University:
Kentucky State University
Course:
BIO 307 | Genetics
Academic year:

2024
Views:

64

Pages:

152
Author:

omiliar74be

Single-Gene Inheritance Importance of Family History • Understanding the past is the key to predicting the future. OBJECTIVES • Construct and interpret pedigrees using standard nomenclature • Describe the general features of Mendelian patterns of single gene inheritance. • Identify the mode of inheritance of traits discussed in lecture. • Describe aspects of phenotypic expression, using traits discussed in lecture as examples. • Understand basic concepts of probability. • Recognize the pattern of inheritance of a trait segregating in a family. • Apply basic concepts of probability and principles of Mendelian inheritance to calculate the probabilities that offspring of specified mating types will be affected and unaffected. Concept 14.3: Inheritance patterns are often more complex than predicted by simple Mendelian genetics • The relationship between genotype and phenotype is rarely as simple as in the pea plant characters Mendel studied • Many heritable characters are not determined by only one gene with two alleles • However, the basic principles of segregation and independent assortment apply even to more complex patterns of inheritance Extending Mendelian Genetics for a Single Gene • Inheritance of characters by a single gene may deviate from simple Mendelian patterns in the following situations: – When alleles are not completely dominant or recessive – When a gene has more than two alleles – When a gene produces multiple phenotypes Degrees of Dominance • Complete dominance occurs when phenotypes of the heterozygote and dominant homozygote are identical • In incomplete dominance, the phenotype of F1 hybrids is somewhere between the phenotypes of the two parental varieties • In codominance, two dominant alleles affect the phenotype in separate, distinguishable ways The Relation Between Dominance and Phenotype • A dominant allele does not subdue a recessive allele; alleles don’t interact that way • Alleles are simply variations in a gene’s nucleotide sequence • For any character, dominance/recessiveness relationships of alleles depend on the level at which we examine the phenotype • Tay-Sachs disease is fatal; a dysfunctional enzyme causes an accumulation of lipids in the brain – At the organismal level, the allele is recessive – At the biochemical level, the phenotype (i.e., the enzyme activity level) is incompletely dominant – At the molecular level, the alleles are codominant Frequency of Dominant Alleles • Dominant alleles are not necessarily more common in populations than recessive alleles • For example, Polydactyly one baby out of 400 in the United States is born with extra fingers or toes • The allele for this unusual trait is dominant to the allele for the more common trait of five digits per appendage • In this example, the recessive allele is far more prevalent than the population’s dominant allele Multiple Alleles • Most genes exist in populations in more than two allelic forms • For example, the four phenotypes of the ABO blood group in humans are determined by three alleles for the enzyme (I) that attaches A or B carbohydrates to red blood cells: IA, IB, and i. • The enzyme encoded by the IA allele adds the A carbohydrate, whereas the enzyme encoded by the IB allele adds the B carbohydrate; the enzyme encoded by the i allele adds neither Figure 14.11 (a) The three alleles for the ABO blood groups and their carbohydrates IA Allele Carbohydrate IB i none B A (b) Blood group genotypes and phenotypes Genotype IAIA or IAi IBIB or IBi IAIB ii A B AB O Red blood cell appearance Phenotype (blood group) Pleiotropy • Most genes have multiple phenotypic effects, a property called pleiotropy • For example, pleiotropic alleles are responsible for the multiple symptoms of certain hereditary diseases, such as cystic fibrosis and sickle-cell disease Extending Mendelian Genetics for Two or More Genes • Some traits may be determined by two or more genes Epistasis • In epistasis, a gene at one locus alters the phenotypic expression of a gene at a second locus • For example, in Labrador retrievers and many other mammals, coat color depends on two genes • One gene determines the pigment color (with alleles B for black and b for brown) • The other gene (with alleles C for color and c for no color) determines whether the pigment will be deposited in the hair Figure 14.12 BbEe Eggs 1/ 4 BE 1/ 4 bE 1/ 4 Be 1/ 4 be Sperm 1/ BE 4 1/ BbEe 4 bE 1/ 4 Be 1/ 4 be BBEE BbEE BBEe BbEe BbEE bbEE BbEe bbEe BBEe BbEe BBee Bbee BbEe bbEe Bbee bbee 9 : 3 : 4 Polygenic Inheritance • Quantitative characters are those that vary in the population along a continuum • Quantitative