A quantitative trait locus for variation in dopamine metabolism mapped in a primate model using reference sequences from related species

Center for Neurobehavioral Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2007; 104(40):15811-6. DOI: 10.1073/pnas.0707640104
Source: PubMed


Non-human primates (NHP) provide crucial research models. Their strong similarities to humans make them particularly valuable for understanding complex behavioral traits and brain structure and function. We report here the genetic mapping of an NHP nervous system biologic trait, the cerebrospinal fluid (CSF) concentration of the dopamine metabolite homovanillic acid (HVA), in an extended inbred vervet monkey (Chlorocebus aethiops sabaeus) pedigree. CSF HVA is an index of CNS dopamine activity, which is hypothesized to contribute substantially to behavioral variations in NHP and humans. For quantitative trait locus (QTL) mapping, we carried out a two-stage procedure. We first scanned the genome using a first-generation genetic map of short tandem repeat markers. Subsequently, using >100 SNPs within the most promising region identified by the genome scan, we mapped a QTL for CSF HVA at a genome-wide level of significance (peak logarithm of odds score >4) to a narrow well delineated interval (<10 Mb). The SNP discovery exploited conserved segments between human and rhesus macaque reference genome sequences. Our findings demonstrate the potential of using existing primate reference genome sequences for designing high-resolution genetic analyses applicable across a wide range of NHP species, including the many for which full genome sequences are not yet available. Leveraging genomic information from sequenced to nonsequenced species should enable the utilization of the full range of NHP diversity in behavior and disease susceptibility to determine the genetic basis of specific biological and behavioral traits.


Available from: Lynn A Fairbanks
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    • "These properties make them appealing to carry out basic and translational research, and in particular have proven to be valuable for studies of metabolic disorders including type 2 diabetes (Kavanagh et al., 2007). Vervets have been used for cognitive studies relevant to human diseases including schizophrenia (Freimer et al., 2007), aging (Melega et al., 2008), and attention deficit disorder (Seu et al., 2009); and have been used for stem cell transplantation studies addressing Parkinson's disease (Taylor et al., 1997). Interestingly, the apolipoprotein (Apo) E gene which is present as 3 different alleles in humans, is fixed in the vervet as it is in several other OWMs, with an amino acid sequence corresponding to human Apo E4 (Fainman et al., 2007), the allele which significantly increases the risk of developing Alzheimer's disease (AD). "
    [Show abstract] [Hide abstract] ABSTRACT: The vervet is an old world monkey increasingly being used as a model for human diseases. In addition to plaques and tangles, an additional hallmark of Alzheimer's disease is damage to neurons that synthesize noradrenaline (NA). We characterized amyloid burden in the posterior temporal lobe of young and aged vervets, and compared that with changes in NA levels and astrocyte activation. Total amyloid beta (Aβ)40 and Aβ42 levels were increased in the aged group, as were numbers of amyloid plaques detected using antibody 6E10. Low levels of Aβ42 were detected in 1 of 5 younger animals, although diffusely stained plaques were observed in 4 of these. Increased glial fibrillary acidic protein staining and messenger RNA levels were significantly correlated with increased age, as were cortical NA levels. Levels of Aβ42 and Aβ40, and the number of 6E10-positive plaques, were correlated with NA levels. Interestingly messenger RNA levels of glial derived neurotrophic factor, important for noradrenergic neuronal survival, were reduced with age. These findings suggest that amyloid pathology in aged vervets is associated with astrocyte activation and higher NA levels.
    Full-text · Article · Apr 2013 · Neurobiology of aging
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    • "By converting a lengthy and tedious procedure into a series of simple tasks, cgb makes it easier to create custom instances of the UCSC Genome Browser. It has been used to support studies ranging from bacteria (Forgetta et al., 2011; Forgetta et al., 2012), to fungi (, to chordates (Matsumoto et al., 2010), and to mammals (Freimer et al., 2007). Because many of the tasks are non-interactive they can be further automated and customized by wrapping them into another Unix shell program, or more interestingly, through a web-browser interface, allowing users with no knowledge of Unix-like operating systems to create browser instances for non-reference genome sequences. "
    [Show abstract] [Hide abstract] ABSTRACT: The UCSC Genome Browser is a popular tool for the exploration and analysis of reference genomes. Mirrors of the UCSC Genome Browser and its contents exist at multiple geographic locations, and this mirror procedure has been modified to support genome sequences not maintained by UCSC and generated by individual researchers. While straightforward, this procedure is lengthy and tedious and would benefit from automation, especially when processing many genome sequences. We present a Unix shell program that facilitates the creation of custom instances of the UCSC Genome Browser for genome sequences not being maintained by UCSC. It automates many steps of the browser creation process, provides password protection for each browser instance, and automates the creation of basic annotation tracks. As an example we generate a custom UCSC Genome Browser for a bacterial genome obtained from a massively parallel sequencing platform.
    Full-text · Article · Nov 2012
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    • "One study examined the effects of microgravity on single muscle fiber function in young rhesus monkeys (Fitts et al., 2000), and two reported the influence of dietary interventions on gene transcription in aging rhesus monkeys (Kayo et al., 2001; McKiernan et al., 2011 ). The vervet monkey represents a very useful NHP model for biomedical research (Freimer et al., 2007; Jasinska et al., 2007), and their use in translational research as an alternative to the rhesus macaque has grown over the past ten years (Bacopoulos et al., 1980; Palmour et al., 1997 ). Nonetheless , their muscle fiber-type composition, expression of specific MHC isoforms, and the effects of age have not been reported. "
    [Show abstract] [Hide abstract] ABSTRACT: Non-human primates (NHP) represent an emerging animal model for the study of physical function, and provide opportunities for exploration of relationships of muscle biomolecular changes with age. One such primate model, the African green vervet monkey, has been used extensively in biomedical research but little is known regarding skeletal muscle composition, expression of myosin heavy chain (MHC) isoforms, and changes with age. In the present study we examined the effects of age on vastus lateralis (VL) muscle fiber-type composition, fiber cross-sectional area (CSA), and MHC isoforms expressed in 4 young and 4 older adult vervet monkeys. Proteomics analysis, using a human and nonhuman primate protein database, showed five MHC isoforms (I, IIA, IIX, IIB, and IIB') expressed in female vervet VL muscle, which matched the human MHC isoforms. Fast type II fibers predominated and no pure type IIB or IIB' containing fibers were detected. Hybrid fibers containing IIB/IIB' MHC decreased in the old vervets. The CSA of both type I and type II fibers was significantly smaller in older vervet while type IIA fibers showed the most severity of atrophy. The decrease of fast MHC and atrophy of muscle fiber with aging recapitulate observations in human VL muscle. These findings, along with its homology of MHC between the vervet and human suggested that the vervet monkey may be a suitable preclinical model for understanding the cellular and molecular basis of sarcopenia and for developing new interventions to ameliorate the impact of disorders that affect skeletal muscle structure and function.
    Full-text · Article · May 2012 · Experimental gerontology
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