Carlos E Alvarez

The Ohio State University Colleges of Medicine & Veterinary Medicine

DNA structural variation (SV) comprises a major portion of genetic diversity, but its biological impact is unclear. We propose that the genetic history and extraordinary phenotypic variation of dogs make them an ideal mammal in which to study the effects of SV on biology and disease. The hundreds of existing dog breeds were created by selection of...

The complement of fungal cell surface proteins is widely regulated by ubiquitination of membrane proteins, which results in their endocytosis and vacuolar degradation. For diverse fungal transporters, the specificity of ubiquitination is conferred by alpha arrestin adaptors, which recruit the Nedd4 family E3 ubiquitin ligase Rsp5. A recent study sh...

Background Fear/anxiety and anger/aggression greatly influence health, quality of life and social interactions. They are a huge burden to wellbeing, and personal and public economics. However, while much is known about the physiology and neuroanatomy of such emotions, little is known about their genetics – most importantly, why some individuals are...

Background The main function of hemoglobin (Hb) is to transport oxygen in the circulation. It is among the most highly studied proteins due to its roles in physiology and disease, and most of our understanding derives from comparative research. There is great diversity in Hb gene evolution in placental mammals, mostly in the repertoire and regulati...

Background Despite the tremendous therapeutic advances that have stemmed from somatic oncogenetics, survival of some cancers has not improved in 50 years. Osteosarcoma still has a 5-year survival rate of 66%. We propose the natural canine osteosarcoma model can change that: it is extremely similar to the human condition, except for being highly her...

There is growing interest in canine behavioral research specifically for working dogs. Here we take advantage of a dataset of a Transportation Safety Administration olfactory detection cohort of 628 Labrador Retrievers to perform Machine Learning (ML) prediction and classification studies of behavioral traits and environmental effects. Data were av...

Simple Summary It is widely accepted that long term mental stress increases the risk of cancer. However, it has been impossible to show this conclusively in any species due to the complexities of genetic variation and the difficulty of inducing or measuring levels of psychological stress. Here, we report evidence that heritable canine temperament t...

Latent class analysis (LCA) is a type of modeling analysis approach that has been used to identify unobserved groups or subgroups within multivariate categorical data. LCA has been used for a wide array of psychological evaluations in humans, including the identification of depression subtypes or PTSD comorbidity patterns. However, it has never bee...

Introduction: Angiogenesis imbalance is essential for tumour growth, with hypoxia being the most important driver. Moreover, tumour cells can contribute to forming blood vessels by vasculogenic mimicry (VM) or recalling the endothelial-progenitor-cells through vasculogenesis. Microvessel density (MVD) increase and VM are associated with poor progno...

Research on working dogs is growing rapidly due to increasing global demand. Here we report genome scanning of the risk of puppies being eliminated for behavioral reasons prior to entering the training phase of the US Transportation Security Administration’s (TSA) canine olfactory detection breeding and training program through 2013. Elimination of...

Background Very little is known about the etiology of personality and psychiatric disorders. Because the core neurobiology of many such traits is evolutionarily conserved, dogs present a powerful model. We previously reported genome scans of breed averages of ten traits related to fear, anxiety, aggression and social behavior in multiple cohorts of...

Behavioral traits like aggression, anxiety, and trainability differ significantly across dog breeds and are highly heritable. However, the neural bases of these differences are unknown. Here we analyzed structural MRI scans of 62 dogs in relation to breed-average scores for the 14 major dimensions in the Canine Behavioral Assessment and Research Qu...

Very little is known about the etiology of personality and psychiatric disorders. Because the core neurobiology of many such traits is evolutionarily conserved, dogs present a powerful model. We previously reported genome scans of breed averages of ten traits related to fear, anxiety, aggression and social behavior in multiple cohorts of pedigree d...

Genetic studies show a general factor associated with all human psychopathology and strongly correlated with personality and intelligence, but its basis is unknown. We performed genome scans of 17 normal and problem behaviors in three multi-breed dog cohorts. 21 of 90 mapped loci were supported for the same, or a related, trait in a second cohort....

