Medical Genetics 06 Polygenic Inheritance Medical Genetics Multifactorial

Medical Genetics 06疾病的多基因遗传 Polygenic Inheritance

Medical Genetics Multifactorial inheritance is responsible for the greatest number of individuals that will need special care or hospitalization because of genetic diseases.

Medical Genetics Up to 10% of newborn children will express a multifactorial disease at some time in their life. Atopic reactions, diabetes, cancer, spina bifida/anencephaly, pyloric stenosis, cleft lip, cleft palate, congenital hip dysplasia, club foot, and a host of other diseases all result from multifactorial inheritance.

Medical Genetics Some of these diseases occur more frequently in males. Others occur more frequently in females. Environmental factors as well as genetic factors are involved.

Medical Genetics 1. REGRESSION TO THE MEAN Multifactorial inheritance was first studied by Galton, a close relative of Darwin and a contemporary of Mendel. Galton established the principle of what he termed "regression to mediocrity. "

Medical Genetics Galton studied the inheritance of continuous characters, height in humans, intelligence in humans, etc.

Medical Genetics Galton noticed that extremely tall fathers tended to have sons shorter than themselves, and extremely short fathers tended to have sons taller than themselves. "Tallness" or "shortness" didn't breed true like they did in Mendel's pea experiments. The offspring seemed to regress to the median, or "mediocrity. "

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Medical Genetics When comparing height differences between men and women, women are, on average, 3 inches shorter. A woman with a certain number of "tall" genes will be, on average, 3 inches shorter than a man with the same number. When that difference is taken into account, there is no selective bias in matings for tallness in human populations.

Medical Genetics It is true than men tend to marry women who are shorter than themselves, but that is a phenotypic difference, not a genotypic difference. Since the wives of taller than average men tend to represent the general population of women, they will not have, on the average, as many "tall" genes to pass on to their offspring as their husbands.

Medical Genetics Hence, the son will receive half of the father's "tall" genes, on average, and half of the mother's "tall" genes, on average, but his total genes for "tallness, " on average, will be less than his father's.

Medical Genetics Shorter than average males have fewer "tall" genes than average, but they are still as tall as an average female, even though the average female has more "tall" genes.

Medical Genetics Their sons, on average, will be taller than their fathers because their mothers have, on average, more "tall" genes to give to their sons than their husbands have. On average, the son will have more "tall" genes than his father.

Medical Genetics 2. POLYGENIC INHERITANCE For many years the argument raged between the "Mendelians" and the "Galtonians" as to which of the two paradigms was the correct one for human inheritance.

Medical Genetics There was no question that Mendelian inheritance was correct for some diseases, but these were rare, affecting only a small portion of the population. They were considered trivial by the Galtonians.

Medical Genetics On the other hand, the inheritance of quantitative traits could not be used to predict outcomes, only average estimates measured in large population studies. Mendelians considered the study of quantitative traits to be trivial because they had no predictive value.

Medical Genetics R. A. Fisher resolved the dispute by showing that the inheritance of quantitative traits can be reduced to Mendelian inheritance at many loci.

Medical Genetics Consider the following: One locus for height, with three alleles. Allele h 2 adds 2 inches to the average 68 -inch height. Allele h 0 neither adds nor subtracts from the average height of 68 inches. And allele h- subtracts 2 inches from the average height. Suppose h 0 is twice as frequent as either h 2 or h-.

Medical Genetics : The Punnett square for the population would be as follows: h 2 MOTHER'S 2 h 0 GAMETES h- FATHER'S GAMETES h 2 2 h 0 hh 2, h 2 2(h 2, h 0) h 2, h 72" 70" 68" 2(h 2, h 0) 4(h 0, h 0) 2(h-, h 0) 70" 68" 66" h 2, h 68" 2(h-, h 0) 66" h-, h 64"

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Medical Genetics If a second locus, called the tall locus, or t, is also involved in height, with three alleles as above, one adding two inches, one neither adding nor subtracting from the phenotype, and one subtracting 2 inches, with the neutral allele occurring twice as frequently as the either of the others, the histogram becomes:

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Medical Genetics 3. THE MULTIFACTORIAL MODEL As more loci are included, this binomial distribution quickly approaches the Gaussian distribution, or the bell-shaped normal curve, observed with human quantitative traits. Three loci, each with three alleles, are enough to produce population frequencies indistinguishable from a normal curve.

Medical Genetics The multifactorial model is then: (1) Several, but not an unlimited number, loci are involved in the expression of the trait. (2) There is no dominance or recessivity at each of these loci. (3) The loci act in concert in an additive fashion, each adding or detracting a small amount from the phenotype. (4) The environment interacts with the genotype to produce the final phenotype.

Medical Genetics 4. THRESHOLD MODEL OF DISEASE If multifactorial traits are quantitative traits with continuous distribution, how can they control diseases, such as cleft lip or spina bifida? One either has the disease or doesn't. There is no intermediate. Multifactorial diseases are best explained by the threshold model.

Medical Genetics The threshold model for multifactorial traits. Below the threshold the trait is not expressed. Individuals above threshold have the disease.

Medical Genetics As the number of multifactorial genes for the trait increases, the liability for the disease increases. When it reaches a threshold, the liability is so great that abnormality, what we call disease, results.

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Medical Genetics For example, consider the development of the cleft palate. Early in embryonic development the palatal arches are in a vertical position. Through embryonic and fetal development the head grows larger, making the arches farther apart, the tongue increases in size, making it more difficult to move, and the arches themselves are growing and turning horizontal.

