4. Epigenetics
5.3. Phenomena that fine-tune classical monogenic inheritance
Most but not all of the following phenomena alter the „one gene – one trait” pure relationship, at the same time practically all of them pose difficulties for the geneticist or for the physician in pedigree analysis.
Expressivity: it determines the strength of the gene, i.e. it shows how strong the manifestation is of a given trait/disease. In autosomal dominantly inherited diseases the severeness of the illness can often vary in the affected persons even suffering from the very same mutation. This phenomenon is called variable expressivity.
Penetrance: it is the frequency with which a heritable disease is manifested in a given population (family) by individuals carrying the dominant mutated allele. Complete penetrance means that the allele for a trait is expressed in all members of the population who carry that allele. In autosomal dominant inheritance all heterozygotes are supposed to show the trait, but in the case of incomplete penetrance it does not always appear. In this case a heterozygous parent does not show the trait, but inheriting the mutant dominant allele, his/her offspring does. The penetrance of the phenotype (the percent of the manifestation in the carriers) can be calculated in a family
P % = 100 x number of affected persons / number of obligate carriers.
That individual is considered to be an obligate carrier who has minimum one affected parent and he(she) himself(herself) has minimum one affected offspring or he himself is affected. For instance if 3 persons manifest the disease out of 4 obligate carriers (heterozygotes) in the same family, the disease shows a 75 % penetrance, meaning that the penetrance is incomplete.
Neither incomplete penetrance nor variable expressivity can be interpreted by Mendel’s principles. These two phenomena modulate the most the rules of classical Mendelian inheritance, interfering with the pedigree analysis as well. In these cases supposedly more than one gene is expressed, suggesting that an interplay between the products of other genes and their mutual effect can influence the pure expression of the
„main” gene. (See later modifier genes!) Besides, a whole arsenal of epigenetic regulatory mechanisms (see Chapter 4.) may alter the expression of a gene, either at transcriptional or at translational level. These fine regulatory mechanisms are orchestrated not only by intracellular, but also by environmental factors. The for long time accepted two most typical characteristics of Mendelian monogenic inheritance – the effect of only one gene and the lack of any environmental effect – seems to be untrue.
The effect of additional genes mentioned above shift the monogenic inheritance pattern toward an oligogenic one, furthermore the influence of the environment cannot be excluded either.
Anticipation: in each generation the disease gets manifested either earlier and/or in a more severe form. Anticipation could be considered as a specific case of the variable expressivity; still, it is somewhat different. Variable expressivity is explained by the modifying effect of the environment and of other genes; meanwhile different genetic reasons lie in the background of anticipation. It is well known by now, that the earlier manifestation of the disease from generation to generation is caused by a trinucleotide repeat expansion and has probably no connection with environmental or modifier genes’ effects. If the person, carrying the mutant allele, dies earlier than the disease could have been manifested, the case can be considered as incomplete penetrance in
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respect to the examined family. Obviously, anticipation complicates the exact analysis of a pedigree as well.
Complex or compound heterozygotes: the offspring often inherits two differently mutated alleles of the same gene from the heterozygous parents in recessive inheritance, which means that the „aa” genotype should rather be described as „a1a2”.
The differently mutated alleles can result in differences in the severeness of the manifestation of the disease. At some extent, theoretically, the effect of the two alleles could even quench each other.
Pleiotropy: a single gene controlling or influencing multiple (and possibly unrelated) phenotypic traits. Mutation in this type of gene will simultaneously affect more than one trait. The explanation is that the gene is expressed in multiple organs;
furthermore, fulfilling perhaps completely different functions (see Chapter 11, the example of EDAR gene). The protein coded by the gene may be an intermediate molecule of further metabolic cascades or the protein can serve as regulatory molecule, participating in the regulation of several different processes. As for structural proteins, they are practically present in all tissues.
Heterogeny: it seems to be the opposite of pleiotropy as the expression of multiple genes, independent one from the other, results in the same phenotype. In this case two affected parents can have phenotypically healthy, unaffected children if the disease is recessive.
Phenocopy: an inherited disease, due to environmental influences, will be less or will not be manifested at all despite the presence of the mutant alleles. This can occur by the effect of medicaments or for instance in Phenylketonuria by proper diet. The oppository situation is when environmental factors induce the manifestation of a genetic disease despite the presence of fully healthy alleles (for example deafness caused by Rubella virus infection). The phenocopy is called pathological when the phenotype is pathological despite a healthy genetic background, and it is called normal when the phenotype is healthy despite a mutated genotype.
„de novo”, new mutation: a genetic mutation that individuals neither possessed nor transmitted in a population through many generations, but the disease appears in one of the offsprings unexpectedly. In this case the new spontaneous mutation must have occurred in the germ line of one of the parents of the affected child. Certain genes undergo mutations time to time, this explains why certain diseases never disappear from a population, as mutations of their genes can be „recreated” in some individuals.
For instance Rett syndrome occurs in 95%, Achondroplasia in 80% due to new mutation.
