Culpability and Modern Crime

Criminal law has developed to prohibit new forms of intrusion on the autonomy and mental processes of others. Examples include modern understandings of fraud, extortion, and bribery, which pivot on the concepts of deception, coercion, and improper influence. Sometimes core offenses develop to include similar concepts, such as when reforms in the law of sexual assault make consent almost exclusively material. Many of these projects are laudable. But progressive programs in substantive criminal law can raise difficult problems of culpability. Modern iterations of criminal offenses often draw lines using concepts involving relative mental states among persons whose conduct is embedded within socially welcome activities. With such offenses, legal institutions struggle in borderline cases to locate sufficient fault to satisfy the demands of justification for punishment. This Article demonstrates this problem through exploration of the law of each of these offenses in modern form. To address the problem, the Article turns to criminal law theory, finding a connection between culpability and the principle of notice in criminal law. Rather than its absence serving to exculpate, notice can profitably be understood to inculpate. To manage the problem of culpability in modern crime, the Article concludes, legal institutions should attend more explicitly — in both criminalization and adjudication — to the questions whether the actor was aware of the normative wrongfulness of her conduct and, if not, whether punishment is justified on a negligence level of fault. This orientation is especially advisable when further expansive moves in American criminal justice are now difficult to justify

Refining the evolutionary tree of the horse Y chromosome

The Y chromosome carries information about the demography of paternal lineages, and thus, can prove invaluable for retracing both the evolutionary trajectory of wild animals and the breeding history of domesticates. In horses, the Y chromosome shows a limited, but highly informative, sequence diversity, supporting the increasing breeding influence of Oriental lineages during the last 1500 years. Here, we augment the primary horse Y-phylogeny, which is currently mainly based on modern horse breeds of economic interest, with haplotypes (HT) segregating in remote horse populations around the world. We analyze target enriched sequencing data of 5 Mb of the Y chromosome from 76 domestic males, together with 89 whole genome sequenced domestic males and five Przewalski’s horses from previous studies. The resulting phylogeny comprises 153 HTs defined by 2966 variants and offers unprecedented resolution into the history of horse paternal lineages. It reveals the presence of a remarkable number of previously unknown haplogroups in Mongolian horses and insular populations. Phylogenetic placement of HTs retrieved from 163 archaeological specimens further indicates that most of the present-day Y-chromosomal variation evolved after the domestication process that started around 4200 years ago in the Western Eurasian steppes. Our comprehensive phylogeny significantly reduces ascertainment bias and constitutes a robust evolutionary framework for analyzing horse population dynamics and diversity

Multiple congenital ocular anomalies in Icelandic horses

<p>Abstract</p> <p>Background</p> <p>Multiple congenital ocular anomalies (MCOA) syndrome is a hereditary congenital eye defect that was first described in Silver colored Rocky Mountain horses. The mutation causing this disease is located within a defined chromosomal interval, which also contains the gene and mutation that is associated with the Silver coat color (<it>PMEL17</it>, exon 11). Horses that are homozygous for the disease-causing allele have multiple defects (MCOA-phenotype), whilst the heterozygous horses predominantly have cysts of the iris, ciliary body or retina (Cyst-phenotype). It has been argued that these ocular defects are caused by a recent mutation that is restricted to horses that are related to the Rocky Mountain Horse breed. For that reason we have examined another horse breed, the Icelandic horse, which is historically quite divergent from Rocky Mountain horses.</p> <p>Results</p> <p>We examined 24 Icelandic horses and established that the MCOA syndrome is present in this breed. Four of these horses were categorised as having the MCOA-phenotype and were genotyped as being homozygous for the <it>PMEL17 </it>mutation. The most common clinical signs included megaloglobus, iris stromal hypoplasia, abnormal pectinate ligaments, iridociliary cysts occasionally extending into the peripheral retina and cataracts. The cysts and pectinate ligament abnormalities were observed in the temporal quadrant of the eyes. Fourteen horses were heterozygous for the <it>PMEL17 </it>mutation and were characterized as having the Cyst-phenotype with cysts and occasionally curvilinear streaks in the peripheral retina. Three additional horses were genotyped as <it>PMEL17 </it>heterozygotes, but in these horses we were unable to detect cysts or other forms of anomalies.</p> <p>One eye of a severely vision-impaired 18 month-old stallion, homozygous for the <it>PMEL17 </it>mutation was examined by light microscopy. Redundant duplication of non-pigmented ciliary body epithelium, sometimes forming cysts bulging into the posterior chamber and localized areas of atrophy in the peripheral retina were seen.</p> <p>Conclusions</p> <p>The MCOA syndrome is segregating with the <it>PMEL17 </it>mutation in the Icelandic Horse population. This needs to be taken into consideration in breeding decisions and highlights the fact that MCOA syndrome is present in a breed that are more ancient and not closely related to the Rocky Mountain Horse breed.</p

A missense mutation in PMEL17 is associated with the Silver coat color in the horse