This chapter highlights the unique traits that make dog models effective in the integration of biomedical genomics and translational medicine. A great advantage of dog models is simplified genetics. Most of the strengths of dog models are relevant across all human disease areas, but there are aspects of cancer that differ from all other diseases. I...

Breast cancer represents the second most frequent neoplasm in humans and sexually intact female dogs after lung and skin cancers, respectively. Many similar features in human and dog cancers including, spontaneous development, clinical presentation, tumor heterogeneity, disease progression and response to conventional therapies have supported devel...

Background It has been an open question how similar human and canine lung cancers are. This has major implications in availability of human treatments for dogs and in establishing translational models to test new therapies in pet dogs. The prognosis for canine advanced lung cancer is poor and new treatments are needed. Heat shock protein 90 (HSP90)...

Here, we briefly review the state of knowledge of human cancer genetics to elaborate on the need for different types of mammalian models, highlighting the strengths of the dog. Mouse models are unparalleled for their experimental tractability and rapid genetic manipulation but have some key limitations in the area of human relevance. Companion dog...

Deregulated B cell differentiation contributes to autoimmune disorders, hematological cancers, and aging. Vitamin A metabolite retinoic acid regulates key immune responses. Here, we explore the role of the retinoic acid‐producing enzyme aldehyde dehydrogenase 1a1 (Aldh1a1) in protection against B cell‐mediated oncogenesis. We showed that Aldh1a1 re...

The deregulation of B cell differentiation has been shown to contribute to autoimmune disorders, hematological cancers, and aging. We provide evidence that the retinoic acid-producing enzyme aldehyde dehydrogenase 1a1 (Aldh1a1) is an oncogene suppressor in specific splenic IgG1(+)/CD19(-) and IgG1(+)/CD19(+) B cells populations. Aldh1a1 regulated t...

Post-translational modifications of aArrs and gene expression analysis of aArrs and bArrs in cancer. (A, B) Use of PhosphositePlus to mine posttranslational modifications of ARRDC3/4 reveals residues that are ubiquitinated (-u; protein location mapped in schematic and sequence context shown below) and phosphorylated (-p).1 MS No. preceding the modi...

Specificity of coIP western blotting for aArrs and receptors, and proteosomal/lysosomal inhibition studies of aArr stability. (A) aArrs and 7TMRs are specifically detected by coIP/western blotting. Here we rule out the possibility that those 50 kD western bands are the result of contamination with IgG from the IP step. CoIP of aArr ARRDC3 with b2AR...

Evolutionary conservation of alpha arrestin PY motifs. Multiple sequence alignment of alpha arrestin Tail domains from vertebrate ARRDC2, 3, 4, and TXNIP show evolutionary conservation of PY motifs. BLAST analysis was used to identify arrestin orthologues from representative species (all but ARRDC4 have orthologues in human, chick, frog and fish; A...

Arrdc3 knockout mouse. (A) We acquired Bay Genomics ES cell line CSE513, which is a gene trap insertion of the pGT0lxf gene trap vector (see Methods) and conducted a blastocyst injection (parental ES 129 line; blastocyst C57BL/6). (B) Genotyping with assay to detect gene trap vector (musArrdc3ex1L -Geo5prR, Methods) showed germ line transmission fr...

Materials and Methods: Arrdc3 knockout mouse. Design and genotyping analysis of Arrdc3 gene trap knockout mouse. (DOCX)

The genomics era has yielded great advances in the understanding of cancer biology. At the same time, the immense complexity of the cancer genome has been revealed, as well as a striking heterogeneity at the whole-genome (or omics) level that exists between even histologically similar tumors. The vast accrual and public availability of multi-omics...

Differences in the content and organization of DNA, collectively referred to as structural variation, have emerged as a major source of genetic and phenotypic diversity within and between species. In addition, structural variation provides an important substrate for evolutionary innovations. Here, we review recent progress in characterizing pattern...

