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Chapter p 8 Patterns of Single-gene I h it Inheritance O tli Outline Pedigree • Symbols • Sketching Patterns of single-gene inheritance • • • • • • Autosomall d A dominant i iinheritance h i Autosomal recessive inheritance X-linked recessive inheritance X-linked dominant inheritance Y-linked inheritance Mitochondrial inheritance Genetic heterogeneity Standard symbols Male Aff Affected Female Sex unspecified C i Carrier X li k d carrier X-linked i Siblings S g Proband Deceased affected individual Dizygotic twins Deceased individual M i Marriage or union i Consanguineous mating Monozygotic twins ? Twins of unknown zygosity No offspring Ⅰ Ⅱ Numbers of generations 1、2、3 Numbers N b off individuals E Example l Cathy is pregnant for the second time. Her first child, Donald, has CF. Cathy has two brothers, Charles and Colin, and a sister, Cindy. Colin and Cindy are unmarried. Charles is married to an unrelated l t d woman, Carolyn, C l and dh has a 2 2-year-old ld daughter, Debbie. Cathy’s parents are Bob and Betty Betty Betty. Betty’ss sister Barbara is the mother of Cathy’s husband, Calvin, who is 25. There is no previous family history of CF. • Sketch the pedigree, using standard symbols. P di Pedigree off C Cathy th Ⅰ 1 2 3 1 2 3 1 2 Ⅱ Ⅲ 4 5 6 3 Ⅰ-1 Barbara Ⅰ-2 Betty Ⅰ-3 Bob Ⅱ-1 Calvin Ⅱ-2 Cathy Ⅱ-3 Colin Ⅱ-4 Cindy Ⅱ-5 Charles Ⅱ-6 Carolyn Ⅲ-1 Ⅲ Donald Ⅲ-2 Ⅲ fetus Ⅲ Ⅲ-3 Debbie Genetic disorders with classical Mendelian inheritance The patterns shown by single-gene disorders in pedigrees depend chiefly on two factors: • The chromosomal location of the gene locus Autosomal (located on an autosome) X X-linked linked (located on the X chromosome) • Whether the phenotype is dominant or recessive Dominant Recessive 4b basic i patterns off single-gene i l inheritance Dominant Recessive Autosomal Autosomal dominant Autosomal recessive X-linked X-linked dominant X-linked recessive Patterns of autosomal dominant inheritance Autosomal dominant inheritance, AD • The gene concerned to single-gene disorder was located on an autosome autosome, and the phenotype is dominant. G Genotypes t & phenotypes h t A – mutant allele a – normal allele AA aa Affected Normal Complete dominance Incomplete dominance Irregular dominance Codominance D l Delayed d d dominance i Aa ? C Complete l t dominance d i Definition • A phenotype expressed in the same way in both h homozygotes t and dh heterozygotes t t iis completely l t l dominant. d i t Genotype & phenotype • AA affected Aa affected aa normal Ⅰ 1 2 Ⅱ 1 2 3 4 5 6 Ⅲ 1 2 3 4 5 6 7 8 9 P Progeny off Aa×aa A × mating ti N Normal l parentt aa a a A Aa Affected Aa Affected a aa Normal aa Normal Affected parent Aff Aa Brachydactyly y yy Syndactyly typeⅠ Characteristics of autosomal dominant inheritance The phenotype usually appears in every generation, each affected person havingg an affected pparent. p Any child of an affected parent has a 50 percent risk of inheriting the trait. trait Phenotypically normal family members do not transmit the phenotype h to their h i children. hild Males and females are equally likely to transmit the phenotype, to children of either sex. A significant proportion of isolated cases are due to new mutation. I Incomplete l t dominance d i § Definition • The phenotype due to a heterozygous genotype is diff different t from f the th phenotype h t seen in i both b th homozygous genotypes and its severity is intermediate between them them. § AA ((severelyy affected)) > Aa ((slightly g y affected)) > aa ((normal)) § Achondroplasia • Improper development of cartilage at the ends of the long bones, resulting in a form of congenital dwarfism. Incomplete dominance Aa Aa A Aa aa AA Slightly affected parent Progeny of Aa×Aa mating Slightly affected parent Aa A Aa a A Aa AA Severely affected Slightly affected a Aa Slightly affected aa Normal I Irregular l dominance