Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcripts by excessive ethanol drinking.

The underlying genetic and epigenetic mechanisms driving functional adaptations in neuronal excitability and excessive alcohol intake are poorly understood. Small-conductance Ca-activated K (K2 or SK) channels encoded by the KCNN family of genes have emerged from preclinical studies as a key contributor to alcohol-induced functional neuroadaptations in alcohol-drinking monkeys and alcohol-dependent mice. Here, this cross-species analysis focused on KCNN3 DNA methylation, gene expression, and single nucleotide polymorphisms, including alternative promoters in KCNN3, that could influence surface trafficking and function of K2 channels.

Cross-species epigenetic regulation of nucleus accumbens KCNN3 transcripts by excessive ethanol drinking.

The underlying genetic and epigenetic mechanisms driving functional adaptations in neuronal excitability and excessive alcohol intake are poorly understood. Small-conductance Ca-activated K (K2 or SK) channels encoded by the family of genes have emerged from preclinical studies as a key contributor to alcohol-induced functional neuroadaptations in alcohol-drinking monkeys and alcohol dependent mice. Here, this cross-species analysis focused on DNA methylation, gene expression, and single nucleotide polymorphisms including alternative promoters in that could influence surface trafficking and function of K2 channels.

Genetic variants in melanogenesis proteins TYRP1 and TYR are associated with the golden rhesus macaque phenotype.

Nonhuman primates (NHPs) are vital translational research models due to their high genetic, physiological, and anatomical homology with humans. The "golden" rhesus macaque (Macaca mulatta) phenotype is a naturally occurring, inherited trait with a visually distinct pigmentation pattern resulting in light blonde colored fur. Retinal imaging also reveals consistent hypopigmentation and occasional foveal hypoplasia.

Nonhuman primate genetic models for the study of rare diseases.

Pre-clinical research and development relies heavily upon translationally valid models of disease. A major difficulty in understanding the biology of, and developing treatments for, rare disease is the lack of animal models. It is important that these models not only recapitulate the presentation of the disease in humans, but also that they share functionally equivalent underlying genetic causes.

Neurobeachin, a promising target for use in the treatment of alcohol use disorder.

Hazardous, heavy drinking increases risk for developing alcohol use disorder (AUD), which affects ~7% of adult Americans. Thus, understanding the molecular mechanisms promoting risk for heavy drinking is essential to developing more effective AUD pharmacotherapies than those currently approved by the FDA. Using genome-wide bisulfate sequencing, we identified DNA methylation (DNAm) signals within the nucleus accumbens core (NAcC) that differentiate nonheavy and heavy ethanol-drinking rhesus macaques.

A novel non-human primate model of Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease (PMD) is a severe hypomyelinating disorder of the central nervous system (CNS) linked to mutations in the proteolipid protein-1 (PLP1) gene. Although there are multiple animal models of PMD, few of them fully mimic the human disease. Here, we report three spontaneous cases of male neonatal rhesus macaques with the clinical symptoms of hypomyelinating disease, including intention tremors, progressively worsening motor dysfunction, and nystagmus.

Myelin-specific T cells in animals with Japanese macaque encephalomyelitis.

Objective: To determine whether animals with Japanese macaque encephalomyelitis (JME), a spontaneous demyelinating disease similar to multiple sclerosis (MS), harbor myelin-specific T cells in their central nervous system (CNS) and periphery.

Methods: Mononuclear cells (MNCs) from CNS lesions, cervical lymph nodes (LNs) and peripheral blood of Japanese macaques (JMs) with JME, and cervical LN and blood MNCs from healthy controls or animals with non-JME conditions were analyzed for the presence of myelin-specific T cells and changes in interleukin 17 (IL-17) and interferon gamma (IFNγ) expression.

Results: Demyelinating JME lesions contained CD4 T cells and CD8 T cells specific to myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), and/or proteolipid protein (PLP).

Sequence diversity analyses of an improved rhesus macaque genome enhance its biomedical utility.

The rhesus macaque () is the most widely studied nonhuman primate (NHP) in biomedical research. We present an updated reference genome assembly (Mmul_10, contig N50 = 46 Mbp) that increases the sequence contiguity 120-fold and annotate it using 6.5 million full-length transcripts, thus improving our understanding of gene content, isoform diversity, and repeat organization.

Spontaneous Gene Mutation in Rhesus Macaques (): A Novel Nonhuman Primate Model of Epidermolysis Bullosa Simplex.

Epidermolysis bullosa simplex (EBS) is an inherited skin disorder characterized by increased skin and mucous membrane fragility. Most cases are caused by mutations in keratin 5 () and keratin 14 (). Mutations of these genes result in cytoskeletal disruption of the basal keratinocytes.

Bardet-Biedl Syndrome in rhesus macaques: A nonhuman primate model of retinitis pigmentosa.

The development of therapies for retinal disorders is hampered by a lack of appropriate animal models. Higher nonhuman primates are the only animals with retinal structure similar to humans, including the presence of a macula and fovea. However, few nonhuman primate models of genetic retinal disease are known.

VariantQC: a visual quality control report for variant evaluation.

Summary: Large scale genomic studies produce millions of sequence variants, generating datasets far too massive for manual inspection. To ensure variant and genotype data are consistent and accurate, it is necessary to evaluate variants prior to downstream analysis using quality control (QC) reports. Variant call format (VCF) files are the standard format for representing variant data; however, generating summary statistics from these files is not always straightforward.

Analysis of 100 high-coverage genomes from a pedigreed captive baboon colony.