variation usually indicates polygenic inheritance, an additive effect of two or more genes on a single phenotype • Skin color in humans is an example of polygenic inheritance Figure 14.13 AaBbCc AaBbCc Sperm 1/ 1/ 8 8 1/ 1/ Eggs 8 1/ 1/ 8 8 1/ 8 1/ 1/ 8 8 8 8 1/ 8 1/ 8 1/ 1/ 8 1/ 8 1/ 8 1/ 8 Phenotypes: Number of dark-skin alleles: 1/ 64 0 6/ 64 1 15/ 64 2 20/ 64 3 15/ 64 4 6/ 64 5 1/ 64 6 Nature and Nurture: The Environmental Impact on Phenotype • Another departure from Mendelian genetics arises when the phenotype for a character depends on environment as well as genotype • The norm of reaction is the phenotypic range of a genotype influenced by the environment • For example, hydrangea flowers of the same genotype range from blue-violet to pink, depending on soil acidity • Norms of reaction are generally broadest for polygenic characters • Such characters are called multifactorial because genetic and environmental factors collectively influence phenotype Integrating a Mendelian View of Heredity and Variation • An organism’s phenotype includes its physical appearance, internal anatomy, physiology, and behavior • An organism’s phenotype reflects its overall genotype and unique environmental history Concept 14.4: Many human traits follow Mendelian patterns of inheritance • Humans are not good subjects for genetic research – Generation time is too long – Parents produce relatively few offspring – Breeding experiments are unacceptable • However, basic Mendelian genetics endures as the foundation of human genetics Pedigree Analysis • A pedigree is a family tree that describes the interrelationships of parents and children across generations • Inheritance patterns of particular traits can be traced and described using pedigrees • Pedigrees can also be used to make predictions about future offspring • We can use the multiplication and addition rules to predict the probability of specific phenotypes Concept 14.4: Many human traits follow Mendelian patterns of inheritance • Humans are not good subjects for genetic research – Generation time is too long – Parents produce relatively few offspring – Breeding experiments are unacceptable • However, basic Mendelian genetics endures as the foundation of human genetics Pedigree Analysis • A pedigree is a family tree that describes the interrelationships of parents and children across generations • Inheritance patterns of particular traits can be traced and described using pedigrees • Pedigrees can also be used to make predictions about future offspring • We can use the multiplication and addition rules to predict the probability of specific phenotypes Sample Pedigree IMPORTANT TERMS locus codominant compound heterozygote allele dominant carrier (obligate heterozygote) genotype recessive genetic heterogeneity phenotype homozygous pleiotropy autosomal heterozygous age of onset X-linked hemizygous sex-limited penetrance expressivity sex-influenced pedigree proband imprinting trinucleotide repeat A pedigree is a concise summary of the medical family history; it is the symbolic language of clinical genetics and human genetics research. • It is an easy, fast, and efficient means of recording a wealth of information about the family. • Standardization of symbols is essential to facilitate communication - See Robin Bennett’s article referenced in resources at the end of the syllabus for more details if interested. • Nomenclature is an evolving process. • Several ethical and legal dilemmas - Potential for discrimination, issues of privacy raised, and need for guidelines. Designation of generations and individuals 1. 2. 3. 4. 5. 6. 7. Each horizontal line is a generation Place the oldest generation at the top Use Roman numerals to identify generations Use Arabic numbers to identify individuals within a generation List siblings from oldest to youngest, from left to right Male partner is usually placed to the left of the female partner Record full name, current age and date of birth, or age at death for each individual 8. Record race and ethnic origin of each individual 9. Note health problems and/or cause of death for each individual 10.There are appropriate symbols to use for both adoption and assistedreproductive technologies • The proband is an affected individual coming to medical attention independently of other • family members. The proband is designated with an arrow in the pedigree, and there may be more than one proband per family. Medical status and results of genetic evaluation/testing of family members 1. Shading or fill (hatches, dots, etc.) is used to denote medical status or symptoms of individuals. A key/legend is used to define meaning 2. Results of an evaluation (E) are recorded below the symbol and a key/legend defines the