d i Definition • The p phenotypes yp of some of the heterozygotes, yg for some reason, do not appear as affected. It can be seen as a skipped generation. aa Normal AA Affected A Aa Irregular (normal or affected) Ⅰ Ⅱ Ⅲ Ⅳ 2 1 1 2 3 1 1 4 2 2 3 3 4 4 5 A pedigree of polydactyly, showing the skipped generation because of Ⅱ3 who appeared phenotypically normal. Expressivity • expressivity— the variation of severity of the disease. It refers to the extent of expression of the disease phenotype. Penetrance • Th The frequency, f under d given i environmental i t l conditions, diti with ith which hi h a specific genotype is expressed by those individuals that possess it. • Usually, y, penetrance p is expressed p by yp percentage. g Affected heterozygotes Penetrance = ————————————×100% Total heterozygotes Genomic imprinting (P36) • P Parent-specific t ifi expression i or repression i off genes or chromosomes h in offspring. Marfan syndrome Polydactyly (h (hyperdactylia) d t li ) C d i Codominance definition • Both alleles of a gene pair are expressed in a heterozygote. Blood group MN • A pair of alleles alleles, LM and LN, located on 4q28 4q28-31, 31 are concerned to the blood group MN. Genotype LMLM LM LN LNLN Phenotype M MN N MM NN MN Blood group ABO • Alleles IA , IB and i located on 9q34 9q34, are concerned to the blood group ABO. Phenotype A B O AB Genotype IA IA IA i IB IB ii IA IB IB i P Parents’ ’ bl bloodd type P Progeny’s ’ bl bloodd type A×A A,O A×O A,O A×B A,B,O,AB A×AB A,B,AB B×B B,O B×O B,O B×AB O×O O×AB AB AB AB×AB A,B,AB O A,B A B AB A,B,AB D l Delayed d dominance d i Definition • The individual who carries mutant allele doesn’t onset until particular age. A pedigree of Huntington’s Disease from Venezuela Huntington disease T i l t repeatt di Triplet disorders d Normal # of copies Disease # of copies Disease Repeat Fragile X syndrome CGG or CCG 6-50 200-2000 Freidreich ataxia GAA 6-29 200-900 H Haw Ri River syndrome d CAG 7-25 2 49 49-75 Huntington disease CAG 10-34 40-121 J Jacobsen b syndrome d CGG 11 100 1000 100-1000 Myotonic dystrophy type 1 CTG 5-37 50-1000 Myotonic dystrophy type 2 CCTG < 10 > 100 Spinal and bulbar muscular atrophy CAG 14-32 40-55 Spinocerebellar ataxia CAG 4-44 4 44 40-130 40 130 Ⅰ 1 Ⅱ 1 2 41 44 2 3 30 46 4 5 6 42 Ⅲ 1 Ⅳ 2 3 4 5 6 7 8 9 10 11 20 1 2 A pedigree of Huntington Disease (showing (s o g ge genetic et c a anticipation t c pat o ) Genetic G ti anticipation ti i ti is i a phenomenon h whereby h b th the symptoms t off a genetic disorders become apparent at an earlier age as it is passed on to the next generation. M t i d Myotonic dystrophy t h 5 -37 37 copies i off CTG repeatt normall phenotype h t 50-1000 repeats myotonic dystrophy Genes with 40+ copies are unstable and can gain (or less commonly lose) repeat copies in successive generations. Patterns of autosomal recessive inheritance Autosomal recessive inheritance, AR • The gene concerned to single-gene single gene disorder is located on an autosome, and the phenotype is recessive. G Genotypes t & phenotypes h t A – normal allele a – mutant allele AA Aa aa Normal Carrier Affected Ⅰ 1 3 2 4 Ⅱ 1 Ⅲ Ⅳ 1 2 2 3 4 3 4 5 5 6 7 1 6 7 8 9 8 2 9 10 11 12 3 10 11 12 13 13 14 15 16 17 4 Typical pedigree showing autosomal recessive inheritance Parents Risk to offspring Carrier×Carrier: Aa×Aa ¼ AA, ½ Aa, ¼ aa ¾ unaffected, ¼ affected Carrier×Affected: Aa×aa ½ Aa, ½ aa ½ unaffected, ½ affected Affected×Affected: aa×aa aa only All affected C Consanguinity i it Relationship by blood or by a common ancestor. ancestor The chance that both parents are carriers of a mutant allele at the same locus is y if the parents p are increased substantially related and could each have inherited the mutant allele from a single common ancestor, a situation called consanguinity. Ⅰ 1 Ⅱ Ⅲ Ⅳ 1 1 2 2 3 2 4 3 1 4 2 5 6 3 Pedigree g in which parental p consanguinity g y suggests gg autosomal