Baboons (genus ) are broadly studied in the wild and in captivity. They are widely used as a nonhuman primate model for biomedical studies, and the Southwest National Primate Research Center (SNPRC) at Texas Biomedical Research Institute has maintained a large captive baboon colony for more than 50 yr. Unlike other model organisms, however, the genomic resources for baboons are severely lacking.

mGAP: the macaque genotype and phenotype resource, a framework for accessing and interpreting macaque variant data, and identifying new models of human disease.

Background: Non-human primates (NHPs), particularly macaques, serve as critical and highly relevant pre-clinical models of human disease. The similarity in human and macaque natural disease susceptibility, along with parallel genetic risk alleles, underscores the value of macaques in the development of effective treatment strategies. Nonetheless, there are limited genomic resources available to support the exploration and discovery of macaque models of inherited disease.

Modulation of Gpr39, a G-protein coupled receptor associated with alcohol use in non-human primates, curbs ethanol intake in mice.

Alcohol use disorder (AUD) is a chronic condition with devastating health and socioeconomic effects. Still, pharmacotherapies to treat AUD are scarce. In a prior study aimed at identifying novel AUD therapeutic targets, we investigated the DNA methylome of the nucleus accumbens core (NAcc) of rhesus macaques after chronic alcohol use.

Discovery of a CLN7 model of Batten disease in non-human primates.

We have identified a natural Japanese macaque model of the childhood neurodegenerative disorder neuronal ceroid lipofuscinosis, commonly known as Batten Disease, caused by a homozygous frameshift mutation in the CLN7 gene (CLN7). Affected macaques display progressive neurological deficits including visual impairment, tremor, incoordination, ataxia and impaired balance. Imaging, functional and pathological studies revealed that CLN7 macaques have reduced retinal thickness and retinal function early in disease, followed by profound cerebral and cerebellar atrophy that progresses over a five to six-year disease course.

Allogeneic stem cell transplantation in fully MHC-matched Mauritian cynomolgus macaques recapitulates diverse human clinical outcomes.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a critically important therapy for hematological malignancies, inborn errors of metabolism, and immunodeficiency disorders, yet complications such as graft-vs.-host disease (GvHD) limit survival. Development of anti-GvHD therapies that do not adversely affect susceptibility to infection or graft-vs.

Whole genome sequencing predicts novel human disease models in rhesus macaques.

Rhesus macaques are an important pre-clinical model of human disease. To advance our understanding of genomic variation that may influence disease, we surveyed genome-wide variation in 21 rhesus macaques. We employed best-practice variant calling, validated with Mendelian inheritance.

Vitamin C Prevents Offspring DNA Methylation Changes Associated with Maternal Smoking in Pregnancy.

Rationale: Infants whose mothers smoked during pregnancy demonstrate lifelong decreases in pulmonary function. DNA methylation changes associated with maternal smoking during pregnancy have been described in placenta and cord blood at delivery, in fetal lung, and in buccal epithelium and blood during childhood. We demonstrated in a randomized clinical trial ( ClinicalTrials.

The population genomics of rhesus macaques (Macaca mulatta) based on whole-genome sequences.

Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate in biomedical research, have the largest natural geographic distribution of any nonhuman primate, and have been the focus of much evolutionary and behavioral investigation. Consequently, rhesus macaques are one of the most thoroughly studied nonhuman primate species. However, little is known about genome-wide genetic variation in this species.

Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking.

Alcohol-use disorders encompass a range of drinking levels and behaviors, including low, binge, and heavy drinking. In this regard, investigating the neural state of individuals who chronically self-administer lower doses of alcohol may provide insight into mechanisms that prevent the escalation of alcohol use. DNA methylation is one of the epigenetic mechanisms that stabilizes adaptations in gene expression and has been associated with alcohol use.

Anti-Müllerian hormone is produced heterogeneously in primate preantral follicles and is a potential biomarker for follicle growth and oocyte maturation in vitro.

Purpose: The main goals of this study were to investigate the expression of anti-Müllerian hormone (AMH) and its receptor (AMHR2) during follicular development in primates, and to evaluate the potential of AMH as a biomarker for follicle growth and oocyte maturation in vitro.

Methods: The mRNA and protein expression of AMH and AMHR2 were determined using isolated follicles and ovarian sections from rhesus macaques (n = 4) by real-time PCR and immunohistochemistry, respectively. Isolated secondary follicles were cultured individually.

Whole-genome characterization in pedigreed non-human primates using genotyping-by-sequencing (GBS) and imputation.

Background: Rhesus macaques are widely used in biomedical research, but the application of genomic information in this species to better understand human disease is still in its infancy. Whole-genome sequence (WGS) data in large pedigreed macaque colonies could provide substantial experimental power for genetic discovery, but the collection of WGS data in large cohorts remains a formidable expense. Here, we describe a cost-effective approach that selects the most informative macaques in a pedigree for 30X WGS, followed by low-cost genotyping-by-sequencing (GBS) at 30X on the remaining macaques in order to generate sparse genotype data at high accuracy.

Immunopathology of Japanese macaque encephalomyelitis is similar to multiple sclerosis.

Japanese macaque encephalomyelitis (JME) is an inflammatory demyelinating disease that occurs spontaneously in a colony of Japanese macaques (JM) at the Oregon National Primate Research Center. Animals with JME display clinical signs resembling multiple sclerosis (MS), and magnetic resonance imaging reveals multiple T2-weighted hyperintensities and gadolinium-enhancing lesions in the central nervous system (CNS). Here we undertook studies to determine if JME possesses features of an immune-mediated disease in the CNS.

A new rhesus macaque assembly and annotation for next-generation sequencing analyses.

Background: The rhesus macaque (Macaca mulatta) is a key species for advancing biomedical research. Like all draft mammalian genomes, the draft rhesus assembly (rheMac2) has gaps, sequencing errors and misassemblies that have prevented automated annotation pipelines from functioning correctly. Another rhesus macaque assembly, CR_1.