Genomic selection has revolutionized genetic improvement in animals and plants, but little is known about its long-term effects. Here, we investigated the long-term effects of genomic selection on response to selection, genetic variance, and the genetic architecture of traits using stochastic simulations. We defined the genetic architecture as the set of causal loci underlying each trait, their allele frequencies, and their statistical additive effects. We simulated a livestock population under 50 generations of phenotypic, pedigree, or genomic selection for a single trait, controlled by either only additive, additive and dominance, or additive, dominance, and epistatic effects. The simulated epistasis was based on yeast data.

Variations in climatic variables (temperature, humidity and solar radiation) negatively impact livestock growth, reproduction, and production. Heat stress, for instance, is a source of huge financial loss to livestock production globally. There have been significant advances in physical modifications of animal environment and nutritional interventions as tools of heat stress mitigation. Unfortunately, these are short-term solutions and may be unsustainable, costly, and not applicable to all production systems. Accordingly, there is a need for innovative, practical, and sustainable approaches to overcome the challenges posed by global warming and climate change-induced heat stress. This review highlights attempts to genetically select and breed ruminants for thermotolerance and thereby sustain production in the face of changing climates. One effective way is to incorporate sustainable heat abatement strategies in ruminant production. Improved knowledge of the physiology of ruminant acclimation to harsh environments, the opportunities and tools available for selecting and breeding thermotolerant ruminants, and the matching of animals to appropriate environments should help to minimise the effect of heat stress on sustainable animal genetic resource growth, production, and reproduction to ensure protein food security.

Pervasive natural selection can strongly influence observed patterns of genetic variation, but these effects remain poorly understood when multiple selected variants segregate in nearby regions of the genome. Classical population genetics fails to account for interference between linked mutations, which grows increasingly severe as the density of selected polymorphisms increases. Here, we describe a simple limit that emerges when interference is common, in which the fitness effects of individual mutations play a relatively minor role. Instead, similar to models of quantitative genetics, molecular evolution is determined by the variance in fitness within the population, defined over an effectively asexual segment of the genome (a "linkage block"). We exploit this insensitivity in a new "coarse-grained" coalescent framework, which approximates the effects of many weakly selected mutations with a smaller number of strongly selected mutations that create the same variance in fitness. This approximation generates accurate and efficient predictions for silent site variability when interference is common. However, these results suggest that there is reduced power to resolve individual selection pressures when interference is sufficiently widespread, since a broad range of parameters possess nearly identical patterns of silent site variability.

Since the first Spanish settlers brought horses to America centuries ago, several local varieties and breeds have been established in the New World. These were generally a consequence of the admixture of the different breeds arriving from Europe. In some instances, local horses have been selectively bred for specific traits, such as appearance, endurance, strength, and gait. We looked at the genetics of two breeds, the Puerto Rican Non-Purebred (PRNPB) (also known as the "Criollo") horses and the Puerto Rican Paso Fino (PRPF), from the Caribbean Island of Puerto Rico. While it is reasonable to assume that there was a historic connection between the two, the genetic link between them has never been established. In our study, we started by looking at the genetic ancestry and diversity of current Puerto Rican horse populations using a 668 bp fragment of the mitochondrial DNA D-loop (HVR1) in 200 horses from 27 locations on the island. We then genotyped all 200 horses in our sample for the "gait-keeper" DMRT3 mutant allele previously associated with the paso gait especially cherished in this island breed. We also genotyped a subset of 24 samples with the Illumina Neogen Equine Community genome-wide array (65,000 SNPs). This data was further combined with the publicly available PRPF genomes from other studies. Our analysis show an undeniable genetic connection between the two varieties in Puerto Rico, consistent with the hypothesis that PRNPB horses represent the descendants of the original genetic pool, a mix of horses imported from the Iberian Peninsula and elsewhere in Europe. Some of the original founders of PRNRB population must have carried the "gait-keeper" DMRT3 allele upon arrival to the island. From this admixture, the desired traits were selected by the local people over the span of centuries. We propose that the frequency of the mutant "gait-keeper" allele originally increased in the local horses due to the selection for the smooth ride and other characters, long before the PRPF breed was established. To support this hypothesis, we demonstrate that PRNPB horses, and not the purebred PRPF, carry a signature of selection in the genomic region containing the DMRT3 locus to this day. The lack of the detectable signature of selection associated with the DMRT3 in the PRPF would be expected if this native breed was originally derived from the genetic pool of PRNPB horses established earlier and most of the founders already had the mutant allele. Consequently, selection specific to PRPF later focused on allels in other genes (including CHRM5, CYP2E1, MYH7, SRSF1, PAM, PRN and others) that have not been previously associated with the prized paso gait phenotype in Puerto Rico or anywhere else.

Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.

Pervasive purifying selection on non-synonymous substitutions is a hallmark of papillomavirus genome history, but the role of selection on and the drift of non-coding DNA motifs on HPV diversification is poorly understood. In this study, more than a thousand complete genomes representing Alphapapillomavirus types, lineages, and SNP variants were examined phylogenetically and interrogated for the number and position of non-coding DNA sequence motifs using Principal Components Analyses, Ancestral State Reconstructions, and Phylogenetic Independent Contrasts. For anciently diverged Alphapapillomavirus types, composition of the four nucleotides (A, C, G, T), codon usage, trimer usage, and 13 established non-coding DNA sequence motifs revealed phylogenetic clusters consistent with genetic drift. Ancestral state reconstruction and Phylogenetic Independent Contrasts revealed ancient genome alterations, particularly for the CpG and APOBEC3 motifs. Each evolutionary analytical method we performed supports the unanticipated conclusion that genetic drift and different evolutionary drivers have structured Alphapapillomavirus genomes in distinct ways during successive epochs, even extending to differences in more recently formed variant lineages.

With modern methods in biotechnology, the search for biomarkers has advanced to a challenging statistical task exploring high dimensional data sets. Feature selection is a widely researched preprocessing step to handle huge numbers of biomarker candidates and has special importance for the analysis of biomedical data. Such data sets often include many input features not related to the diagnostic or therapeutic target variable. A less researched, but also relevant aspect for medical applications are costs of different biomarker candidates. These costs are often financial costs, but can also refer to other aspects, for example the decision between a painful biopsy marker and a simple urine test. In this paper, we propose extensions to two feature selection methods to control the total amount of such costs: greedy forward selection and genetic algorithms. In comprehensive simulation studies of binary classification tasks, we compare the predictive performance, the run-time and the detection rate of relevant features for the new proposed methods and five baseline alternatives to handle budget constraints.

Maize is one of the most important staple crops and is widely grown throughout the world. Stalk lodging can cause enormous yield losses in maize production. However, rind penetrometer resistance (RPR), which is recognized as a reliable measurement to evaluate stalk strength, has been shown to be efficient and useful for improving stalk lodging-resistance. Linkage mapping is an acknowledged approach for exploring the genetic architecture of target traits. In addition, genomic selection (GS) using whole genome markers enhances selection efficiency for genetically complex traits. In the present study, two recombinant inbred line (RIL) populations were utilized to dissect the genetic basis of RPR, which was evaluated in seven growth stages.

Testing for associations in big data faces the problem of multiple comparisons, wherein true signals are difficult to detect on the background of all associations queried. This difficulty is particularly salient in human genetic association studies, in which phenotypic variation is often driven by numerous variants of small effect. The current strategy to improve power to identify these weak associations consists of applying standard marginal statistical approaches and increasing study sample sizes. Although successful, this approach does not leverage the environmental and genetic factors shared among the multiple phenotypes collected in contemporary cohorts. Here we developed covariates for multiphenotype studies (CMS), an approach that improves power when correlated phenotypes are measured on the same samples. Our analyses of real and simulated data provide direct evidence that correlated phenotypes can be used to achieve increases in power to levels often surpassing the power gained by a twofold increase in sample size.

The Kalash represent an enigmatic isolated population of Indo-European speakers who have been living for centuries in the Hindu Kush mountain ranges of present-day Pakistan. Previous Y chromosome and mitochondrial DNA markers provided no support for their claimed Greek descent following Alexander III of Macedon's invasion of this region, and analysis of autosomal loci provided evidence of a strong genetic bottleneck. To understand their origins and demography further, we genotyped 23 unrelated Kalash samples on the Illumina HumanOmni2.5M-8 BeadChip and sequenced one male individual at high coverage on an Illumina HiSeq 2000. Comparison with published data from ancient hunter-gatherers and European farmers showed that the Kalash share genetic drift with the Paleolithic Siberian hunter-gatherers and might represent an extremely drifted ancient northern Eurasian population that also contributed to European and Near Eastern ancestry. Since the split from other South Asian populations, the Kalash have maintained a low long-term effective population size (2,319-2,603) and experienced no detectable gene flow from their geographic neighbors in Pakistan or from other extant Eurasian populations. The mean time of divergence between the Kalash and other populations currently residing in this region was estimated to be 11,800 (95% confidence interval = 10,600-12,600) years ago, and thus they represent present-day descendants of some of the earliest migrants into the Indian sub-continent from West Asia.

