Ghat: an R package for identifying adaptive polygenic traits.

Identifying selection on polygenic complex traits in crops and livestock is important for understanding evolution and helps prioritize important characteristics for breeding. Quantitative trait loci (QTL) that contribute to polygenic trait variation often exhibit small or infinitesimal effects. This hinders the ability to detect QTL-controlling polygenic traits because enormously high statistical power is needed for their detection. Recently, we circumvented this challenge by introducing a method to identify selection on complex traits by evaluating the relationship between genome-wide changes in allele frequency and estimates of effect size. The approach involves calculating a composite statistic across all markers that capture this relationship, followed by implementing a linkage disequilibrium-aware permutation test to evaluate if the observed pattern differs from that expected due to drift during evolution and population stratification. In this manuscript, we describe "Ghat," an R package developed to implement this method to test for selection on polygenic traits. We demonstrate the package by applying it to test for polygenic selection on 15 published European wheat traits including yield, biomass, quality, morphological characteristics, and disease resistance traits. Moreover, we applied Ghat to different simulated populations with different breeding histories and genetic architectures. The results highlight the power of Ghat to identify selection on complex traits. The Ghat package is accessible on CRAN, the Comprehensive R Archival Network, and on GitHub.

MoBPSweb: A web-based framework to simulate and compare breeding programs.

In this study, we introduce a new web-based simulation framework ("MoBPSweb") that combines a unified language to describe breeding programs with the simulation software MoBPS, standing for "Modular Breeding Program Simulator." Thereby, MoBPSweb provides a flexible environment to log, simulate, evaluate, and compare breeding programs. Inputs can be provided via modules ranging from a Vis.js-based environment for "drawing" the breeding program to a variety of modules to provide phenotype information, economic parameters, and other relevant information. Similarly, results of the simulation study can be extracted and compared to other scenarios via output modules (e.g., observed phenotypes, the accuracy of breeding value estimation, inbreeding rates), while all simulations and downstream analysis are executed in the highly efficient R-package MoBPS.

A unifying concept of animal breeding programmes.

Modern animal breeding programmes are constantly evolving with advances in breeding theory, biotechnology and genetics. Surprisingly, there seems to be no generally accepted succinct definition of what exactly a breeding programme is, neither is there a unified language to describe breeding programmes in a comprehensive, unambiguous and reproducible way. In this work, we try to fill this gap by suggesting a general definition of breeding programmes that also pertains to cases where genetic progress is not achieved through selection, but, for example, through transgenic technologies, or the aim is not to generate genetic progress, but, for example, to maintain genetic diversity. The key idea of the underlying concept is to represent a breeding programme in modular form as a directed graph that is composed of nodes and edges, where nodes represent cohorts of breeding units, usually individuals, and edges represent breeding activities, like "selection" or "reproduction." We claim, that by defining a comprehensive set of nodes and edges, it is possible to represent any breeding programme of arbitrary complexity by such a graph, which thus comprises a full description of the breeding programme. This concept is implemented in a web-based tool (MoBPSweb, available at www.mobps.de) and has a link to the R-package MoBPS (Modular Breeding Program Simulator) to simulate the described breeding programmes. The approach is illustrated by showcasing three different breeding programmes of increasing complexity. The concept allows a formal description of breeding programmes, which is requested, for example, in legal regulations of the European Union, but so far cannot be provided in a standardized format. In the discussion, we point out potential limitations of the concept and argue that the general approach can be easily extended to account for novel breeding technologies, to breeding of crops or experimental species, but also to modelling diversity dynamics in natural populations.

Genome-wide detection of signatures of selection in indicine and Brazilian locally adapted taurine cattle breeds using whole-genome re-sequencing data.

