Lecture 3-Ch 4, 5, 6, 23.1-23.3
Lecture 3-Ch 4, 5, 6, 23.1-23.3 30156
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© Hannah Kennedy, Kent State University th July 20 Lecture—Ch. 4, 5, 6: Sex Determination and Extension of Mendelian Inheritance 1. Problem Solving a. Q: As Mendel discovered, tall plant height is dominant to short. In the following experiments, parents with known phenotypes but unknown genotypes produced the following progeny: Using the letter T for tall and t for short, give the most probable genotype of each parent b. Q: On average, about 1 child in every 10 thousand live births in the United States has phenylketonuria (PKU). What is the probability that… i. The next child born in a Boston hospital will have PKU? ii. After that child with PKU is born, the next child born will have PKU? iii. 2 children born in a row will have PKU? 2. Poodle problem: A woman who owned a purebred (aka homozygous) albino poodle (an autosomal recessive phenotype) wanted white puppies; so she took the dog to a breeder, who said he would mate the female with an albino stud male, also from a pure stock. When 6 puppies were born, all of them were black; so the woman sued the breeder, claiming that he replaced the stud male with a black dog, giving her 6 unwanted puppies. You are called in as an expert witness, and the defense asks you if it is possible to produce black offspring from 2 pure-breeding recessive albino parents. What testimony do you give? a. Epistasis = the masking of a phenotypic effect of alleles at one gene by alleles of another gene; a gene is epistatic when its presence suppresses the effect of a gene at another locus b. The testimony: Yes, this is possible. We have 2 loci mutations of which result in albino phenotype. It’s possible in the combination of each other they could complement the other. Therefore, if one of these dogs is mutated in such a way that it lacks the substrate gene but has the enzyme, no substrate is made and no phenotype is made. And if the other has the substrate gene but it lacks the proper protein for deposition of color, then when they are bred, we are creating a complement in which one has the substrate and the other has the enzyme and they are now functional and black puppies are made. 1. Note: albinism means that their gene is mutated and they carry the allele for albinism. 2. There can be sequence changes in the protein responsible for the color (e.g. enzyme responsible for deposition) or there might be changes at other genes responsible for producing the color (e.g. if we have a substrate that is used to make the color and the gene responsible for the substrate is mutated, it wouldn’t have the same affect.) so, when thinking about phenotypes, there may be many pathways the organism can take to reach that phenotype 3. Mendelian diseases are generally single gene diseases but in medical genetics (like diabetes or HBP are phenotypes) there are multiple genes involved. 3. Non-Mendelian phenotype ratios a. Recessive alleles cause reduction in amt/function of encoded proteins 1 © Hannah Kennedy, Kent State University i. Wild type alleles = an allele that is fairly prevalent in a natural population, generally greater than 1% of the population 1. Molecularly, these alleles encode a protein that is made in the proper amount and functions normally ii. Genetic polymorphism = when 2+ alleles occur in a population; each allele is found at a frequency of 1% or higher iii. Mutant alleles = alleles that have been created by altering a wild-type allele by mutation; often defective in ability to express functional protein and often inherited in a recessive pattern iv. human genetic diseases are example of how recessive alleles cause decrease in expression of functional protein bc the recessive allele doesn’t produce a specific cell protein in active form 1. phenylketonuria: inability to metabolize phenylalanine 2. albinism: lack of pigmentation in skin/eyes/hair 3. tay-sachs: defect in lipid metabolism 4. cystic fibrosis: inability to regulate ion balance across epithelial cells a. why defective mutant alleles are inherited recessively: protein function (2 possible explanations) i. (1) diploid ppl have 2 copies of every gene and in simple dom/rec relationship, rec allele doesn’t affect phenotype of heterozygote aka single copy of dom allele is enough to mask rec allele effect 1. ex: PP and Pp each make enough functional protein to yield purple flowers (i.e. the homozygous make 2x as much of the protein than it really needs to make purple flowers so the amt is reduced to 50% in heteros) ii. (2) heterozygote produces more than 50% of functional protein but bc of gene regulation, expression of normal gene is increased to compensate for lack of function of defective allele b. 2 questions after chi-square tests: i. What if observed phenotypic ratios significantly differ from the Mendelian 3:1 and 9:3:3:1 ratios? 