This is old lecture 14 with some added material on polygenic inheritance
from old lecture 8. Material on eugenics has been moved to lecture 40
this year.
Revised September 13, 1998
Textbook Assignment: Chapter 4, Pages 95-100; Chapter 7, Pages 180-194.
Major concepts:
Introduction: This lecture combines introductory material on continuous variation and polygenic inheritance from Chapter 4 (pages 95-100) with more advanced coverage of those topics from chapter 7 (pages 186-194). It also introduces a number of other topics related to variable phenotypic expression from Chapter 7 (pages 180-186).
Possible problems: After being frustrated by fragmentation of topics in the textbook last year, I decided to bring related materials together in the lecture schedule whenever possible this year. This will cause some minor problems based on your need to understand some of the material that the text book introduces between the sections we are combining. However, I will attempt to fill in the missing information in the notes and the lectures.. If I miss any essential background explanations, please call my attention to them.
Continuous variation: Continuous variation occurs when a phenotypic trait is governed by the additive effects of multiple alleles at several different loci. These effects are usually seen in traits like the color of wheat seeds or the heights of individual plants. We only have time for a rather brief coverage of these topics. The main points to be learned are 1) that many traits are controlled by multiple genes whose effects are more or less additive; and 2) that the interplay of genetics and environment makes it difficult to determine the extent to which continuously variable traits are inherited.
Eugenics: Later in the semester (lecture 40), we will examine early attempts to control polygenic variables in human populations, which proved to be far more complex and controversial than originally anticipated by its advocates. At that time, we will review some of the serious offenses have been committed in the name of eugenics (the supposed "science" of improving the human population genetically), as well as the major ethical questions that are raised by our ability to alter patterns of human heredity.
Additive effects: The example of incomplete dominance in flower color that we examined in lecture 7 probably reflects the same basic phenomenon as continuous variation, except that only a single genetic locus is involved. This limits the number of levels of color intensity that can be achieved to 3, making them easy to distinguish as discrete and discontinuous steps.. With two separate loci whose alleles exhibit partial dominance and additive effects, it is possible to obtain 5 shades of color (Fig. 4.14), which begin to blend together, particularly if there is some phenotypic variation within each of the five genetically determined classes.
Multiple gene pairs: As the number of gene pairs at separate loci is increased, the number of different discrete steps increases, such that they become increasingly difficult to distinguish from one another (Fig. 4.15). In addition, the extreme phenotypes (all red or all shite in the example in Fig 4.15) become increasingly rare, so nearly all of the individually observed phenotypes are distributed around a median value that reflects the relative frequency of the two classes of alleles. (Table 4.4)
Importance of polygenic control: Many traits that are important in agriculture appear to be under polygenic control, such as height, weight, crop yields, etc. Many human traits are probably also under polygenic control, including skin pigmentation, obesity, intelligence, and predisposition to certain diseases. There is an unfortunate tendancy to try to oversimplify such relationships, particularly in cases where there are also major non-genetic influences, such as nutrition, environmental exposures, etc. We will return to this theme later in the semester when we discuss eugenics.
Mathematical formulations: Much of the material related to polygenic inheritance and heritability tends to be expressed in complex mathematical formulati ns. For this course, you will not need to learn the mathematical forumlations in greater detail than they are presented in these notes.
Quantitative genetics:: As the number of genetic loci involved increases, the number of intermediate states also increases. Wheat is particularly well suited for such studies because of the common occurrence of allopolyploid strains (derived originally by combining two or more separate genomes, as will be discussed in a future lecture). If two separate loci contribute equally to color, a total of four alleles are involved. Five shades of color can be recognized with F2 ratios of 1:4:6:4:1 for the presence of 0, 1, 2, 3, or 4 alleles that contribute to color intensity (Fig 4.14, page 98). When three loci are involved, seven shades can be recognized with F2 ratios of 1:6:15:20:15:6:1 for zero to six color producing alleles, as shown in Fig. 4.15. When generalized for n loci, the total number of alleles involved is 2n and the total number of different F2 phenotypes is 2n+1 (Table 4.4). The phenotypic ratios are determined by the binomial coefficients with n equal to the number of alleles involved (twice the number of loci).