Modern dogs are distinguished among domesticated species by the vast breadth of phenotypic variation produced by strong and consistent human-driven selective pressure. The resulting breeds reflect the development of closed populations with well-defined physical and behavioral attributes. The sport-hunting dog group has long been employed in assistance to hunters, reflecting strong behavioral pressures to locate and pursue quarry over great distances and variable terrain. Comparison of whole-genome sequence data between sport-hunting and terrier breeds, groups at the ends of a continuum in both form and function, reveals that genes underlying cardiovascular, muscular, and neuronal functions are under strong selection in sport-hunting breeds, including ADRB1, TRPM3, RYR3, UTRN, ASIC3, and ROBO1 We also identified an allele of TRPM3 that was significantly associated with increased racing speed in Whippets, accounting for 11.6% of the total variance in racing performance. Finally, we observed a significant association of ROBO1 with breed-specific accomplishments in competitive obstacle course events. These results provide strong evidence that sport-hunting breeds have been adapted to their occupations by improved endurance, cardiac function, blood flow, and cognitive performance, demonstrating how strong behavioral selection alters physiology to create breeds with distinct capabilities.

Mating systems are an important factor influencing the variance in reproductive success among individuals within natural populations and thus have important ecological and evolutionary implications. We used molecular pedigree reconstruction techniques with microsatellite DNA data to characterize the genetic mating system and mate selection in adult smallmouth bass spawning in Lake Opeongo. The genetic mating system of smallmouth bass in this system can be characterized as predominantly monogamous with a low rate of polygynandry particularly among larger individuals. Iteroparous individuals showed a complete absence of interannual mate fidelity, presumably due to the low annual return rate of spawning adults. Within a season, individuals from both sexes pursued additional mating opportunities with males showing greater variance in mate number than females. Female mate selection appeared to be largely random with little evidence for elevated levels of inbreeding in this population. Multiple mating females pursued additional males to whom they were less related than the first male with which they spawned within a given season, however, this pattern varied among years. The mating pattern observed in this population would likely limit the strength of sexual selection and thus could account for the lack of sexual dimorphism and the absence of alternative reproductive tactics in this species.

Animal temperament can be defined as a response to environmental or social stimuli. There are a number of temperament traits in cattle that contribute to their welfare, including their response to handling or milking, response to challenge such as human approach or intervention at calving, and response to conspecifics. In a number of these areas, the genetic basis of the trait has been studied. Heritabilities have been estimated and in some cases quantitative trait loci (QTL) have been identified. The variation is sometimes considerable and moderate heritabilities have been found for the major handling temperament traits, making them amenable to selection. Studies have also investigated the correlations between temperament and other traits, such as productivity and meat quality. Despite this, there are relatively few examples of temperament traits being used in selection programmes. Most often, animals are screened for aggression or excessive fear during handling or milking, with extreme animals being culled, or EBVs for temperament are estimated, but these traits are not commonly included routinely in selection indices, despite there being economic, welfare and human safety drivers for their. There may be a number of constraints and barriers. For some traits and breeds, there may be difficulties in collecting behavioral data on sufficiently large populations of animals to estimate genetic parameters. Most selection indices require estimates of economic values, and it is often difficult to assign an economic value to a temperament trait. The effects of selection primarily for productivity traits on temperament and welfare are discussed. Future opportunities include automated data collection methods and the wider use of genomic information in selection.

Rare breeds represent a valuable resource for future market demands. These populations are usually well-adapted, but their low census compromises the genetic diversity and future of these breeds. Since improvement of a breed for commercial traits may also confer higher probabilities of survival for the breed, it is important to achieve good responses to artificial selection. Therefore, efficient genetic management of these populations is essential to ensure that they respond adequately to genetic selection in possible future artificial selection scenarios. Scenarios that maximize the maximum genetic variance in a unique population could be a valuable option. The aim of this work was to study the effect of the maximization of genetic variance to increase selection response and improve the capacity of a population to adapt to a new environment/production system.

The mechanisms by which genetic variation affects transcription regulation and phenotypes at the nucleotide level are incompletely understood. Here we use natural genetic variation as an in vivo mutagenesis screen to assess the genome-wide effects of sequence variation on lineage-determining and signal-specific transcription factor binding, epigenomics and transcriptional outcomes in primary macrophages from different mouse strains. We find substantial genetic evidence to support the concept that lineage-determining transcription factors define epigenetic and transcriptomic states by selecting enhancer-like regions in the genome in a collaborative fashion and facilitating binding of signal-dependent factors. This hierarchical model of transcription factor function suggests that limited sets of genomic data for lineage-determining transcription factors and informative histone modifications can be used for the prioritization of disease-associated regulatory variants.

