L5 mendelian.ppt

MENDELIAN INHERITANC E Mendel made the first descriptions of unifactorial inheritance in 1865, when he published the results of his experiments. His work was largely ignored until Bateson republished it in 1901, from which time the term Mendelian inheritance became synonymous with unifactorial inher...

MENDELIAN INHERITANC E Mendel made the first descriptions of unifactorial inheritance in 1865, when he published the results of his experiments. His work was largely ignored until Bateson republished it in 1901, from which time the term Mendelian inheritance became synonymous with unifactorial inheritance. Mendel published the results of his experiments on the garden pea in which he crossed pure lines differing in one or two clear characteristics and followed the progeny of the crosses for two or three generations. From those experiments he described the laws of heredity. Genes come in pairs One factor inherited from each parent (“factor” used by Mendelequivalent today with “gene”). Mendel stated that blending of the characteristics of the parents did not occur, but, although they might not be expressed in the first generation, the parental traits could reappear unchanged in a later generation. Moreover, there may be different alleles, some of which - dominant - exert their effects over the other - recessive. In Mendel's own words, those characters which are transmitted entirely, unchanged in the hybridization are termed dominant, and those which become latent in the process (in phenotype), are termed recessive. LOCUS Every gene occupies a specific locus along the chromosome s. PAIRS of ALLELES The same gene loci along the homologous chromosomes contain a pair of genes named pair of alleles. A person who has different alleles (one dominant and one recessive) is heterozygous (a heterozygote), but when a person has a pair of identical alleles, is said to be homozygous (a homozygote). Law of Segregation At meiosis, alleles segregate from each other, with each gamete receiving only one allele. The two members of a single gene pair (alleles) always segregate and pass to different gametes. We can also distinguish between an individual's outward appearance, its phenotype, and its inward genetic constitution, its genotype. When each parent is a heterozygote, the genotypes in offsprings will be in the following proportions: 1/4 homozygote for the dominant gene, 1/2 heterozygote with both genes: dominant and recessive, 1/4 homozygote for recessive genes. In these last cases, the recessive trait will be expressed in the phenotype. Law of "Independent Assortment" Members of different gene pairs assort independently of one another. In other words, each pair of alleles segregates independently of the other pairs of alleles during gamete formation (exception: genes closely linked on the same chromosome, which tend to remain together from generation to generation). Patterns of single gene inheritance Single-gene traits - often called Mendelian - segregate within families and, on average, occur in fixed proportions among the offspring of specific types of matting. The singlegene phenotypes described so far are listed containing more than 6000 loci. A single-gene disorder is one that is determined by a specific allele at a single locus on one or both members of a chromosome pair. Single-gene disorders are characterized by their patterns of transmission in families. To establish the pattern of transmission, a usual first step is to obtain information about the family history of the patient and to summarize the details in the form of a pedigree, using standard symbols. PEDIGREE CONSTRUCTION The patterns of single-gene disorders in pedigrees depend on two factors: 1. Chromosomal location of the gene, which may be autosomal (located on an autosome), or X-linked (located on the X chromosome). 2. Whether the phenotype is dominant (expressed even when only one chromosome of a pair carries a mutant allele heterozygote state), or recessive (expressed only when both chromosomes of a pair carry a mutant allele –homozygote state). There are four basic patterns of single-gene inheritance: Dominant (D) Autosomal Recessive (r) Dominant (D) X-linked Recessive (r) Fundamental for understanding Mendelian inheritance are the concepts of dominance and recessiveness. By formal definition, a phenotype expressed in the some way in both homozygotes and heterozygotes is dominant, and a phenotype expressed only in homozygotes is recessive. AD disorders are typically more severe in homozygotes than in heterozygotes. If expression of each allele can be detected even in the presence of the other, the two alleles are termed codominant (ABO system). Although a recessive phenotype is defined as being clinically undetectable in heterozygotes, many traits classified as recessive do have some manifestations in heterozygotes when examined at the cellular, biochemical, or molecular level. https://www.nature.com/scitable/nated/topicpage/genetic-dominance-genotype-phenotype-relationships-489 EX: Sickle cell anemia Disorder of Hb, inherited as an a. r. disease.. Patients are homozygotes for a defective allele at the -globin locus and produces the abnormal Hb S instead of the