Significant Genetic Component Research Articles

The dyslexia susceptibility KIAA0319 gene shows a specific expression pattern during zebrafish development supporting a role beyond neuronal migration.

Dyslexia is a common neurodevelopmental disorder caused by a significant genetic component. The KIAA0319 gene is one of the most robust dyslexia susceptibility factors but its function remains poorly understood. Initial RNA‐interference studies in rats suggested a role in neuronal migration whereas subsequent work with double knock‐out mouse models for both Kiaa0319 and its paralogue Kiaa0319‐like reported effects in the auditory system but not in neuronal migration. To further understand the role of KIAA0319 during neurodevelopment, we carried out an expression study of its zebrafish orthologue at different embryonic stages. We used different approaches including RNAscope in situ hybridization combined with light‐sheet microscopy. The results show particularly high expression during the first few hours of development. Later, expression becomes localized in well‐defined structures. In addition to high expression in the brain, we report for the first time expression in the eyes and the notochord. Surprisingly, kiaa0319‐like, which generally shows a similar expression pattern to kiaa0319, was not expressed in the notochord suggesting a distinct role for kiaa0319 in this structure. This observation was supported by the identification of notochord enhancers enriched upstream of the KIAA0319 transcription start site, in both zebrafish and humans. This study supports a developmental role for KIAA0319 in the brain as well as in other developing structures, particularly in the notochord which, is key for establishing body patterning in vertebrates.

New phylogeographic insights support the distinctiveness and conservation value of the little-known Greek roe deer populations

Despite their conservation status as Vulnerable and the need for targeted management actions, very little is actually known about the genetic diversity and phylogeography of the remnant populations of the roe deer (Capreolus capreolus) in Greece. In order to investigate these aspects we collected samples from nine locations in Greece and retrieved 80 sequences (834–836bp) for a fragment of the mtDNA control region. Analysis revealed high overall haplotype diversity, low nucleotide diversity and significant population structuring with site-specific haplotypes. In order to assign Greek roe deer haplotypes to previously identified haplogroups, we integrated our data with available roe deer sequences from across Europe. The analysis of the combined dataset showed that most of the haplotypes retrieved from Greek populations are novel, geographically confined and belong exclusively to the "Eastern" phylogeographic group. The indigenous populations of Greece are genetically distinct from other Balkan populations, which have a significant genetic component from the "Central" group. The Greek populations carry part of the ancestral gene pool of Late Pleistocene Balkan refugium, which has not contributed to the postglacial expansion of the species. The current phylogeographic pattern of roe deer in Greece seems to be the result of genetic drift due to habitat fragmentation and population decline. The genetic integrity of Greek roe deer should be maintained by avoiding uncontrolled reintroductions or translocations that could lead to admixture with allochthonous roe deer.

Association of Chemerin rs17173608 and Vaspin rs2236242 Polymorphisms with Type Two Diabetes Mellitus and its Impact on their Corresponding Serum Levels in Egyptian Population

Type-2 diabetes mellitus (T2DM) is an endocrine disease having a significant genetic component.

Genetic predictors of the development and recurrence of Graves' disease.

Graves' disease affects approximately 3 % of women and 0.5 % of men. The first-choice therapy is based on the administration of thyrostatic drugs. However, approximately half of patients relapse within two years of discontinuation. These patients must then decide whether to re-initiate thyrostatics, which may have serious side effects, or to undergo surgery or radioiodine treatment. Familial forms of Graves' disease indicate a significant genetic component, with twin studies demonstrating a contribution of genetic factors up to 70-80 %. The autoimmune nature of the disease involves the human leukocyte antigen (HLA) complex, which has a decisive impact on each individual's immune response. Within HLA, some variants of the DRB1, DQA1 and DQB1 genes appear to be possible predictors of the development and recurrence of Graves' disease. Outside the HLA region, many variants of immunocompetent genes have also been identified as potential Graves' disease predictors. Apart from the immune system, some thyroid-specific genes have been described in relation to the disease. Here, we present current knowledge regarding the genetic components involved in the development and recurrence of Graves' disease. Further, we present original pilot results from a cohort of Czech Graves' disease patients regarding the HLA variants.