1. Modifications of 3:1 ratio: types of Mendelian Inheritance Patterns Involving single genes (i.e. relationships within a single locus) Inheritance Pattern Inheritance Description Molecular Description Incomplete - Occurs when heterozygote has a phenotype - 50% of a dominance*** that is intermediate between either functional corresponding homozygote (e.g. a cross protein isn’t btwn homozygous red flower and enough to homozygous white flower produce produce the heterozygous pink flower offspring) same trait as the - 1 allele can’t completely mask the other homozygote - leads to phenotypic ratio of 1:2:1 making 100% Codominance*** - occurs when heterozygote expresses both - codominant alleles simultaneously without forming an alleles encode intermediate phenotype proteins that - Ex: blood type groups (occurs from what function slightly kind of glycoprotein cells present on their differently from cell surface) In MN blood groups: 2 each other. different alleles, both will be present on Function of each 2 © Hannah Kennedy, Kent State University cell surface which will render the protein in phenotype different and distinct from if we heterozygote M hNd only 1 allele for 1 glycoprotein. L and affects L can produce 3 possible phenotype in a phenotype/genotypes (1:2:1) unique way c. L L M M N d. L N N e. L L - Ex: ABO group of antigens (blood type) exhibits co-dominance in combination with 2+ alleles in a population: 3 alleles, I , I , I are based on surface antigen and can yield 4 possible phenotypes i. Multiple alleles = when the same gene exists in 2+ alleles within a population ii. A and B are codominant to each other (glycoprotein alleles on cell surface so both will be present in cell phenotype) iii. A and B can mask presence of O allele so that nothing is presented Phenotyp Genotype e (i.e. blood type) A A A - I I - I i SimpleBMendelian - I IB- inheritance of alleles that obey Mendel’s - dominant allele B laws and follow a strict dominant/recessive encodes a - I i relationship functional AB - I IB protein and 50% O - ii of the protein is sufficient to produce a dominant trait X-linked - inheritance of genes located on the X - if pair of X-linked chromosome alleles show a simple dominant/recessi ve relationship, dominant allele encodes functional protein and 50% of it is enough to make a dominant trait in heterozygous 3 © Hannah Kennedy, Kent State University femal Incomplete - occurs when a dominant phenotype isn’t - dominant gene penetrance*** = expressed even though an individual may be present a pattern of carries a dominant allele (Ex: a person but the protein inheritance in who carries the polydactyly allele but has encoded by the which a dominant normal # of fingers and toes) gene doesn’t allele doesn’t - a lot of loci don’t have complete exert effects. always control the penetrance. So someone might be positive Can be due to phenotype of the for cancer but never express it (this is a evmt or to other individual risk in the medical world) genes that - measure of penetrance described at encode proteins populational level (e.g. if 60% of heteros that counteract carrying dom allele exhibit, the trait is 60% effects of protein penetrant) encoded by dominant allele Sex-influenced - the effect of sex on the phenotype of the - sex hormones individual. Some alleles are recessive in 1 regulate sex and dominant in the opposite sex (Ex: molecular pattern baldness linked to testosterone) expression of - phenomenon of heterozygotes genes which can - autosomal therefore they’re not located on influence X or Y phenotypic effects of alleles Sex-limited - traits that occur in only 1 of the 2 sexes - sex hormones (ex: breast development (e.g. beard regulate development in men/ovaries in women) molecular - sexual dimorphism = species in which expression of the males and females are morphologically genes so sex distinct; sex-limited traits are responsible hormones for this primarily produced in only 1 sex are essential to produce a particular phenotype Lethal alleles*** - an allele that has the potential of causing - most commonly the death of an organism, usually inherited loss-of-function in a recessive manner; many prevent cell alleles that division encode proteins - essential gene = a gene that is essential necessary for for survival because it encodes a protein survival. Allele necessary for life may be due to a - non-essential genes = genes that aren’t mutation in a necessarily essential for survival but are nonessential beneficial gene that - conditional lethal alleles = an allele that changes a is lethal, but only under certain envmtal protein to 4 © Hannah Kennedy, Kent