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ScienceWeek
GENOME BIOLOGY: ON HUMAN GENETIC VARIANTS
Notes by ScienceWeek
A genetic polymorphism is a naturally occurring variation in the normal nucleotide sequence of the genome within individuals in a population, and an allele is one of two or more forms of a given gene that control a particular characteristic, with the alternative forms occupying corresponding loci on homologous chromosomes. Variations are denoted as polymorphisms only if they cannot be accounted for by recurrent mutation and occur with a frequency of at least about 1%. In general, perverse polymorphisms (as opposed to benign polymorphisms) are genetic variations that are linked to pathological processes.
The following points are made by Greg Gibson (Current Biology 2003 13:R901):
1) Each of us differs from one another by several million snippets of genetic information, and untold millions of life experiences. Out of this complex milieu of variation arise propensities that define our individuality -- whether we are likely to suffer from heart disease or depression, explore new worlds or perform great athletic exploits, find contentment raising six kids or discontent working 80 hour weeks. The "promise" of post-genome human genetics is that we should be able to pinpoint the dozen or so genetic variants that affect any particular predisposition, and as if that is not enough, decipher how and why we differ from our closest primate relatives.
2) For the past decade or so, the accepted approach to this problem has been some combination of linkage and association mapping [1]. Every year, for hundreds of complex human diseases, several studies are published documenting success or failure in the effort to implicate a candidate gene with the condition. Classical linkage studies are conducted on pedigrees, and basically ask whether affected relatives are more likely to share alleles by descent than are unaffecteds. They can localize a genetic factor to a chromosomal interval, but more resolution is now provided by so-called "linkage disequilibrium mapping" [2]. This can take the form of population-based case/control studies -- which basically ask, Is a particular single nucleotide polymorphism (SNP) over-represented among individuals with or without the disease? -- or family-based transmission disequilibrium methods -- for example, Do heterozygous parents transmit both alleles to affected offspring with equal frequency? Sample sizes of several hundred affecteds are required to attain even marginal significance for an association that might explain several percent of the population attributable risk, but replication across multiple studies is required before a finding begins to be taken seriously.
3) Rockman et al.[3] argue that population genetic approaches might be used to identify candidate disease-promoting polymorphisms. On the widely accepted assumption that common diseases are caused by common polymorphisms that are nevertheless relatively young in the human gene pool, they suggest that different populations will tend to show different allele frequencies [4] as the species as a whole is not at genetic equilibrium. Their strategy is to search for SNPs that disrupt highly conserved regulatory sequences. If these occur in likely transcription factor binding sites, they then ask whether the SNP frequency varies more than expected by chance among populations.(5)
References (abridged):
1. Hoh, J. and Ott, J. (2003). Mathematical multi-locus approaches to localizing complex human trait genes. Nat. Rev. Genet. 4, 701-709
2. Clark, A.G. (2003). Finding genes underlying risk of complex disease by linkage disequilibrium mapping. Curr. Opin. Genet. Dev. 13, 296-302
3. Rockman, M.V., Hahn, M.W., Soranzo, N., Goldstein, D.B., and Wray, G.A. (2003). Positive selection on a human-specific transcription factor binding site regulating IL4 expression. Curr. Biol. 13,2118-2123
4 Lewontin, R.C. and Krakauer, J. (1973). Distribution of gene frequency as a test of the theory of the selective neutrality of polymorphisms. Genetics 74, 175-195
5 Rosenwasser, L.J. and Borish, L. (1997). Genetics of atopy and asthma: the rationale behind promoter-based candidate gene studies. Am. J. Respir. Crit. Care Med. 156, S152-S155
Current Biology http://www.current-biology.com
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GENOMIC MEDICINE: CARDIOVASCULAR DISEASE
The following points are made by Elizabeth G. Nabel (New Engl. J. Med. 2003 349:60
1) Cardiovascular disease, including stroke, is the leading cause of illness and death in the US. There are an estimated 62 million people with cardiovascular disease and 50 million people with hypertension in the US. In 2000, approximately 946,000 deaths were attributable to cardiovascular disease, accounting for 39 percent of all deaths in the US. Epidemiologic studies and randomized clinical trials have provided compelling evidence that coronary heart disease is largely preventable. However, there is also reason to believe that there is a heritable component to the disease. As future genomic discoveries are translated to the care of patients with cardiovascular disease, it is likely that what we can do will change.