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background/Purpose: The genetic complexity of lymphoma is gradually being unraveled; however, new and better approaches to a molecular understanding are needed. Dogs make an exceptional model for the study of lymphoma because lymphoma occurs spontaneously in this species with...

Structural and sequence variation have been described in several members of the contactin (CNTN) and contactin-associated protein (CNTNAP) gene families in association with neurodevelopmental disorders, including autism. Using array comparative genome hybridization (CGH), we identified a maternally inherited ∼535 kb deletion at 3p26.3 encompassing...

Supplemental Table 1 - List of 18 drugs analyzed in this study. Supplemental Table 2 - List of lung cancer cell lines with either SNP 6.0 copy number, miRNA expression, or IC50 response. Supplemental Table 3 - Summary of copy number alteration comparisons for all miRNAs across all drugs. Supplemental Table 4 - miRNAs significantly differentially ex...

Studies using dogs provide an ideal solution to the gap in animal models for natural disease and translational medicine. This is evidenced by approximately 400 inherited disorders being characterized in domesticated dogs, most of which are relevant to humans. There are several hundred isolated populations of dogs (breeds) and each has a vastly redu...

Squamous cell carcinomas (SqCCs) arise in a wide range of tissues including skin, lung, and oral mucosa. Although all SqCCs are epithelial in origin and share common nomenclature, these cancers differ greatly with respect to incidence, prognosis, and treatment. Current knowledge of genetic similarities and differences between SqCCs is insufficient...

Chemotherapy resistance is a key contributor to the dismal prognoses for lung cancer patients. While the majority of studies have focused on sequence mutations and expression changes in protein-coding genes, recent reports have suggested that microRNA (miRNA) expression changes also play an influential role in chemotherapy response. However, the ro...

We thank Drs Yilmaz, Suttie, and Petersen for recognizing the novelty and value of our approach that incorporates protein structure information into genotype-phenotype studies. In their letter, they pointed out the limitations in sensitivity of conventional echocardiography to detect the earliest signs of cardiac involvement in patients with dystr...

Advances in high-throughput, genome-wide profiling technologies have allowed for an unprecedented view of the cancer genome landscape. Specifically, high-density microarrays and sequencing-based strategies have been widely utilized to identify genetic (such as gene dosage, allelic status, and mutations in gene sequence) and epigenetic (such as DNA...

Background—Becker muscular dystrophy (BMD) and X-linked dilated cardiomyopathy often result from deletion mutations in the dystrophin gene that may lead to expression of an altered dystrophin protein in cardiac muscle. Cardiac involvement is present in 􏰅70% of BMD and all X-linked dilated cardiomyopathy cases. To date, the timing of cardiomyopathy...

DNA methylation regulates gene expression primarily through modification of chromatin structure. Global methylation studies have revealed biologically relevant patterns of DNA methylation in the human genome affecting sequences such as gene promoters, gene bodies, and repetitive elements. Disruption of normal methylation patterns and subsequent gen...

Phylogeny of canarypox virus alpha arrestin. A PDF file showing the phylogeny of canarypox virus (CNPV) alpha arrestin. This analysis shows CNPV arrestin is a highly divergent vertebrate Arrdc3 that was acquired by horizontal gene transfer.

Supplementary methods. A Doc file with the methods used in the discovery and analysis of protist arrestins, discovery and protein sequence alignment of zebrafish and human arrestins, secondary and tertiary structure predictions of alpha arrestins, and phylogenetic analysis of canarypox virus arrestin. All protein sequence annotations are also provi...

Multiple sequence alignment of human and zebrafish arrestins. A PDF file showing a multiple sequence alignment of the human arrestin family and select fish arrestins. It shows protein conservation and divergence of different vertebrate arrestins. Alignment region of beta arrestin helix I suggests this structural element is absent in alpha arrestins...