BACKGROUND: The Silver coat color, also called Silver dapple, in the horse is characterized by dilution of the black pigment in the hair. This phenotype shows an autosomal dominant inheritance. The effect of the mutation is most visible in the long hairs of the mane and tail, which are diluted to a mixture of white and gray hairs. Herein we describe the identification of the responsible gene and a missense mutation associated with the Silver phenotype. RESULTS: Segregation data on the Silver locus (Z) were obtained within one half-sib family that consisted of a heterozygous Silver colored stallion with 34 offspring and their 29 non-Silver dams. We typed 41 genetic markers well spread over the horse genome, including one single microsatellite marker (TKY284) close to the candidate gene PMEL17 on horse chromosome 6 (ECA6q23). Significant linkage was found between the Silver phenotype and TKY284 (θ = 0, z = 9.0). DNA sequencing of PMEL17 in Silver and non-Silver horses revealed a missense mutation in exon 11 changing the second amino acid in the cytoplasmic region from arginine to cysteine (Arg618Cys). This mutation showed complete association with the Silver phenotype across multiple horse breeds, and was not found among non-Silver horses with one clear exception; a chestnut colored individual that had several Silver offspring when mated to different non-Silver stallions also carried the exon 11 mutation. In total, 64 Silver horses from six breeds and 85 non-Silver horses from 14 breeds were tested for the exon 11 mutation. One additional mutation located in intron 9, only 759 bases from the missense mutation, also showed complete association with the Silver phenotype. However, as one could expect to find several non-causative mutations completely associated with the Silver mutation, we argue that the missense mutation is more likely to be causative. CONCLUSION: The present study shows that PMEL17 causes the Silver coat color in the horse and enable genetic testing for this trait

An endothelial regulatory module links blood pressure regulation with elite athletic performance

The control of transcription is crucial for homeostasis in mammals. A previous selective sweep analysis of horse racing performance revealed a 19.6 kb candidate regulatory region 50 kb downstream of the Endothelin3 (EDN3) gene. Here, the region was narrowed to a 5.5 kb span of 14 SNVs, with elite and sub-elite haplotypes analyzed for association to racing performance, blood pressure and plasma levels of EDN3 in Coldblooded trotters and Standardbreds. Comparative analysis of human HiCap data identified the span as an enhancer cluster active in endothelial cells, interacting with genes relevant to blood pressure regulation. Coldblooded trotters with the sub-elite haplotype had significantly higher blood pressure compared to horses with the elite performing haplotype during exercise. Alleles within the elite haplotype were part of the standing variation in pre-domestication horses, and have risen in frequency during the era of breed development and selection. These results advance our understanding of the molecular genetics of athletic performance and vascular traits in both horses and humans.A previous study discovered that a genomic region close to the Endothelin3 gene was associated with harness racing performance. Here, careful phenotypic documentation of athletic performance and blood pressure measurements in horses, followed by state-of-the-art genomics, allowed us to identify a 5.5 kb regulatory region located approximately 50 kb 3' of the EDN3 gene. A comparative analysis of the region using human HiCap data supported a regulatory role as, in endothelial cells, interaction was observed between the region and multiple genes relevant to blood pressure regulation and athletic performance. Long range cis-regulatory modules are critical for cooperatively controlling multiple genes located within transcriptionally active domains. We measured blood pressure in Coldblooded trotters during exercise and demonstrated that horses with two copies of the elite-performing haplotype had lower blood pressure during exercise and better racing performance results, compared to horses with two copies of the sub-elite performing haplotype. In addition, horses with the elite-performing haplotype also had higher levels of Endothelin3 in plasma. The results reported here are important for understanding the biological mechanisms behind blood pressure regulation in relation to racing performance in both horses and humans

The genetics of gaits in Icelandic horses goes beyond DMRT3, with RELN and STAU2 identified as two new candidate genes

BackgroundIn domesticated animals, many important traits are complex and regulated by a large number of genes, genetic interactions, and environmental influences. The ability of Icelandic horses to perform the gait ‘pace’ is largely influenced by a single mutation in the DMRT3 gene, but genetic modifiers likely exist. The aim of this study was to identify novel genetic factors that influence pacing ability and quality of the gait through a genome-wide association study (GWAS) and correlate new findings to previously identified quantitative trait loci (QTL) and mutations.ResultsThree hundred and seventy-two Icelandic horses were genotyped with the 670 K+ Axiom Equine Genotyping Array, of which 362 had gait scores from breeding field tests. A GWAS revealed several SNPs on Equus caballus chromosomes (ECA) 4, 9, and 20 that were associated (p ConclusionsOur findings provide valuable information about the genetic architecture of pace beyond the contribution of the DMRT3 gene and indicate genetic interactions that contribute to the complexity of this trait. Further investigation is needed to fully understand the underlying genetic factors and interactions

