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Session 4: Genetics
Pages 105-140

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From page 105...
... Session 4 Genetics
From page 107...
... This information can * Southwest National Primate Research Center Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas 107
From page 108...
... Nonhuman primate colonies frequently have complex pedigree structures, making them well suited to genetic analyses of common diseases. Nonhuman primates serve as excellent models for human disease studies because of their phylogenetic proximity to humans, the large degree of conservation of gene maps between human and nonhuman primates, the genetic and physiological similarities between humans and nonhuman primates, and the natural occurrence of many of the complex diseases that represent the greatest health burdens to the human population (VandeBerg and Williams-Blangero 1996, 1997~.
From page 109...
... Nonhuman primates are ideal models for genetic studies of complex disease processes that have significant environmental components. For example, the level of dietary control possible with pedigreed nonhuman primates allows explicit assessment of the interactions between genetic effects and dietary effects in determining physiological correlates of heart disease.
From page 110...
... One of the primary risk factors for development of osteoporosis is low bone mineral density. Genetic studies of this disease in human populations are hampered by the need to assess bone mineral density in the large numbers of related individuals required for genetic epidemiological analysis and the immeasurable variability in lifetime diet and exercise patterns.
From page 111...
... The identification of specific genes with significant effects on disease traits requires linkage analysis of genetic marker data in conjunction with disease trait data and information about the distribution of genes across chromosomes. Although a gene map exists for baboons, none is available for any other nonhuman primate species.
From page 112...
... 1997. A quantitative trait locus on chromosome 11 may influence bone mineral density at several sites: Linkage analysis in pedigreed baboons.
From page 113...
... 1997. Advantages and limitations of nonhuman primates as animal models in genetic research on complex disease.
From page 114...
... t INTRODUCTION Genetic management is an important component of the management of nonhuman primate colonies regardless of whether the animals will be used for genetic or nongenetic research (VandeBerg 1995; WilliamsBlangero 1993~. Genetic management techniques can be used to maintain the long-term viability of nonhuman primate colonies for continued production of healthy breeders.
From page 115...
... The baboon population at the Southwest Foundation is being used in ongoing genome scans for genes influencing risk factors associated with cardiovascular disease and osteoporosis (VandeBerg and Williams-Blangero 2002~. The animals are predominantly olive baboons (P.h.
From page 116...
... Recent work by Marthas (Marthas and others 2003; Marthas and others 2001) has shown that colonies of Chinese-origin rhesus macaques may be of significant utility for AIDS-related research, despite differences from rhesus macaques in immune response to simian immunodeficiency virus.
From page 117...
... If single-male breeding groups are used, colony records may be sufficient to enable pedigree construction for genetic management purposes and for quantitative genetic analyses. Extended pedigrees can be reconstructed from colony record information on the individual's identification number, the dam's identification number, and the sire's identification number for each colony animal (providing that each animal has a unique identification number)
From page 118...
... Nonhuman primate colonies frequently have complex extended pedigrees that can be used in quantitative genetic analyses of variation in normal and disease-related phenotypes for both biomedical research and management purposes. Generation of detailed genotypic information for extended nonhuman primate pedigrees as part of a genome scan is the ultimate way to increase their value for biomedical research.
From page 119...
... To maximize the utility of nonhuman primate colonies for genetic research, it is imperative to maintain detailed pedigree information, clinical histories, and management records. The development of new gene maps for nonhuman primates will be essential for linkage analyses designed to localize disease genes in species other than baboons.
From page 120...
... 2001. Titration of an SIVmac251 stock by vaginal inoculation of Indian and Chinese origin rhesus macaques: transmission efficiency, viral loads, and antibody responses.
From page 121...
... 1993. Research-oriented genetic management of nonhuman primate colonies.
From page 122...
... Therefore, there remains an urgent need to develop an effective prophylactic vaccine against this virus. Crucial insights about AIDS virus pathogenesis and vaccine efficacy have come from the simian immunodeficiency virus-infected rhesus macaque, the best available animal model for HIV infection of humans.
From page 123...
... Finally, almost all infected individuals succumb to the infection, showing an increase in virus load and a precipitous loss of CD4+ T cells, resulting in an increased susceptibility to opportunistic infections. ROLE OF CTLs IN THE IMMUNE RESPONSE TO HIV/SIV The eventual death of most individuals infected with immunodeficiency viruses stands in apparent contradiction to the observation of strong humoral and cellular immune responses in most infected hosts.
