24 - Aya Alomoush - Talal Al-Zabin - Belal Azab 1 P a g e
1) Features of autosomal dominant inheritance: A) Vertical transmission: direct transmission from grandparent to parent to child without skipping generations. B) Both sexes are affected in 1:1 ratio. C) Both sexes may transmit the trait (affected mother and affected father can transmit the trait to their daughters and sons). D) May see variable expressivity (severity) and variable ages of onset. E) Homozygous individuals are usually more seriously affected (have a more severe disease) than heterozygous individuals, fortunately homozygous for autosomal dominant traits are less common than heterozygous. F) May be due to new mutations and this is the challenging feature. G) Gene product is usually a structural (non-enzymatic) protein, why? structural proteins are usually defective when one of the allelic products is non-functional; enzymes usually require both allelic products to be non-functional to produce a mutant phenotype. *there are no carriers, either affected or not * (Autosomal dominant pedigree) *probabilities of inheritance of autosomal dominant trait (use Punnett square: each percentage = probability of having a child with this genotype in each pregnancy -remember that each pregnancy is an independent event -, X = relationship, A=mutant allele, a=normal allele, no sexes are indicated since they have equal chances). 2 P a g e
1- Affected heterozygous (Aa) X normal (aa) -> 50% is aa (normal), the other 50% is Aa (affected heterozygous). 2- affected heterozygous (Aa) X affected heterozygous (Aa) -> 50% is Aa (affected heterozygous), 25%is aa (normal),25% is AA )affected homozygous). 3- Affected homozygous (AA) X affected homozygous(aa) -> 100% Is AA (affected homozygous). 4- Affected homozygous (AA) X affected heterozygous (Aa) -> 50% is AA (affected homozygous), 50% is Aa (affected heterozygous) 5- Affected homozygous (AA) X normal (aa) -> 100% is Aa (affected heterozygous). 2) Autosomal recessive disorders: Many genetic disorders are inherited in an autosomal recessive manner (such as taysachs, albinism, cystic fibrosis,pku, sickle cell anaemia and most inborn errors of metabolism) and they range from relatively mild to life-threatening. For an individual to be affected they must have a homozygous mutant genotype, while the one that has a heterozygous genotype is known as a carrier and is phenotypically normal. Most individuals with recessive disorders are born to carrier parents. -features of autosomal recessive disorders: 1- Horizontal transmission: affected individuals are usually within the same generation, AR is skipping generations. 2-Both sexes are affected in 1:1 ratio and may equally transmit the mutant allele. 3-May observe consanguinity (mating between close relatives): This increases the chance of mating of two carriers of the same rare allele, and because of that most societies and cultures have laws against marriages between close relatives, BUT recent studies show that the chance of recessive disorders is the same whether it s close relatives' marriage or nonrelatives' marriage EXCEPT if there is a disease running in the family. 4-Gene product is usually an enzymatic protein. 3 P a g e
(autosomal recessive pedigree) -probabilities in inheritance of autosomal recessive traits (use punnett square: each percentage = probability of having a child with this genotype in each pregnancy -remember that each pregnancy is an independent event -, A=normal, a=mutant, no sexes are indicated since they have equal chances). 1-affected (aa) X affected (aa)->100% affected (aa) 2-affected (aa) X carrier (Aa)->50% affected(aa) and 50% carrier(aa) 3-affected (aa) X normal (AA) - >100% carrier (Aa) 4-carrier (Aa) X normal (AA) - >50% carrier(aa) and 50%normal (AA) 5-carrier (Aa) X carrier (Aa) - >50%carrier(Aa),25% affected(aa) and 25%normal(AA). -examples of autosomal recessive disorders A) sickle cell disease: affects one out of 400 African-Americans. 4 P a g e
The disease is caused by the substitution of a single amino acid (glutamic acid is substituted by valine) in the haemoglobin protein (especially in the beta subunit) in red blood cells. In homozygous individuals, all haemoglobin is abnormal (sicklecell) while heterozygotes (said to have sickle-cell trait) are usually healthy but may suffer from some symptoms. About one out of ten African Americans has sickle cell trait, an unusually high frequency of an allele with detrimental effects in homozygotes. Heterozygotes are less susceptible to the malaria parasite (infection), so there is an advantage to being heterozygous. Sickled RBCs are poor oxygen carrier and they aggregate causing blockage of blood vessels (vaso-occlusive crisis). Also those sickled RBCs are destroyed by the spleen resulting in anaemia. Other symptoms include physical weakness, failure to thrive, pain, increased risk of infections, organ damage, and even paralysis. B ) Cystic fibrosis : is the most common lethal genetic disease in the United States, striking one out of every 2500 people of European descent (European Caucasians ) The Cystic fibrosis allele results in defective or absent Chloride transport channels in plasma membranes leading to a build-up of chloride ions outside the cell. Symptoms include mucus build-up in some internal organs and abnormal absorption of nutrients in the small intestines and because of that it is a chronic progressive pulmonary disease with pancreatic insufficiency and elevated chloride sweat. -Features of cystic fibrosis- 5 P a g e
C ) Phenylketonuria (PKU) : Inborn error of metabolism, caused by deficiency in phenylalanine hydroxylase enzyme( PAH )- which is responsible for metabolism of phenylalanine and converts it to tyrosine-which will result in increased phenylalanine in blood, which will be converted to phenyl pyruvate, phenyllactate and phenylacetate, which will result in musty odor secretions (sweat, urine). Other symptoms include neurologic disorders (mental retardation,seizures, tremors,microcephaly ), due to reduced production of catecholamines(epinephrine, norepinephrine and dopamine).also hypopigmentation (light hair and skin, blue eyes) due to reduced melanin production not complete loss of pigmentation because tyrosine can be obtained from diet. Treatment is by phenylalanine restriction. 6 P a g e
