Hartl, Jones - Genetics. Principlers and analysis - 1998, страница 14

The proliferation of the parasite among the red blood cells is thereby checked, and the severity ofthe malarial infection is reduced. There is consequently a genetic balancing act between the prevalence of thegenetic disease sickle-cell anemia and that of the parasitic disease malaria. If the mutant β-hemoglobin becomestoo frequent, more lives are lost from sickle-cell anemia than are gained by the protection against malaria; on theother hand, if the mutant β-hemoglobin becomes too rare, fewer lives are lost from sickle-cell anemia but the gainis offset by more deaths from malaria. The end result of this kind of genetic balancing act is discussed inquantitative terms in Chapter 15.Page 19Epistasis: One Trait Can Be Affected by More Than One GeneEvery trait requires numerous genes for its proper development, metabolism, and physiology.

Consequently, onetrait can be affected by more than one gene. An example of this principle is illustrated in Figure 1.14, which showsthe effects of two genes that function in eye pigmentation in Drosophila. The genes are vermilion (v) and cinnabar(cn). These genes encode enzymes, denoted V and Cn, respectively, that are used in the biochemical pathway thatconverts the amino acid tryptophan into the brown eye pigment xanthommatin through a series of intermediatesubstances I1, 12, and so forth (Figure 1.14A). Each step in the pathway is catalyzed by a different enzymeencoded by a different gene. The nonmutant, or wildtype, eye color of Drosophila is a brick-like red because theFigure 1.14The Drosophila mutants vermilion and cinnabar exemplify epistasis between mutant genes affecting eye color.

(A) Metabolicpathwayfor the production of the brown pigment xanthommatin. The intermediate substances are denoted I1, 12, and so forth,and eachsingle arrow represents one step in the pathway. (The multiple arrows at the end represent an unspecifiednumber of steps.) (B) The cn gene codes for an enzyme, Cn, that converts 12 to 13. In flies mutant for cn, the pathwayis blocked at this step. (C) The v gene codes for a different enzyme, V, that catalyzes the conversion of tryptophaninto intermediate I1. In flies mutant for v, the pathway is blocked at this step.

(D) In v cn double mutants,the pathway is blocked at the earlier step, in this case theconversion of tryptophan to I1.Page 20pigment cells contain not only xanthommatin but also a bright red pigment called drosopterin synthesized by adifferent bio-chemical pathway.As indicated in Figure 1.14B, flies that are mutant for cn lack xanthommatin. They have bright red eyes because ofthe drosopterin. Flies mutant for cn have a nonfunctional Cn enzyme, so the pathway is blocked at the step atwhich Cn should function. Because there is no functional Cn enzyme to convert intermediate 12 into the nextintermediate along the way, 12 accumulates in cn flies.

Mutant v flies also lack xanthommatin but for a differentreason (Figure 1.14C). In these flies the pathway is blocked because there is no functional V enzyme. It does notmatter whether the Cn enzyme is present, because without the V enzyme, there is no 12 for Cn to work on.The pathway in flies with a mutation in both v and cn is illustrated in Figure 1.14D. The situation is identical to thatin flies with a v mutation only because, lacking functional V enzyme, the pathway is blocked at this step.

Thegeneral term for gene interaction is epistasis. Freely translated from the Greek, epistasis means ''standing over."Epistasis means that the presence of one mutation "stands over," or conceals, the effects of a different mutation. Inthe example in Figure 1.14, we would say that v is epistatic to cn, because in flies with a v mutation, it isimpossible to determine from the status of the xanthommatin pathway whether the cn gene is mutant or wildtype.The converse is not true: In flies with a cn mutation, the presence or absence of intermediate 12 shows whether thev gene is mutant or wildtype. If 12 accumulates, the V enzyme must be present (and the v gene wildtype); whereasif 12 is absent, the V enzyme must be non-functional (and the v gene mutant.)The example in Figure 1.14 also illustrates an important feature of genetic terminology.

Although both vermilionand cinnabar are needed for the synthesis of the brown pigment, the names of the genes are shades of bright red.At first this seems illogical, but mutant genes are named for their effects on the organism. Because mutations ineither vermilion or cinnabar result in bright red eyes, the gene names make sense even though the products of bothgenes function in the brown-pigment pathway.Effects of the EnvironmentGenes and environment also interact. To appreciate the interaction between genes and environment, consider thetrait "anemia," which refers to a generalized weakness resulting from an insufficient number of red blood cells orfrom an inadequate volume of blood. There are many different types of anemia. Some forms of anemia aregenetically determined, such as sickle-cell anemia (Figure 1.13).

