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Genes through families and populations Linkage and Mapping REFERENCES Textbooks: Gelehrter, Collins, and Ginsburg, Chapter 9, 10 Strachan and Read: Chapters 11, 12, 13 Gelehrter, Collins, and Ginsburg, Chapters 3, 4 Strachan and Read: Chapter 3 Important terms in linkage and mapping Use of informatics in human genetics SUMMARY The study of genes in families and in populations is the study of human variation and of the principles which govern the role which genes play in determining that variation. The frequency of any given gene in a population determines how often the effects of that gene will be seen. The rules of Mendelian inheritance determine the patterns with which the effects of any given gene will be seen within a family. The distribution of genes in populations and in families obeys mathematical rules which allow for calculations which approximate these frequencies. As the number of genes under consideration increases, the complexity of the mathematics does as well. When several genes in large families or in large populations are being considered, the mathematical treatment requires sophisticated computer programs. Such programs are also helpful in testing models of inheritance of traits for which the modes of inheritance have not been determined. The goal of these lectures is to review the principles of Mendelian inheritance and the behavior of genes in populations, with particular attention to human genes which are important in determining disease. This should allow the student to calculate simple risks for the appearance of genetic traits in families or populations and to understand the uses of such calculations. Autosomal dominant: •Except for new mutations, every affected child has an affected parent •Affected persons are usually heterozygous •Each child of an affected person has a 50% chance of inherited the gene •The two sexes are affected in equal numbers Autosomal recessive: •Both parents of an affected person are heterozygous for the mutant gene •Heterozygotes can sometimes be detected using special tests •For rare traits there is a high frequency of consanguinity •Each sibling of an affected person has a 25% chance of being affected •Each phenotypically normal person has a 2/3 chance of being heterozygous •The two sexes are affected in equal numbers If the recessive genes are allelic, all children of affected parents are affected •An affected person may have two different mutations at the locus involved X-linked recessive •Males carrying the mutant gene show the trait •Females carrying the mutant gene generally do not show the trait •Heterozygous mothers have a 50% chance to transmit the gene to each son or daughter •Hemizygous affected males transmit the gene to all their daughters but none of their sons •The gene frequency in females is about twice that in males X-linked dominant Both males and females carrying the mutant gene show the trait •Heterozygous mothers have a 50% chance to transmit the gene to each son and daughter •Hemizygous affected males transmit the gene to all their daughters but to none of their sons •The gene frequency in females is about twice that in males The Hardy-Weinberg Equilibrium p+q=1 where p=frequency of the one allele; q=frequency of the other allele (p+q)2 is a special case of the binomial theorem (x+y)n where n=2 because a person is a random sample of alleles, taken 2 at a time. This binomial expression can be expanded to p2+2pq+q2=1 if p is a normal allele and q is a mutant allele at that locus Homozygous normal (p*p) or p2 Homozygous affected (q*q) or q2 Heterozygous (p*q*2) or 2pq The conditions under which equilibrium is reached and the Hardy-Weinberg proportions apply are the following: •Random mating •Large population size •No selection of the alleles under consideration •No significant mutation •No migration Obviously no real population meets these constraints precisely, so the use of the Hardy-Weinberg equation is necessarily an approximation. However, very large deviations from the ideal conditions noted above are required to cause major differences in the results of Hardy-Weinberg calculations. Note that with random mating the allele frequencies remain the same generation after generation. This constancy is one very important implication of the Hardy-Weinberg equilibrium, as it leads to the preservation of genetic variation. In human populations, inbreeding represents one of the most important deviations from Hardy-Weinberg equilibrium. As seen above, blood relatives share genes inherited from a common ancestor. Other deviations from Hardy-Weinberg equilibrium include the following: Stratification of the population: A subpopulation within a population can alter the observed gene frequency since the sample is not homogeneous. Assortative mating: Usually the genotype is unknown, but inherited factors can sometimes be observable and thus influence choice of mate. Stature and skin color are but two examples. Unequal viability of gametes: If some gametes do not survive to accomplish fertilization, their genetic contribution will be lost. This is a special case of fitness. The strict definition of fitness for genetic purposes is the ability to reproduce. Genes from an individual will be lost from the population if that individual does not reproduce. If genotype alters the ability to reproduce, it is said to decrease fitness. Mutant genes can lead to selection in favor of the gene or against the gene, in either the homozygous or heterozygous state. If there is complete selection against a recessive phenotype, the frequency of the gene will decreased until the frequency of the gene decreases to the number maintained by mutation. The graph shows the change in gene frequency over 40 generations with complete selection against the homozygote for the recessive gene. Consanguinity The reason that consanguinity in a population or a family leads to an increase in frequency genetic conditions derives from the fact that consanguineous individuals share genes which have been inherited from a common ancestor. If one of the genes inherited from such a common ancestor carries a mutation, then the related individuals will have a higher risk of each carrying a copy of this mutant gene. Thus, if two consanguineous persons have a child, that child has an increased chance, compared to a child born to unrelated people, of being homozygous by descent for this mutant gene. If the mutation, when homozygous, causes an abnormal phenotype, the child will be abnormal. Two terms frequently used to describe consanguinity include coefficient of relationship and coefficient of inbreeding. The coefficient of relationship is the probability that the individuals will share a common gene by descent; the coefficient of inbreeding is the probability that their child will be homozygous for that gene. The reasons for consanguinity include geographic and ethnic. It becomes empirically important when the relationship is that of first cousins, or closer. Linkage and mapping: In the past, chromosomal location of specific genes was made by inference from pedigree information in the case of the X chromosome, and for autosomes by linkage to identifiable markers such as particular proteins. With the development of recombinant DNA technology and the molecular genetic tools which have followed, the specific chromosomal location of many more genes is known, linkage to specific markers has been established, and many genes of clinical importance have been cloned and sequenced. It is likely that within the next two decades, the entire human genome will be mapped and eventually it will be entirely sequenced. The Human Genome Project has been a central part of this effort. This project builds on earlier scientific advances; in addition, it has spawned other projects that build on these advances. Investigator-initiated research, clinical research based on human genetic disease, and serendipitous observations have also made a major contribution. Genetic mapping has made use the concepts of polymorphism and non-random assortment of genes due to linkage. Physical mapping has made use of chromosomal deletions and translocations, in situ hybridization, as well as recombinant DNA techniques. To arrive at the final goal of identification of mutant genes that result in genetic disease requires that mutant DNA be separated out of the rest of the genome of the individual. The gene of interest needs to be identified, separated from the rest of DNA and the disease-causing mutations identified. Genes can be tracked through families and populations. Consider genetic maps and physical maps. Concepts that are important here include linkage, linkage disequilibrium, haplotype (for haploid genotype); restriction analysis; polymorphic Use of LOD scores: While the concepts of linkage analysis are straight forward, the actual analyses often require statistical methods for refinement, particularly when recombination is involved. The landmarks of the map are restriction sites which provide a background upon which mutations have taken place. The usefulness of linked markers depends on their proximity to the gene and mutation of interest. Because recombination can be a confounding problem, markers to either side of the gene (flanking markers) are useful. If the marker is not the gene itself, the possibility of recombination between the gene and the marker exists. The statistical way to handle that problem is by determining the odds that the association took place by chance rather than because of linkage. Because logarithms make this handling simpler, the log of the odds is used, and is called the LOD score. A LOD score of 3 is taken as evidence for linkage. This represents an odds ratio of 1000:1 (log10 of 1000 = 3). The calculations require a consideration of the likelihood of the data if the loci
linked compared to When the day comes that we have the genome sequenced and all disease genes are known, these methods will become obsolete.
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