Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000) / Chapter Skim
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5 Human Genetics and the Human Genome Project
5 Human Genetics and the Human Genome Project
Pages 88-107
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From page 88... ...
The transcripts of most, but not all, genes are then translated into proteins, which are composed of amino acid sequences and which perform most of the cell's functions by virtue of their catalytic activity and the interactions occurring at their specific binding sites. Hence, the gene is required for a phenotypic trait, because it encodes a protein involved in the generation of the trait.
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From page 89... ...
Traits of phenotype that show such easily interpretable patterns of inheritance are called simple, or Mendelian, traits, and these generally are governed by a single genetic locus. However, the relationship between genotype and phenotype is almost always very complex.
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From page 90... ...
POLYMORPHISMS A polymorphism denotes the presence of two or more alleles of a particular gene within a population of organisms; the minority allele is present at a gene frequency of at least 1% (Hartl and Taubes 1998~. That frequency is a somewhat arbitrary cutoff set by population geneticists and minority alleles of still lower frequency are called "rare alleles." In keeping with the Hardy-Weinberg distribution (p2 + 2pq + q2)
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From page 91... ...
, conservative, or located in a region of the protein where any of several amino acids is acceptable, protein activity or stability might not be affected. If a DNA sequence change occurs in the transcribed region of the gene but not in the coding region, it might affect the reading frame, splicing, mRNA stability, translation efficiency, or transcriptional regulation.
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From page 92... ...
. The functional analysis of the genome, in terms of the time and place of expression of genes and the functions of the gene products, is sometimes called "functional genomics" or even "post-genomics." The analysis of a protein's function might be simple if the protein sequence resembles that of another well-understood protein and might be difficult if sequence motifs are absent.
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From page 93... ...
The sequencing of the mouse genome is running well ahead of schedule. New technologies, resources, and applications have become increasingly available to researchers of many diverse scientific fields, including cancer research, drug discovery, medical genetics, and environmental genetics, and their availability should also accelerate numerous major advances in developmental toxicology in the next decade, as discussed later in this chapter.
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From page 94... ...
DNA microarray techniques recently have made possible the description of simultaneous changes of thousands of genes as cells and tissues undergo development or various changes of environmental conditions. In the study of toxicant effects on the organism, the analysis sometimes is called "toxicogenomics" or, in the study of the effects of pharmaceuticals, "pharmacogenomics." DNA microarray approaches are gaining widespread use (see Nuwaysir et al.
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From page 95... ...
The RNAs are then mixed and added to the microarray slide (in their case, carrying 8,900 human DNA sequences) under conditions suitable for RNADNA hybridization, and then washed to remove unbound RNA.
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From page 96... ...
toxicants can be grouped by their similarities of effect, and the analysis of toxicant action can be pursued on a more systematic basis. The DNA microarray method is already in use to compare normal cells and cancer cells.
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From page 97... ...
Although the various microarray techniques promise to reveal exciting new information about where, when, and under what conditions the genes of the genome are transcribed, this approach will not provide information concerning the translation and post-translational modification of proteins encoded by these mRNAs that is, information about when and where the proteins are present and active. Protein function is almost always the immediate cause of cell function.
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From page 98... ...
They also provide sequences for functional analysis by way of DNA microarrays. As data are obtained, they are entered on the CGAP Web site for ready access and use by other investigators and for integration with other data in the large repository.
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From page 99... ...
Management of Genome Sequence and Functional Genomics Data The explosion of molecular biology in the past two decades has led to enormous advances in DNA sequencing, which in turn has led to the increasingly rapid identification of genes as ORFs and as EST sites and the identification of the function of gene products by sequence motifs (e.g., homeodomains, zincfinger domains, kinase domains, and SH2 and SH3 domains)
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From page 100... ...
The EMBL Nucleotide Sequence Database, which originated in 1982, is now maintained by the European Bioinformatics Institute (EBI) , located near Cambridge, England which also oversees the SWISS-PROT Protein Sequence Database and more than 30 other specialty databases.
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From page 101... ...
These categories include single gene causation, chromosomal causation, multifactorial causation with high heritability, multifactorial causation with low heritability, infectious causes, and environmental causes (Khoury et al.
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From page 102... ...
was 8.7, a 10-fold increase compared with infants of smoking mothers who did not have this variant allele. The variant allele alone was not associated with increased risk for oral clefts.
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From page 103... ...
As those four examples indicate, further investigation of gene-environment interactions using the tools of molecular epidemiology is likely to yield important new information on multifactorial causes of developmental defects. Two of the above-cited examples concern polymorphisms of genes encoding enzymes involved in the metabolism of an agent, namely, phenytoin or alcohol, and two of the examples concern polymorphisms of genes encoding protein intermediates of signal transduction pathways and genetic regulatory circuits (TGFa or MSX1)
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From page 104... ...
It seems likely that the fetus is at increased risk of developmental defects, because either the mother or the fetus cannot metabolize chemicals as well as others can or because they metabolize them better. The other large area to investigate for the correlation of polymorphisms with developmental defects is that of the components of the developmental processes themselves, namely, key components of developmental processes, such as those of signal transduction pathways and genetic regulatory circuits.
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From page 105... ...
Epoxide hydrolase (HYL1) Atypical alcohol dehydrogenase (ADH)
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From page 106... ...
Whether allelic variants of genes controlling development, such as those encoding components of the major signal transduction pathways, will be more important, as important, or less important than those controlling DMEs remains to be determined and should be given high priority for future research.
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From page 107... ...
Other kinds of gene products that might be important in susceptibility but are less well known, include components of developmental processes, particularly the components of signal transduction pathways and genetic regulatory circuits. These components will be discussed in later chapters.
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