BACKGROUND: The cattle introduced by European conquerors during the Brazilian colonization period were exposed to a process of natural selection in different types of biomes throughout the country, leading to the development of locally adapted cattle breeds. In this study, whole-genome re-sequencing data from indicine and Brazilian locally adapted taurine cattle breeds were used to detect genomic regions under selective pressure. Within-population and cross-population statistics were combined separately in a single score using the de-correlated composite of multiple signals (DCMS) method. Putative sweep regions were revealed by assessing the top 1% of the empirical distribution generated by the DCMS statistics. RESULTS: A total of 33,328,447 biallelic SNPs with an average read depth of 12.4X passed the hard filtering process and were used to access putative sweep regions. Admixture has occurred in some locally adapted taurine populations due to the introgression of exotic breeds. The genomic inbreeding coefficient based on runs of homozygosity (ROH) concurred with the populations' historical background. Signatures of selection retrieved from the DCMS statistics provided a comprehensive set of putative candidate genes and revealed QTLs disclosing cattle production traits and adaptation to the challenging environments. Additionally, several candidate regions overlapped with previous regions under selection described in the literature for other cattle breeds. CONCLUSION: The current study reported putative sweep regions that can provide important insights to better understand the selective forces shaping the genome of the indicine and Brazilian locally adapted taurine cattle breeds. Such regions likely harbor traces of natural selection pressures by which these populations have been exposed and may elucidate footprints for adaptation to the challenging climatic conditions.

Multiple loci linked to inversions are associated with eye size variation in species of the Drosophila virilis phylad.

The size and shape of organs is tightly controlled to achieve optimal function. Natural morphological variations often represent functional adaptations to an ever-changing environment. For instance, variation in head morphology is pervasive in insects and the underlying molecular basis is starting to be revealed in the Drosophila genus for species of the melanogaster group. However, it remains unclear whether similar diversifications are governed by similar or different molecular mechanisms over longer timescales. To address this issue, we used species of the virilis phylad because they have been diverging from D. melanogaster for at least 40 million years. Our comprehensive morphological survey revealed remarkable differences in eye size and head shape among these species with D. novamexicana having the smallest eyes and southern D. americana populations having the largest eyes. We show that the genetic architecture underlying eye size variation is complex with multiple associated genetic variants located on most chromosomes. Our genome wide association study (GWAS) strongly suggests that some of the putative causative variants are associated with the presence of inversions. Indeed, northern populations of D. americana share derived inversions with D. novamexicana and they show smaller eyes compared to southern ones. Intriguingly, we observed a significant enrichment of genes involved in eye development on the 4th chromosome after intersecting chromosomal regions associated with phenotypic differences with those showing high differentiation among D. americana populations. We propose that variants associated with chromosomal inversions contribute to both intra- and interspecific variation in eye size among species of the virilis phylad.

Assessing breed integrity of Göttingen Minipigs.

BACKGROUND: Göttingen Minipigs (GMP) is the smallest commercially available minipig breed under a controlled breeding scheme and is globally bred in five isolated colonies. The genetic isolation harbors the risk of stratification which might compromise the identity of the breed and its usability as an animal model for biomedical and human disease. We conducted whole genome re-sequencing of two DNA-pools per colony to assess genomic differentiation within and between colonies. We added publicly available samples from 13 various pig breeds and discovered overall about 32 M loci, ~ 16 M. thereof variable in GMPs. Individual samples were virtually pooled breed-wise. FST between virtual and DNA pools, a phylogenetic tree, principal component analysis (PCA) and evaluation of functional SNP classes were conducted. An F-test was performed to reveal significantly differentiated allele frequencies between colonies. Variation within a colony was quantified as expected heterozygosity. RESULTS: Phylogeny and PCA showed that the GMP is easily discriminable from all other breads, but that there is also differentiation between the GMP colonies. Dependent on the contrast between GMP colonies, 4 to 8% of all loci had significantly different allele frequencies. Functional annotation revealed that functionally non-neutral loci are less prone to differentiation. Annotation of highly differentiated loci revealed a couple of deleterious mutations in genes with putative effects in the GMPs . CONCLUSION: Differentiation and annotation results suggest that the underlying mechanisms are rather drift events than directed selection and limited to neutral genome regions. Animal exchange seems not yet necessary. The Relliehausen colony appears to be the genetically most unique GMP sub-population and could be a valuable resource if animal exchange is required to maintain uniformity of the GMP.

Genetic mechanism underlying sexual plasticity and its association with colour patterning in zebrafish (Danio rerio).