notations. Currently this is the least standardized pedigree nomenclature The Gene is the Unit of Inheritance The location of a gene on a chromosome is its locus. Alternative forms of a gene at a particular locus are referred to as alleles. An individual’s genotype (genetic composition) at a particular locus is defined by the nature of the alleles at that locus If both alleles are identical, then the individual is homozygous at the locus. Homozygosity may refer to the presence of two normal or two mutant alleles. If the alleles differ, then the individual is heterozygous at the locus. If two different mutant alleles are present, then the individual is a compound heterozygote. A A homozygote A allele A a heterozygote a a homozygote a allele a1 a2 compound heterozygote The genotype at a particular locus and the environment in which it is expressed determines the phenotype or observed characteristics of an individual. Traits that are determined by loci on one of the 22 autosomes are autosomal. Traits determined by loci on the X chromosome are X-linked, and those determined by loci on the Y chromosome are Ylinked. Gregor Mendel’s Laws of Inheritance – Law of Unit Inheritance - parental characteristics do not blend because there is a unit of inheritance. Mendel’s “units” are now known as genes or alleles. – Law of Segregation - the two alleles at a particular locus segregate into different gametes. – Law of Independent Assortment - alleles at different loci are transmitted independently of each other. Linkage is an exception to this rule. Dominant and Recessive Inheritance – Nomenclature: For dominant traits the capital letter (e.g. A) represents the mutant allele and the small letter (e.g. a) represents the normal allele. For recessive traits, the small letter (e.g. a) represents the mutant allele and the capital letter (e.g. A) represents the normal allele. – Autosomal dominant traits are those traits in which the phenotype of the heterozygote and the homozygote for the dominant allele are the same, i.e., Aa and AA have the same phenotype where A=dominant allele. These traits are expressed when only one copy of the dominant allele is present. In practice, if the heterozygote expresses the trait, then the trait is classified as dominant, even if the phenotype of the homozygote (AA) and heterozygote (Aa) are different. – Autosomal recessive traits are those traits in which the phenotype is expressed only if homozygous for the recessive allele, i.e., aa where a=recessive allele. Two copies of the recessive allele are necessary for expression. Dominant and Recessive Inheritance – If the heterozygote (AB) has a different phenotype than either of the homozygotes (AA or BB), then the alleles are said to be codominant. – X-linked dominant traits are those expressed when either males or females have one copy of the dominant allele, i.e., XAY or XAXa where A=dominant allele. – X-linked recessive traits are those expressed in males who carry one copy of the recessive allele (i.e., are hemizygous, XaY where a=recessive allele). Two copies of the recessive allele are generally required for females to express the trait, i.e., XaXa. Types of Genetic Disease • • • • Chromosomal Single gene (Mendelian) Multifactorial Teratogenic Examples and Features of Autosomal Dominant Inheritance A a a a Unaffected individual Affected individual A=mutant allele a=normal allele Examples • • • • • • familial hypercholesterolemia Huntington disease neurofibromatosis type I (NF1) myotonic dystrophy Marfan syndrome achondroplasia Dominantly Inherited Disorders • Some human disorders are caused by dominant alleles • Dominant alleles that cause a lethal disease are rare and arise by mutation • Achondroplasia is a form of dwarfism caused by a rare dominant allele Figure 14.17 Parents Dwarf Dd Normal dd Sperm D d d Dd Dwarf dd Normal d Dd Dwarf dd Normal Eggs Achondroplasia Neurofibromatosis Type 1 Neurofibromatosis Type 1 Neurofibromatosis Type 1 Features of Autosomal Dominant Inheritance 1. Vertical transmission – direct transmission from grandparent to parent to child without skipping generations 2. Both sexes affected in 1:1 ratio 3. Both sexes may transmit the trait 4. Heterozygotes much more common than homozygotes 5. May see variable expressivity and variable age of onset 6. Homozygotes usually more seriously affected than heterozygotes 7. May be due to new mutation 8. Gene product is usually a structural (non-enzymatic) protein Autosomal Dominant Pedigree Transmission probabilities and the use of the Punnett square 1. If one parent has the disorder (assumed to be Aa) and the other does not (aa) then there is a 50% chance that the child will inherit the disorder and a 50% chance that they will not. 2. If both parents have