Helix I region in vertebrate arrestins. A PDF file showing evidence that helix I of visual/beta arrestins is absent in alpha arrestins. Protein sequence alignment and secondary structure prediction of alpha arrestins suggests they lack the helix I present in beta arrestins.

Supplementary text. A Doc file with discussion of arrestin protein sequence analysis, comparison of human and fish arrestin proteins, human complement of arrestin genes, and the horizontal gene transfer of vertebrate Arrdc3 to a poxvirus.

Table of protist arrestins. A PDF file with Table 1. Details of protist arrestins.

G protein coupled receptors (GPCRs) are the most numerous proteins in mammalian genomes, and the most common targets of clinical drugs. However, their evolution remains enigmatic. GPCRs are intimately associated with trimeric G proteins, G protein receptor kinases, and arrestins. We conducted phylogenetic studies to reconstruct the history of arres...

DNA methylation is integral to normal development and disease processes. However, the genomic distribution of methylated sequences--the methylome--is poorly understood. We have recently developed a platform technology for rapid assessment of methylation status throughout the human genome in a high-resolution, high-throughput manner. This is achieve...

Insulin receptor substrate p53/p58 (IRSp53) is involved in cytoskeletal dynamics and is a candidate disease sensor in polyglutamine expansion neurodegeneration. It is widely expressed throughout the body, but its levels are dramatically elevated in forebrain regions. IRSp53 functions as a signal transducing adaptor between activated Rho family GTPa...

Recent studies have revealed that the hypothalamic hypocretin (Hcrt) neuropeptide system is centrally involved in mammalian REM sleep and that it may have other diverse physiological roles. The aims of this work were to learn when HCRT emerged and to test our previous hypothesis that it was created by a circular permutation of an incretin superfami...

Dentatorubral-pallidoluysian atrophy (DRPLA) is a neurodegenerative disease that results from the expansion of an unstable CAG repeat within the coding regions of the DRPLA gene. Recently it was shown that the DRPLA gene product, atrophin-1, interacts with the human insulin receptor tyrosine kinase substrate protein, IRSp53. We have isolated rat an...

Jingwei ( jgw ) is the first gene found to be of sufficiently recent origin in Drosophila to offer insights into the origin of a gene. While its chimerical gene structure was partially resolved as including a retrosequence of alcohol dehydrogenase ( Adh ), the structure of its non- Adh parental gene, the donor of the N-terminal domain of jgw, is un...

Using an in situ hybridization screen for cDNA clones of brain region-specific mRNAs, we isolated a rat transcript that encodes a ribosomal protein S27. Searching GenBank DNA databases, we found two S27 protein isoforms. One isoform, encoded by multiple genes, is extant in archaea and eukarya, but not bacteria. The second isoform appears to be rece...

DGq is the alpha subunit of the heterotrimeric GTPase (Galpha) which couples rhodopsin to phospholipase C (PLC) in Drosophila vision. Keith Robison, of this, the Walter Gilbert Laboratory, uncovered three duplicated exons in dgq by scanning GenBank for unrecognized coding sequences. These alternative exons encode sites involved in GTPase activity a...

DGq is the alpha subunit of the heterotrimeric GTPase (G alpha), which couples rhodopsin to phospholipase C in Drosophila vision. We have uncovered three duplicated exons in dgq by scanning the GenBank data base for unrecognized coding sequences. These alternative exons encode sites involved in GTPase activity and G beta-binding, NorpA (phospholipa...

The propensity for narcolepsy, a clinical sleep disorder of unknown etiology, is virtually totally included within the HLA-DR2,DQw1 (DRw15,DQw6) phenotype. The disorder is characterized by decreased sleep latency, early onset of rapid eye movement sleep, and a paucity of nocturnal slow-wave sleep. Muramyl peptides, naturally occurring bacterial cel...

In the past, the analysis of recombinations within the HLA system have led to the establishment of the HLA region map as we know it today. Recombination events are of prime importance in the generation of new constellations of alleles in the cis position or new alleles if the cross-over takes place within a structural gene. In addition, unequal cro...