Human Mendelian Diseases Research Articles

TAD boundary deletion causes PITX2-related cardiac electrical and structural defects

While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.

Increased homozygosity due to endogamy results in fitness consequences in a human population.

Recessive alleles have been shown to directly affect both human Mendelian disease phenotypes and complex traits. Pedigree studies also suggest that consanguinity results in increased childhood mortality and adverse health phenotypes, presumably through penetrance of recessive mutations. Here, we test whether the accumulation of homozygous, recessive alleles decreases reproductive success in a human population. We address this question among the Namibian Himba, an endogamous agro-pastoralist population, who until very recently practiced natural fertility. Using a sample of 681 individuals, we show that Himba exhibit elevated levels of "inbreeding," calculated as the fraction of the genome in runs of homozygosity (FROH). Many individuals contain multiple long segments of ROH in their genomes, indicating that their parents had high kinship coefficients. However, we do not find evidence that this is explained by first-cousin consanguinity, despite a reported social preference for cross-cousin marriages. Rather, we show that elevated haplotype sharing in the Himba is due to a bottleneck, likely in the past 60 generations. We test whether increased recessive mutation load results in observed fitness consequences by assessing the effect of FROH on completed fertility in a cohort of postreproductive women (n = 69). We find that higher FROH is significantly associated with lower fertility. Our data suggest a multilocus genetic effect on fitness driven by the expression of deleterious recessive alleles, especially those in long ROH. However, these effects are not the result of consanguinity but rather elevated background identity by descent.

Transcriptome - wide bioinformatics analysis of the binding sites of RNA - binding proteins and their putative role in mendelian diseases

Background: Post-transcriptional regulation is the control of gene expression at the RNA level. After produced, the stability and distribution of the different transcripts are regulated by means of RNA-binding proteins (RBPs). Mutations in RNA-binding proteins can cause Mendelian diseases - prominently neuromuscular disorders and cancers. This study determines the interaction between RBPs and target-RNA complexes from public data of the ENCODE project and identifies mutations associated with Mendelian diseases that could disrupt the RBP-RNA interactions. Materials and methods: we performed a transcriptome - wide bioinformatics prediction of the binding sites of RBPs in the human transcriptome from public data of the ENCODE project. Results: The majority (54%) of pathogenic mutation putatively affecting the binding sites of RBPs are located in protein - coding genes and are mainly classified as loss - of - function mutations. Mutations located in the binding sites of RBPs related to RNA processing. For 13 diseases, Familial hypercholesterolemia is the most significant disease with about 40% of mutations in ClinVar database located into the binding sites of RBPs (p=2.3e-65), but congenital hypogonadotropic hypogonadism is the disease with the highest percentage of mutations affecting the binding sites of RBPs (98%, p=2.7e-25). The RBPs most involved in human Mendelian diseases by binding sites-disrupting mutations are YBX3, AQR and PRPF8. Conclusions: A large number of Mendelian diseases are potentially mediated by disease - causing variants that potentially disrupt the binding sites of RBPs. This will provide insight sharper on post - transcriptional mechanisms. Besides, it is useful to know the role of protein - RNA interactome networks in pathologies, thereby serving the treatment of diseases. Key words: bioinformatics analysis, ENCODE project, ClinVar, RNA-binding proteins, Mendelian diseases

The phers R package: using phenotype risk scores based on electronic health records to study Mendelian disease and rare genetic variants.

Electronic health record (EHR) data linked to DNA biobanks are a valuable resource for understanding the phenotypic effects of human genetic variation. We previously developed the phenotype risk score (PheRS) as an approach to quantify the extent to which a patient's clinical features resemble a given Mendelian disease. Using PheRS, we have uncovered novel associations between Mendelian disease-like phenotypes and rare genetic variants, and identified patients who may have undiagnosed Mendelian disease. Although the PheRS approach is conceptually simple, it involves multiple mapping steps and was previously only available as custom scripts, limiting the approach's usability. Thus, we developed the phers R package, a complete and user-friendly set of functions and maps for performing a PheRS-based analysis on linked clinical and genetic data. The package includes up-to-date maps between EHR-based phenotypes (i.e. ICD codes and phecodes), human phenotype ontology terms and Mendelian diseases. Starting with occurrences of ICD codes, the package enables the user to calculate PheRSs, validate the scores using case-control analyses, and perform genetic association analyses. By increasing PheRS's transparency and usability, the phers R package will help improve our understanding of the relationships between rare genetic variants and clinically meaningful human phenotypes. The phers R package is free and open-source and available on CRAN and at https://phers.hugheylab.org. Supplementary data are available at Bioinformatics online.