Other forms of anemia are caused by theenvironment; an example is anemia resulting from chronic deficiency of dietary iron or from infection withmalaria. Still other forms of anemia are caused by genetic and environmental factors acting together. For example,people with a mutant form of the enzyme glucose-6-phosphate dehydrogenase (G6PD), an enzyme important inmaintaining the integrity of the membrane of red blood cells, become severely anemic when they eat fava beans,because a substance in the beans triggers destruction of red cells. Because of its association with fava beans, thedisease is called favism, but a more common name is G6PD deficiency. Red-cell destruction in people with G6PDdeficiency can also be triggered by various chemicals such as naphthalene (used in mothballs) as well as by certainantibiotics and other drugs. G6PD deficiency, which affects primarily males, has a relatively high frequency inpopulations in coastal regions around the Mediterranean Sea.

It is thought that the defect in the red blood cells mayincrease resistance to malaria.With these examples as background, consider this question: Is anemia caused by heredity or environment? There isno simple answer. As we have seen, a complex trait such as anemia has many possible causes. Some types aregenetically determined, some environmental in origin, and some require both genes and environment for theirexpression.

The genes-versus-environment issue is exceptionally clear in the example of anemia only becausevarious forms of the disorder have already been sorted out and assigned causes, whether they be genetic orenvironmental or both. However, before the various forms were distinguished, anemia was regarded as atremendously complex condition, andPage 21all varieties were lumped together. Without separating the disorder into categories, all that one could conclude wasthat family history seemed to be important in some cases, but not all, and that the environment certainly played arole as well.Most complex traits are analogous to anemia in consisting of different conditions lumped together because of theiroverall similarity. A familiar example is heart disease. It is well known that inherited risk factors in heart diseaseare related to the metabolism of saturated fats and cholesterol.

Some rare forms of the disease with a strong geneticcomponent have already been identified. There are also environmental risk factors in heart disease—cigarettesmoking, being overweight, lack of exercise, high dietary intake of saturated fats and cholesterol, and so forth. Inthe population as a whole, the overall risk of heart disease is determined by both genetic and environmental factors,and some of the factors act synergistically, which means that the risk from two factors together is greater thanwould be predicted from the risk of each factor considered by itself.The example of heart disease also illustrates that genetic and environmental effects can be offsetting.

For example,a person with a family history of heart disease can considerably mitigate the risk by careful diet, exercise,abstention from smoking, and other behaviors. Taking drugs to control high blood pressure is also an example ofan environmental intervention that reduces the overall risk of heart disease.Heart disease is a typical example of a complex trait influenced by multiple genes as well as by manyenvironmental factors. Most of the variation found in human beings falls into this category, including personalityand other behavioral characteristics. Some traits are more strongly influenced by genetic factors than others, and itis extremely difficult to sort out the forms of a trait that might share a single cause. An illustration of complexgenetic and environmental causation is shown in Figure 1.15. The boxes labeled mild, moderate, and so forthrepresent various different severities in which a trait can be expressed; these are analogous to the different forms ofanemia.

Across the top are three genes and three environmental factors that influence the trait. The heavy linesrepresent major effects, the thin lines minor effects. If the four types of expression of the traitFigure 1.15Most complex traits are affected by multiple genetic and environmental factors, not all of them equal in influence.In this example, the severity of expression of a complex disease is affected by three genes (1, 2, 3) and threeenvironmental factors (X, Y, Z) that, in various combinations, determine the particular manner in which thedisease will be expressed. Heavy arrows depict major influences, light arrows minor influences.

For example, themild expression of the disease is determined primarily by gene 1 with a minor influence of environmental factorsX. The moderate expression of the disease is determined by two genes (2 and 3) and two environmental factors(X having a major effect and Y a minor effect). In a complex trait, therefore, some forms of expression of thedisease (mild in this example) may have a relatively simple form of genetic causation, whereas other forms of thesame disease (moderate in this example) may have a more complex causation that even includes different genes.The genetic basis of such diseases is difficult to determine unless the different forms of the disease can bedistinguished.Page 22were regarded as a single entity without being distinguished, then the genetic and environmental causation could becharacterized only as "three genes and three environmental factors, each with major effects." However, when thedifferent levels of severity of the trait are considered separately, the situation can be clarified.

For example, themild form is determined by one major genetic factor and one minor environmental factor, and the very severe formis determined by one minor genetic factor and one major environmental factor. Real complexity remains in themoderate and severe forms, however: The moderate form is determined by two major genes together with onemajor and one minor environmental factor, and the severe form is determined by two major environmental factorstogether with one major and one minor genetic factor. Figure 1.15 also illustrates the more general point that traitsdo not present themselves already classified in the most informative manner.