normal adult hemoglobin (Hb A) in their red cells. Heterozygotes produce both Hb A and Hb S and they have a mild anemia. Thus at the level of hemoglobin synthesis, the normal -globin allele and the defective allele are expressed as codominant alleles. Sickle cell disease suggested by the typical clinical picture of chronic hemolytic anemia and vascular obstruction and ischemia. HbS undergoes marked decrease in solubility, increased viscosity, and polymer formation. It forms a gel-like substance containing Hb crystals Aspects of phenotypic expression Many genetic conditions segregate sharply within families; the abnormal phenotype can be distinguished clearly from the normal one. In clinical experience, however, some disorders are not expressed at all in individuals who carry a diseasecausing mutation and others with the same disease-causing mutation have extremely variable expressions in terms of clinically severity, onset age, or both. Expression of an abnormal genotype may be modified by: Modifier genes Environmental factors Allelic variation Complex genetic and environmental interactions These differences in expression, often can lead to difficulties in diagnosis and pedigree interpretation. A genetic modifier, when expressed, is able to alter the expression of another gene. Modifier genes can affect transcription and alter the immediate gene transcript expression, or they can affect phenotypes at other levels of organization by altering phenotypes at the cellular or organismal level (Nadeau, 2001). https://www.nature.com/scitable/topicpage/same-genetic-mutation-different-geneticdisease-phenotype-938# expressivity penetrance onset age pleiotropy sex influence genetic heterogeneity environmental factors Variable Expressivity When the manifestation of a phenotype differs in people who have the same genotype, the phenotype is said to have variable expressivity. Multiple phenotypic effects characterize many single-gene disorders, and patients with one of these disorders may differ with respect both to the spectrum of abnormalities present and to the severity of any one manifestation. Example of autosomal dominant disorders with variable expressivity: Marfan syndrome is an A.D. disease caused by a mutation in collagen formation. Symptoms include skeletal, optical, and cardiovascular abnormalities. Each patient may express all of the symptoms, or only a few. That is variable expressivity. The extent of severity of affected does not affect the severity of expression in the next generation, that is, the offspring of mildly affected individuals range from mildly affected to severely affected, with equal probability. Marfan syndrome Example of autosomal dominant disorders with variable expressivity: Neurofibromatosis (NF) is a common autosomal dominant disorder of the nervous system, with a great variability in its expression. The clinical features consist of “café au lait” spots, peripheral dermal neurofibromas and Lisch nodules; They are tan or brown benign (non-cancerous) tumors on the iris of the eye, usually less than two millimeters in diameter. Neurofibromatosis Penetrance is the probability that a gene will have a phenotypic expression. In other words, the penetrance of a disorder is in an index of the proportion of individuals with an allele who has manifestations of it. An allele is said to be penetrant in an individual known to be heterozygous for the allele, show signs of the disorder, either by clinical symptoms or pedigree analysis and molecular investigation. When the frequency of expression of a phenotype is below 100% - when some of those who have the appropriate genotype completely fail to express it - the gene is said to show reduced penetrance. In statistical terms, it is the percentage of people with a particular genotype who are actually affected. Ex: ectrodactily (split-hand deformity). The disorder has about 70% penetrance (i.e. 70% of the people who have the gene exhibit the defect). Onset age many disorders are expressed later in life, some at a characteristic age and others at variable ages. A classic example of a genetic disorder usually of a late onset is Huntington disease, characterized by choreic movements, progressive dementia and onset typically in 4-5th decade. in this disorder, the penetrance is age dependent and it is said to show delayed penetrance. This degeneration causes uncontrolled movements, loss of intellectual faculties, and emotional disturbance. Pleiotropy refers to the phenomenon in which a single gene is responsible for a number of distinct and seemingly unrelated phenotypic effects. Ex: the allele causing neurofibromatosis (previously discussed as a dominant autosomal disorder) can produce abnormalities of skin pigmentation, neurofibromas of the peripheral nerves, short stature, skeletal abnormalities and other symptoms. Clinical syndromes offer many examples of pleiotropy, for most of these, the connection between the various manifestations has not yet been established. In Marfan syndrome, the underlying defect appears to be in the primary structure of fibrillin, a critical component of connective tissue. In contrast, in the a. r. disorder BardetBiedl the manifestations of