the disorder (assumed to be Aa x Aa) then there is a 75% chance that their children will inherit the disorder, and a 25% chance that they will not. Examples and Features of Autosomal Recessive Inheritance Recessively Inherited Disorders • Many genetic disorders are inherited in a recessive manner • These range from relatively mild to lifethreatening Examples • • • • • cystic fibrosis sickle cell anemia Tay-Sachs disease Phenylketonuria most inborn errors of metabolism The Behavior of Recessive Alleles • Recessively inherited disorders show up only in individuals homozygous for the allele • Carriers are heterozygous individuals who carry the recessive allele but are phenotypically normal; most individuals with recessive disorders are born to carrier parents • Albinism is a recessive condition characterized by a lack of pigmentation in skin and hair and eyes Cystic Fibrosis • Cystic fibrosis is the most common lethal genetic disease in the United States, striking one out of every 2,500 people of European descent • The cystic fibrosis allele results in defective or absent chloride transport channels in plasma membranes leading to a buildup of chloride ions outside the cell • Symptoms include mucus buildup in some internal organs and abnormal absorption of nutrients in the small intestine Cystic fibrosis (CF) Figure 14.16 Parents Normal Aa Normal Aa Sperm A a A AA Normal Aa Normal (carrier) a Aa Normal (carrier) aa Albino Eggs • If a recessive allele that causes a disease is rare, then the chance of two carriers meeting and mating is low • Consanguineous matings (i.e., matings between close relatives) increase the chance of mating between two carriers of the same rare allele • Most societies and cultures have laws or taboos against marriages between close relatives Sickle-Cell Disease: A Genetic Disorder with Evolutionary Implications • Sickle-cell disease affects one out of 400 African-Americans • The disease is caused by the substitution of a single amino acid in the hemoglobin protein in red blood cells • In homozygous individuals, all hemoglobin is abnormal (sickle-cell) • Symptoms include physical weakness, pain, organ damage, and even paralysis Fig. 14-UN1 • Heterozygotes (said to have sickle-cell trait) are usually healthy but may suffer 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, so there is an advantage to being heterozygous Sickle Cell Anemia Autosomal Recessive A A Unaffected, not a carrier A=normal allele a=mutant allele A a Carrier, unaffected a a Affected Autosomal Recessive Pedigree Autosomal Recessive Pedigree Features of Autosomal Recessive Inheritance 1. Horizontal transmission – affected individuals usually within the same sibship or generation 2. Both sexes affected in 1:1 ratio 3. Both sexes may equally transmit the mutant allele 4. May observe consanguinity 5. Gene product is usually an enzymatic protein Transmission probabilities and use of the Punnett square If both parents are carriers (Aa x Aa) then there is 25% chance that the child will have the disorder (aa) 50% chance that the child will be a carrier (Aa), and 25% chance that the child will be neither affected nor a carrier (AA). Thus the chance that an unaffected child of carrier parents is also a carrier is two in three. Affected homozygotes are commonly the offspring of two heterozygote carriers. Sex Linkage and X-Inactivation XA Y XA Xa Xa Xa Dosage compensation 1. For autosomal traits, two doses lead to a normal phenotype, while one dose or more than two doses often have clinical significance 2. For X-linked traits two doses in females and one dose in males both lead to a normal phenotype X-inactivation in females allows compensation for this difference in dosage for X-linked traits • Lyon hypothesis • In early embryonic life (3-7 days after fertilization) one X chromosome is inactivated. The inactive X chromosome is condensed in a Barr body. • Inactivation of the maternal or paternal X chromosome is 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, i.e., 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. X-Inactivation • Allows dosage compensation between males and females for genes on the X chromosome • In females, early in embryonic life, one of the X chromosomes is inactivated • The process is random and clonal • Some genes escape X-inactivation • A gene that is located on either sex chromosome is called a sex-linked gene • Genes on the Y chromosome are called Y-linked genes; there are few of these • Genes on the X chromosome are called X-linked genes Inheritance of X-Linked Genes • X chromosome have genes for many characters unrelated to sex, whereas the Y chromosome mainly encodes genes related to sex determination • X-linked genes follow specific patterns of inheritance • For a recessive X-linked trait to be expressed – A female needs two copies of the allele (homozygous) – A male needs only one copy of the allele (hemizygous) • X-linked recessive disorders are much more common in males than in females Figure 15.7 X NX N Sperm Xn X NX n XnY Sperm XN Y X NY X NX n Sperm Xn Y XnY Y Eggs XN X NX n X NY Eggs XN X NX N X NY Eggs XN X NX n X NY XN XNX n XNY Xn XNXn XnY Xn XnXn XnY (a) (b) (c) • Some disorders caused by recessive alleles on the X chromosome in humans – Color blindness (mostly X-linked) (Red-green color blindness) – Duchenne muscular dystrophy (dystrophy muscle weakness and loss of muscle tissue) – Hemophilia X Inactivation in Female Mammals • In mammalian females, one of the two X chromosomes in each cell is randomly inactivated during embryonic development • The inactive X condenses into a Barr body •If a female is heterozygous for a particular gene located on the X chromosome, she will be a mosaic for that character Examples and Features of X-Linked Recessive Inheritance Examples: Duchenne muscular dystrophy X-Linked Recessive Pedigree Features of X-Linked Recessive Inheritance 1. Diagonal inheritance – affected males related through females of the maternal line 2. Absence of male-to-male transmission 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 Transmission probabilities and use of the Punnett square 1. A son never inherits the disorder from his father. 2. All daughters of a male with the disorder are obligate carriers. 3. Sons of carrier females have a 50% chance of inheriting the disorder. 4. Daughters of carrier females have a 50% chance of being carriers too. Examples and Features of X-Linked Dominant Inheritance X-Linked Dominant Pedigree Features of X-Linked Dominant Inheritance 1. Twice as many females with the disorder as males 2. Absence of male-to-male transmission 3. Males with the disorder transmit it to all daughters and no sons 4. Females usually have more mild and variable expression due to X-inactivation 5. Few disorders classified as X-linked dominant Transmission probabilities and use of the Punnett square 1. A son never inherits the disorder from his father 2. All daughters of male with the disorder will also have the disorder 3. Sons of affected females have a 50% chance of inheriting the disorder 4. Daughters of affected females also have a 50% chance of inheriting the disorder 5. Can distinguish between autosomal and X-linked dominant by looking at offspring of affected males Phenotypic Expression 1. 2. 3. 4. 5. 6. 7. Penetrance Expressivity Variable age of onset Pleiotropy Genetic heterogeneity Sex-limited Sex-influenced Penetrance • Penetrance refers to the all or none expression of a mutant genotype. It usually refers to dominant traits in heterozygotes, and means that even though an individual has inherited the mutant allele, there may be no expression of the phenotype. If a condition is expressed in less than 100 % of persons who have one copy of the mutant allele, it is said to have reduced penetrance. If a condition/feature is expressed in less than 100% of individuals who carry the responsible allele, then it is said to have reduced penetrance • The probability of expression of the phenotype given the genotype • Term used for dominant conditions Reduced Penetrance Retinoblastoma, a malignant eye tumor. About 10% of individuals who transmit the mutant allele are unaffected. Therefore, the mutant allele is 90% penetrant. Retinoblastoma Reduced Penetrance Waardenburg syndrome, a congenital sensorineural deafness, heterochromia, displacement of the inner canthi, white forelock, and other features. Since only about 20% of people with Waardenburg syndrome are deaf, this shows reduced penetrance of this feature of this syndrome Deafness in Waardenburg syndrome Variable Expressivity • The extent to which a trait is expressed • If expression ranges from mild to severe then it is said to have variable expressivity • However, it is never completely unexpressed – Eg. Neurofibromatosis & myotonic dystrophy Variable age of onset & pleiotropy Variable age of onset refers to the variation in the time to phenotypic expression of mutant gene (s). Example: the onset of Huntington disease is typically in the 40’s, however, age of onset may range from the 20’s to 60’s. A mutant gene is said to be pleiotropic when it produces a wide range of phenotypic effects. Example: Marfan syndrome involves the skeletal, cardiovascular, and ocular systems. Anticipation: Earlier Age of Onset & Increasing Severity Myotonic dystrophy Genetic heterogeneity allelic heterogeneity locus heterogeneity At the CF locus on 7q a1 = ΔF508 allele a2 = S549R allele a1 a2 GJB2 on 13q Auto rec HL PAX3 on 2q Auto dom HL Genetic heterogeneity