The Slovenian territory played a crucial role in the past serving as gateway for several human migrations. Previous studies used Slovenians as a source population to interpret different demographic events happened in Europe but not much is known about the genetic background and the demographic history of this population. Here, we analyzed genome-wide data from 96 individuals to shed light on the genetic role and history of the Slovenian population. Y chromosome diversity splits into two major haplogroups R1b and R1a with the latter suggesting a genetic contribution from the steppe. Slovenian individuals are more closely related to Northern and Eastern European populations than Southern European populations even though they are geographically closer. This pattern is confirmed by an admixture and clustering analysis. We also identified a single stream of admixture events between the Slovenians with Sardinians and Russians around ∼2630 BCE (2149-3112). Using ancient samples, we found a significant admixture in Slovenians using Yamnaya and the early Neolithic Hungarians as sources, dated around ∼1762 BCE (1099-2426) suggesting a strong contribution from the steppe to the foundation of the observed modern genetic diversity. Finally, we looked for signals of selection in candidate variants and we found significant hits in HERC2 and FADS responsible for blue eye color and synthesis of long-chain unsaturated fatty acids, respectively, when Slovenians were compared to Southern Europeans. While the comparison was done with Eastern Europeans, we identified significant signals in PKD2L1 and IL6R which are genes associated with taste and coronary artery disease, respectively.

A combination of selective and neutral evolutionary forces shape patterns of genetic diversity in nature. Among the insects, most previous analyses of the roles of drift and selection in shaping variation across the genome have focused on the genus Drosophila A more complete understanding of these forces will come from analyzing other taxa that differ in population demography and other aspects of biology. We have analyzed diversity and signatures of selection in the neotropical Heliconius butterflies using resequenced genomes from 58 wild-caught individuals of Heliconius melpomene and another 21 resequenced genomes representing 11 related species. By comparing intraspecific diversity and interspecific divergence, we estimate that 31% of amino acid substitutions between Heliconius species are adaptive. Diversity at putatively neutral sites is negatively correlated with the local density of coding sites as well as nonsynonymous substitutions and positively correlated with recombination rate, indicating widespread linked selection. This process also manifests in significantly reduced diversity on longer chromosomes, consistent with lower recombination rates. Although hitchhiking around beneficial nonsynonymous mutations has significantly shaped genetic variation in H. melpomene, evidence for strong selective sweeps is limited overall. We did however identify two regions where distinct haplotypes have swept in different populations, leading to increased population differentiation. On the whole, our study suggests that positive selection is less pervasive in these butterflies as compared to fruit flies, a fact that curiously results in very similar levels of neutral diversity in these very different insects.

The power of Drosophila melanogaster as a model system relies on tractable germline genetic manipulations. Despite Drosophila's expansive genetics toolbox, such manipulations are still accomplished one change at a time and depend predominantly on phenotypic screening. We describe a drug-based genetic platform consisting of four selection and two counterselection markers, eliminating the need to screen for modified progeny. These markers work reliably individually or in combination to produce specific genetic outcomes. We demonstrate three example applications of multiplexed drug-based genetics by generating (1) transgenic animals, expressing both components of binary overexpression systems in a single transgenesis step; (2) dual selectable and counterselectable balancer chromosomes; and (3) selectable, fluorescently tagged P[acman] bacterial artificial chromosome (BAC) strains. We perform immunoprecipitation followed by proteomic analysis on one tagged BAC line, demonstrating our platform's applicability to biological discovery. Lastly, we provide a plasmid library resource to facilitate custom transgene design and technology transfer to other model systems.

The protein-folding chaperone Hsp90 has been proposed to buffer the phenotypic effects of mutations. The potential for Hsp90 and other putative buffers to increase robustness to mutation has had major impact on disease models, quantitative genetics, and evolutionary theory. But Hsp90 sometimes contradicts expectations for a buffer by potentiating rapid phenotypic changes that would otherwise not occur. Here, we quantify Hsp90's ability to buffer or potentiate (i.e., diminish or enhance) the effects of genetic variation on single-cell morphological features in budding yeast. We corroborate reports that Hsp90 tends to buffer the effects of standing genetic variation in natural populations. However, we demonstrate that Hsp90 tends to have the opposite effect on genetic variation that has experienced reduced selection pressure. Specifically, Hsp90 tends to enhance, rather than diminish, the effects of spontaneous mutations and recombinations. This result implies that Hsp90 does not make phenotypes more robust to the effects of genetic perturbation. Instead, natural selection preferentially allows buffered alleles to persist and thereby creates the false impression that Hsp90 confers greater robustness.

Onchocerca volvulus is the causative agent of onchocerciasis, or "river blindness". Ivermectin has been used for mass treatment of onchocerciasis for up to 18 years, and recently there have been reports of poor parasitological responses to the drug. Should ivermectin resistance be developing, it would have a genetic basis. We monitored genetic changes in parasites obtained from the same patients before use of ivermectin and following different levels of ivermectin exposure.