recessive inheritance Ⅰ 1 2 3 1 2 3 1 2 Ⅱ Ⅲ 4 A pedigree of Cystic Fibrosis 5 6 3 AR di disorders d Albinism Sickle Cell Anemia Characteristics of autosomal recessive inheritance A An AR phenotype, h if iit appears iin more than h one member b off a kindred, typically is seen only in the sibship of the proband, not in parents, offspring, or other relatives. For most AR diseases, males and females are equally likely to be affected. Parents of an affected child are asymptomatic carriers of mutant alleles. The parents of the affected person may in some cases be consanguineous. • This is especially likely if the gene responsible for the condition is rare in the population. The recurrence risk for each sib of the proband is 1 in 4. X li k d iinheritance X-linked h it XA– dominant allele of the gene on the X Xa – recessive allele of the gene on the X Genotypes Males Females Phenotypes XAY Hemizygous Xa Y Hemizygous XA XA Homozygous XA Xa Heterozygous Xa Xa Homozygous X li k d recessive X-linked i iinheritance h it XH – normal allele Genotypes yp Males Females l Xh – mutant allele Phenotypes XHY Unaffected Xh Y Affected XH XH XH Xh Xh Xh Homozygous unaffected Heterozygous (carrier) Homozygous affected Ⅰ Ⅱ Ⅲ Ⅳ 3 2 5 3 Pedigree pattern demonstrating an X-linked recessive disorder such as hemophilia A, transmitted from an affected male through females to an affected grandson and great-grandson. Ⅰ Ⅱ Ⅲ Ⅳ 3 2 Affected male × Normal female: 5 3 XhY×XH XH Xh XH XH Xh Daughters: ALL carriers Y XHY Sons: ALL unaffected Ⅰ Ⅱ Ⅲ Ⅳ 3 2 5 Normal male × Carrier female: 3 XHY×XH Xh XH XH XH XH Xh XH Xh Daughters: ½ normal; ½ carriers Y XHY Xh Y S Sons: ½ normal; l ½ affected ff d carrier girl normal girl affected boy normal boy 1 out of 4 chance 1 out of 4 chance 1 out of 4 chance 1 out of 4 chance 25% 25% 25% 25% Ⅰ Ⅱ Ⅲ Ⅳ 3 2 5 3 The hemophilia of an affected grandfather, which did not appear in any of his own children, has a 50% chance of appearing in any son of any of his daughters. It will NOT reappear among the descendants of his sons, however. Ⅰ Ⅱ Ⅲ Ⅳ 3 2 5 3 A daughter of a carrier has a 50% chance of being a carrier herself. By chance, an X-linked recessive allele may be transmitted undetected through a series of female carriers before it is expressedd in i a male l descendant. d d t Consanguinity in an X-linked recessive pedigree for red-green color blindness, resulting in a homozygous affected female female. Ⅰ Ⅱ Ⅲ Ⅳ Affected male × Carrier female: XhY×XH Xh Xh XH XH Xh Xh Xh Xh Daughters:½ carriers; ½ affected Y XHY Xh Y S Sons: ½ normal; l ½ affected ff d Characteristics of X-linked recessive inheritance The incidence of the trait is much higher in males than in females. The gene responsible for the condition is transmitted from an affected man through th h allll hi his d daughters. ht A Any off hi his d daughters’ ht ’ sons h has a 50% chance of inheriting it. The gene is ordinarily never transmitted directly from father to son son, but it is transmitted by an affected male to all his daughters. The g gene may y be transmitted through g a series of carrier females;; if so,, the affected males in a kindred are related through females. Heterozygous females are usually unaffected, but some may express the condition with ith variable ariable se severity erit as determined b by the pattern of X inactivation. X li k d d X-linked dominant i t iinheritance h it An X-linked phenotype is described as dominant if it is regularly expressed in heterozygotes. X li k d d X-linked dominant i t iinheritance h it Xh– normal allele Genotypes yp Males Females l XH– mutant allele Phenotypes XHY Affected Xh Y Unaffected XH XH XH Xh Xh Xh Homozygous affected Heterozygous affected Homozygous unaffected Ⅰ Ⅱ Ⅲ Ⅳ P di Pedigree pattern tt d demonstrating t ti X X-linked li k d d dominant i t iinheritance h it XD XD Hypophosphatemic rickets ((vitamin D-resistant rickets)) The abilityy of the