hypogonadism, polydactyly, deafness, obesity, pigmentary retinopathy and mental retardation are together expressed in the phenotype. Bardet- Biedl syndrome Sex influence, involves the expression of an autosomal allele that occurs more frequently in one sex than the other. Ex: gout, with males affected more frequently than females, an effect probably mediated by gonosomal alleles and then by hormonal differences. Ex: hemochromatosis, more common in males. In this disorder of iron metabolism, there is enhanced absorption of dietary iron, which leads to iron overload with serious pathological consequences. Ex: congenital adrenal hyperplasia female infants have ambiguous genitalia, but it may go unrecognized in males; without treatment, affected males develop consequences of excessive androgen production. GOUT Gout is a type of arthritis that causes inflammation, usually in one joint, that begins suddenly. It is caused by the deposition of crystals of uric acid in a joint. hemochromatosis Genetic heterogeneity Genetic heterogeneity means that any one of several genetic mechanisms can lead to the same or similar phenotype. When a genetic disorder that appears to be a single entity is thoroughly analyzed, it is frequently found to be genetically heterogeneous; that is, it includes a number of phenotypes that are similar but are actually determined by different genotypes. Heterogeneity = the phenomenon by which a clinical phenotype results from different genetic defects, representing: - either mutations at separate locus (nonallelic heterogeneity=locus level) or - different mutations at a single locus (allelic heterogeneity). Allelic heterogeneity is an important cause of clinical variation, in which mutations of a single gene cause quite distinct phenotypes. many loci can contain more than one mutant allele and therefore, at a given locus there may be several or many mutations, resulting in clinically indistinguishable or closely similar disorders. In other cases, different mutant alleles at the same locus result in very different clinical presentations. CFTR gene (7q31.2)- for making a protein called the cystic fibrosis transmembrane conductance regulator. This protein functions as a channel across the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. The channel transports negatively charged particles called chloride ions into and out of cells. The transport of chloride ions helps control the movement of water in tissues, which is necessary for the production of thin, freely flowing mucus. The CFTR protein also regulates the function of other channels, such as those that transport positively charged particles called sodium ions across cell membranes. These channels are necessary for the normal function of organs such as the lungs and pancreas. Nonallelic heterogeneity (locus level) is the situation in which mutations at two or more distinct loci (on different chromosomes) can produce the same or closely similar phenotypes. For example, Alzheimer disease is genetically heterogeneous, genetic heterogeneity refers to the locus level, being involved either mutations on chromosome 21, chromosome 14 or chromosome 19. Environmental factors. Environmental influences can affect the expression of genes. This can involve factors of the internal environment, such as hormones, or the external environment, such as the effect of certain drugs, diet, a.o. Autosomal inheritance Patterns of autosomal dominant inheritance A.D. inheritance Among over 7000 known Mendelian phenotypes, more than half are autosomal dominant traits. The incidence of some autosomal dominant disorders is higher in specific geographic areas than in others. Although many autosomal dominant disorders are much less common, they are so numerous that their total incidence is appreciable. A.D. inheritance In classical A.D. inheritance, every affected person in a pedigree has an affected parent, who also has an affected parent and so on. A.D. inheritance Since individuals with A.D. disorders are heterozygotes for a mutant and a normal gene, there is a 1 in 2 (50%) chance a gamete will carry the normal allele and a 1 in 2 (50%) chance a gamete will carry the mutant allele. Assuming that the individual s partner will contribute a normal allele, there is a 1 in 2 (50%) chance that the offspring will inherit the disorder with each pregnancy. A.D. inheritance Statistically speaking, each pregnancy is an “independent event”, not governed by the outcome of previous pregnancies; thus within a family the distribution of affected and unaffected children may be quite different from the theoretical 1:1, although in the population as a whole the offspring of A/a + a/a parents are approximately 50% A/a and 50% a/a. A.D. inheritance The pattern of AD inheritance is perhaps the easiest type of Mendelian inheritance to recognize in a pedigree. One dose of the mutant gene, one mutant allele, is all that is required for the expression of the phenotype. There are three reasons why an individual with an autosomal dominant disease should always be considered as being a heterozygote until proven otherwise: AD heterozygotes 1. The disease is usually rare, with only about 1/10,000 individuals affected. To produce a homozygote, two affected heterozygotes would have to mate. This probability is 1/1,000,000 and then they would have only a 1/4 chance of having a homozygous affected offspring. AD heterozygotes 2. In the extremely rare instances where two affected individuals have mated, the homozygous affected individuals usually are so severely affected they are not compatible with life. The exceptions are the autosomal dominant diseases caused by the somatic expansion of trinucleotide repeat sequences (e.g., Huntington's disease). AD heterozygotes 3. The mating of very closely related individuals, the most likely way for two affected individuals to know each other, is forbidden in our society. There are four hallmarks of autosomal dominant inheritance. 