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Mendelian Genetics 101Last modified on June 1, 2010 Population genetics: the Hardy-Weinburg equilibrium Polygenic characters; quantitative trait loci The Cold Spring Harbor Laboratory has a great online learning site called "DNA From the Beginning", which takes you from Gregor Mendel in 1865 through to the Cre Lox system for conditional gene expression. The mouse has 40 chromosomes, including an XX pair in females and an XY pair in males (in birds, the females are the heterogametic sex). Genes constitute only 2-3% of the DNA, with the remaining 97-98% consisting of repetitive sequences, non-functional "pseudogenes", and small amounts of DNA introduced by viruses. Within a gene, the exon codes for a polypeptide, while the intron appears to be non-coding. Outside the gene there may be DNA sequences, promoters and enhancers, controlling gene expression. During transcription, the exons are pasted together and the introns are discarded.{4535} A mutation occurs when an abnormality occurs in a gene or larger segment of a chromosome, leading to the production of defective gene products. Mutations such as albinism are usually inherited by Mendelian laws. Other characteristics, such as body weight and reproductive performance, may have different genes at several chromosomal locations that control them; these are inherited by polygenic modes. Most polygenic characteristics are also highly susceptible to environmental influences.{4535} There are other, less common, modes of inheritance. Aneuploidy (the total gain or loss of a chromosome) is rare because it is usually fatal. Two chromosomes may fuse, such that one chromosome is much larger than normal and the total number is reduced; this is termed Robertsonian translocation, and has been found in wild rodents. A reciprocal translocation occurs when parts of two chromosomes break and join together; this does not change the chromosome number but may alter the sizes of each chromosome involved. There are also non-chromosomal methods of inheritance, in which characteristics are transmitted vertically through the placenta, cytoplasm, or the milk. The best known of these is the Bittner mammary tumor virus, passed from mother to offspring through the milk.{4535} Monohybrid crossesHere is a reminder of several simple Mendelian modes of inheritance as they are expressed in mouse coat color:{4535} 1. Recessive non-agouti mutant x wild type agouti
Approximately 3/4 of the mice in the F2 generation will be agouti. 2. Dominant mutant (white-bellied agouti) x wild type (agouti)
Approximately 3/4 of the F2 mice will be white-bellied agouti. 3. Dominant homozygous lethal mutation (Ay) resulting from mating two heterozygotes.
Since the homozygous mutants all die in utero, 1/3 of the surviving mice will be agouti, and 2/3 will be yellow. Sex linkageAn example in the mouse of a sex-linked gene is the tabby gene (Ta), carried on the X chromosome. Males that are XTa/Y (hemizygous) have greasy coats. In females, a phenomenon called X-chromosome inactivation occurs. During embryonic development, one of the X chromosomes becomes inactive on a cell-by-cell basis. If a female is heterozygous, i.e. for the tabby gene, she becomes a mosaic of cells, some of which will have the greasy coat phenotype and some of which will have the wild type. This gives the adult a striped coat of alternating hair types, giving a tabby appearance.{4535} Dihybrid crossesDihybrid crosses are those in which the parents differ at two genetic loci. They are used to determine how closely linked the two genes are on a chromosome. The F2 generation of parents will be produced in a 9:3:3:1 ratio if the two genes are not linked closely. For this 9:3:3:1 ratio, the genetic ratios for each gene alone should be examined. If the two genes are unlinked or independent, there will be the standard 3:1 ratio for each. If this 3:1 ratio is not preserved, the genes must be linked in some way. For example, the non-agouti (a) gene and the albino (c) gene are unlinked. A cross between black and albino parents produces the following:
Since the albino allele is epistatic, those F2 offspring that are homozygous cc will be albino, regardless of the agouti allele. Examine the ratios for each gene separately. Assuming you knew that the A-cc mice were agouti, note that the ratio of colored (C-) to albino (cc) is 12:4 (= 3:1), as is the ratio of agouti (A-) to black (aa). Therefore, the genes for albinism and agouti are unlinked.{4535} If the two genes were linked, the overall 9:3:3:1 ratio would be upset, but when considered separately each gene would still occur in a 3:1 ratio. If one of the genes is lethal, the individual 3:1 ratios of the loci would be off.{4535} Linkage maps are constructed by making test crosses and observing the results for polymorphic loci. Crossover events in the chromosomes occur during meiosis. If two alleles are close together on the chromosome, they are more likely to both be involved in the crossover than if they are far apart. Although F1 crosses can be used as described above, it is more efficient to perform a backcross to the wild type, as this allows one to make calculations of the percentage of recombination{4535} The Hardy-Weinburg EquilibriumIn 1908 Hardy and Weinburg independently described a set of genetic laws to calculate the distribution of genetic variants in a population. Such an ideal population is infinitely large, maintained by random mating, and is closed to the introduction of new animals. No selection of offspring occurs, and the gene locus has no effect on viability or reproductive performance. In this idealized situation, the following genetic ratios will be found:
where p= frequency of gene A and q=frequency of gene a=1-p.{4535} Polygenic characters and quantitative trait lociMany characteristics of animals (body weight, organ weights, reproductive performance, metabolic rats, histocompatibility) are governed by polygenes, each of which has a small effect on phenotype and has a Mendelian mode of inheritance. The loci involved are called quantitative trait loci or QTLs. The use of recombinant inbred mouse strains has enabled more information to be gathered about QTLs. In particular, the histocompatibility loci of the mouse have been studied, testing whether skin grafts between animals would survive. The speed of rejection depends mostly on one locus, H2 (which is really a complex cluster of genes), and on 30 minor loci. Mice which differ at either the H2 locus or at several minor loci will reject a skin graft.{4535} Heritability (h2) is the ratio of the portion of variance in a single polygenic characteristic that is due to genetics to the variation of the entire population. Directional selection is a method of selective breeding used to develop several models of importance, such as hypertension in the rat. It utilizes selection of animals that exceed a certain value (i.e. blood pressure) for breeding. Progress toward development of the new strain is measured by the heritability of the trait x the selection differential used. Brother x sister mating should be avoided, as inbreeding tends to decrease genetic variation and heritability, thus eventually limiting the progress that can be made using selection. At least 10 parents from each generation should be selected. Mass selection like this is not very efficient for polygenic characteristics with low heritability, such as reproductive performance.{4535} Inbreeding, the mating of related individuals, is measured in terms of the coefficient of inbreeding (F). This is the probability that two alleles at any given locus (one from each parent) are identical by descent (i.e. both copies of the DNA came from the same ancestor). Inbreeding is obviously associated with high levels of homozygosity. It is also associated with inbreeding depression, a general decline in reproductive performance, vigor and survivability. This is due to the uncovering of deleterious recessive genes as they become homozygous during the inbreeding process. An inbred strain is produced by brother x sister mating for at least 20 generations from a single founding pair. As the strain development progresses, total additive genetic variation approximately doubles when compared to another subline. This means that inbred strains differ from each other more than do individuals of an outbred stock, and are more extreme in their characteristics. This is important when designing experiments: using a range of inbred strains will cover a much wider range of phenotypes than will using many individuals from the same outbred stock.{4535} For more information on breeding systems and maintenance of laboratory animal strains, go to the rodent husbandry page. |