Decreased recent adaptation at human mendelian disease genes as a possible consequence of interference between advantageous and deleterious variants

Advances in genome sequencing have improved our understanding of the genetic basis of human diseases, and thousands of human genes have been associated with different diseases. Recent genomic adaptation at disease genes has not been well characterized. Here, we compare the rate of strong recent adaptation in the form of selective sweeps between mendelian, non-infectious disease genes and non-disease genes across distinct human populations from the 1000 Genomes Project. We find that mendelian disease genes have experienced far less selective sweeps compared to non-disease genes especially in Africa. Investigating further the possible causes of the sweep deficit at disease genes, we find that this deficit is very strong at disease genes with both low recombination rates and with high numbers of associated disease variants, but is almost non-existent at disease genes with higher recombination rates or lower numbers of associated disease variants. Because segregating recessive deleterious variants have the ability to interfere with adaptive ones, these observations strongly suggest that adaptation has been slowed down by the presence of interfering recessive deleterious variants at disease genes. These results suggest that disease genes suffer from a transient inability to adapt as fast as the rest of the genome.

Zebrafish modeling mimics developmental phenotype of patients with RAPGEF1 mutation.

RAPGEF1 is a guanine nucleotide exchange factor responsible for transmitting extracellular signals to the Ras family of GTPase located at the inside of membrane. Here, we report for the first time a homozygous mutation of RAPGEF1 in a consanguineous family with two siblings affected by neuropsychiatric disorder. To confirm the correlation of the mutation and the phenotype, we utilized in silico analysis and established a zebrafish model. Survival rate was reduced in the rapgef1a-knockdown model, and the zebrafish showed global morphological abnormalities, particularly of brain and blood vessels. Co-application of human RAPGEF1 wildtype mRNA effectively rescued the abnormal phenotype, while that of RAPGEF1 mRNA carrying the human mutation did not. This work is the first report of a human Mendelian disease associated with RAPGEF1 and the first report of a zebrafish model built for this gene. The phenotype of zebrafish model provides further evidence that defective RAPGEF1 may lead to global developmental delay in human patients.

Intestinal immunoregulation: lessons from human mendelian diseases.

The mechanisms that maintain intestinal homeostasis despite constant exposure of the gut surface to multiple environmental antigens and to billions of microbes have been scrutinized over the past 20 years with the goals to gain basic knowledge, but also to elucidate the pathogenesis of inflammatory bowel diseases (IBD) and to identify therapeutic targets for these severe diseases. Considerable insight has been obtained from studies based on gene inactivation in mice as well as from genome wide screens for genetic variants predisposing to human IBD. These studies are, however, not sufficient to delineate which pathways play key nonredundant role in the human intestinal barrier and to hierarchize their respective contribution. Here, we intend to illustrate how such insight can be derived from the study of human Mendelian diseases, in which severe intestinal pathology results from single gene defects that impair epithelial and or hematopoietic immune cell functions. We suggest that these diseases offer the unique opportunity to study in depth the pathogenic mechanisms leading to perturbation of intestinal homeostasis in humans. Furthermore, molecular dissection of monogenic intestinal diseases highlights key pathways that might be druggable and therapeutically targeted in common forms of IBD.

Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator.

Long non-coding RNAs (lncRNAs) can be important components in gene-regulatory networks1, but the exact nature and extent of their involvement in human Mendelian disease is largely unknown. Here we show that genetic ablation of a lncRNA locus on human chromosome 2 causes a severe congenital limb malformation. We identified homozygous 27-63-kilobase deletions located 300kilobases upstream of the engrailed-1 gene (EN1) in patients with a complex limb malformation featuring mesomelic shortening, syndactyly and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of En1 expression in the limb and a double dorsal-limb phenotype that recapitulates the human disease phenotype. Genome-wide transcriptome analysis in the developing mouse limb revealed a four-exon-long non-coding transcript within the deleted region, which we named Maenli. Functional dissection of the Maenli locus showed that its transcriptional activity is required for limb-specific En1 activation in cis, thereby fine-tuning the gene-regulatory networks controlling dorso-ventral polarity in the developing limb bud. Its loss results in the En1-related dorsal ventral limb phenotype, a subset of the full En1-associated phenotype. Our findings demonstrate that mutations involving lncRNA loci can result in human Mendelian disease.