D) Albinism: a recessive condition characterized by a lack of pigmentation in skin, hair and eyes due to defect in the enzyme tyrosinase, so they are more prone to skin cancers. 3) X chromosome inactivation: we all know that we must control the amount of proteins in our cells and if we don t there will be a problem. For example: mec gene, if it is overproduced it will cause cancer, although it isn t mutated. This is what we call Dosage compensation which says: -for autosomal traits, two doses lead to a normal phenotype, while one dose or more than two doses often have clinical significance. - For X-linked traits two doses in females and one dose in males both lead to a normal phenotype, although females have two X chromosomes, only one is active and this is why females and males have the same amount of proteins which is encoded by genes on the X chromosome and this is what we call lyon hypothesis ( X chromosome inactivation ). In early embryonic life (3-7 days after fertilization) one X chromosome is inactivated. The inactive X chromosome is condensed in a Barr body. 7 P a g e
Inactivation of the maternal or paternal X chromosome is clonal and random, but once it occurs, the same X will be inactive in all descendants of a particular cell. Some genes on the inactive X chromosome remain active, they escape inactivation. These include the genes in the pseudoautosomal region that have matching genes on the Y chromosome, genes outside the pseudoautosomal region that have related copies on the Y chromosomes, and others. 4) Sex-linked genes: genes that are located on either sex chromosome: -located on Y chromosome-> Y-linked genes (few genes only). -located on X chromosome -> X-linked genes. - The X chromosome has genes for many characters unrelated to sex, whereas the Y chromosome mainly encodes genes related to sex determination. - Sex-linked genes follow a specific pattern of inheritance. - Sex-linked disorders are less common than autosomal disorders. 8 P a g e
A ) X-linked recessive disorders : much more common in males than in females because females need two copies of the allele to be affected (homozygous) since they have two X chromosomes, while males need one copy of the allele to be affected (hemizygous), since they have one X chromosome only. *probabilities in inheritance of X-linked recessive traits.* X N Y-> normal male, X n Y->affected male X N X N -> normal female, X N X n -> carrier female (called mosaic), X n X n -> affected female - Examples on X-linked recessive disorders : 9 P a g e
A) Color blindness: it has many types, but the most common type is redgreen color blindness. B) Duchenne muscular dystrophy: dystrophy means muscle weakness and loss of muscle tissue; mutation in the DMD gene which is carried on the X chromosome can cause two types of muscular dystrophy: -less severe -> Becker. -more severe -> Duchenne. *genetic tests are required to determine the type and subtype of muscular dystrophy.* B) hemophilia: -features of X-linked recessive inheritance: 1. Diagonal inheritance affected males related through females of the maternal line (affected father transmits the mutant gene to his daughters only since he gives Y for the son and X for the girl while affected mother transmit the mutant gent to her sons and daughters). 2. Absence of male-to-male transmission (a son never inherits the disorder from his father). 3. Incidence of trait much higher in males than females. 4. Full expression in hemizygous males. 5. No or mild expression in carrier females due to X-inactivation. (X-linked recessive pedigree) 10 P a g e
B) X-linked dominant disorders: )الك ساح) Example: vitamin D resistant rickets - Features of X-linked dominant disorders : 1. Twice as many females with the disorder as males, because females have TWO X chromosomes so they have twice the chance of getting a mutant dominant allele. 2. Absence of male-to-male transmission and Males with the disorder transmit it to all their daughters and no sons. 3. Females usually have more mild and variable expression due to X- inactivation 4. Few disorders are classified as X-linked dominant. 5. Like any dominant every generation is affected and there are no carriers either you are affected or not. 11 P a g e
6. Heterozygous females have milder symptoms than both homozygous females and hemizygous males. - Probabilities in inheritance of X-linked recessive traits (using punnet square, each percentage = probability within each gender, B=mutant allele, b= normal allele) 1- X B Y * X B X B -> 100% affected homozygous in females and 100% affected hemizygous in males. 2-X B Y * X B X b -> all females are affected but 50 % of them heterozygous and the other 50% homozygous while 50% of males affected and the other 50% normal. 3-X B Y * X b X b -> all males are normal while all females are heterozygous and affected. 4-X b Y * X B X B -> all males are affected while all females are heterozygous and affected. 5-X b Y * X B X b -> 50% in females is heterozygous affected and the other 50% is normal while 50% in males is normal and the other 50% is affected. 6-X b Y *X b X b -> congratulations, all males and females are normal. -What about some practice on pedigrees (which is very important) to know the most likely mode of inheritance?(remember that carriers aren t shown in pedigrees to make it difficult to us, no not because of that only, but because we don t know carriers until we make genetic testing which is done after we drew the pedigree). The answers and explanations are in the next page after pedigrees to let you think. 12 P a g e
A B C D E F G H Answers are based on exclusion principle ( F and H are extras - not mentioned by the doctor). 13 P a g e
A-> autosomal recessive, how did we know? Not present in every generation so it is recessive, affected male transmits to his son so it isn t X-linked, females are also affected so it isn t Y-linked, so the answer is autosomal recessive. B-> autosomal recessive (it is the most proper but it could be X-linked). C-> autosomal recessive (it isn t necessary that every generation affected means dominant). D-> autosomal dominant. E-> Y linked because only males are affected in every generation. F -> most common is autosomal dominant but it could be autosomal recessive or X-linked recessive but those are less common. G -> X-linked recessive. H-> most common X-dominant. {Straight roads don t make skillful drivers} 14 P a g e