State University conditions function - temperature-sensitive lethal alleles = abnormally an allele that is lethal at a certain temp - we are missing phenotypic classes - Mutations are often tolerated in heterozygous conditions but are lethal if they are homozygous recessive (e.g. Tays- Sach disease) Overdominance - occurs bc in some genes, heterozygotes can - 2 alleles produce = an inheritance display characteristics that are more proteins with diff pattern in which a beneficial for survival in certain envmt (e.g. AA sequences heterozygote is heterozygote may be larger/more disease- more vigorous than resistant/better able to withstand hard either of the evmt conditions) correspond - Ex: sick cell disease in homozygous homozygotes individuals. Heterozygotes that are carriers of the disease are protected against malaria bc RBCs rupture when infected preventing parasite from spreading a. Variable expressivity i. Expressivity = the degree to which a trait is expressed (e.g. flowers with deep red color have high expressivity of red allele) 1. Ex: dogs have same genotype but have differing variances of expressed phenotypes not attributed to environment b. ABO blood type cont… i. Molecular characteristics of blood types 1. RBC plasma membranes have oligosaccharides that act as surface antigens; 2 diff types of surface antigens can be found (A and B) 2. synthesis of surface antigens is controlled by 2 A B alleles (I and I ). i allele is recessive to both so a person who is ii has type O block and doesn’t make either antigen c. pleiotrophy = the multiple effects of a single gene on the phenotype of an organism (occurs for 3 reasons) 5 © Hannah Kennedy, Kent State University i. expression of single gene can affect cell function in 1+ way (e.g. defect in MT protein can affect cell division and cell movement) ii. gene may be expressed in diff cell types (e.g. gene may be expressed in muscle and nerve cell) iii. gene may be expressed at diff stages of development (e.g. during embryonic development and expressed in adult) 2. Modifications of the 9:3:3:1 ratio: Mendelian inheritance patterns involving 2 genes a. Gene interaction = when 2+ diff genes influence the outcome of a single trait—when both/either loci have multiple alleles in a population Inheritance Pattern Description Epistasis = phenomenon - The alleles of 1 gene mask the phenotypic effects of in which the phenotype of the alleles of a diff gene 1 gene in one locus masks - Recessive epistasis = a form of epistasis in which an another gene in another individual must be homozygous for either recessive locus; occurs when 2 gene allele to mask a particular phenotype loci control the same - Ex: melanin (i.e. pigment locus: making a lot, little, or phenotypic character— intermediate pigment. Structural protein interacts w occurs across 2 separate, pigment or enzyme transports pigment to hair follicle): different loci; often occurs BB = black (dominant), bb = brown (recessive), Bb = bc 2+ diff protein black (dominant); c controls pigment deposition and is participate in common epistatic to B or b (i.e. pigment formation) function (e.g. 2+ proteins o cc = albino whether it is BBcc or bbcc may be part of an - Ex: breeding Labrador Retrievers –9:3:4 ratio enzymatic pathway that o Have 2 loci responsible; will be dependent upon lead to the formation of a if there exists 2 dominant or 2 recessive alleles single product) in these loci P: Black (BBEE) x Yellow (bbee) F1: Black (BbEe) F2: 895 black, 280 brown, and 425 yellow (Do a chi-square test to see if this is a 9:3:4 or a 9:3:3:1: set up both and see which hypothesis will be accepted or rejected) - Diff kinds of epistasis: Ratio Genotype Type of Interaction 9:3:3:1*** - 9 A_B_ None - 3 A_bb - 3 aaB_ - 1 aabb 9:3:4 - 9 A_B_ Recessive - 3 A_bb epistasis - 4 aaB_ 12:3:1 - 12 A_B_ Dominant - 3 aaB_ epistasis - 1 aabb 6 © Hannah Kennedy, Kent State University Complementation = a - 2 diff parents that express the same or similar phenomenon in which the recessive phenotypes produce offspring with a wild- presence of 2 diff mutant type phenotype alleles in the same - each recessive allele is complemented by a wild-type organism produces a wild- allele which indicates recessive alleles are in diff type phenotype. It occurs genes usually bc the 2 mutation are in diff genes, so the organism carries 1 copy of each mutant allele and 1 copy of each wild-type allele Modifying genes - an allele of 1 gene modifies the phenotypic outcome of the alleles of a diff gene Gene redundancy = the - the loss of function in a single gene has no phenotypic phenomenon in which an effect but the loss of function of 2 genes has an effect inactive gene is - functionality of only 1 of 2 genes is necessary for compensated for by normal phenotype