The domestic dog: man's best friend in the genomic era

The domestic dog genome - shaped by domestication, adaptation to human-dominated environments and artificial selection - encodes tremendous phenotypic diversity. Recent developments have improved our understanding of the genetics underlying this diversity, unleashing the dog as an important model organism for complex-trait analysis

The role of big data management, data registries, and machine learning algorithms for optimizing safe definitive surgery in trauma: a review

Digital data processing has revolutionized medical documentation and enabled the aggregation of patient data across hospitals. Initiatives such as those from the AO Foundation about fracture treatment (AO Sammelstudie, 1986), the Major Trauma Outcome Study (MTOS) about survival, and the Trauma Audit and Research Network (TARN) pioneered multi-hospital data collection. Large trauma registries, like the German Trauma Registry (TR-DGU) helped improve evidence levels but were still constrained by predefined data sets and limited physiological parameters. The improvement in the understanding of pathophysiological reactions substantiated that decision making about fracture care led to development of patient's tailored dynamic approaches like the Safe Definitive Surgery algorithm. In the future, artificial intelligence (AI) may provide further steps by potentially transforming fracture recognition and/or outcome prediction. The evolution towards flexible decision making and AI-driven innovations may be of further help. The current manuscript summarizes the development of big data from local databases and subsequent trauma registries to AI-based algorithms, such as Parkland Trauma Mortality Index and the IBM Watson Pathway Explorer

Genetic recombination is targeted towards gene promoter regions in dogs

The identification of the H3K4 trimethylase, PRDM9, as the gene responsible for recombination hotspot localization has provided considerable insight into the mechanisms by which recombination is initiated in mammals. However, uniquely amongst mammals, canids appear to lack a functional version of PRDM9 and may therefore provide a model for understanding recombination that occurs in the absence of PRDM9, and thus how PRDM9 functions to shape the recombination landscape. We have constructed a fine-scale genetic map from patterns of linkage disequilibrium assessed using high-throughput sequence data from 51 free-ranging dogs, Canis lupus familiaris. While broad-scale properties of recombination appear similar to other mammalian species, our fine-scale estimates indicate that canine highly elevated recombination rates are observed in the vicinity of CpG rich regions including gene promoter regions, but show little association with H3K4 trimethylation marks identified in spermatocytes. By comparison to genomic data from the Andean fox, Lycalopex culpaeus, we show that biased gene conversion is a plausible mechanism by which the high CpG content of the dog genome could have occurred.Comment: Updated version, with significant revision

SNP identification, verification, and utility for population genetics in a non-model genus

<p>Abstract</p> <p>Background</p> <p>By targeting SNPs contained in both coding and non-coding areas of the genome, we are able to identify genetic differences and characterize genome-wide patterns of variation among individuals, populations and species. We investigated the utility of 454 sequencing and MassARRAY genotyping for population genetics in natural populations of the teleost, <it>Fundulus heteroclitus </it>as well as closely related <it>Fundulus </it>species (<it>F. grandis</it>, <it>F. majalis </it>and <it>F. similis</it>).</p> <p>Results</p> <p>We used 454 pyrosequencing and MassARRAY genotyping technology to identify and type 458 genome-wide SNPs and determine genetic differentiation within and between populations and species of <it>Fundulus</it>. Specifically, pyrosequencing identified 96 putative SNPs across coding and non-coding regions of the <it>F. heteroclitus </it>genome: 88.8% were verified as true SNPs with MassARRAY. Additionally, putative SNPs identified in <it>F. heteroclitus </it>EST sequences were verified in most (86.5%) <it>F. heteroclitus </it>individuals; fewer were genotyped in <it>F. grandis </it>(74.4%), <it>F. majalis </it>(72.9%), and <it>F. similis </it>(60.7%) individuals. SNPs were polymorphic and showed latitudinal clinal variation separating northern and southern populations and established isolation by distance in <it>F. heteroclitus </it>populations. In <it>F. grandis</it>, SNPs were less polymorphic but still established isolation by distance. Markers differentiated species and populations.</p> <p>Conclusions</p> <p>In total, these approaches were used to quickly determine differences within the <it>Fundulus </it>genome and provide markers for population genetic studies.</p

IQCB1 and PDE6B Mutations Cause Similar Early Onset Retinal Degenerations in Two Closely Related Terrier Dog Breeds

Purpose.: To identify the causative mutations in two early-onset canine retinal degenerations, crd1 and crd2, segregating in the American Staffordshire terrier and the Pit Bull Terrier breeds, respectively. Methods.: Retinal morphology of crd1- and crd2-affected dogs was evaluated by light microscopy. DNA was extracted from affected and related unaffected controls. Association analysis was undertaken using the Illumina Canine SNP array and PLINK (crd1 study), or the Affymetrix Version 2 Canine array, the “MAGIC” genotype algorithm, and Fisher\u27s Exact test for association (crd2 study). Positional candidate genes were evaluated for each disease. Results.: Structural photoreceptor abnormalities were observed in crd1-affected dogs as young as 11-weeks old. Rod and cone inner segment (IS) and outer segments (OS) were abnormal in size, shape, and number. In crd2-affected dogs, rod and cone IS and OS were abnormal as early as 3 weeks of age, progressing with age to severe loss of the OS, and thinning of the outer nuclear layer (ONL) by 12 weeks of age. Genome-wide association study (GWAS) identified association at the telomeric end of CFA3 in crd1-affected dogs and on CFA33 in crd2-affected dogs. Candidate gene evaluation identified a three bases deletion in exon 21 of PDE6B in crd1-affected dogs, and a cytosine insertion in exon 10 of IQCB1 in crd2-affected dogs. Conclusions.: Identification of the mutations responsible for these two early-onset retinal degenerations provides new large animal models for comparative disease studies and evaluation of potential therapeutic approaches for the homologous human diseases