MIgGGly (mouse IgG glycosylation analysis) - a high-throughput method for studying Fc-linked IgG N-glycosylation in mice with nanoUPLC-ESI-MS

Immunoglobulin G (IgG) N-glycosylation is crucial for its effector functions. It is a complex trait, and large sample sets are needed to discover multiple genetic factors that underlie it. While in humans such high-throughput studies of IgG N-glycans became usual, only one has been carried out in mice. Here we describe and validate a method for the relative quantification of IgG Fc-linked N-glycans in a subclass-specific manner using nano-reverse phase liquid chromatography coupled with mass-spectrometry (nanoRP-LC-MS) applied to murine IgG. High-throughput data processing is ensured by the LaCyTools software. We have shown that IgG isolation procedure is the main source of technical variation in the current protocol. The major glycoforms were quantified reliably with coefficients of variation below 6% for all the analytes with relative abundances above 5%. We have applied our method to a sample set of 3 inbred strains: BALB/c, C57BL/6 and C3H and observed differences in subclass-specific and strain-specific N-glycosylation of IgG, suggesting a significant genetic component in the regulation of Fc-linked IgG N-glycosylation.

Whole exome sequencing in Finnish families identifies new candidate genes for osteoarthritis.

IntroductionOsteoarthritis (OA) is the most common degenerative joint disease and one of the major causes of disability worldwide. It is a multifactorial disorder with a significant genetic component. The heritability of OA has been estimated to be 60% for hip OA and 39% for knee OA. Genetic factors behind OA are still largely unknown. Studying families with strong history of OA, facilitates examining the co-segregation of genetic variation and OA. The aim of this study was to identify new, rare genetic factors and novel candidate genes for OA.MethodsEight patients from three Finnish families with hip and knee OA were studied using whole exome sequencing. We focused on rare exonic variants with predicted pathogenicity and variants located in active promoter or strong enhancer regions. Expression of identified candidate genes were studied in bone and cartilage tissues and the observed variants were investigated using bioinformatic analyses.ResultsTwo rare variants co-segregated with OA in two families. In Family 8 a missense variant (c.628C>G, p.Arg210Gly) was observed in the OLIG3 gene that encodes a transcription factor known to be associated with rheumatoid arthritis and inflammatory polyarthritis. The Arg210Gly variant was estimated to be pathogenic by Polyphen-2 and Mutation taster and the locus is conserved among mammals. In Family 12 the observed variant (c.-127G>T) was located in the transcription start site of the FIP1L1 gene. FIP1L1 participates in the regulation of polyadenylation. The c.-127G>T is located in the transcription start site and may alter the DNA-binding of transcription factors. Both, OLIG3 and FIP1L1 were observed in human bone and cartilage.ConclusionThe identified variants revealed novel candidate genes for OA. OLIG3 and FIP1L1 have specific roles in transcription and may effect expression of other genes. Identified variants in these genes may thus have a role in the regulatory events leading to OA.

Abstract B51: Genetic etiology of ER low/HER2- breast tumors

Abstract Background: In 2010, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) issued guidelines that tumors with >1% positively staining cells should be considered ER positive. Numerous studies have demonstrated that tumors with 1-9% ER-positive cells (low staining) represent ER-negative intrinsic subtypes with outcomes similar to ER-negative tumors. Given the similarities between low-staining tumors and TNBC, we investigated whether low-staining tumors share a germline etiology with TNBC. Methods: The Clinical Breast Care Project was queried to identify all tumors with percent ER-positive cells and HER2 data available. Genomic DNA was isolated from available blood samples from patients with HER2-negative tumors with either negative (TNBC) or low-staining (1-9%) ER status. Targeted sequencing was performed using the Illumina TruSight Cancer panel. Pathogenic mutations were identified using VariantStudio and classified as pathogenic, likely pathogenic, uncertain significance (VUS), likely benign, or benign using ClinVar. Results: Low ER/HER2- tumors and TNBC represented 50 (2.7%) and 223 (12.2%) of the 1819 tumors in the database. Patients with low-staining tumors and TNBC did not differ significantly by age at diagnosis, ethnicity, family history, tumor stage, size, grade, or survival, and all the low ER/HER2- tumors with gene expression data available (n=17) were basal-like. Four (9%) of the women with low ER/HER2- tumors had pathogenic mutations in BRCA1 or BRCA2; an additional 4 (9%) had pathogenic mutations in the cancer predisposition genes BLM (n=2), FH (n=1), and MUTYH (n=1). Seven others had VUS in BRCA2, BRIP1, CHEK2, MSH2, MSH6, and SMAD4. Frequency of pathogenic mutations did not differ significantly (P=0.139) between low-staining tumors (18%) and TNBC (13%). Discussion: Low ER/HER2- tumors share similar clinicopathologic characteristics and outcomes with TNBC and have a significant genetic component, with 9% of patients having BRCA1 or BRCA2 germline mutations and an additional 9% having mutations in other cancer-predisposing genes. These data suggest that while ASCO/CAP guidelines define low ER tumors as ER positive, women with low ER/HER2- tumors may benefit from the clinical care and genetic testing provided to women with TNBC. The views expressed in this article are those of the author and do not reflect the official policy of the Department of Army/Navy/Air Force, the Department of Defense, or the U.S. Government. Citation Format: Leann A. Lovejoy, Craig D. Shriver, Rachel E. Ellsworth. Genetic etiology of ER low/HER2- breast tumors [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B51.