aka genes are functionally another gene with similar redundant function - may be due to gene duplication (paralogs = homologous genes within a single species that constitute a gene fam so if one is missing another paralog may be able to carry out missing function) b. Combinations of inheritance patterns (i.e. if both/either loci have multiple alleles in a population) A B A B i. Ex: AaI I x AaI I 1. This is a cross that involves 2 traits a. ABO blood type (found at 1 locus, alleles I A and I ) b. Albinism (found at second locus, alleles A and a) iv. What if offspring phenotype differs from both parental phenotypes? (e.g. getting pink plants in the F1 generation when crossing red and white plants) 1. The conclusion: not all allele systems have only dominant or recessive alleles 4. Differences between sexes/sex chromosomes a. Key terminology: i. Sex chromosomes = a pair of chromosomes (e.g. X and Y in mammals) that determines sex in a species; certain genes found on them play key role in the development of sex ii. Chromosome theory of inheritance = state that chromosomes carry the genes that determine an organism’s traits iii. Heterogametic sex = in species with 2 types of sex chromosomes, the heterogametic sex produces 2 types of gametes. For example, the male is the heterogametic sex, bc a sperm can contain either an X or a Y chromosome iv. Homogametic sex = the sex that produces only 1 type of gamete. For example, in mammals, the female is the homogametic sex, bc an egg can only contain an X chromosome 7 © Hannah Kennedy, Kent State University v. Autosomes = chromosomes that aren’t sex chromosomes vi. X-linked inheritance = an inheritance pattern in certain species that involves genes that are located only on the X chromosome; males transmit X- linked genes only to their daughters and sonce receive their X-linked genes from their mothers vii. Hemizygous = describes the single copy of an X-linked gene in the male viii. X-linked alleles = genes (or alleles of genes) that are physically located within the X chromosome ix. Testcross = an experimental cross between a recessive individual and an individual whose genotype the experimenter wishes to determine x. X-linked recessive pattern = an allele or trait in which the gene is found on the X chromosome and the allele is recessive relative to a corresponding dominant allele (e.g. Duchenne muscular dystrophy) b. Sex-linkage explains the observed ratio (e.g. color blindness with X-linkage. E.g. female and male roosters) i. Chromosomal theory of inheritance: If mom is a carrier of an X-linked trait, then half of her sons would be affected and half of daughters would be affected. But if dad is affected then all daughters will be carriers because they get the X from him and all sons will be normal because they get the X from their mom. 1. Ex: color blindness gene is a mutation in which the locus is located on the X chromosome (i.e. it is an X-linked trait) a. Affected mom: all sons will be affected and daughters will be carriers 2. When thinking about pedigree: if an affected Dad has an affected daughter, it excludes the X-linked inheritance so it must be autosomal ii. Heteromorphy of sex-determining X and Y chromosomes 1. The reason why we mostly think about the X chromosome is bc its larger and contains 100s of more genes than the Y chromosome c. Nondisjunction and Sex chromosomes d. X-inactivation (i.e. dosage compensation) i. Key terminology: 1. Dosage compensation = the phenomenon in which the level of expression of many genes on the sex chromosomes (i.e. the X chromosome) is similar in both sexes, even though males and females have a different complement of sex chromosomes. 2. X inactivation = a process in which mammals equalize the expression of X-linked genes by randomly turning off 1 X chromosome in the somatic cells of females 3. X-inactivation center = Xic = a site on the X chromosome that appears to play a critical role in X inactivation; counting X chromosomes is done by counting Xics; must be found on X chromosome for inactivation to occur ii. Ex: Calico cat: female cats are mosaic: half their cells have an active black X and half have an active red X. Only heterozygous females can be calico. So, for a black and orange fur on a cat, the orange patches are due to the inactivation of the X chromosome that carries the black allele and the black 8 © Hannah Kennedy, Kent State University patches are due to the inactivation of the X chromosome that carries the orange allele iii. Lyon hypothesis = hypothesis proposed by Mary Lyon that stated that dosage compensation in mammals occurs by the inactivation of a single X chromosome in femals; there is a random inactivation of X in embryo and it is permanent 1. Ex: White and black coat colors found in