Fluctuating selection models and Mcdonald-Kreitman type analyses

It is likely that the strength of selection acting upon a mutation varies through time due to changes in the environment. However, most population genetic theory assumes that the strength of selection remains constant. Here we investigate the consequences of fluctuating selection pressures on the quantification of adaptive evolution using McDonald-Kreitman (MK) style approaches. In agreement with previous work, we show that fluctuating selection can generate evidence of adaptive evolution even when the expected strength of selection on a mutation is zero. However, we also find that the mutations, which contribute to both polymorphism and divergence tend, on average, to be positively selected during their lifetime, under fluctuating selection models. This is because mutations that fluctuate, by chance, to positive selected values, tend to reach higher frequencies in the population than those that fluctuate towards negative values. Hence the evidence of positive adaptive evolution detected under a fluctuating selection model by MK type approaches is genuine since fixed mutations tend to be advantageous on average during their lifetime. Never-the-less we show that methods tend to underestimate the rate of adaptive evolution when selection fluctuates

A population genetic approach to mapping neurological disorder genes using deep resequencing

Deep resequencing of functional regions in human genomes is key to identifying potentially causal rare variants for complex disorders. Here, we present the results from a large-sample resequencing (n  =  285 patients) study of candidate genes coupled with population genetics and statistical methods to identify rare variants associated with Autism Spectrum Disorder and Schizophrenia. Three genes, MAP1A, GRIN2B, and CACNA1F, were consistently identified by different methods as having significant excess of rare missense mutations in either one or both disease cohorts. In a broader context, we also found that the overall site frequency spectrum of variation in these cases is best explained by population models of both selection and complex demography rather than neutral models or models accounting for complex demography alone. Mutations in the three disease-associated genes explained much of the difference in the overall site frequency spectrum among the cases versus controls. This study demonstrates that genes associated with complex disorders can be mapped using resequencing and analytical methods with sample sizes far smaller than those required by genome-wide association studies. Additionally, our findings support the hypothesis that rare mutations account for a proportion of the phenotypic variance of these complex disorders

How and why DNA barcodes underestimate the diversity of microbial eukaryotes

Background: Because many picoplanktonic eukaryotic species cannot currently be maintained in culture, direct sequencing of PCR-amplified 18S ribosomal gene DNA fragments from filtered sea-water has been successfully used to investigate the astounding diversity of these organisms. The recognition of many novel planktonic organisms is thus based solely on their 18S rDNA sequence. However, a species delimited by its 18S rDNA sequence might contain many cryptic species, which are highly differentiated in their protein coding sequences. Principal Findings: Here, we investigate the issue of species identification from one gene to the whole genome sequence. Using 52 whole genome DNA sequences, we estimated the global genetic divergence in protein coding genes between organisms from different lineages and compared this to their ribosomal gene sequence divergences. We show that this relationship between proteome divergence and 18S divergence is lineage dependant. Unicellular lineages have especially low 18S divergences relative to their protein sequence divergences, suggesting that 18S ribosomal genes are too conservative to assess planktonic eukaryotic diversity. We provide an explanation for this lineage dependency, which suggests that most species with large effective population sizes will show far less divergence in 18S than protein coding sequences. Conclusions: There is therefore a trade-off between using genes that are easy to amplify in all species, but which by their nature are highly conserved and underestimate the true number of species, and using genes that give a better description of the number of species, but which are more difficult to amplify. We have shown that this trade-off differs between unicellular and multicellular organisms as a likely consequence of differences in effective population sizes. We anticipate that biodiversity of microbial eukaryotic species is underestimated and that numerous ''cryptic species'' will become discernable with the future acquisition of genomic and metagenomic sequences

Genomic and Transcriptomic Characterization of Atypical Recurrent Flank Alopecia in the Cesky Fousek.

Non-inflammatory alopecia is a frequent skin problem in dogs, causing damaged coat integrity and compromised appearance of affected individuals. In this study, we examined the Cesky Fousek breed, which displays atypical recurrent flank alopecia (aRFA) at a high frequency. This type of alopecia can be quite severe and is characterized by seasonal episodes of well demarcated alopecic areas without hyperpigmentation. The genetic component responsible for aRFA remains unknown. Thus, here we aimed to identify variants involved in aRFA using a combination of histological, genomic, and transcriptomic data. We showed that aRFA is histologically similar to recurrent flank alopecia, characterized by a lack of anagen hair follicles and the presence of severely shortened telogen or kenogen hair follicles. We performed a genome-wide association study (GWAS) using 216 dogs phenotyped for aRFA and identified associations on chromosomes 19, 8, 30, 36, and 21, highlighting 144 candidate genes, which suggests a polygenic basis for aRFA. By comparing the skin cell transcription pattern of six aRFA and five control dogs, we identified 236 strongly differentially expressed genes (DEGs). We showed that the GWAS genes associated with aRFA are often predicted to interact with DEGs, suggesting their joint contribution to the development of the disease. Together, these genes affect four major metabolic pathways connected to aRFA: collagen formation, muscle structure/contraction, lipid metabolism, and the immune system