Systematic identification of functional SNPs interrupting 3'UTR polyadenylation signals.

Alternative polyadenylation (APA) is emerging as a widespread regulatory layer since the majority of human protein-coding genes contain several polyadenylation (p(A)) sites in their 3'UTRs. By generating isoforms with different 3'UTR length, APA potentially affects mRNA stability, translation efficiency, nuclear export, and cellular localization. Polyadenylation sites are regulated by adjacent RNA cis-regulatory elements, the principals among them are the polyadenylation signal (PAS) AAUAAA and its main variant AUUAAA, typically located ~20-nt upstream of the p(A) site. Mutations in PAS and other auxiliary poly(A) cis-elements in the 3'UTR of several genes have been shown to cause human Mendelian diseases, and to date, only a few common SNPs that regulate APA were associated with complex diseases. Here, we systematically searched for SNPs that affect gene expression and human traits by modulation of 3'UTR APA. First, focusing on the variants most likely to exert the strongest effect, we identified 2,305 SNPs that interrupt the canonical PAS or its main variant. Implementing pA-QTL tests using GTEx RNA-seq data, we identified 330 PAS SNPs (called PAS pA-QTLs) that were significantly associated with the usage of their p(A) site. As expected, PAS-interrupting alleles were mostly linked with decreased cleavage at their p(A) site and the consequential 3'UTR lengthening. However, interestingly, in ~10% of the cases, the PAS-interrupting allele was associated with increased usage of an upstream p(A) site and 3'UTR shortening. As an indication of the functional effects of these PAS pA-QTLs on gene expression and complex human traits, we observed for few dozens of them marked colocalization with eQTL and/or GWAS signals. The PAS-interrupting alleles linked with 3'UTR lengthening were also strongly associated with decreased gene expression, indicating that shorter isoforms generated by APA are generally more stable than longer ones. Last, we carried out an extended, genome-wide analysis of 3'UTR variants and detected thousands of additional pA-QTLs having weaker effects compared to the PAS pA-QTLs.

Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation.

NF-κB is a master transcription factor that activates the expression of target genes in response to various stimulatory signals. Activated NF-κB mediates a plethora of diverse functions including innate and adaptive immune responses, inflammation, cell proliferation, and NF-κB is regulated through interactions with IκB inhibitory proteins, which are in turn regulated by the inhibitor of κB kinase (IKK) complex. Together, these 3 components form the core of the NF-κB signalosomes that have cell-specific functions which are dependent on the interactions with other signaling molecules and pathways. The activity of NF-κB pathway is also regulated by a variety of post-translational modifications including phosphorylation and ubiquitination by Lys63, Met1, and Lys48 ubiquitin chains. The physiologic role of NF-κB is best studied in the immune system due to discovery of many human diseases caused by pathogenic variants in various proteins that constitute the NF-κB pathway. These disease-causing variants can act either as gain-of-function (GoF) or loss-of-function (LoF) and depending on the function of mutated protein, can cause either immunodeficiency or systemic inflammation. Typically, pathogenic missense variants act as GoF and they lead to increased activity in the pathway. LoF variants can be inherited as recessive or dominant alleles and can cause either a decrease or an increase in pathway activity. Dominantly inherited LoF variants often result in haploinsufficiency of inhibitory proteins. Here, we review human Mendelian immunologic diseases, which results from mutations in different molecules in the canonical NF-κB pathway and surprisingly present with a continuum of clinical features including immunodeficiency, atopy, autoimmunity, and autoinflammation.

Understanding human DNA variants affecting pre-mRNA splicing in the NGS era.

