prediction method that accommodates a wider degree of incompleteness than SS-BLUP. It does not employ imputation or approximations and is based on basic Bayesian principles of combining distinct prior opinions. The proposed method, Hy-BLUP ("Hy" for "hybrid") uses a prior that combines knowledge from the population about variation derived from pedigree and from markers, as if these two sources of information were independent. Such assumption may over-state prior precision, but Bayesian theory dictates that it should be over-ridden as information from data accrues.The Bayesian logic defines the weights assigned to the sources implictly. However, additional weights (wAand wG for pedigree and genomic information, respectively) may be introduced as tuning parameters. From an inferential perspective, the weights and the variance components are not jointly identified in the likelihood function. However, given the variance components, some Bayesian learning about the weights can be obtained. The prior induces a precision matrix (inverse of the covariance matrix) automatically, without use of cumbersome matrix algebra arguments or approximations. The prior is combined with the data and, given the weights (if any) and variance parameters, the estimating "mixed model" equations can be built and computed directly. The method was evaluated using a publicly available data set consisting of 599 inbred lines of wheat genotyped for binary markers and with full pedigree information; the target trait was grain yield. The evaluation used several experiments that simulated various patterns of incompleteness and a training-testing layout supplemented by bootstrapping or random reconstruction of sets. There were minor differences between SS-BLUP and Hy-BLUP in predictive ability.The discussion includes a multiple-trait generalization of Hy-BLUP that may be useful in situations where some individuals are not phenotyped for some trait (e.g., animal carcass weight in a fully-pedigreed breeding nucleus) while others (not pedigreed) are genotyped, scored and destroyed for commercial or laboratory purposes. The study provides a proof-of-concept of the potential usefulness of Hy-BLUP for routine genome-enabled prediction in individuals with irregular patterns of information.

genetics↗

Genome-wide methylation prediction of biological age using reproducing kernel Hilbert spaces and Bayesian ridge regressions

The use of DNA methylation signatures to predict chronological age and the aging rate is of interest in many fields, including disease prevention and treatment, forensics, and anti-aging medicine. Although a large number of methylation markers have been found to be significantly associated with age, most age-prediction methods use a small number of markers selected based on either previously published studies or datasets containing methylation information. Here, we implemented reproducing kernel Hilbert spaces (RKHS) regression and ridge regression model in a Bayesian framework that utilized phenotypic and methylation profiles simultaneously to predict chronological age. We used over 450,000 CpG sites from the whole blood of a large cohort of 4,409 human individuals with a range of 10-101 years of age. Models were fitted using adjusted and un-adjusted methylation measurements for cell heterogeneity. Non-adjusted methylation scores delivered a significantly higher prediction accuracy than adjusted methylation data, with a correlation between age and predicted age of 0.98 and a root-mean-square error (RMSE) of 3.54 years in non-adjusted data, 0.90 (correlation) and 7.16 (RMSE) years in adjusted data. Reducing the number of predictors through subset selection improved predictive power with a correlation of 0.98 and an RMSE of 2.98 years in the RKHS model. We found distinct global methylation patterns, with significant hypermethylation in CpG islands and hypomethylation in other CpG types including CpG shore, shelf, and open sea (p < 5e-06). Epigenetic drift seemed to be a widespread phenomenon as more than 97% of the age-associated methylation sites had heteroscedasticity. Apparent methylomic aging rate (AMAR) had a sex-specific pattern, with an increase in AMAR in females with age compared to males.

genomics↗

Including phenotypic causal networks in genome-wide association studies using mixed effects structural equation models

BackgroundPhenotypic networks describing putative causal relationships among multiple phenotypes can be used to infer single-nucleotide polymorphism (SNP) effects in genome-wide association studies (GWAS). In GWAS with multiple phenotypes, reconstructing underlying causal structures among traits and SNPs using a single statistical framework is essential for understanding the entirety of genotype-phenotype maps. A structural equation model (SEM) can be used for such purposes.\n\nMethodsWe applied SEM to GWAS (SEM-GWAS) in chickens, taking into account putative causal relationships among body weight (BW), breast meat (BM), hen-house production (HHP), and SNPs. We assessed the performance of SEM-GWAS by comparing the model results with those obtained from traditional multi-trait association analyses (MTM-GWAS).\n\nResultsThree different putative causal path diagrams were inferred from highest posterior density (HPD) intervals of 0.75, 0.85, and 0.95 using the inductive causation algorithm. A positive path coefficient was estimated for BM[->]BW, and negative values were obtained for BM[->]HHP and BW[->]HHP in all implemented scenarios. Further, the application of SEM-GWAS enabled the decomposition of SNP effects into direct, indirect, and total effects, identifying whether a SNP effect is acting directly or indirectly on a given trait. In contrast, MTM-GWAS only captured overall genetic effects on traits, which is equivalent to combining the direct and indirect SNP effects from SEMGWAS.\n\nConclusionsAlthough MTM-GWAS and SEM-GWAS use the same probabilistic models, we provide evidence that SEM-GWAS captures complex relationships and delivers a more comprehensive understanding of SNP effects compared to MTM-GWAS. Our results showed that SEM-GWAS provides important insight regarding the mechanism by which identified SNPs control traits by partitioning them into direct, indirect, and total SNP effects.

genetics↗