2) Our understanding of the mechanism by which single genes can cause disease, even though such mechanisms are uncommon, has led to an understanding of the pathophysiological basis of more common cardiovascular diseases, which clearly are genetically complex. This point can be illustrated by a description of the genetic basis of specific diseases.
3) Low-density *lipoprotein (LDL) is the major cholesterol-carrying lipoprotein in plasma and is the causal agent in many forms of coronary heart disease. Four monogenic diseases elevate plasma levels of LDL by impairing the activity of hepatic LDL receptors, which normally clear LDL from the plasma. Familial hypercholesterolemia was the first monogenic disorder shown to cause elevated plasma cholesterol levels. The primary defect in familial hypercholesterolemia is a deficit of LDL receptors, and more than 600 mutations in the LDLR gene have been identified in patients with this disorder. One in 500 people is *heterozygous for at least one such mutation, whereas only 1 in a million is *homozygous at a single locus. Those who are heterozygous produce half the normal number of LDL receptors, leading to an increase in plasma LDL levels by a factor of 2 or 3, whereas LDL levels in those who are homozygous are 6 to 10 times normal levels. Homozygous persons have severe coronary *atherosclerosis and usually die in childhood from *myocardial infarction.
4) Deficiency of lipoprotein transport abolishes transporter activity, resulting in elevated cholesterol absorption and LDL synthesis. For example, mutations in the APOB-100 gene, which encodes apolipoprotein B-100, reduce the binding of apolipoprotein B-100 to LDL receptors and slow the clearance of plasma LDL, causing a disorder known as familial ligand-defective apolipoprotein B-100. One in 1000 people is heterozygous for one of these mutations; lipid profiles and clinical disease in such persons are similar to those of persons heterozygous for a mutation causing familial hypercholesterolemia.
5) Sitosterolemia, a rare *autosomal disorder, results from loss-of-function mutations in genes encoding two ATP-binding cassette (ABC) transporters, ABC G5 and ABC G8, which act in concert to export cholesterol into the intestinal lumen, thereby diminishing cholesterol absorption. Autosomal recessive hypercholesterolemia is extremely rare (prevalence, less than 1 case per 10 million persons). The molecular cause is the presence of defects in a putative hepatic adaptor protein, which then fails to clear plasma LDL with LDL receptors. Mutations in the gene encoding that protein (ARH) elevate plasma LDL to levels similar to those seen in homozygous familial hypercholesterolemia.(1-5)
References (abridged):
1. NHLBI morbidity and mortality chartbook, 2002. Bethesda, Md.: National Heart, Lung, and Blood Institute, May 2002. (Accessed June 10, 2003, at http://www.nhlbi.nih.gov/resources/docs/cht-book.htm.)
2. NHLBI fact book, fiscal year 2002. Bethesda, Md.: National Heart, Lung, and Blood Institute, February 2003. (Accessed June 10, 2003, at http://www.nhlbi.nih.gov/about/factpdf.htm.)
3, Cooper R, Cutler J, Desvignes-Nickens P, et al. Trends and disparities in coronary heart disease, stroke, and other cardiovascular diseases in the United States: findings of the National Conference on Cardiovascular Disease Prevention. Circulation 2000;102:3137-3147.[Abstract/Full Text]
4. Goldstein JL, Brown MS. The cholesterol quartet. Science 2001;292:1310-1312.[Full Text]
5. Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic & molecular bases of inherited disease. 8th ed. Vol. 2. New York: McGraw-Hill, 2001:2863-913.
New Engl. J. Med. http://www.nejm.org
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Notes by ScienceWeek
atherosclerosis: "Arteriosclerosis" is a generic term for several diseases in which the arterial wall becomes thickened and loses elasticity, and "atherosclerosis" is a form of arteriosclerosis characterized by patchy thickening (atheroma) in the subintimal layer (i.e., immediately below the innermost layer [intima]) of medium and large arteries, the thickening capable of reducing or obstructing blood flow.
autosomal disorder: In general, a genetic disorder involving one or more chromosomes that are not sex chromosomes.
heterozygous: Having two different alleles at a specific autosomal (or X chromosome in a female) gene locus.
homozygous: Having two identical alleles at a specific autosomal (or X chromosome in a female) gene locus.
lipoprotein: In general, a micellar complex of protein and lipids.
myocardial infarction: In general, an area of necrosis of cardiac tissue resulting from a sudden insufficiency of arterial or venous blood supply. The most common cause is thrombosis of an atherosclerotic coronary artery.
ScienceWeek http://scienceweek.com
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