Genetic parameters of the upper-jaw abnormalities in Gilthead seabream Sparus aurata

The development of skeletal abnormalities is a frequent problem of quality in finfish hatcheries, resulting from unfavourable environmental conditions, often under the control of genetic background. In the present study, the heritability of jaw abnormalities in Gilthead seabream was estimated at the end of the larval rearing phase (39 dph, days post hatching). All larvae came from eggs obtained by mass spontaneous spawn of a common brood stock of a commercial hatchery. Skeletal abnormalities were examined after the double staining of the larvae for bone and cartilage. Macroscopically, three abnormality types were recorded in the studied larvae, pugheadness (Pug, 6.7%), lateral displacement of the upper jaw (LdUj, 2.3%) and crossbite (Crbt, 0.9%). The microscopic examination of the specimens revealed the frequent presence of internal abnormalities (e.g. fusions, size reductions, bending) which had not any clear effect on the external morphology of the fish (silent abnormalities). Each stained larva was genotyped and parentally assigned. Heritability estimates were insignificant for the three types of gross, externally-visible, abnormalities of the jaws (Pug, LdUj, Crbt). On the contrary, significant heritabilities were estimated for the internal abnormalities which are associated to LdUj (e.g. fusion of maxillaries with pre-maxillaries, 0.22 ± 0.06). Interestingly, the consideration of all the abnormalities of the upper jaw as a uniform trait resulted to the estimation of insignificant heritabilities, and therefore to the masking of the significant genetic component of the LdUj abnormality. Results are discussed in respect to their potential value for the selective breeding programs of Gilthead seabream.

Abstract 3276: Whole exome sequencing identifies significantly linked regions on multiple chromosomes in families with a history of lung cancer

Abstract Lung cancer is the deadliest cancer in the United States, contributing approximately 25% of all cancer deaths. Lung cancer risk is well-documented to increase in response to environmental factors, particularly tobacco smoking. As one might expect for a complex trait, there is also a significant genetic risk component in lung cancer, though it is not very well studied. We obtained whole exome sequencing (WES) genotype data from Washington University on 204 subjects from 25 extended families. These individuals were recruited from families with a history of lung cancer and previous analyses showed these 25 families be informative. The purpose of this study is to identify potential risk variants for lung cancer by performing genetic linkage analysis. Quality control was performed on the sequence data, filtering on parameters such as depth (less than 10), genotype quality (less than 10), missingness, and Mendelian inconsistencies. Identity-by-descent (IBD) values were also calculated to verify correct familial relationships. Quality control procedures left approximately 500,000 SNVs and indels for analysis. We performed two-point parametric linkage analysis assuming an autosomal dominant mode of inheritance with a disease allele frequency of 1%, a 10% penetrance for carriers and a 1% penetrance for non-carriers. Two discrete sets of linkage analyses were performed. One was a variant-based analysis, which evaluated linkage between the phenotype and individual SNVs or indels. The second was gene-based analysis, which created a multi-allelic pseudomarker corresponding to a gene from haplotypes of rare variants (minor allele frequency <= 0.01) located within that particular gene. Two-point linkage analysis was then performed on the pseudomarkers. While the variant-based analysis did not identify any genome-wide significant results, several were identified by the gene-based analysis. The highest HLOD scores were both greater than the genome-wide significance level of HLOD = 3.3 and were located on two regions of chromosome 1q: 1q42.13-43 and 1q21.2-21.1. In both regions, the significant HLOD scores clustered around known cancer genes. At the 1q42.13-43 region, signals centered on the cancer-implicated genes OBSCN and RYR2 (also a known mesothelioma gene), while at 1q21.2-21.1 the signals centered on five genes in the neuroblastoma breakpoint family (NBPF) genes, a cluster of recently duplicated genes. NBPF genes have previously been implicated in a variety of different cancers including lung cancer. We are currently performing additional analyses to corroborate the significant results, as well as examining the individual families to determine which families are driving the significant signals. Citation Format: Anthony M. Musolf, Haiming Sun, Bilal A. Moiz, Diptasri Mandal, Mariza de Andrade, Colette Gaba, Ping Yang, Yafang Li, Ming You, Elena Y. Kupert, Marshall W. Anderson, Ann G. Schwartz, Susan M. Pinney, Christopher I. Amos, Joan E. Bailey-Wilson. Whole exome sequencing identifies significantly linked regions on multiple chromosomes in families with a history of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3276.