1. Except for new mutations, which are rare in nature and extremely rare on examination pedigrees, and the complexities of incomplete penetrance, every affected individual has an affected biological parent. There is no skipping of generations. AD hallmarks 2. Males and females have an equally likely chance of inheriting the mutant allele and being affected. The recurrence risk of each child of an affected parent is 1/2. 3. Normal siblings of affected individuals do not transmit the trait to their offspring. AD hallmarks 4. The defective product of the gene is usually a structural protein, not an enzyme. Structural proteins are usually defective when one of the allelic products is nonfunctional; enzymes usually require both allelic products to be nonfunctional to produce a mutant phenotype. Huntington disease characterized by choreic (abnormal involuntary) movements and progressive dementia. The onset age of Huntington disease is almost later, by the age 40 years. Huntington disease is one of the first diseases in which molecular genetic methods led to the discovery of a DNA marker closely linked to the gene, which in suitable families allows presymptomatic and even prenatal diagnosis of individuals at risk. Huntingt on disease Neurofibromatosis. It is a common disorder of the nervous system. Since the gene is said to be clinically expressed in everyone who carries it, there is a great variability in its expression and moreover, some individuals with pathological gene are severely affected, whereas others show only mild symptoms; it is appropriate example for reduced penetrance and variable expressivity. Neurofibromatosis Neurofibromatosis Approximately half the cases of neurofibromatosis result from new mutation. If the patient has inherited the defect, the risk that any of his or her sibs will also inherit it is 50 percent, but if the child has a new mutant gene, there is almost no risk that any sib will be affected. The disorder can be detected presymptomatically and even prenatal by molecular analysis. Achondroplasia Achondroplasia is the most common form of dwarfism, occurring at a rate of 1:14000. Symptoms usually include: - enlarged head, - shorter arms and legs, - prominent forehead, protruding jaw, crowded and misaligned teeth, - forward curvature of the lower spine, - The average adult height of someone with achondroplasia is approximately 4 feet. In some cases, a child inherits achondroplasia from a parent who also has the condition. If one parent has the condition and the other does not, with each pregnancy there is a 50% chance that each child will be affected. If both parents have achondroplasia, there is a 50% chance that the child will inherit the condition, a 25% chance that the child will not have it, and a 25% chance that the child will inherit one abnormal gene from each parent and have severe skeletal abnormalities that lead to early death. A child who does not inherit the gene will be completely free of the condition, and cannot pass it on to his or her own children. Achondroplasia In most cases (~80%), however, achondroplasia is not inherited but results from a spontaneous new mutation that occurred in the egg or sperm cell that formed the embryo. The parents of children with achondroplasia resulting from new mutations are usually averagesized. Brachydactyly Familial hypercholesterolemia an autosomal dominant disorder of receptor for plasma lowdensity lipoprotein leading to premature coronary heart disease, in which the rare homozygous patients have a much more severe disease, than do the relatively common heterozygotes. Familial hypercholesterolemia Marfan syndrome skeletal deformities: disproportionately long limbs and digits, chest deformity, joint laxity, and vertebral column deformities such as scoliosis. Ocular findings: myopia, dislocation of the lens of the eye represents a hallmark clinical feature. cardiovascular anomalies: mitral valve prolapse, aneurysm of the aorta, aortic regurgitation. Marfan syndrome Patterns of autosomal recessive inheritance Autosomal recessive phenotypes represent about 1/3 of the recognized Mendelian disorders. In contrast to AD disorders, in which affected persons are usually heterozygous, autosomal recessive disorders are expressed only in homozygotes, who thus must have inherited a mutant allele from each parent (the both parents are heterozygotes = carriers). Characteristics of autosomal recessive inherited disorders both males and females are affected