Statistical approaches: As the number of loci influencing a trait increases beyond 3 (and sometimes even before that number is reached), the individual steps become increasingly difficult to distinguish and the distribution of intensities begins to appear to be continuous (Fig. 4.15). In cases where all of the loci contribute equally to the final result, higher order binomial expansions generate a bell-shaped normal curve for the distribution of intensities around a mean value. In such cases, the distribution is described as continuous and the pattern of inheritance is said to be polygenic or quantitative. In addition, because a normal curve based on the binomial expansion is involved, many of the standard tools and terminology of statistical analysis are used to evaluate quantitative inheritance.
Shapes of distributions: We do not have time to get into the detailed mathematics of statistical distributions, which are presented in brief outline in the textbook. One key feature that we need to examine, however, is the shape of a distribution around a mean value (Fig. 7.8a). The mean is simply the arithmetic average of all of the individual values. However, within the family of possible bell-shaped normal distributions, the width of the curve relative to its height will be determined by the amount of variation from the mean. Several different parameters, variance, standard deviation, and standard error of the mean, are used to describe the extent of variation. All of them are derived from the variance, which is obtained by summation of the squares of all of the individual deviations from the mean and dividing by the the sample size minus one (pages 189-190). Squaring the deviations makes larger deviations count more than small ones, and also makes all values positive. An alternative value that is often used is the standard deviation, which is simply the square root of the variance.
Heritability: One of the key issues in quantitative genetics is the extent to which a continuous variable is influenced by inheritance, as opposed to environmental or chance effects. This is often expressed as heritability. Mathematical calculations of heritability become quite complex and involve many assumptions that we do not have time to go into. In general, heritability describes the fraction of total observed phenotypic variance that can be ascribed specifically to genetic factors. In animal breeding experiments, it becomes important to know how much a particular trait can be enhanced by selective breeding of individuals that express the trait strongly. Table 7.4 provides estimates of the degree of heritability of a number of traits in domestic and laboratory animals.
Human quantitative genetics: Studies of quantitative genetics are particularly difficult in humans because controlled matings cannot be done. One of the favorite tools of geneticists is to examine concordance of twins, with particular emphasis on identical twins that have been reared apart, which minimizes possible effects of growing up in similar environments. Table 7.5 lists a number of human phenotypic phenomena and their relative concordance in identical and fraternal twins. We will return to issues related to human quantitative genetics when we analyze eugenics in lecture 40.
Variable phenotypic expression: We are jumping now to the first part of Chapter 7 (pages 180-186). Thus far in the course, we have assumed that phenotype is strictly determined by dominance and recessiveness relationships in the genotype of an organism, with some further modifications due to genetic interactions such as epistasis, as well as additive effects in polygenic inheritance. However, as will be illustrated below, there are many cases in which environmental influences and other variables that remain poorly understood can alter the relationship between genotype and phenotype, as well as the extent of expression of the phenotype.
Penetrance: For some genotypes, the expected phenotype is not always expressed. This phenomenon is referred to as penetrance, which is defined as the fraction of individuals with a particular genotype that express at least some degree of the expected phenotype. As an example, a genetic predisposition to cancer is not expressed in everyone with the genotype. Thus, for genotypes known to have less than 100% penetrance, it is not safe to assume that absence of the phenotype means absence of the genotype.
Expressivity: Among those individuals that express a phenotype to some extent, the intensity of the expression is referred to expressivity. The textbook cites the variable expressivity of the eyeless mutation in Drosophila. Another good example is the expression of genes that cause white spotting in mice and various other animals, such as cats, in which the area of pigmentation loss can vary greatly from one individual to another. Expressivity is also very much influenced by environmental factors, such as temperature of various body parts, as will be discussed below.
Suppression: Gene products usually have their effects as a result of complex interactions with other gene products. Thus, there are many situations in which a change in a second gene product can alter the phenotypic response to a change in the product coded by a particular gene. When this results in the reversal of phenotypic effects, it is referred to as suppression. The textbook cites examples of suppressor mutations that reverse the effects of several mutations in Drosophila. Suppressors are also known in bacterial genetics. For example, nonsense mutations, such as amber, cause premature termination of translation by introducing stop codons into coding sequences. The corresponding suppressor strains have altered transfer-RNAs that can sometimes misread the stop codons as specifying the insertion of an amino acid, which allows a full-length protein to be synthesized, and can restore function if the inserted amino acid is an adequate replacement for the one originally specified by the coding sequence.