kidney y tubules to reabsorb filtered phosphate is impaired. Although both sexes are affected, the serum phosphate level is less depressed and the rickets less severe in heterozygous females than in affected males. Characteristics of X-linked dominant inheritance Affected males with normal mates have no affected sons and no normal daughters. Both male and female offspring of female carriers have a 50% risk of inheriting the phenotype. phenotype • The pedigree pattern is the same as that seen with autosomal dominant inheritance. For rare phenotypes, affected females are about twice as common as affected males, but affected females typically have milder (though variable) expression of the phenotype. Y li k d iinheritance Y-linked h it Disease genes are on Y chromosome Affects males only All sons of affected father are affected Ⅰ 1 2 Ⅱ 1 Ⅲ 1 2 2 3 3 4 4 5 5 6 Mit h d i l di Mitochondrial diseases Disease genes are on mitochondria Matrilinear inheritance Ⅰ 1 2 Ⅱ 1 Ⅲ 1 2 2 3 3 4 4 5 5 6 G Genetic ti heterogeneity h t it Genetic heterogeneity g y includes a number of phenotypes that are similar but are actually determined by different genotypes genotypes. Genetic heterogeneity may be the result of ( different mutations at the same locus (allelic heterogeneity), mutations at different loci (locus heterogeneity) heterogeneity), or both both. L Locus h heterogeneity t it Retinitis pigmentosa • 12 autosomal dominant forms • 5 autosomal recessive forms • 3 X-linked forms Congenital g deafness: I 2 1 II 1 2 3 4 5 III 1 aa 2 3 4 5 aa 6 6 XR 7 aaBB Aa AAbb AaBb Aa/AA aa All li h Allelic heterogeneity t it Allelic heterogeneity • Allelic heterogeneity is an important cause of clinical variation. Many loci possess more than one mutant allele; in fact, at a given locus there may be several or many mutations. Sometimes, these different mutations result in clinically indistinguishable or closely similar disorders. In other cases, different mutant alleles at the same locus result in very different clinical presentations. For example - mutations in the RET gene • Hirschsprung Hi h di disease • Multiple endocrine neoplasia type Ⅱa and Ⅱb H How tto estimate ti t inheritance i h it pattern tt in i a kindred ki d d Initial estimation • Based on the continuity of the transmission in the generations – dominant or recessive • Based on the proportion of onset in males and f females l – autosomal t l or X-linked X li k d Genotypical estimation • If the genotypes are totally tallied with the phenotypes of the individuals Example 1 AD----Irregular g dominance Aa Ⅰ aa 1 2 Aa Ⅱ aa Aa 1 Ⅲ 1 Aa Ⅳ 2 aa 2 3 Aa 1 Aa 3 4 aa Aa Example 2 XAY Ⅰ X AXa 1 2 XAXa Ⅱ 1 Ⅲ 1 2 3 2 5 4 XAXa XAXA XR 3 4 5 XAY XaY Example 3 Aa Ⅰ aa 1 2 Ⅱ 1 2 4 3 5 Ⅲ 1 3 2 AD 6 4 Example 4 Ⅰ 1 2 Ⅱ 1 4 3 2 A Aa Ⅲ A Aa 3 2 1 Ⅳ aa 1 2 AR 3 Aa AA END P di Pedigree A diagram of a family history indicating the family members members, their relationship to the proband, and their status with respect to a particular ti l h hereditary dit condition. diti P b d Proband The affected person through which a pedigree is discovered and explored explored. M t i dystrophy Myotonic d t h Myotonic dystrophy is an inherited disorder in which the muscles contract but have decreasing power to relax. With this condition, the muscles also become weak and waste away. Myotonic dystrophy can cause mental t ld deficiency, fi i h hair i lloss and d cataracts. t t O Onsett off this thi rare disorder commonly occurs during young adulthood. However, it can occur at any age and is extremely variable in degree of severity. The myotonic dystrophy gene gene, found on chromosome 19 19, codes for a protein kinase that is found in skeletal muscle, where it likely plays a regulatory role. An unusual feature of this illness is that its symptoms usually become more severe with each successive generation. This is because mistakes in the faithful copying of the