the disorder normally occurs in only one generation, usually within a single sibship the percent of affected persons along 2-3 generations does not go over 25% the parents often are consanguineous autosomal reccessive pedigree consanguineous couple= when they have at least one ancestor in common in the precedent few generations. This means that they are more likely to carry identical alleles inherited from this common ancestor and could both transmit an identical allele to their offspring, who would then be homozygous for that allele. A consanguineous couple has an increased risk that their offspring will be affected with a recessive disorder. Recurrence risk. When two parents carrying the same disease allele reproduce, there is an equal chance that gametes contain the abnormal allele. Because the increased risk of birth defects in their offspring is well known, consanguineous couples request genetic counseling before they will have children. In a mating of an affected homozygote with a heterozygote (r / r + R/r), the offspring each have a 50 percent chance of being affected, just like in autosomal dominant inheritance, showing a quasidominant or pseudodominant pattern. Cystic fibrosis Cystic fibrosis is an inherited disease of the mucus glands that affects many body systems. In particular, this disorder causes progressive damage to the respiratory system and chronic digestive system problems. Cystic fibrosis Cystic fibrosis Cystic fibrosis is a common genetic disease in the Caucasian (white) population. More than 1000 cystic fibrosis mutations have been reported, many of which are rare. The most common mutation is DF508. Cystic fibrosis has a simple Mendelian autosomal recessive inheritance Sex -linked inheritance refers to the inheritance patterns shown by genes on the sex chromosomes. gene on the X-chromosome: X-linked inheritance and, gene on the Y chromosome, Y-linked or holandric inheritance. Patterns of X-linked recessive inheritance Males have one X-chromosome and are therefore hemizygous for most of the alleles on the X chromosome, so if they have a mutant allele, they will manifest the disorder. Females, will usually only manifest the disorder if they are homozygous for the disease allele and if heterozygous will be unaffected. Since it is rare for females to be homozigous for a mutant allele, X-linked recessive disorders usually only affect males. A carrier female has one X chromosome with disease allele and one X chromosome with normal allele; her sons have 1 in 2 (50%) chance of being affected, while her daughters have an 1 in 2 (50%) chance of being carriers (as their mother). Characteristics of X-linked recessive inherited disorders: Males are affected almost exclusively Transmission occurs through unaffected or carrier females to their sons Male - to - male transmission is never observed Affected males are at risk of transmitting the disorder to their grandsons through their obligate carrier daughters X-linked recessive disorders Hemophilia A Duchenne muscular dystrophy Patterns of X - linked dominant inheritance An X - linked phenotype is described, as dominant if is regularly expressed in heterozygotes. The distinguishing feature of an X - linked dominant pedigree is that all the daughters and none of the sons of affected males are affected; if any daughter is unaffected or any son is affected, the inheritance must be autosomal, not X - linked. The pattern of inheritance through females is no different from the autosomal dominant pattern; because females have a pair of X chromosomes just as they have pairs of autosomes, each child of an affected female has a 50 percent chance of inheriting the trait, regardless of sex. As a general rule, rare X - linked dominant phenotypes are about twice as common in females as in males, although the expression is usually much milder in females, who are almost always heterozygotes. Criteria for X - linked dominant inheritance: Affected males with normal mates have no affected sons and no normal daughters. Both male and female offspring of carrier have a 50% risk of inheriting the phenotype. This is the same as the autosomal dominant pedigree pattern. For rare phenotypes, affected females are about twice as common as affected males, but affected females typically have milder expression of the phenotype. Only a few genetic disorders are classified as X - linked dominants. One example is X - linked hypophosphatemic rickets (also called vitamin - D resistant rickets), in which the ability of the kidney tubules to reabsorb filtered phosphate is impaired. X - linked hypophosphatemic rickets Y - linked (holandric) inheritance refers to genes carried on the Y chromosome. They therefore will be present only in males and the disorder would be passed on only to all their sons. Although a number of traits such as hairy ears, have been postulated to be inherited in this manner, there is no good evidence for this type of inheritance being associated with disease in humans. The disease is probably caused by a mutation on one locus which is: A. recessive, autosomal B. dominant, autosomal C. recessive, related to the X-chromosome D. related to the Y-chromosome E. situated in the mitochondrial genome