Reviewing the Fault Line - Monoamine Oxidase-A Genotype Evidence and the Criminal Law.

Recent advances in behavioural genetics suggest that there is a significant genetic component associated with the risk of criminality. This paper focusses on the MAOA gene, a gene which has been linked to aggressive and antisocial behaviour, and analyses what role such genetic evidence should play in the criminal law. In particular, this paper will explore the role of genetic predisposition evidence during sentencing, and will reflect on some associated ethical concerns, and the dangers of misinterpretation. This research highlights that genetic predisposition evidence may be relevant in sentencing. However, there is a potential for the evidence to be construed as both an aggravating and mitigating factor. This is a field in which we must proceed with care. Science has a huge potential to assist decision makers, improve the criminal process and allow justice to be done. However, the other side of the coin is misinterpretation and abuse.

Glomerular Endothelial Cell Stress and Cross-Talk With Podocytes in Early [corrected] Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is one of the major causes of morbidity and mortality in diabetic patients and also the leading single cause of end-stage renal disease in the United States. A large proportion of diabetic patients develop DKD and others don’t, even with comparable blood glucose levels, indicating a significant genetic component of disease susceptibility. The glomerulus is the primary site of diabetic injury in the kidney, glomerular hypertrophy and podocyte depletion are glomerular hallmarks of progressive DKD, and the degree of podocyte loss correlates with severity of the disease. We know that chronic hyperglycemia contributes to both microvascular and macrovascular complications, as well as podocyte injury. We are beginning to understand the role of glomerular endothelial injury, as well as the involvement of reactive oxygen species and mitochondrial stress, which play a direct role in DKD and in other diabetic complications. There is, however, a gap in our knowledge that links genetic susceptibility to early molecular mechanisms and proteinuria in DKD. Emerging research that explores glomerular cell’s specific responses to diabetes and cell cross-talk will provide mechanistic clues that underlie DKD and provide novel avenues for therapeutic intervention.

Diagnostic efficacy and new variants in isolated and complex autism spectrum disorder using molecular karyotyping.

Autism spectrum disorder (ASD) is a group of the neurodevelopment disorders presenting as an isolated ASD or more complex forms, where a broader clinical phenotype comprised of developmental delay and intellectual disability is present. Both the isolated and complex forms have a significant causal genetic component and submicroscopic genomic copy number variations (CNV) are the most common identifiable genetic factor in these patients. The data on microarray testing in ASD cohorts are still accumulating and novel loci are often identified; therefore, we aimed to evaluate the diagnostic efficacy of the method and the relevance of implementing it into routine genetic testing in ASD patients. A genome-wide CNV analysis using the Agilent microarrays was performed in a group of 150 individuals with an isolated or complex ASD. Altogether, 11 (7.3%) pathogenic CNVs and 15 (10.0%) variants of unknown significance (VOUS) were identified, with the highest proportion of pathogenic CNVs in the subgroup of the complex ASD patients (14.3%). An interesting case of previously unreported partial UPF3B gene deletion was identified among the pathogenic CNVs. Among the CNVs with unknown significance, four VOUS involved genes with possible correlation to ASD, namely genes SNTG2, PARK2, CADPS2 and NLGN4X. The diagnostic efficacy of aCGH in our cohort was comparable with those of the previously reported and identified an important proportion of genetic ASD cases. Despite the continuum of published studies on the CNV testing in ASD cohorts, a considerable number of VOUS CNVs is still being identified, namely 10.0% in our study.

Genetic factors have a major effect on growth, number of vertebrae and otolith shape in Atlantic herring (Clupea harengus).