Position effects: Chromosomal rearrangements that place a gene in a different environment can sometimes alter the expression of that gene without any direct effect on the coding sequence. Thus, for example, if a gene is close to a heterochromatic region of a chromosome (an area in which the chromatin tends to stay more condensed), the intensity of its expression can be reduced. The example cited in the textbook is the wild-type allele of the white eye locus in Drosophila, which becomes only partially dominant in a heterozygote when placed adjacent to a heterochromatic area of the X-chromosome. (The white-eyed locus is sex-linked, and thus is normally found on the X-chromosome. The effect being described here results from moving it to a different region on the X-chromosome).
Temperature effects: Many mutations are known that confer temperature sensitivity on phenotypic expression. In the most common cases, a gene product is functional at a lower temperature and loses function at a higher temperature. This generally reflects loss of heat stability of a functional protein (usually an enzyme) due to an amino acid substitution. Such mutations are referred to as conditional or temperature sensitive. The temperature at which normal function is retained is referred to as permissive, and that at which function is lost as restrictive (or non-permissive). The ability to produce temperature sensitive mutations makes it possible to assemble collections of mutations that are lethal at restrictive temperatures, but capable of being maintained as genetic stocks at permissive temperatures. This allows analysis of genetic control over many processes that are essential for survival and could not otherwise be studied because of lethality.
Siamese cats and Himalayan rabbits: Two common examples of temperature sensitivity are seen in Siamese cats and Himalayan rabbits. In both cases, pigment production is temperature sensitive and occurs only in extremities such as ears, nose and limbs that have a lower surface temperature than the main part of the body (see figure 7.3 in the textbook). .
Nutritional effects: The textbook introduces a variety of other conditional mutations at this point, including auxotrophic mutations in molds and bacteria. These are mutations that render the bacteria unable to synthesize an essential nutrient, such as an amino acid or vitamin that wild-type mold cells are capable of synthesizing, and thus render the mutant strain dependent on an external source of that nutrient for growth. Several metabolic diseases are also discussed in which pathology is experienced only in response to certain nutrients, which can be avoided by careful dietary planning. One example is phenylketonuria. This autosomal recessive metabolic disease causes severe pathology, including mental retardation if left untreated. However, most of the effects can be avoided if an afflicted newborn is quickly placed on a diet that contains a greatly reduced amount of phenylalanine.
Time of onset of genetic expression: Many sequential changes in gene expression occur during embryonic and fetal development, and some of these continue into post-natal and adult life. Thus, many inherited human genetic diseases are not expressed at birth and only become evident later in life.
Huntington disease and other triplet repeats: Under the heading of "Genetic Anticipation", the textbook introduces several human diseases that tend to become more severe as they are inherited from generation to generation. These diseases are associated with the presence of trinucleotide repeats in coding sequences, which result in long strings of the same amino acid in proteins. Typically, the normal gene contains a substantial number of trinucleotide repeats, with a much larger number in the diseased state. Recent studies on Huntington's disease have provided a good example.
Increased numbers of triplet repeats. In the case of Huntington's disease, the gene that is involved codes for a protein that normally contains approximately 3144 amino acids, including a sequence of about 23 glutamines in a row, coded for by CAG repeats in the coding sequence. (Total size and number of repeats reported here reflect the first "normal" gene isolated). Studies of Huntington's disease patients have revealed the presence of 42-100 repeats, whereas normal controls have been found to have between 11 and 34 repeats, with 98% of unaffected people having under 24.
Paternal inheritance: The onset of Huntington disease tends to be earlier in individuals who inherit it from their fathers and somewhat later in individuals who inherit it from their mothers. Similar phenomena are also observed for other triplet repeat diseases, although in some cases, such as myotonic dystrophy, earlier onset is associated with maternal inheritance. These phenomena are often cited as examples of imprinting (discussed below), but molecular studies of the mechanisms that are involved make it difficult to describe the differences in such terms.