Medical Genetics There is a critical stage in development by which the two arches must meet and fuse. Head growth, tongue growth, and palatal arch growth are all subject to many genetic and environmental factors.

Medical Genetics If the two arches start to grow in time, grow at the proper rate, and begin to move soon enough to the horizontal they will meet and fuse in spite of head size and tongue growth. The result is no cleft palate.

Medical Genetics They may fuse well ahead of the critical developmental stage or just barely make it in time, we have no way of telling. However, if they don't meet by the critical stage a cleft palate results. If they are close together at the critical stage, a small cleft will result, perhaps only a bifurcated uvula. If they are far apart, a more severe cleft will result.

Medical Genetics We call that critical difference in liability the threshold. Beyond the threshold, disease results. Below the threshold, normal development is observed.

Medical Genetics Since one is not following a single locus with dominance or recessivity but is following several loci that act in concert, counseling for multifactorial inheritance diseases requires a different approach from that taken for Mendelian inheritance diseases.

Medical Genetics One has to calculate the number of genes in common. The easiest way to do that is to change the way we construct pedigrees. Instead of the familiar sibship method we use the pathway to common ancestor method.

Medical Genetics Pedigree A represents the standard method of pedigree construction. Pedigree B represents the pathway system of pedigree construction.

Medical Genetics It is much easier to see how genes flow from generation to generation in Pedigree B. II-2 and II-3 are brother and sister. They have two common ancestors, I-1 and I-2.

Medical Genetics To determine the fraction of genes II-2 and II-3 have in common one simply counts all of the pathways and their connecting lines through the common ancestors. There is one line from II-2 to I-1, and a line from I-1 to II 3. That is one pathway with two lines of descent.

Medical Genetics There is another line from II-2 to I-2, and a line from I-2 to II-3. These are the only pathways from II-2 to II-3. The fraction 1/2 is then raised to the power of the number of lines of descent and summed for each possible pathway, (1/2)2 for the pathway through I-1, and (1/2)2 for the pathway through I-2, making a total of 1/2. Brothers and sisters have, on average, 1/2 of their genes in common.

Medical Genetics A parent and offspring, say I-1 and II-2 also have 1/2 of their genes in common. There is only one pathway between them and only one line in that pathway, (1/2)1.

Medical Genetics Other relationships follow in the same manner. III-1 and III-3 are first cousins. There are two pathways connecting the two individuals, one through I-1 and the other through I-2, each with four lines. Their fraction of genes in common is then (1/2)4 + (1/2)4 or 1/8. First cousins have 1/8 of their genes in common. A grandparent and grandchild have 1/4 of their genes in common. There is a single pathway with two lines of descent. III-1 and IV-1 are first cousins once removed. Again there are two pathways, one through I-1 and the other through I-2, each with 5 lines, (1/2)5 + (1/2)5 or 1/16 of their genes in common.

Medical Genetics The degree of relationship is often used rather than the fraction of genes in common. The degree of relationship is simply the power to which (1/2) is raised to reach the fraction of genes in common. First degree relatives have (1/2) of their genes in common. Second degree relatives have 1/4, (1/2)2, of their genes in common, etc.

Medical Genetics Method of calculating the recurrence risk of a multifactorial trait to first degree relatives

Medical Genetics Recurrence risk to first degree relatives of affected individuals.

Medical Genetics 5. SEVERITY OF DISEASE AND RECURRENCE RISK Unlike Mendelian traits with variable expressivity, where the recurrence risk is the same no matter how severely the individual is affected, multifactorial traits have a higher recurrence risk if the relative is more severely affected.

Medical Genetics In multifactorial traits, the more severely affected the individual, the more genes he/she has to transmit, and the higher the recurrence risk.

Medical Genetics 6. MULTIPLE AFFECTED OFFSPRING AND RECURRENCE RISK Another difference is the presence of multiple affected individuals within a sibship.

Medical Genetics In Mendelian traits the number of affected in a family did not change the recurrence risks.

Medical Genetics But multiple affected children does change the recurrence risk for multifactorial traits.

Medical Genetics The presence of one affected child means the parents probably are midway between the mean for affected and the mean of the normal population, but the presence of a second affected child means they probably are closer to the threshold, and hence, have a higher recurrence risk should they choose to have another child.

Medical Genetics 7. CONSANGUINITY Consanguinity also increases the probability of an affected child for a multifactorial trait, but only slightly when compared to rare autosomal recessive diseases. First cousin matings may increase the risk for two normal individuals to have a child with a multifactorial disease by about two fold when compared to the risk for unrelated individuals.

Medical Genetics 8. HALLMARKS OF MULTIFACTORIAL INHERITANCE The hallmarks for multifactorial inheritance are:

Medical Genetics (1) Most affected children have normal parents. This is true of diseases and quantitative traits. Most geniuses come from normal parents, most mentally challenged come from normal parents. (2) Recurrence risk increases with the number of affected children in a family. (3) Recurrence risk increases with severity of the defect. A more severely affected parent is more likely to produce an affected child. (4) Consanguinity slightly increases the risk for an affected child. (5) Risk of affected relatives falls off very quickly with the degree of relationship. Contrast this with autosomal dominant inheritance with incomplete penetrance, where the recurrence risk falls off proportionately with the degree of relationship. (6) If the two sexes have a different probability of being affected, the least likely sex, if affected, is the most likely sex to produce an affected offspring.