Pre-mRNA splicing, an essential step in eukaryotic gene expression, relies on recognition of short sequences on the primary transcript intron ends and takes place along transcription by RNA polymerase II. Exonic and intronic auxiliary elements may modify the strength of exon definition and intron recognition. Splicing DNA variants (SV) have been associated with human genetic diseases at canonical intron sites, as well as exonic substitutions putatively classified as nonsense, missense or synonymous variants. Their effects on mRNA may be modulated by cryptic splice sites associated to the SV allele, comprehending exon skipping or shortening, and partial or complete intron retention. As splicing mRNA outputs result from combinatorial effects of both intrinsic and extrinsic factors, in vitro functional assays supported by computational analyses are recommended to assist SV pathogenicity assessment for human Mendelian inheritance diseases. The increasing use of next-generating sequencing (NGS) targeting full genomic gene sequence has raised awareness of the relevance of deep intronic SV in genetic diseases and inclusion of pseudo-exons into mRNA. Finally, we take advantage of recent advances in sequencing and computational technologies to analyze alternative splicing in cancer. We explore the Catalog of Somatic Mutations in Cancer (COSMIC) to describe the proportion of splice-site mutations in cis and trans regulatory elements. Genomic data from large cohorts of different cancer types are increasingly available, in addition to repositories of normal and somatic genetic variations. These are likely to bring new insights to understanding the genetic control of alternative splicing by mapping splicing quantitative trait loci in tumors.

Systematic screening for skin, hair, and nail abnormalities in a large-scale knockout mouse program.

The International Knockout Mouse Consortium was formed in 2007 to inactivate (“knockout”) all protein-coding genes in the mouse genome in embryonic stem cells. Production and characterization of these mice, now underway, has generated and phenotyped 3,100 strains with knockout alleles. Skin and adnexa diseases are best defined at the gross clinical level and by histopathology. Representative retired breeders had skin collected from the back, abdomen, eyelids, muzzle, ears, tail, and lower limbs including the nails. To date, 169 novel mutant lines were reviewed and of these, only one was found to have a relatively minor sebaceous gland abnormality associated with follicular dystrophy. The B6N(Cg)-Far2tm2b(KOMP)Wtsi/2J strain, had lesions affecting sebaceous glands with what appeared to be a secondary follicular dystrophy. A second line, B6N(Cg)-Ppp1r9btm1.1(KOMP)Vlcg/J, had follicular dystrophy limited to many but not all mystacial vibrissae in heterozygous but not homozygous mutant mice, suggesting that this was a nonspecific background lesion. We discuss potential reasons for the low frequency of skin and adnexal phenotypes in mice from this project in comparison to those seen in human Mendelian diseases, and suggest alternative approaches to identification of human disease-relevant models.

Using high-resolution variant frequencies to empower clinical genome interpretation

PurposeWhole-exome and whole-genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognized as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants.MethodsWe present a statistical framework for the frequency-based filtering of candidate disease-causing variants, accounting for disease prevalence, genetic and allelic heterogeneity, inheritance mode, penetrance, and sampling variance in reference datasets.ResultsUsing the example of cardiomyopathy, we show that our approach reduces by two-thirds the number of candidate variants under consideration in the average exome, without removing true pathogenic variants (false-positive rate<0.001).ConclusionWe outline a statistically robust framework for assessing whether a variant is “too common” to be causative for a Mendelian disorder of interest. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.

Susceptibility to type 2 diabetes may be modulated by haplotypes in G6PC2, a target of positive selection

BackgroundThe endoplasmic reticulum enzyme glucose-6-phosphatase catalyzes the common terminal reaction in the gluconeogenic/glycogenolytic pathways and plays a central role in glucose homeostasis. In most mammals, different G6PC subunits are encoded by three paralogous genes (G6PC, G6PC2, and G6PC3). Mutations in G6PC and G6PC3 are responsible for human mendelian diseases, whereas variants in G6PC2 are associated with fasting glucose (FG) levels.ResultsWe analyzed the evolutionary history of G6Pase genes. Results indicated that the three paralogs originated during early vertebrate evolution and that negative selection was the major force shaping diversity at these genes in mammals. Nonetheless, site-wise estimation of evolutionary rates at corresponding sites revealed weak correlations, suggesting that mammalian G6Pases have evolved different structural features over time. We also detected pervasive positive selection at mammalian G6PC2. Most selected residues localize in the C-terminal protein region, where several human variants associated with FG levels also map. This region was re-sequenced in ~560 subjects from Saudi Arabia, 185 of whom suffering from type 2 diabetes (T2D). The frequency of rare missense and nonsense variants was not significantly different in T2D and controls. Association analysis with two common missense variants (V219L and S342C) revealed a weak but significant association for both SNPs when analyses were conditioned on rs560887, previously identified in a GWAS for FG. Two haplotypes were significantly associated with T2D with an opposite effect direction.ConclusionsWe detected pervasive positive selection at mammalian G6PC2 genes and we suggest that distinct haplotypes at the G6PC2 locus modulate susceptibility to T2D.