Changes in numbers of repeats: Detailed analysis has demonstrated that the time of onset is directly related to the number of triplet repeats, which tends to increase from one generation to the next (presumably reflecting mispairing during crossing over). For Huntington disease, it has been shown specifically that there is more liklihood of a substantial increase in the number of triplet repeats in the progeny of afflicted males than of afflicted females. Thus, the observed differences in time of onset involve actual changes in genetic coding and probably should not be called imprinting, even though our textbook discusses it under that heading.
Imprinting: Imprinting is a phenomenon in which a gene behaves differently when inherited from one parent than from the other. Typically one copy of the gene is totally inactivated, such that the individual has only one functional copy of that gene. This phenomenon is similar in some ways to the inactivation of one of the X-chromosomes in each cell of most female mammals (including human females), which will be discussed in the next lecture. However, it differs in two important aspects: the effect is on single genes rather than an entire chromosome, and the inactivation is specific for the copy of the gene from one of the parents, rather than being randomly determined. Depending on the individual gene, it can be either the maternal or the paternal copy that is inactivated. (As an aside, it should be noted that in certain species, such as kangaroos, the X chromosome derived from the father is uniformly inactivated in all cells of female progeny. However, such patterns are the exception, rather than the rule, among mammals in general.)
Insulin-like growth factor-II (IGF-II): One of the better studied examples of imprinting is the Igf2 gene in mice, which codes for IGF-II. This is a particularly convenient system to use for studying imprinting, since Igf2 knockout mice (which totally lack the ability to synthesize IGF-II) have been generated and found to be smaller than normal, but both viable and fertile. Crosses of these mice with wild-type mice have verified that imprinting occurs and have shown that the maternally-derived gene is the one that is inactivated. The Igf2 phenotype of a mouse is always determined by the allele inherited from the father, with no phenotypic effect whatsoever from the maternal allele. Thus, the progeny of an Igf2-minus father and a wild-type mother will all be dwarf despite the fact that they carry an inactivated wild-type allele from their mother. Conversely, the progeny of a mutant mother and a wild-type father will always be normal sized.
Reactivation in the male: Imprinting does not involve any change in the coding sequence of the gene. When a dwarf male mouse that carries a paternally-derived Igf2-minus allele and an inactivated maternally-derived wild-type allele is mated to any type of female, half of the progeny will be normal sized due to reactivation of the maternally-derived wild-type allele that is now passed to the progeny from the male, and the other half will be dwarf due to the mutant allele passed to them from the male. Because of imprinting, the genotype of the mother has no effect on the phenotype of her progeny in such a cross.
Nomenclature of imprinting: Be sure that you understand how to describe imprinting. The allele that is TURNED OFF is said to be imprinted. Do not use the term "imprinted" to describe the allele that remains active!
Mechanism: The exact mechanism responsible for imprinting is not yet fully understood, but there are data suggesting that methylation may be involved. Whatever the mechanism may be, it is fully reversible when an inactivated gene passes through a parent of the opposite sex. Also, some imprinted genes are inactivated in the female, while others are inactivated in the male. Thus, the gene for the IGF-II receptor, which is also subject to imprinting, is expressed from the maternal chromosome, with the paternal copy inactivated.
The need for genomes from two parents: Because imprinting turns off different sets of genes in gametes derived from each sex, it is absolutely essential for an embryo to receive both a maternally-derived genome and a paternally-derived genome. Experiments in which two haploid nuclei from the same sex are artificially introduced into activated mouse eggs have shown that normal development cannot be obtained either in embryos with two maternal genomes (gynogenones) or in embryos with two paternal genomes (androgenones).
Uniparental disomies: In more sophisticated manipulations, embryos have been generated that contain complete genomes from both parents, except that both copies of one particular chromosome are from the same parent. These experiments suggest that the total number of imprinted genes is probably relatively small. One such study was done with mouse chromosome 11, which carries the Igf2 gene. Embryos with maternal disomy 11 are smaller than normal, whereas embryos with paternal disomy 11 are larger than normal. These results are consistent with the presence of maternal imprinting of the Igf2 gene and a normal pattern of expression of only one copy of that gene. Thus, when two non-imprinted paternally-derived copies are present, the embryos become larger than normal. The data also suggest that no other chromosome 11 genes are subject to imprinting, since no effects other than differences in size are observed in the uniparental disomies.