mice a. Female mouse inherits X chromosome from its mom that carries an allele for a while coat color = X b. X chromosome from its dad carries a black coat color allele = B X i. Initially, both X chromosomes are active but at early stage of embryonic development, 1 of 2 X chromosomes is randomly inactivated in each somatic cell and becomes Barr body B c. 1 embryonic cell has the X chromosome inactivated d. embryo grows and matures, embryonic cells divide and gives rise to other cells e. epithelial cells derived from the above embryonic cell produce white fur path bc the X chromosome had been permanently inactivated iv. cells count their X chromosomes in their somatic cells and allow only 1 to remain active v. Barr bodies = inactivated X chromosome 1. number of Barr bodies: inactive X = n-1 2. can determine if male or female by looking for a Barr body vi. Process of X inactivation: Expression of specific gene within Xic is required for the X chromosome to compact into Barr body. Gene is Xist = X-inactive specific transcript. Xist gene on the inactivated X chromosome is active. Xist gene produces RNA molecule that doesn’t encode a protein. RNA coats X chromosome and inactivate it. Protein then associate with Xist RNA and promote chromosomal compaction into Barr body. 1. Initiation—during embryonic development a. 1 X chromosomes stays active and the other is inactivated 2. Spreading—inactivation begins near Xic and spreads along the X chromosome a. Chosen X chromosome is inactiviated and Xist gene is expressed. Xist RNA coats inactivated X chromosome and recruits proteins to compact it. 3. Maintenance a. X chromosome is maintained during subsequent cell divisions 5. Properties of the X and Y chromosome a. Key terminology: i. Sex-linked genes = a gene that is located on one of the sex chromosomes (i.e. X or Y) ii. X-linked genes = genes (or alleles of genes) that are physically located within the X chromosome 9 © Hannah Kennedy, Kent State University iii. Y-linked genes = holandric genes = genes (or alleles of genes) that are located only on the Y chromosome iv. Pseudoautosomal genes = genes that are located in the regions that are found on both the X and Y chromosome v. Pseudoautosomal inheritance = the inheritance pattern of genes that are found on both the X and Y chromosomes. Even though such genes are located physically on the sex chromosomes, their pattern of inheritance is identical to that of autosomal genes b. General i. Sex determination is determined by the presence of the Y chromosome— which carries the Sry gene ii. X chromosome is larger than the Y and carries more genes iii. X and Y chromosomes have 3 homologous regions that promote the pairing of the X and Y chromosomes occurring during meiosis I of spermatogenesis 10 © Hannah Kennedy, Kent State University Ch. 6—Extranuclear inheritance, imprinting, and maternal effect 1. 6.1: Extranuclear inheritance: chloroplasts a. Key terminology: i. Extranuclear inheritance = cytoplasmic inheritance = the inheritance of genetic material that isn’t found within the nucleus; cause of non- Mendelian inheritance patterns b. Most impt ex of Extranuclear inheritance is due to genetic material in cell organelles: chloroplasts and mitochondria have own DNA i. Chloroplasts contain circular chromosomes with many genes 1. Nucleoid = a darkly staining region that contains the genetic material of mitochondria/chloroplasts/bacteria; may contain multiple copies of a single circular chromosome a. Often have 1+ nucleoid ii. Extranuclear inheritance produces non-Mendelian results in reciprocal crosses 1. Nuclear genes = genes that are located on chromosomes found in the cell nucleus of eukaryotic cells 2. Chloroplasts and mitochondria aren’t sorted during meiosis and therefore don’t separate into games like nuclear chromosomes 3. Maternal inheritance = inheritance of DNA that occurs through the cytoplasm of the egg 4. Heteroplasmy = phenomenon that occurs when a cell contains variation in a particular type of organelle. E.g. a plant cell could contain some chloroplasts that make chlorophyll and other chloroplasts that don’t 2. 6.2: Extranuclear inheritance: mitochondria a. mitochondria also contain circular chromosomes with many genes i. genetic material is located in the nucleoid that contain multiple copies of the chromosome; have more than one nucleoid ii. sizes of genomes vary among species iii. mtDNA carries few genes that encode rRNA and tRNA b. transmission of mitochondria follows a maternal inheritance pattern i. mitochondria are inherited via egg cells therefore the female parent passes mitochondrial genes to offspring and male doesn’t 1. paternal parent can sometimes provide mitochondria via the sperm = paternal leakage c. a lot of human diseases are caused by mitochondrial mutations i. can occur in 2 ways 1. mitochondrial mutations are transmitted from mom to offspring bc its transmitted via cytoplasm of the egg 2. mitochondrial mutations may occur in somatic cells and accumulate as a person ages ii. when more o2 is consumes than used to make ATP, mitochondria produce free radicals that damage DNA and mtDNA can’t repair itself easily so it gets damaged 3. 