Phenotype-driven strategies for exome prioritization of human Mendelian disease genes.

Whole exome sequencing has altered the way in which rare diseases are diagnosed and disease genes identified. Hundreds of novel disease-associated genes have been characterized by whole exome sequencing in the past five years, yet the identification of disease-causing mutations is often challenging because of the large number of rare variants that are being revealed. Gene prioritization aims to rank the most probable candidate genes towards the top of a list of potentially pathogenic variants. A promising new approach involves the computational comparison of the phenotypic abnormalities of the individual being investigated with those previously associated with human diseases or genetically modified model organisms. In this review, we compare and contrast the strengths and weaknesses of current phenotype-driven computational algorithms, including Phevor, Phen-Gen, eXtasy and two algorithms developed by our groups called PhenIX and Exomiser. Computational phenotype analysis can substantially improve the performance of exome analysis pipelines.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0199-2) contains supplementary material, which is available to authorized users.

Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases.

Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

Clinical Exome/Genome Reports‐Announcement

I am delighted to announce that Clinical Genetics will be starting a new online only section on Clinical Exome/ Genome Reports. Exome sequencing and analysis is an important novel approach for the discovery of “new” human Mendelian diseases. This section will highlight cases of high quality patient data to the medical genetics community and will serve as excellent resource for finding exome publications. The articles published will also be indexed on Pubmed. Drs. Sergio Pena and Stefan Mundlos will be the co-Section Editors for this new feature. Dr. Pena is a Professor of Biochemistry at the Universidade Federal de Minas Gerais in Brazil, and Dr.Mundlos is the Director of the Institute for Medical and Human Genetics at the Charité in Germany. They are both experts in the field and will bring new insights to this section. For more information about the author guidelines-go to (http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1399-0004/homepage/ForAuthors.html). We welcome your submissions to this section. Best wishes, Michael R.Hayden, Editor-in-Chief, Clinical Genetics Whole exome sequencing (WES) and whole genome sequencing (WGS) have revolutionized clinical genetics through the discovery of new genes, the characterization of new genetic diseases, and the description of new phenotypic features in previously known disorders. However, as pointed out in recent papers 1, 2 these genomic techniques are not optimal in a purely diagnostic setting because of the problem of establishing with certainty whether an individual genomic variant is responsible for the disease afflicting an individual patient. After one narrows down the list of candidate genes to a most likely one that has clear pathogenic features and whose product has an obvious connection with the abnormal phenotype, one cannot be certain that it is indeed “the culprit” of the disease in the specific patient unless the specific variant has already been previously described in association with the abnormal phenotype. To establish causation, it is often necessary to embark in extensive and expensive experiments in cell and developmental biology, including knock-out and knock-in experiments in cell cultures and/or model organisms. An alternative approach would be to collect several patients with a similar clinical picture. If mutations in the same locus were found in similar patients from different families, then one could, at least provisionally, infer a genetic causation from the altered gene to the disease. But to amass a collection of patients is not an easy task for a single genetic service, especially if the disease in rare. This is the motivation for the creation of the “Clinical Exome and Genome Section” in Clinical Genetics. We are open for the evaluation and eventual publication of individual cases providing evidence suggestive of the discovery of new genes, the characterization of new genetic diseases, or the description of new phenotypic features in previously known disorders. We expect that these individual reports will then percolate through the clinical genetics community and will stimulate the WES/WGS study of the indigitated genetic locus (or loci) in other individual patients with similar disease phenotypes. In this fashion, eventual matches will then prompt further publications and stimulate the involvement of basic scientists in the functional confirmation and the elucidation of the appropriate pathogenetic mechanisms. We hope to have thus established a strategy of how the publication of well-studied single cases can reverberate and lead to major advances in molecular genetics. Please send us your interesting cases! Sergio Pena Stefan Mundlos

Allelic variation, aneuploidy, and nongenetic mechanisms suppress a monogenic trait in yeast.