Allelic heterogeneity refers to two or more different mutant alleles at the same genetic locus (Example: Duchenne and (the less severe) Becker muscular dystrophy; cystic fibrosis). At the CF locus on 7q a1 = ΔF508 allele a2 = S549R allele a1 a2 Genetic heterogeneity Locus heterogeneity is when mutations at two different genetic loci result in similar phenotypes (Example: congenital deafness). In some cases, the mode of inheritance of the disorders can vary GJB2 on 13q Auto rec HL PAX3 on 2q Auto dom HL Sex-limited & Sex-influenced – refers to a phenotype that is autosomally transmitted but expressed only in one sex. Example: Autosomal dominant male precocious puberty. – Sex-influenced refers to autosomally inherited traits that are expressed differently, in either degree or frequency, in males and females. Example: hemochromatosis (autosomal recessive disorder of increased absorption of dietary iron) is more commonly found in males due to lower dietary intake and menstruation in females. • Some disorders do not follow Mendelian patterns of inheritance. • These disorders are clearly genetic (inherited) and their inheritance is classified as non-Mendelian. • We now understand why some of these disorders do not follow Mendelian patterns and examples include: mitochondrial inheritance, unstable trinucleotide repeats, and imprinting. Trinucleotide Repeats Some disorders were observed to increase in severity from one generation to another, and/or the age of onset of symptoms became earlier in successive generations. This was termed anticipation and the mechanism was a mystery since mutations were presumed to be inherited in a stable manner from one generation to another. Furthermore, in some disorders the sex of the parent who passed on the disorder seemed to influence the severity or age of onset of symptoms. This too was a puzzle because in Mendelian traits maternal and paternal DNA was assumed to be equivalent. Anticipation and parent of origin effects are now known to be due to a novel type of dynamic mutation known as unstable trinucleotide repeats. Trinucleotide Repeats Tandemly repeated trinucleotides (i.e. CGG, CTG) within or adjacent to a gene that may increase or decrease in number during formation of egg or sperm cells and thus disrupt the functioning of the gene and lead to disease Examples: • Fragile X Mental Retardation syndrome • Huntington disease • myotonic dystrophy • spinocerebellar ataxia • Kennedy disease • Joseph disease • Friedreich Ataxia Trinucleotide Repeat Expansion Fragile X MR Syndrome FX MR Clinical Features 1. Incidence of about 1 in 5000 males; presumed incidence in females is about one-half that of males. 2. Most common cause of inherited mental retardation in males. 3. Phenotype in males includes moderate mental retardation, large head, long face, prominent forehead and chin, protruding and larger ears, large testes after puberty, speech delay, and loose joints. Behavior abnormalities include hyperactivity, hand flapping, hand biting, temper tantrums and sometimes autism spectrum disorder. 4. Approximately 50% of female carriers of a full mutation have mental retardation that is usually less severe than in affected males. 5. About 30% of males who carry a premutation will develop Fragile X-associated tremor/ataxia syndrome (FXTAS) which is characterized by late-onset, progressive cerebellar ataxia and intention tremor. About 20% of females who carry a premutation will develop premature ovarian failure (POF). Genetic Features A. Atypical X-linked inheritance showing parent of origin effect. B. In affected males associated with a fragile site at Xq27.3 in 10-40% of metaphase spreads, however, this cytogenetic testing is no longer used for diagnostic testing. C. Amplified ‘CGG’ trinucleotide repeat as well as abnormal methylation (hypermethylation) of the FMR-1 gene. The normal protein product, FMRP, is an RNA-binding protein that seems to function as a nucleocytoplasmic shuttling protein and it binds several mRNAs including its own. It also seems to affect cytoskeletal structure, synaptic transmission and neuronal maturation. The FMR-1 gene mutation results in gene silencing and the loss of function results in suppression of translation of proteins from its RNA targets. Genetic Features D. Allele sizes (these categories are not absolute): - Normal alleles: 5-54 repeats - Premutation alleles: 55-200 repeats (not associated with MR but there is risk for FXTAS and POF; may expand to full mutation in female carrier) - Full mutation alleles: > 200 repeats (affected individuals) E. Existence of transmitting males who are of normal intelligence but can transmit the Fragile X chromosome to their daughters. These daughters are of normal intelligence, however, their