Atlantic herring, Clupea harengus, have complex population structures. Mixing of populations is known, but the extent of connectivity is still unclear. Phenotypic plasticity results in divergent phenotypes in response to environmental factors. A marked salinity gradient occurs from Atlantic Ocean (salinity 35) into the Baltic Sea (salinity range 2–12). Herring from both habitats display phenotypic and genetic variability. To explore how genetic factors and salinity influence phenotypic traits like growth, number of vertebrae and otolith shape an experimental population consisting of Atlantic purebreds and Atlantic/Baltic F1 hybrids were incubated and co-reared at two different salinities, 16 and 35, for three years. The F1-generation was repeatedly sampled to evaluate temporal variation. A von Bertalanffy growth model indicated that reared Atlantic purebreds had a higher maximum length (26.2 cm) than Atlantic/Baltic hybrids (24.8 cm) at salinity 35, but not at salinity 16 (25.0 and 24.8 cm, respectively). In contrast, Atlantic/Baltic hybrids achieved larger size-at-age than the wild caught Baltic parental group. Mean vertebral counts and otolith aspect ratios were higher for reared Atlantic purebreds than Atlantic/Baltic hybrids, consistent with the differences between parental groups. There were no significant differences in vertebral counts and otolith aspect ratios between herring with the same genotype but raised in different salinities. A Canonical Analysis of Principal Coordinates was applied to analyze the variation in wavelet coefficients that described otolith shape. The first discriminating axis identified the differences between Atlantic purebreds and Atlantic/Baltic hybrids, while the second axis represented salinity differences. Assigning otoliths based on genetic groups (Atlantic purebreds vs. Atlantic/Baltic hybrids) yielded higher classification success (~90%) than based on salinities (16 vs. 35; ~60%). Our results demonstrate that otolith shape and vertebral counts have a significant genetic component and are therefore useful for studies on population dynamics and connectivity.

Association of RAGE gene polymorphism with Type-2 diabetes mellitus in local population.

Objectives:Type-2 diabetes mellitus (T2DM) is an endocrine disease having a significant genetic component. Polymorphisms of many genes may affect hereditary vulnerability of the disease that is characterized by insulin resistance and islet disorder. As the genetic basis of T2DM can vary between ethnic groups, it is important to investigate the genetic link of T2DM in Pakistani populace. This study was aimed to assess the association of receptor for advanced glycation end product (RAGE) gene polymorphism (-429T>C) with Type-2 diabetes mellitus within local populace.Methods:Genomic DNA was isolated by following kit protocol. Genotyping of the RAGE gene was studied by PCR-RFLP on genomic DNA. All research work was done in molecular biochemistry laboratory (MBL), University of Agriculture Faisalabad and Postgraduate Laboratory, The University of Faisalabad, Pakistan from December 2016 to July 2017.Results:We found distribution of -429T>C genotypes between T2DM and healthy controls as 24.7% (tt), 24.7% (Tt) and 50.7% (TT). The outcomes were highly compatible statistically.Conclusion:The techniques of PCR and RFLP when performed simultaneously can be helpful in tracing vital information regarding polymorphism of AGE receptor.

Autizam i MMR vakcina

Autism is a complex neurological developmental disorder with wide range of symptoms. Among them, poor social interaction, limited and repeated behavioral patterns are the most important for diagnosing the disorder. The prevalence of autism is rising constantly. One of the theories drawing the greatest public attention for a long time is a possible association between MMR vaccine and risk of autism. The first study aimed to investigate this association is the one conducted in 1998. As the results supported the theory that MMR vaccine increased the risk of autism, MMR immunization coverage decreased dramatically which further led to measles outbreaks, even in those countries where the disease was almost eradicated. Soon after that publication, new studies denying any association between MMR vaccine and risk of autism were published. Among them, systematic review published in 2012, including 57 epidemiological studies with 14.700.000 children is particularly important. Although the etiology of autism is not completely clarified, there are strong evidence on the presence of neurobiological changes with significant genetic component underlying the etiology. According to recent literature data, morphological changes in brain of children age 6 to 12 months, that is, before the administration of MMR vaccine, precede clinical symptoms of autism.

Failure of eruption of permanent tooth

Primary failure of eruption (PFE) is a rare condition that can lead to posterior open bites. It is difficult to diagnose and difficult to treat. PFE appears to be a condition that predominantly affects the molar dentition. The increased frequency of hypodontia in affected individuals and common findings of a family history regarding tooth eruption problems suggests a significant genetic component to the etiology of this rare condition.