BACKGROUND: Elevated water temperature, as is expected through climate change, leads to masculinization in fish species with sexual plasticity, resulting in changes in population dynamics. These changes are one important ecological consequence, contributing to the risk of extinction in small and inbred fish populations under natural conditions, due to male-biased sex ratio. Here we investigated the effect of elevated water temperature during embryogenesis on sex ratio and sex-biased gene expression profiles between two different tissues, namely gonad and caudal fin of adult zebrafish males and females, to gain new insights into the molecular mechanisms underlying sex determination (SD) and colour patterning related to sexual attractiveness. RESULTS: Our study demonstrated sex ratio imbalances with 25.5% more males under high-temperature condition, resulting from gonadal masculinization. The result of transcriptome analysis showed a significantly upregulated expression of male SD genes (e.g. dmrt1, amh, cyp11c1 and sept8b) and downregulation of female SD genes (e.g. zp2.1, vtg1, cyp19a1a and bmp15) in male gonads compared to female gonads. Contrary to expectations, we found highly differential expression of colour pattern (CP) genes in the gonads, suggesting the 'neofunctionalisation' of those genes in the zebrafish reproduction system. However, in the caudal fin, no differential expression of CP genes was identified, suggesting the observed differences in colouration between males and females in adult fish may be due to post-transcriptional regulation of key enzymes involved in pigment synthesis and distribution. CONCLUSIONS: Our study demonstrates male-biased sex ratio under high temperature condition and support a polygenic SD (PSD) system in laboratory zebrafish. We identify a subset of pathways (tight junction, gap junction and apoptosis), enriched for SD and CP genes, which appear to be co-regulated in the same pathway, providing evidence for involvement of those genes in the regulation of phenotypic sexual dimorphism in zebrafish.

Lost in Translation: On the Problem of Data Coding in Penalized Whole Genome Regression with Interactions.

Mixed models can be considered as a type of penalized regression and are everyday tools in statistical genetics. The standard mixed model for whole genome regression (WGR) is ridge regression best linear unbiased prediction (RRBLUP) which is based on an additive marker effect model. Many publications have extended the additive WGR approach by incorporating interactions between loci or between genes and environment. In this context of penalized regressions with interactions, it has been reported that translating the coding of single nucleotide polymorphisms -for instance from -1,0,1 to 0,1,2- has an impact on the prediction of genetic values and interaction effects. In this work, we identify the reason for the relevance of variable coding in the general context of penalized polynomial regression. We show that in many cases, predictions of the genetic values are not invariant to translations of the variable coding, with an exception when only the sizes of the coefficients of monomials of highest total degree are penalized. The invariance of RRBLUP can be considered as a special case of this setting, with a polynomial of total degree 1, penalizing additive effects (total degree 1) but not the fixed effect (total degree 0). The extended RRBLUP (eRRBLUP), which includes interactions, is not invariant to translations because it does not only penalize interactions (total degree 2), but also additive effects (total degree 1). This observation implies that translation-invariance can be maintained in a pair-wise epistatic WGR if only interaction effects are penalized, but not the additive effects. In this regard, approaches of pre-selecting loci may not only reduce computation time, but can also help to avoid the variable coding issue. To illustrate the practical relevance, we compare different regressions on a publicly available wheat data set. We show that for an eRRBLUP, the relevance of the marker coding for interaction effect estimates increases with the number of variables included in the model. A biological interpretation of estimated interaction effects may therefore become more difficult. Consequently, comparing reproducing kernel Hilbert space (RKHS) approaches to WGR approaches modeling effects explicitly, the supposed advantage of an increased interpretability of the latter may not be real. Our theoretical results are generally valid for penalized regressions, for instance also for the least absolute shrinkage and selection operator (LASSO). Moreover, they apply to any type of interaction modeled by products of predictor variables in a penalized regression approach or by Hadamard products of covariance matrices in a mixed model.

A Simple Test Identifies Selection on Complex Traits.

