The advances of the Human Genome Project have renewed appreciation and interest in the study of naturally occurring variation in the human genome.
About 90% of human DNA variation is due to single nucleotide base changes.
On average, a single base-pair difference between two human genomes is observed every 1000 base pairs.
But the odds of finding a difference may be as much as 100-fold greater in some regions of the genome than in others.
Single nucleotide polymorphisms (SNPs) are defined as loci with alleles that differ at a single base, with the rarer allele having a frequency of at least 1% in a random set of individuals in a population.
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In general, the likelihood of finding a SNP is much higher in noncoding regions than in coding regions. (A SNP in a coding region is sometimes called a cSNP.)
Approximately 10 million SNPs are estimated to be present in humans, and a major international initiative is focused on identifying the common SNP haplotypes throughout the genome in four populations.
SNPs provide the population geneticist with a much larger set of densely mapped polymorphisms with low mutation rates for reconciling genome variation with population histories of bottlenecks, admixture, and migration.
Moreover, the knowledge gained from these studies will be applicable to many genetic disciplines including forensics, pharmacogenomics, and complex disease research.
Most SNPs found in the human genome are thought to have originated long after speciation but before the separation into different human populations.
This explains the observation that human SNPs are usually not shared with primates but are common to all populations; only about 15% are thought to be "private".
Also, only a few of the SNP alleles that were present when humans moved out of Africa have become fixed (either 0% or 100%) at this point in time.
Earlier in this chapter, the concept of linkage disequilibrium (LD) was described, and it was mentioned that studies exploiting this phenomenon have been helpful in defining the precise location of disease genes.
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The construction of SNP haplotypes is enabling the identification of regions of strong LD.
This feature of the genome may mean that LD-based association studies will be successful in mapping genes that contribute to common disease phenotypes and to differences in drug response among individuals.
However, the complexity of patterns of LD and the extent and explanation of variability among populations are critical factors that are far from being understood.
The answers to questions concerning these factors as well as the usefulness of SNP haplotypes and LD patterns as tools for identifying genes involved in the etiology of common human disorders, specifically complex disorders, are currently being explored both methodologically and empirically.
Summary
1. Hardy-Weinberg equilibrium at a single autosomal locus is established in one generation of random mating.
2. The carrier frequency for a rare, autosomal recessive disease is approximately twice the square root of the disease frequency in the population.
3. Equilibrium at an X-linked locus is not reached in one generation.
The equilibrium allele frequency is two thirds of the frequency in females plus one third of the frequency in males.
4. A population that is in equilibrium with respect to two loci considered jointly must be in equilibrium with respect to each locus separately, but the converse is not true.
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5. Linkage does not imply linkage disequilibrium and vice versa.
In other words, D may be zero for linked loci, and D may be different from zero for unlinked loci.
6. The effect of inbreeding in a population is to increase the frequency of homozygotes and decrease the frequency of heterozygotes.
The genotype frequencies are not in Hardy-Weinberg proportions, but the allele frequencies are not affected.
7. Random genetic drift is the change in allele frequencies that occurs from one generation to the next in small populations by chance.
The eventual result of random drift is fixation or loss of each allele in the initial population.
Like inbreeding, random genetic drift can lead to an excess of homozygotes at the expense of heterozygotes.
8. Founder effect is a special case of random genetic drift in which population size is severely reduced by such events as famine, disease epidemics, or migration of a small subset of individuals to a new homeland.
9. Mutations are the source of variation in a population and lead to changes in allele frequencies and increased heterozygosity.
However, mutation pressure alone is a very weak evolutionary force.
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10. The effect of selection on allele frequencies depends on the relative fitnesses of the genotypes.
In general, selection will lead to the eventual loss of an allele, but a large number of generations of selection may be required.
However, if selection favors the heterozygote over both homozygotes, equilibrium allele frequencies will be reached.
Migration (gene flow), like mutation, increases heterozygosity in a population.
It can lead to substantial changes in allele frequencies over short periods of time.
11. Ethnic diversity in allele frequencies is a result of mutation, random genetic drift, selection, and gene flow.
Analysis of this diversity provides inferences about evolutionary patterns.
In addition, population genetic studies provide insight into the mechanisms by which certain disease alleles have become more frequent in some populations than in
others.
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