Equine Multiple Congenital Ocular Anomalies maps to a 4.9 megabase interval on horse chromosome 6

<p>Abstract</p> <p>Background</p> <p>Equine Multiple Congenital Ocular Anomalies (MCOA) syndrome consists of a diverse set of abnormalities predominantly localized to the frontal part of the eye. The disease is in agreement with a codominant mode of inheritance in our horse material. Animals presumed to be heterozygous for the mutant allele have cysts originating from the temporal ciliary body, peripheral retina and/or iris. In contrast, animals predicted to be homozygous for the disease-causing allele possess a wide range of multiple abnormalities, including iridociliary and/or peripheral retinal cysts, iridocorneal angle abnormalities, cornea globosa, iris hypoplasia and congenital cataracts. MCOA is most common in the Rocky Mountain horse breed where it occurs at a high frequency among Silver colored horses. The Silver coat color is associated with mutations in <it>PMEL17 </it>that resides on ECA6q23. To map the <it>MCOA </it>locus we analyzed 11 genetic markers on ECA6q and herein describe a chromosome interval for the <it>MCOA </it>locus.</p> <p>Results</p> <p>We performed linkage analysis within 17 paternal half-sib families of the Rocky Mountain horse breed. More than half of the 131 offspring had the Cyst phenotype and about one third had MCOA. Segregation data were obtained by genotyping 10 microsatellite markers most of which are positioned on ECA6q22-23, as well as the missense mutation for the Silver phenotype in <it>PMEL17</it>. Significant linkage was found between the <it>MCOA </it>locus and eight of the genetic markers, where marker <it>UPP5 </it>(Theta = 0, z = 12.3), <it>PMEL17ex11 </it>(Theta = 0, z = 19.0) and <it>UPP6 </it>(Theta = 0, z = 17.5) showed complete linkage with the <it>MCOA </it>locus. DNA sequencing of <it>PMEL17 </it>in affected and healthy control individuals did not reveal any additional mutations than the two mutations associated with the Silver coat color.</p> <p>Conclusion</p> <p>The <it>MCOA </it>locus can with high confidence be positioned within a 4.9 megabase (Mb) interval on ECA6q. The genotype data on <it>UPP5</it>, <it>PMEL17ex11 </it>and <it>UPP6 </it>strongly support the hypothesis that horses with the Cyst phenotype are heterozygous for the mutant allele and that horses with the MCOA phenotype are homozygous for the mutant allele.</p

Characterization of a Homozygous Deletion of Steroid Hormone Biosynthesis Genes in Horse Chromosome 29 as a Risk Factor for Disorders of Sex Development and Reproduction

Disorders of sex development (DSD) and reproduction are not uncommon among horses, though knowledge about their molecular causes is sparse. Here we characterized a 200 kb homozygous deletion in chromosome 29 at 29.7-29.9 Mb. The region contains AKR1C genes which function as ketosteroid reductases in steroid hormone biosynthesis, including androgens and estrogens. Mutations in AKR1C genes are associated with human DSDs. Deletion boundaries, sequence properties and gene content were studied by PCR and whole genome sequencing of select deletion homozygotes and control animals. Deletion analysis by PCR in 940 horses, including 622 with DSDs and reproductive problems and 318 phenotypically normal controls, detected 67 deletion homozygotes of which 79% were developmentally or reproductively abnormal. Altogether, 8-9% of all abnormal horses were homozygous for the deletion, with the highest incidence (9.4%) among cryptorchids. The deletion was found in 4% of our phenotypically normal cohort, 1% of global warmblood horses and ponies, and 7% of draught breeds of general horse population as retrieved from published data. Based on the abnormal phenotype of the carriers, the functionally relevant gene content, and the low incidence in general population, we consider the deletion in chromosome 29 as a risk factor for equine DSDs and reproductive disorders

An intronic copy number variation in Syntaxin 17 determines speed of greying and melanoma incidence in Grey horses.

The Greying with age phenotype in horses involves loss of hair pigmentation whereas skin pigmentation is not reduced, and a predisposition to melanoma. The causal mutation was initially reported as a duplication of a 4.6 kb intronic sequence in Syntaxin 17. The speed of greying varies considerably among Grey horses. Here we demonstrate the presence of two different Grey alleles, G2 carrying two tandem copies of the duplicated sequence and G3 carrying three. The latter is by far the most common allele, probably due to strong selection for the striking white phenotype. Our results reveal a remarkable dosage effect where the G3 allele is associated with fast greying and high incidence of melanoma whereas G2 is associated with slow greying and low incidence of melanoma. The copy number expansion transforms a weak enhancer to a strong melanocyte-specific enhancer that underlies hair greying (G2 and G3) and a drastically elevated risk of melanoma (G3 only). Our direct pedigree-based observation of the origin of a G2 allele from a G3 allele by copy number contraction demonstrates the dynamic evolution of this locus and provides the ultimate evidence for causality of the copy number variation of the 4.6 kb intronic sequence