Important traits in agricultural, natural, and human populations are increasingly being shown to be under the control of many genes that individually contribute only a small proportion of genetic variation. However, the majority of modern tools in quantitative and population genetics, including genome-wide association studies and selection-mapping protocols, are designed to identify individual genes with large effects. We have developed an approach to identify traits that have been under selection and are controlled by large numbers of loci. In contrast to existing methods, our technique uses additive-effects estimates from all available markers, and relates these estimates to allele-frequency change over time. Using this information, we generate a composite statistic, denoted [Formula: see text] which can be used to test for significant evidence of selection on a trait. Our test requires pre- and postselection genotypic data but only a single time point with phenotypic information. Simulations demonstrate that [Formula: see text] is powerful for identifying selection, particularly in situations where the trait being tested is controlled by many genes, which is precisely the scenario where classical approaches for selection mapping are least powerful. We apply this test to breeding populations of maize and chickens, where we demonstrate the successful identification of selection on traits that are documented to have been under selection.

Phenotypic and genetic relationships between age at first calving, its component traits, and survival of heifers up to second calving.

The aim of this study was to answer the question whether models for genetic evaluations of longevity should include a correction for age at first calving (AFC). For this purpose, phenotypic and genetic relationships between AFC, its component traits age at first insemination (AFI) and interval from first to last insemination (FLI), and survival of different periods of the first lactation (S1: 0 to 49 d, S2: 50 to 249 d, S3: 250 d to second calving) were investigated. Data of 721,919 German Holstein heifers, being inseminated for the first time during the years from 2003 to 2012, were used for the analyses. Phenotypic correlations of AFI, FLI, and AFC to S1 to S3 were negative. Mean estimated heritabilities were 0.239 (AFI), 0.007 (FLI), and 0.103 (AFC) and 0.023 (S1), 0.016 (S2), and 0.028 (S3) on the observed scale. The genetic correlation between AFI and FLI was close to zero. Genetic correlations between AFI and the survival traits were -0.08 (S1), -0.02 (S2), and -0.10 (S3); those between FLI and the survival traits were -0.14 (S1), -0.20 (S2), and -0.44 (S3); and those between AFC and the survival traits were -0.09 (S1), -0.06 (S2), and -0.20 (S3). Some of these genetic correlations were different from zero, which suggests that correcting for AFC in genetic evaluations for longevity in dairy cows might remove functional genetic variance and should be reconsidered.

Gene-based mapping and pathway analysis of metabolic traits in dairy cows.

The metabolic adaptation of dairy cows during the transition period has been studied intensively in the last decades. However, until now, only few studies have paid attention to the genetic aspects of this process. Here, we present the results of a gene-based mapping and pathway analysis with the measurements of three key metabolites, (1) non-esterified fatty acids (NEFA), (2) beta-hydroxybutyrate (BHBA) and (3) glucose, characterizing the metabolic adaptability of dairy cows before and after calving. In contrast to the conventional single-marker approach, we identify 99 significant and biologically sensible genes associated with at least one of the considered phenotypes and thus giving evidence for a genetic basis of the metabolic adaptability. Moreover, our results strongly suggest three pathways involved in the metabolism of steroids and lipids are potential candidates for the adaptive regulation of dairy cows in their early lactation. From our perspective, a closer investigation of our findings will lead to a step forward in understanding the variability in the metabolic adaptability of dairy cows in their early lactation.

Coverage and efficiency in current SNP chips.

To answer the question as to which commercial high-density SNP chip covers most of the human genome given a fixed budget, we compared the performance of 12 chips of different sizes released by Affymetrix and Illumina for the European, Asian, and African populations. These include Affymetrix' relatively new population-optimized arrays, whose SNP sets are each tailored toward a specific ethnicity. Our evaluation of the chips included the use of two measures, efficiency and cost-benefit ratio, which we developed as supplements to genetic coverage. Unlike coverage, these measures factor in the price of a chip or its substitute size (number of SNPs on chip), allowing comparisons to be drawn between differently priced chips. In this fashion, we identified the Affymetrix population-optimized arrays as offering the most cost-effective coverage for the Asian and African population. For the European population, we established the Illumina Human Omni 2.5-8 as the preferred choice. Interestingly, the Affymetrix chip tailored toward an Eastern Asian subpopulation performed well for all three populations investigated. However, our coverage estimates calculated for all chips proved much lower than those advertised by the producers. All our analyses were based on the 1000 Genome Project as reference population.