Clinically relevant features of monogenic diseases, including severity of symptoms and age of onset, can vary widely in response to environmental differences as well as to the presence of genetic modifiers affecting the trait’s penetrance and expressivity. While a better understanding of modifier loci could lead to treatments for Mendelian diseases, the rarity of individuals harboring both a disease-causing allele and a modifying genotype hinders their study in human populations. We examined the genetic architecture of monogenic trait modifiers using a well-characterized yeast model of the human Mendelian disease classic galactosemia. Yeast strains with loss-of-function mutations in the yeast ortholog (GAL7) of the human disease gene (GALT) fail to grow in the presence of even small amounts of galactose due to accumulation of the same toxic intermediates that poison human cells. To isolate and individually genotype large numbers of the very rare (∼0.1%) galactose-tolerant recombinant progeny from a cross between two gal7Δ parents, we developed a new method, called “FACS-QTL.” FACS-QTL improves upon the currently used approaches of bulk segregant analysis and extreme QTL mapping by requiring less genome engineering and strain manipulation as well as maintaining individual genotype information. Our results identified multiple distinct solutions by which the monogenic trait could be suppressed, including genetic and nongenetic mechanisms as well as frequent aneuploidy. Taken together, our results imply that the modifiers of monogenic traits are likely to be genetically complex and heterogeneous.

Managing large-scale genomic datasets and translation into clinical practice.

To summarize excellent current research in the field of Bioinformatics and Translational Informatics with application in the health domain. We provide a synopsis of the articles selected for the IMIA Yearbook 2014, from which we attempt to derive a synthetic overview of current and future activities in the field. A first step of selection was performed by querying MEDLINE with a list of MeSH descriptors completed by a list of terms adapted to the section. Each section editor evaluated independently the set of 1,851 articles and 15 articles were retained for peer-review. The selection and evaluation process of this Yearbook's section on Bioinformatics and Translational Informatics yielded three excellent articles regarding data management and genome medicine. In the first article, the authors present VEST (Variant Effect Scoring Tool) which is a supervised machine learning tool for prioritizing variants found in exome sequencing projects that are more likely involved in human Mendelian diseases. In the second article, the authors show how to infer surnames of male individuals by crossing anonymous publicly available genomic data from the Y chromosome and public genealogy data banks. The third article presents a statistical framework called iCluster+ that can perform pattern discovery in integrated cancer genomic data. This framework was able to determine different tumor subtypes in colon cancer. The current research activities still attest the continuous convergence of Bioinformatics and Medical Informatics, with a focus this year on large-scale biological, genomic, and Electronic Health Records data. Indeed, there is a need for powerful tools for managing and interpreting complex data, but also a need for user-friendly tools developed for the clinicians in their daily practice. All the recent research and development efforts are contributing to the challenge of impacting clinically the results and even going towards a personalized medicine in the near future.

Genetic Complexity in a Drosophila Model of Diabetes-Associated Misfolded Human Proinsulin

Drosophila melanogaster has been widely used as a model of human Mendelian disease, but its value in modeling complex disease has received little attention. Fly models of complex disease would enable high-resolution mapping of disease-modifying loci and the identification of novel targets for therapeutic intervention. Here, we describe a fly model of permanent neonatal diabetes mellitus and explore the complexity of this model. The approach involves the transgenic expression of a misfolded mutant of human preproinsulin, hINSC96Y, which is a cause of permanent neonatal diabetes. When expressed in fly imaginal discs, hINSC96Y causes a reduction of adult structures, including the eye, wing, and notum. Eye imaginal discs exhibit defects in both the structure and the arrangement of ommatidia. In the wing, expression of hINSC96Y leads to ectopic expression of veins and mechano-sensory organs, indicating disruption of wild-type signaling processes regulating cell fates. These readily measurable “disease” phenotypes are sensitive to temperature, gene dose, and sex. Mutant (but not wild-type) proinsulin expression in the eye imaginal disc induces IRE1-mediated XBP1 alternative splicing, a signal for endoplasmic reticulum stress response activation, and produces global change in gene expression. Mutant hINS transgene tester strains, when crossed to stocks from the Drosophila Genetic Reference Panel, produce F1 adults with a continuous range of disease phenotypes and large broad-sense heritability. Surprisingly, the severity of mutant hINS-induced disease in the eye is not correlated with that in the notum in these crosses, nor with eye reduction phenotypes caused by the expression of two dominant eye mutants acting in two different eye development pathways, Drop (Dr) or Lobe (L), when crossed into the same genetic backgrounds. The tissue specificity of genetic variability for mutant hINS-induced disease has, therefore, its own distinct signature. The genetic dominance of disease-specific phenotypic variability in our model of misfolded human proinsulin makes this approach amenable to genome-wide association study in a simple F1 screen of natural variation.