6.3: theory of endosymbiosis a. Key terminology: i. Endosymbiosis = a symbiotic relationship in which the symbiont actually lives inside (endo) the larger of the 2 species ii. Endosymbiosis theory = the theory that the ancient origin of plastids and mitochondria was the result of certain species of bacteria taking up residence within a primordial eukaryotic cell 1 © Hannah Kennedy, Kent State University b. Chloroplasts were descended from an endosymbiotic relationship btwn cyanobacteria and eukaryotic cells c. Mitochondria are derived from an endosymbiotic relationship btwn gram-negative nonsulfur purple bacteria and eukaryotic cells d. Endosymbiosis theory proposes that relationship provided eukaryotic cells with impt characteristics (photosynthesis, synthesize greater amounts of ATP) 4. 6.4: Epigenetics: Imprinting a. Key terminology i. Epigenetic inheritance = a pattern in which a modification occurs to a nuclear gene or chromosome that alters gene expression, but isn’t permanent over the course of many generations; the results of DNA and chromosomal modifications that occur during oogenesis/spermatogenesis, or early stages of embryogenesis (e.g. X inactivation) ii. Genomic imprinting = imprinting = a process in which a modification occurs to a nuclear gene that alters gene expression, but isn’t permanent over the course of many generations b. The expression of an imprinted gene depends on the sex of the parent from which the gene was inherited i. Genomic imprinting is a process in which a segment of DNA is marked and that mark is retained and recognized throughout the life of the organism inheriting the marked dna 1. Phenotypes this causes follow non-Mendelian pattern of inheritance ii. Monoallelic expression = in the case of imprinting, refers to the phenomenon that only 1 of the 2 alleles of a given gene is transcriptionally expressed iii. Imprinting can be divided into 3 stages 1. The establishment of the impring during gametogenesis 2. The maintenance of the imprint during embryogenesis and in adult somatic cells 3. The erasure and reestablishment of the imprint in the germ cells c. Imprinting of genes and chromosomes is a molecular marking process that involves DNA methylation; usually a marking process that silences gene expression by preventing transcription i. DNA methylation = the phenomenon in which an enzyme covalently attaches a methyl group to a base in DNA (a or c) to regulate gene expression (usually inhibits it) ii. Imprinting control region = ICR = DNA region that is differentially methylated and plays a role in genomic imprinting; contains binding sites for 1 or more proteins that regulate the transcription of the imprinted gene 1. When ICR is not methylated, CTC-binding factor can bind and cause 2 things a. Prevents activator proteins from activating certain gene and shutting it off b. Permits activator proteins to turn on specific gene d. Imprinting from generation to generation involves maintenance, erasure, and de Novo methylation steps i. Maintence methylation retains imprinting in somatic cells during embryogenesis and in adulthood ii. Erasure aka demethylation occurs in cells that are going to be gametes 5. 6.5: Maternal Effect = an inheritance pattern for certain nuclear genes in which the genotype of the mother directly determines the phenotype of her offspring a. the genotype of the mother determines the phenotype of the offspring for maternal effect genes 2 © Hannah Kennedy, Kent State University i. reciprocal cross = a pair of crosses in which the traits of the 2 parents differ with regard to sex. For example, 1 cross could be a red-eyed female fly and a white-eyes male fly, and the reciprocal cross would be a red-eyed male fly and a white-eyes female fly b. female gametes receive gene products from the mother that affect early developmental stages of the embryo i. non-Mendelian inheritance pattern of maternal effect genes can be explained by oogenesis 1. as an oocyte (i.e. egg) matures, surrounding maternal cells provide egg with nutrients 2. these nurse cells produce both gene products (mRNA and/or proteins) that are then transported into the egg 3. egg can receive whatever it wants a. gene products of the nurse cells reflect the genotype of the mother and influence early developmental stages of the embryo ii. maternal effect genes encode proteins that are impt in early steps of embryogenesis; play role in cell division, cleavage pattern, and body axis orientation 3 © Hannah Kennedy, Kent State University Ch. 23—Medical Genetics and Cancer 1. 