From page 124...
... In fact, there is now overwhelming evidence that HIV, SIV, and other viruses are capable of spawning variants that allow them to "escape" from specific CTL responses, and furthermore that this escape can occur within the first weeks of infection. IMMUNODOMINANCE OF SIV-SPECIFIC CTL AND CONTROL OF SIV INFECTION Most studies of CTL activity against SIV in the rhesus macaque have centered on responses restricted by a single common MHC class I molecule, Mamu-A*
From page 125...
... Tat SL8-specific CTLs appear rapidly able to eliminate susceptible viruses, such that viruses with wild-type epitope sequences are not detected in Mamu-A* 01-positive animals by 6 weeks after infection.
From page 126...
... 01-positive animals. SUMMARY AND RECOMMENDATIONS The SIV-infected rhesus macaque remains the best available animal model for HIV infection of humans.
From page 127...
... In humans, it is thought that approximately 250 to 1000 unprotected sexual encounters with HIV-infected men are needed to cause HIV infection. There is thus a critical need to develop a low-dose intravaginal challenge model in the rhesus macaque.
From page 128...
... Miller,* ~ # INTRODUCTION The use of rhesus macaques as a nonhuman primate model for human HIV infection and AIDS has resulted in an unprecedented demand that has far exceeded the supply of domestically bred animals; thus, researchers must use monkeys from other sources.
From page 129...
... in plasma of Chinese- and Indian-origin animals were found to be high but not significantly different. However, by 6 weeks PI, the plasma SIV RNA levels were significantly lower in Chinesecompared with Indian-origin rhesus macaques, despite large overlap in the range of viral loads among Indian- and Chinese-origin animals.
From page 130...
... 2001. Titration of an SIVmac251 stock by vaginal inoculation of Indian and Chinese origin rhesus macaques: transmission efficiency, viral loads, and antibody responses.
From page 131...
... VandeBerg Session Chair, Southwest Foundation for Biomedical Research, USA Sarah Williams-Blangero Southwest Foundation for Biomedical Research, USA Thomas Friedrich Wisconsin National Primate Research Center, USA Marta L Marthas California National Primate Research Center, USA QUESTIONS AND ANSWERS PARTICIPANT A: Dr.
From page 132...
... Marthas, California National Primate Research Center) : For this study, we did not measure long-term progression, which we originally began to titrate, so we purposely ended the study by 6 weeks.
From page 133...
... VandeBerg, in terms of the desire to maintain large populations of animals for pedigree, does the population at Southwest contribute to the availability of aged animals down the line, both in terms of genetic studies and availability of cost-effective production of aged animals? Second, Dr.
From page 134...
... DR. WILLIAMS-BLANGERO (Sarah Williams-Blangero, Southwest Foundation for Biomedical Research)
From page 135...
... With this information, which you can obtain from basic colony records for many nonhuman primate colonies, you can begin to ask the simple question: how much variation in this trait is attributable to genetics? As you ask these questions in conjunction with the existing phenotypic data on normal variation and traits in which you might be interested and on disease traits that are recorded in the clinical records, you can get an idea about productive directions for a true genome scan or more detailed genetic research.
From page 136...
... I do not know what primate centers and investigators of disease in nonhuman primates can do to be prepared for this kind of eventuality. We can only make public these findings so that people understand that by placing themselves and nonhuman primates at risk in these high-pressure ecological environments, it is more likely that we are going to find this sort of transmission occurring in the future.
From page 137...
... Where are they originating? When you look at the range of facilities in China, if you can specify the geographic origin of those populations, it helps incredibly in terms of both looking at the genetics of those populations and also developing genetic tools to compare those populations.
From page 138...
... We do not know what the potential is for genetic studies from those sources. I think it helps to recognize that there is potential for working out some of the genetic risk factors and verifying them within the pedigreed colonies, then going to some of these relatively genetically well-defined biogeographic populations and selecting the animals that are appropriate for whatever the target research is.
From page 139...
... We have been doing genetic studies within that pedigreed colony, which is quite large now. Second, we have done some work looking at the genetic variability on the island.
From page 140...
... 140 INTERNATIONAL PERSPECTIVES seems to me a very high priority that for African greens from St. Kilts and Mauritian cynos, this kind of work should be done.


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