Influence of the age: after having had healthy children, originally healthy parents can have an affected child suffering from autosomal dominant disease due to the elderly age of one of the parents. The mutation appears in the germline of the parent as a new mutation. Interestingly, in monogenic diseases, the mutation shows a stronger correlation with the age of the father (~ above 50). The explanation is that gametogenesis is sustained until elderhood in men, spermatogonia undergo multiple divisions, the regulatory mechanisms fail to function properly, and the mutations appearing during replication become stable.
Lethal/sublethal genes: the genetic mutation causes 100% or less than 100 % the death of the affected individual. Sublethal genes cause the death of only some of the individuals. In special cases the dominant allele can cause death before the affected person would have offsprings. (ex. Hutchinson-Guilford – progeria http://ghr.nlm.nih.gov/condition/hutchinson-gilford-progeria-syndrome). This could
lead to the elimination of the mutant allele from a population, but as these lethal mutations recreate themselves, they do not disappear. In the case of Huntington Chorea the situation is different: the onset of the lethal disease appears relatively late in life, so the affected person will have had children by the time of the manifestation, therefore the lethal mutated allele will be transmitted.
„modifier genes”: genes that influence the expression of another gene. These are interactions between two or more genes of different loci. When an originally monogenic disease shows weaker or stronger symptoms, the reason is that the expression of the mutated gene is often altered by other gene effects. The number of these modifier genes is usually one or two. It has been already proven that the manifestation of some diseases is slightly controlled by the mutated forms of specific modifier genes. This offers an explanation to the variable course of the disease in different persons (see above expression, penetrance). Epistasis has been considered for long as a separate phenomenon, by today it has become clear though that it is about an interaction between certain main genes and known or still unknown modifier genes. Until now relatively few modifier genes have been identified, but it is supposed that in most cases not only one gene but a set of modifier genes is involved in the manifestation of the disease. (See Chapter 14 – Systems biology). The picture is further complicated by the fact that the modifier genes themselves follow some kind of hereditary pattern and that they can also be polymorphic, therefore they can differently modify the main gene. The inheritance is called oligogenic in those hereditary diseases, whose development and manifestation have been proven to be influenced by such modifier genes, like in the case of Cystic Fibrosis and polycystic kidney. Until recently both have been outlined as classical monogenic diseases. As the methods of full genome sequencing or exome sequencing (see Chapter 10) have become cheaper, in accordance with the systems biology theory it has become possible to demonstrate that every monogenic disease is caused practically not only by the mutation of the „main gene” but that parallel the mutations of many other genes also contribute to the development of the symptoms.
Heterozygote advantage: it is the superiority of the heterozygous genotype to either homozygous genotype. The key may be that a particular allele may have advantages under given conditions, but that a different allele may be favored when conditions change. In the case of certain autosomal recessive diseases heterozygotes have reproductive advantage due to environmental factors. This alters significantly the frequency of the disease in these populations. Independently of the environmental factors, modifier genes are supposedly also involved in this phenomenon.
Influence of the sex: the manifestation or severeness of certain diseases is different in men and women. (See details in Chapter 6.) In the case of sex influenced traits the autosomal genes are expressed more in one of the sexes (for ex. boldness). In congenital adrenal hyperplasy (CAH) altered phenotypes develop in both sexes. In the so-called sex restricted diseases the phenotype is manifested only in one of the sexes, although the inheritance is autosomal. Due to the fact that specific hormones are needed for the expression of the disease, it will be manifested in one gender only. In Pubertas praecox for instance the level and effect of sex hormones play the main regulatory role in the development of the disease.
The influence of the environment: some monogenic diseases - despite the mutated genotype - are manifested only when particular inducing environmental effects hit the organism. The inducing factors are usually medicament or food. Earlier these diseases used to be called ecogenetic (Porfiria, Malignus hypertermia,
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dehidrogenase deficiency) (see 5.4.4). Either an altered function of the modifier genes or some epigenetic event lies in the background of the inducing effect.
Table 5.2 shows a short summary of the occurrence of the above mentioned terms/phenomena and in connection with some autosomal diseases.
Multiplex allelism Allele heterogeneity Locus heterogeneity Variable expressivity Incomplete penetrance Pleiotropy Influence of paternal age Anticipation Heterozygote advantage Phenocopy
Achondroplasia X X
Marfan Syndrome X X X X
Osteogenesis
imperfecta ? X X X
Familial hypercholes-terolemia
X X
Polydactyly X X X
Huntington Chorea X
Deafness X
Cystic fibrosis X X X X
Phenylketonuria X
Albinism (albino
phenotype) X X
CAH X X X X
Xeroderma
pigmentosum X X
Sickle cell anemia X X
Table 5.2. Summary of the genetic characteristics and phenomena in connection with some AD and AR diseases. In column „Phenocopy” those diseases are shown whose negative (mutated) gene effect can be compensated either by diet or by medicaments. Therefore the
treatment results in fully or partially healthy phenotype.