gene from one generation to the next result in the amplification of a genomic 'AGC/CTG triplet repeat', similar to that found fo nd in Huntington H ntington disease disease. Unaffected indi individuals id als ha have e between 5 and 27 copies of AGC/CTG, myotonic dystrophy patients who are minimally affected have at least 50 repeats, while more severely affected patients have an expansion of up to several kilobase pairs. Albinism Albinism Congenital absence of normal pigmentation or coloration in a p person,, an animal,, or a plant. p People p with albinism have little or no pigment in their eyes, skin, or hair. They have inherited genes that do not make the usual amounts of a pigment called melanin. melanin The albinism gene is "recessive" — it does not result in albinism unless a person has two copies of the gene for albinism and no copy of the gene that makes normal pigment. When both parents carry the gene, and neither parent has albinism, there is a one in four chance at each pregnancy that the baby will be born with albinism. This type of inheritance is called autosomal recessive inheritance. Si kl Cell Sickle C ll Anemia A i Sickle Cell Disease • Sickle Cell Disease is a group of inherited red blood cell disorders. Normal red blood cells are round like doughnuts, and they move through small blood tubes in the body to deliver oxygen. Sickle red blood cells become hard, sticky and shaped like sickles used to cut wheat. When these hard and pointed red cells go through the small blood tube, tube they clog the flow and break apart apart. This can cause pain pain, damage and a low blood count, or anemia. What makes the red cell sickle? • There is a substance in the red cell called hemoglobin that carries oxygen inside the cell. One little change in this substance causes the hemoglobin to form long rods in the red cell when it gives away oxygen These rigid rods change the red cell into a sickle shape oxygen. instead of the round shape. H Hemophilia hili A Hemophilia, hereditary blood disease, characterized by the inability of blood to clot, or coagulate, leading to hemorrhage, or excessive bleeding bleeding, even from minor injuries. The disease is caused by an insufficiency or absence of certain blood proteins (factor Ⅷ) that Ⅷ), h participate i i iin bl blood d clotting. l i • It is caused by a recessive allele on the X chromosome. P di Pedigree off royall h hemophilia hili R d Red-green color l blindness bli d Can not recognize correctly red color and green color. DMD (D (Duchenne h muscular l d dystrophy) t h ) Rapid progression of muscle degeneration Occurs early in life X-linked and affect mainly y males 1 in 3500 boys worldwide. Posture changes during progression of Duchenne muscular dystrophy Duchenne muscular dystrophy Standing from supine position S Symptomatology t t l The extremely enlarged calf DMD The gene for DMD, found on the X chromosome, encodes e codes a large a ge p protein ote dyst dystrophin. op • Dystrophin is required inside muscle cells for structural support; pp ; it is thought g to strengthen g muscle cells by y anchoring elements of the internal cytoskeleton to the surface membrane. Without it, the cell membrane b becomes permeable, bl so th thatt extracellular t ll l components t enter the cell, increasing the internal pressure until the muscle cell "explodes" explodes and dies. dies The subsequent immune response can add to the damage. D t Dystrophin hi complex l DMD E DMD: Early l P Pathology th l Phagocytosis: Invasion of fibers by macrophages Necrotic muscle fibers are pale on NADH stain DMD L DMD: Later t P Pathology th l Left: Normal dystrophinStaining around the rim of muscle fibers. Endomysial connective tissue increased Variable fiber size. Small fibers are rounded. Many hypercontracted muscle fibers Right: Ri ht Absent Ab t dystrophind t hi No staining around the rim of muscle fibers. DMD: Dystrophin staining