23.1: Inheritance patterns of genetic diseases a. genetic basis for a human disease i. several observations are consistent with the idea that a disease is caused by the inheritance of mutant genes: 1. when an individual exhibits a disease, the disorder is more likely to occur in genetic relatives than in the general population 2. identical twins (genetically identical) share the disease more often than nonidentical twins 3. the disease doesn’t spread to individuals sharing similar envmtal situation (i.e. inherited disorders cant spread from person to person) 4. different population tend to have different frequencies of the disease a. frequencies of traits vary among diff populations of human due to evolution 5. the disease tends to develop at a characteristic age (i.e. genetic disorders exhibit a characteristic age of onset) 6. the human disorder may resemble a disorder that is already known to have a genetic basis in an animal 7. a correlation is observed between a disease and a mutant human gene or a chromosomal alteration b. autosomal recessive inheritance—human pedigrees i. 4 common features of an autosomal recessive inheritance 1. an affected offspring may have 2 unaffected parents 2. when 2 unaffected heterozygotes have children, the % of affected children is 25% on average 3. 2 affected individuals have 100% affected children 4. the trait occurs with the same frequency in both sexes ii. common mode of transmission for genetic disorders, especially the ones that involve defective enzymes iii. loss-of-function mutations = a change in a genetic sequence that creates a loss-of-function allele; causes a reduction or loss of function in the encoded protein c. autosomal dominant inheritance i. 5 common features of autosomal dominant inheritance 1. an affected offspring usually has 1 or both affected parents 2. an affected individual with only 1 affected parent is expected to produce 50% affected offspring on average 3. 2 affected, heterozygous individuals have on average 25% unaffected offspring 4. the trait occurs with the same frequency in both sexes 5. for most dominant, disease-causing alleles, the homozygote is more severely affected with the disorder. In some cases, a dominant allele may be lethal in the homozygous condition ii. haploinsufficiency = the phenomenon in which a person has only a single functional copy of a gene, and that single functional copy doesn’t result in a normal phenotype; 50% of the functional protein isn’t sufficient to produce a normal phenotype 1. shows a dominant pattern of inheritance bc heterozygote has the disease a. Ex: aniridia—results in an absence of the iris of the eye iii. gain-of-function mutations = a mutation that causes a gene to be expressed in an additional place where it isn’t normally expressed or during 1 © Hannah Kennedy, Kent State University a stage of development when it isn’t normally expressed; changes the gene so it gains a new and abnormal function 1. Ex: achondroplasia—abnormal bone growth resulting in short stature and short limbs caused by mutation in a gene that encodes the fibroblast growth factor receptor-3 (which has a negative effect on bone growth) a. Mutant form of receptor is overactive which causes bone growth to be inhibited prematurely iv. dominant-negative mutations = a mutation that produces an altered gene product that acts antagonistically to the normal gene product. 1. Ex: Marfan syndrome—due to mutation in fibrillin-1 gene a. Fibrililn-1 gene encodes a glycoprotein that is a structural component of EC matrix to provide structure and elasticity to tissues b. Mutatnt gene encodes a fibrillin-1 protein that antagonizes the effects of the normal protein c. Elasticity of body parts is weakened so the aorta is largely affected d. X-linked recessive inheritance i. Males are hemizygous for these genes 1. Ex: hemophilia ii. Pattern of X-linked recessive inheritance revealed by 3 things 1. Males are more likely to exhibit the trait 2. Mothers of affected males often have brothers or dads who are affected with same trait 3. Daughters of affected males produce 50% affected sons on average e. X-linked dominant inheritance i. Males are more severely affected bc females carry X chromosome with a normal copy of the gene ii. Pattern of X-linked dominant inheritance revealed by 2 things 1. Females are much more likely to exhibit the trait when it is lethal to males 2. Affected mothers have a 50% chance of passing the trait to daughters f. Many genetic disorders exhibit locus heterogeneity i. Locus heterogeneity = the phenomenon in which a particular type of disease or trait may be caused by mutations in 2+ genes (e.g. hemophilia) 2. 