children are at risk for mental retardation. F. The change from phenotypically normal to affected state (i.e. expansion of the trinucleotide repeats into the full mutation range) has only been observed following oogenesis. Huntington’s Disease: A Late-Onset Lethal Disease • Huntington’s disease is a degenerative disease of the nervous system • The disease destroys cells in the basal ganglia, the part of the brain that controls movement, emotion, and cognitive ability • The disease has no obvious phenotypic effects until the individual is about 35 to 40 years of age • Once the deterioration of the nervous system begins the condition is irreversible and fatal Genomic Imprinting • For a few mammalian traits, the phenotype depends on which parent passed along the alleles for those traits • Such variation in phenotype is called genomic imprinting • Genomic imprinting involves the silencing of certain genes that are “stamped” with an imprint during gamete production Figure 15.17 Paternal chromosome Maternal chromosome Normal Igf2 allele is expressed. Normal Igf2 allele is not expressed. Normal-sized mouse (wild type) (a) Homozygote Mutant Igf2 allele inherited from mother Mutant Igf2 allele inherited from father Normal-sized mouse (wild type) Dwarf mouse (mutant) Normal Igf2 allele is expressed. Mutant Igf2 allele is expressed. Mutant Igf2 allele is not expressed. Normal Igf2 allele is not expressed. (b) Heterozygotes Figure 15.17a Paternal chromosome Maternal chromosome Normal Igf2 allele is expressed. Normal Igf2 allele is not expressed. (a) Homozygote Normal-sized mouse (wild type) Figure 15.17b Mutant Igf2 allele inherited from mother Mutant Igf2 allele inherited from father Normal-sized mouse (wild type) Dwarf mouse (mutant) Normal Igf2 allele is expressed. Mutant Igf2 allele is expressed. Mutant Igf2 allele is not expressed. (b) Heterozygotes Normal Igf2 allele is not expressed. • It appears that imprinting is the result of the methylation (addition of –CH3) of cysteine nucleotides • Genomic imprinting is thought to affect only a small fraction of mammalian genes • Most imprinted genes are critical for embryonic development Imprinting Prader-Willi syndrome Angelman syndrome Imprinting I.Definition: the differential expression of a gene depending on the sex of the parent from which it is inherited (i.e., the parental origin of the gene). Implications: A.Implies that there is a critical or sensitive period during development (i.e. during or before gametogenesis) during which the genetic information is marked or imprinted in order to permit differential expression based on parental origin. B.The imprint must persist stably through DNA replication and cell division in the body cells. C.The imprint must be capable of affecting gene expression (i.e. turning genes on or off). D.Imprinting is not a permanent alteration since it must be erased in the germ cell line of every individual so that new imprinting may be introduced. Example of Imprinting in Humans Prader-Willi syndrome (PWS) and Angelman syndrome (AS) 1.Both map to and may involve deletions of 15q11-13 but they have distinct phenotypes. 2.PWS is characterized by obesity, voracious appetite, and mental retardation, whereas, Angelman is characterized by gait ataxia, smiling facies and happy demeanor, and mental retardation. 3.Deletions are found in about 50-60% of cases of PWS and AS. 4.If the deletion is paternally derived (only maternal 15q11-13 present) then PWS. 5.If the deletion is maternally derived (only paternal 15q11-13 present) then AS. 6.Some cases of PWS (about 30%) have been attributed to maternal uniparental disomy and some cases of AS (about 5%) have been attributed to paternal uniparental disomy. About 10-15% of cases of AS are caused by a single gene mutation in the UBE3A gene. Other causes of PWS and AS include defects in the imprinting center, chromosomal translocation within the PWS/AS critical region, and unknown cause. PWS & AS both involve chromo 15q11-13 Deletions account for ~ 70% cases of PWS & AS • If paternal deletion of 15q11-13 → PWS • If maternal deletion of 15q11-13 → AS Causes of PWS and AS Inheritance of Organelle Genes • Extranuclear genes (or cytoplasmic genes) are found in Mitochondria • Extranuclear genes are inherited maternally because the zygote’s cytoplasm comes from the egg • Some defects in mitochondrial genes prevent cells from making enough ATP and result in diseases that affect the muscular and nervous systems – For example, mitochondrial myopathy (myopathy is a muscular disease) and Leber’s hereditary optic neuropathy (damage to nerves)

Patterns of Inheritance

Related Documents

Recommended Documents

Description

Related Documents

Free up your schedule!

Take 5 seconds to unlock