Cells and Surveys Should Biological Measures Be Included in Social Science Research? (2001) / Chapter Skim
Currently Skimming:
Opportunities for Population-Based Research on Aging Human Subjects: Pathology and Genetics
Opportunities for Population-Based Research on Aging Human Subjects: Pathology and Genetics
Pages 133-158
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 133... ...
But highly selected populations, such as large kindreds, and large populations used for genetic association studies, such as comparisons between patients with a late-life disease and age-matched controls, have often been used to enhance our understanding of the basis for varying susceptibilities to late-life disorders. A cogent example of a new tool that is waiting to be exploited for studies of populations of human subjects is the analysis of gene expression using massive microarrays.
|
From page 134... ...
Our third and final goal will be to underscore the value of middle age as a stage of the life course that should receive greater attention by geneticists, physiologists, physicians, and population scientists concerned with the elucidation of varying patterns of aging in our species. GENETICS New Methods for the Comprehensive Assessment of Changes in Gene Expression During the Life Course The expression of a large number of genes changes during the life course.
|
From page 135... ...
A second approach uses cDNAs instead of DNA oligonucleotides to make the microarrays. The symbol "cDNA" refers to a DNA copy made from the cognate mRNA, using an enzyme called reverse transcriptase.
|
From page 137... ...
Third, more modest arrays designed for the investigations of genes of special interest to specific studies are likely to be developed by individual laboratories or by specialized centers within major institutions at reduced costs. Fourth, and most importantly, once a few particularly robust biomarkers of specific processes of aging have been discovered and replicated using microarrays, one can employ other, more rigorously quantitative and more rapid methods based upon the polymerase chain reaction (PCR)
|
From page 138... ...
Other Uses of Microarray Technologies These microarray technologies could also be adapted to determine the prevalence of a wide variety of inborn alterations in gene dosage, either deletions or DNA amplifications (Pinker et al., 1998; Trent et al., 1997~. To do this, one hybridizes fragments of genomic DNA, rather than messenger RNA, against an array of cognate DNA sequences.
|
From page 139... ...
. These can be used for mapping disease genes via hybridization of genomic DNA using the principles of genomic mismatch repair and linkage disequilibrium (Cheung et al., 1998~.
|
From page 140... ...
The discoveries of autosomal dominant mutations at the beta amyloid precursor protein locus and at the two presenilin loci are good examples (Blacker and Tanzi, 1998~. These mutations cause earlyonset DAT.
|
From page 141... ...
All three autosomal dominant DAT mutations, those at the presenilin 1 and 2 loci and those at the beta amyloid precursor protein locus, result in relatively early-onset dementias. There is considerable variation in the age of onset for the case of the presenilin 2 mutations, however, including rare apparent "escapees" who may live into the ninth decade without becoming affected.
|
From page 142... ...
First of all, life span is subject to stochastic events (Finch and Kirkwood, 1999~. Cancer, for example, can result in chance "hits" at particularly vulnerable parts of the genome (e.g., tumor suppressor genes)
|
From page 143... ...
Thus, we are in a position to detect differential rates of change of relevant phenotypes beginning in middle age. Secondly, assays for specific physiological functions are less likely to be compromised by various co-morbidities that would be the case were one to investigate differential rates of decline of specific functions in much older individuals.
|
From page 144... ...
One could then identify sib pairs exhibiting extreme concordance or extreme concordance for the trait of interest; such methods can greatly increase the statistical power of the genetic analysis (Zhang and Risch, 1996; Risch and Zhang 1995, 1996~. Such an experimental design could lead to the definition of alleles that underlie what one might call "elite" aging, as opposed to mere "successful" aging.
|
From page 145... ...
It also provides the potential to uncover new definitive information with the use of an expanding toolkit of monoclonal antibodies to specific protein epitopes that have not been obscured by the formalin fixation. Nucleic acid probes, including those that provide amplification of genomic DNA, the DNA of infectious agents, and, to some extent, messenger RNA species, may also be applied to the archived materials.
|
From page 146... ...
A substantial fraction of older subjects are found to have such lesions, which are routinely fixed in formalin and examined microscopically. A small portion of such lesions and adjacent normal tissues, together with small biopsies from the normal tissues of subjects who are examined but who do not have polyps, could be routinely cryobiologically preserved or simply frozen as materials for a variety of research questions, given suitable informed consent.
|
From page 147... ...
inhibits proliferation. Methylation of the estrogen receptor thus leads to a dysregulation of the proliferative homeostasis of colonic epithelial cells.
|
From page 148... ...
Nothing can take the place of a thorough autopsy for the full description of the burden of disease in an individual and in populations of individuals. Unfortunately, once hospital accreditation no longer required autopsies for a significant proportion of hospital deaths, the autopsy rates, especially in private hospitals, dropped precipitously.
|
From page 149... ...
Third, there is the fear of lawsuits against attending physicians should the diagnosis prove erroneous or should additional treatable pathologies be discovered. Fourth, pathologists and residents avoid doing autopsies, or do them in a very cursory fashion, in part because of the pressures of time and because there is typically little or no financial incentive (the pathologist is not reimbursed for his autopsy services by Medicare)
|
From page 150... ...
Autopsies of such individuals can, in principle, provide samples of well-preserved normal tissues from essentially all organs of the body, as well as body fluids such as cerebrospinal fluid and fluid from the vitreous of the eye. They could thus be utilized, for example, to give information on the rates of deposition of soluble and insoluble moieties of the family of beta amyloid peptides (Lue et al., 1999)
|
From page 151... ...
Another example of an imaginative use of archival clinical pathology material for population-based research has been the application of the powerful method of tandem mass spectrometry for the screening of newborns, using the spare dried-filter paper samples of DNA mentioned above, for a great variety of inborn errors of metabolism about 700,000 newborns, 163 inborn errors of metabolism were detected, including 86 with amino acid metabolic errors, 32 with errors in the metabolism of organic acids, and 45 with errors in fatty acid oxidation (Naylor and Chace, 1999~. These are largely recessive disorders, severe mutations having been inherited from both parents.
|
From page 152... ...
Remarkably, there has never been a valid, systematic population-based autopsy study of geriatric diseases in the United States. The result has been the over-reliance upon highly inaccurate death certificate data.
|
From page 153... ...
Wijsman 2000 The number of trait loci in late-onset Alzheimer disease. American Journal of Human Genetics 66:196-204.
|
From page 154... ...
Human Genetics 97:319-323. Holliday, R
|
From page 155... ...
Kruk, P.A., and N Auersperg 1992 Human ovarian surface epithelial cells are capable of physically restructuring extracellular matrix.
|
From page 156... ...
Naylor, E.W., and D.H. Chace 1999 Automated tandem mass spectrometry for mass newborn screening for disorders in fatty acid, organic acid, and amino acid metabolism.
|
From page 157... ...
Zhang 1996 Mapping quantitative trait loci with extreme discordant sib pairs: Sampling considerations. American Journal of Human Genetics 58:836-843.
|
From page 158... ...
Zhang, H., and N Risch 1996 Mapping quantitative-trait loci in humans by use of extreme concordant sib pairs: Selected sampling by parental phenotypes [published erratum appears in American Journal of Human Genetics 1997 Mar;60~3~:748-9]
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.