23.2: Detection of disease-causing alleles a. Haplotypes exhibit genetic variation i. To ID alleles that cause disease, ppl rely on known locations of genes and molecular markers on the chromosome 1. An allele that causes disease can be ID’d by its proximity to another known gene or the marker ii. Homologous chromosomes exhibit genetic/allelic variation in molecular markers bc of evolution iii. Haplotype = haploid genotype = the linkage of alleles of molecular markers along a small region of a single chromosome iv. Haplotype association study = a study in which disease-causing alleles are ID’d due to their linkage to particular markers along a chromosome; based on 2 assumptions 1. Allele that causes disease has its origin in a single individual (i.e. founder) who lived a long time ago and since them the allele has spread throughout portions of population 2 © Hannah Kennedy, Kent State University 2. When disease-causing allele originated in the founder, it occurred in a region with a specific haplotype that didn’t change a. Ppl with the same haplotype as found (e.g. 1A, 2C, 3B, 4B) is more likely to get the allele 3. Ex: Huntington disease a. Molecular marker G8 is near the tip of p-arm of chromosome 4 (found in diff versions A, B, C, D) b. Pedigree analysis revealed that G8-C marker is associated w mutant gene that causes HD aka G8-C is linked to Huntington allele i. ID’d by chromosome walking v. Linkage disequilibrium = occurs when alleles and molecular markers are associated with each other at a frequency that is significantly higher than expected by random chance; common when a disease-causing allele arises in a founder and the allele is closely linked to other markers along a chromosome b. Genetic testing can ID inherited human diseases i. Genetic testing = the use of testing methods to determine if an individual carries a specific allele, haplotype, or an alteration in chromosome structure or number ii. Testing methods for genetic abnormalities: Method Description Biochemical Enzymatic activity of a protein can be assayed in vitro (protein level— (e.g. Tay-Sachs disease) single gene mutation) Immunological Presence of a protein can be detected using antibodies (protein level— that recognize the specific protein. (e.g. Western single gene blotting) mutation) RFLP analysis Determines likelihood that a person may carry a disease-causing allele DNA sequencing If normal gene has already been ID’d and sequenced, we can design PCR primers that amplify the gene from a sample of cells. The amplified DNA segment can then be subjected to DNA sequencing In situ A DNA probe that hybridizes to a specific gene or gene hybridization segment can be used to determine if the gene is present/absent/altered Karyotyping Chromosomes from cell sample can be stained and microscopically analyzed for abnormalities in chromosome structure/number DNA microarrays Determines expression levels of genes, like the ones that are mutant in certain forms of cancer. Can also be used to detect polymorphisms iii. Genetic testing can be done before birth 1. 3 common ways of obtaining cell material from fetus to genetic test a. amniocentesis = process of genetic testing in which a doctor removes amniotic fluid that contains fetal cells by using a needle that passes through the abdominal wall; cell sample then is tested like karyotyping 3 © Hannah Kennedy, Kent State University b. chorionic villus sampling = CVS = process of genetic testing in which a small piece of the chorion (i.e. the fetal part of the placenta) is removed and genetic testing is done on cell sample; can be performed earlier than amniocentesis c. preimplantation genetic diagnosis = PGD = a time of genetic screening prior to birth in which is conducted before pregnancy to test the embryos made by IVF to check for a specific genetic abnormality (e.g. allele that causes HD) 3. 23.3: Prions a. overview i. prion = proteinaceous disease-causing agent that cause several types of neurodegenerative diseases (contracted from meat); prefers one type of protein folding pattern and catalyzes other proteins to fold in the same manner ii. these diseases exist by the ability of the prion protein to exist in 2 conformatiCns 1. PrP (doesn’t cause disease) 2. PrP Sc(abnormal, causes disease; acts as a catalyst to convert normal prions to misfolded ones. Form aggregated in brain cells and PNS tissues) iii. Gene that encodes the prion rotein is found in mammals and is expressed at low levels in nerve cells; abnormal protein can come from 2 sources 1. Taking in the abnormal protein from animal products 2. Already having the allele that causes a conformational change 4
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