Obesity and obesogenic growth are both highly heritable and modified by diet in a nonhuman primate model, the African green monkey (Chlorocebus aethiops sabaeus)

Objective:In humans, the ontogeny of obesity throughout the life course and the genetics underlying it has been historically difficult to study. We compared, in a non-human primate model, the lifelong growth trajectories of obese and non-obese adults to assess the heritability of and map potential genomic regions implicated in growth and obesity.Study population:A total of 905 African green monkeys, or vervets (Chlorocebus aethiops sabaeus) (472 females, 433 males) from a pedigreed captive colony.Methods:We measured fasted body weight (BW), crown-to-rump length (CRL), body-mass index (BMI) and waist circumference (WC) from 2000 to 2015. We used a longitudinal clustering algorithm to detect obesogenic growth, and logistic growth curves implemented in nonlinear mixed effects models to estimate three growth parameters. We used maximum likelihood variance decomposition methods to estimate the genetic contributions to obesity-related traits and growth parameters, including a test for the effects of a calorie-restricted dietary intervention. We used multipoint linkage analysis to map implicated genomic regions.Results:All measurements were significantly influenced by sex, and with the exception of WC, also influenced by maternal and post-natal diet. Chronic obesity outcomes were significantly associated with a pattern of extended growth duration with slow growth rates for BW. After accounting for environmental influences, all measurements were found to have a significant genetic component to variability. Linkage analysis revealed several regions suggested to be linked to obesity-related traits that are also implicated in human obesity and metabolic disorders.Conclusions:As in humans, growth patterns in vervets have a significant impact on adult obesity and are largely under genetic control with some evidence for maternal and dietary programming. These results largely mirror findings from human research, but reflect shorter developmental periods, suggesting that the vervet offers a strong genetic model for elucidating the ontogeny of human obesity.

Genetic Variance in Homophobia: Evidence from Self- and Peer Reports.

The present twin study combined self- and peer assessments of twins' general homophobia targeting gay men in order to replicate previous behavior genetic findings across different rater perspectives and to disentangle self-rater-specific variance from common variance in self- and peer-reported homophobia (i.e., rater-consistent variance). We hypothesized rater-consistent variance in homophobia to be attributable to genetic and nonshared environmental effects, and self-rater-specific variance to be partially accounted for by genetic influences. A sample of 869 twins and 1329 peer raters completed a seven item scale containing cognitive, affective, and discriminatory homophobic tendencies. After correction for age and sex differences, we found most of the genetic contributions (62%) and significant nonshared environmental contributions (16%) to individual differences in self-reports on homophobia to be also reflected in peer-reported homophobia. A significant genetic component, however, was self-report-specific (38%), suggesting that self-assessments alone produce inflated heritability estimates to some degree. Different explanations are discussed.

Genetics of Alzheimer's Disease: An Update

It is clear that late-onset Alzheimer's disease (AD), the most common form of dementia in western societies, has a significant genetic component. The recent technological advances in high-throughput genome technologies have enabled the identification of more than 20 novel susceptibility loci. These findings have significantly advanced the understanding of the molecular mechanisms potentially underlying AD etiology, and have therefore provided valuable information for the development of targets for genetic testing, prevention and treatment. This article reviews these recent findings in AD genomics and discusses their implications for understanding the molecular underpinnings of the disease.

The MeLiM Minipig: An Original Spontaneous Model to Explore Cutaneous Melanoma Genetic Basis.

Melanoma is the deadliest skin cancer and is a major public health concern with a growing incidence worldwide. As for other complex diseases, animal models are needed in order to better understand the mechanisms leading to pathology, identify potential biomarkers to be used in the clinics, and eventually molecular targets for therapeutic solutions. Cutaneous melanoma, arising from skin melanocytes, is mainly caused by environmental factors such as UV radiation; however a significant genetic component participates in the etiology of the disease. The pig is a recognized model for spontaneous development of melanoma with features similar to the human ones, followed by a complete regression and a vitiligo-like depigmentation. Three different pig models (MeLiM, Sinclair, and MMS-Troll) have been maintained through the last decades, and different genetic studies have evidenced a complex inheritance of the disease. As in humans, pigmentation seems to play a prominent role, notably through MC1R and MITF signaling. Conversely, cell cycle genes as CDKN2A and CDK4 have been excluded as predisposing for melanoma in MeLiM. So far, only sparse studies have focused on somatic changes occurring during oncogenesis, and have revealed major cytological changes and a potential dysfunction of the telomere maintenance system. Finally, the spontaneous tumor progression and regression occurring in these models could shed light on the interplay between endogenous retroviruses, melanomagenesis, and adaptive immune response.