Chapter 5 Beyond Mendel's Laws

Chapter 5 Beyond Mendel's Laws

Human Genetics Concepts and Applications Twelfth Edition Chapter 5 Beyond Mendels Laws McGraw-Hill Education. All rights reserved. Authorized only for instructor use in the classroom. No reproduction or further distribution permitted without the prior written consent of McGraw-Hill Education. Chapter 3 Learning Objectives (1 of 2) 1. 2. 3.

4. 5. 6. Explain the effect of the lethal alleles on Mendelian ratios. State how DNA structure underlies multiple gene variants. Distinguish among complete dominance, incomplete dominance, and codominance. Distinguish epistasis from allele interactions. Describe how penetrance, expressivity, and pleiotropy affect gene expression. Explain how a phenocopy can appear to be inherited. McGraw-Hill Education.

5-2 Chapter 3 Learning Objectives (2 of 2) 7. Describe the mode of inheritance of a mitochondrial trait. 8. Explain how mitochondrial DNA differs from nuclear DNA. 9. Explain how linked traits are inherited differently from Mendelian traits. 10. Discuss the basis of linkage in meiosis. 11. Explain how linkage is the basis of genetic maps and genome-wide association studies.

McGraw-Hill Education. 5-3 Chapter 3 Exceptions to Mendels Law Mendels traits showed two distinct forms Most genes do not exhibit simple inheritance Genotypic ratios persist but phenotypic ratios may vary due to outside-the-gene influences:

Multiple alleles Other nuclear genes Nonnuclear genes Gene linkage Environment McGraw-Hill Education. 5-4 Chapter 3 Lethal Alleles (1 of 5) Lethal genotype causes death before the individual can reproduce.

Removes an expected progeny class following a specific cross Double dose of a dominant allele may be lethal. Examples Achondroplastic dwarfism Mexican hairless dogs McGraw-Hill Education. 5-5

Chapter 3 Lethal Alleles (2 of 5) a: Kevin Winter/Getty Images McGraw-Hill Education. 5-6 Chapter 3 Lethal Alleles (3 of 5) Alleles a = normal height (wild type) A = achondroplasia (mutant)

Genotypes Phenotypes AA lethal Aa achondroplasia aa normal height McGraw-Hill Education.

5-7 Chapter 3 Lethal Alleles (4 of 5) Cross 1 1/4 die as embryos (AA) Of survivors: 2/3 = achondroplasia (Aa) 1/3 = normal height (aa) McGraw-Hill Education. 5-8 Chapter 3

Lethal Alleles (5 of 5) Cross 2 All survive: 1/2 = achondroplasia 1/2 = normal height McGraw-Hill Education. 5-9 Chapter 3 Multiple Alleles Individual carries two alleles for each autosomal gene. Gene can have multiple alleles because its

sequence can deviate in many ways. Different allele combinations can produce variations in the phenotype. PKU gene has hundreds of alleles resulting in four basic phenotypes. CF gene has over 1500 alleles. McGraw-Hill Education. 5-10 Chapter 3 Incomplete Dominance (1 of 2)

Heterozygous phenotype is between those of the two homozygotes Example: Familial hypercholesterolemia (FH) Heterozygote has approximately half the normal number of receptors in the liver for LDL cholesterol Homozygous for the mutant allele totally lacks the receptor, and so their serum cholesterol level is very high McGraw-Hill Education. 5-11

Chapter 3 Incomplete Dominance (2 of 2) Alfred Pasieka/Science Photo Library/Science Source McGraw-Hill Education. 5-12 Chapter 3 Codominance Heterozygous phenotype results from the expression of both alleles. ABO gene encodes a cell surface protein. IA allele produces A antigen.

IB allele produces B antigen. i (IO) allele does not produce antigens. Alleles IA and IB are codominant, and both are completely dominant to i. McGraw-Hill Education. 5-13 Chapter 3 ABO Blood Types Illustrate Codominance McGraw-Hill Education.

5-14 Chapter 3 Offspring from Parents with Blood Type A and Blood Type B McGraw-Hill Education. 5-15 Chapter 3 Epistasis Phenomenon where one gene affects the expression of a second gene.

Example: Bombay phenotype H gene is epistatic to the I gene H protein places a molecule at the cell surface to which the A or B antigens are attached hh genotype = no H protein Without H protein the A or B antigens can not be attached to the surface of the RBC All hh genotypes have the phenotype of type O, although the ABO blood group can be anything (A, B, AB, or O) McGraw-Hill Education.

5-16 Chapter 3 Penetrance and Expressivity Penetrance: All-or-none expression of a single gene Expressivity: Severity or extent Genotype is incompletely penetrant if some individuals do not express the phenotype Phenotype is variably expressive is symptoms vary in intensity among different people McGraw-Hill Education. 5-17

Chapter 3 Pleiotropy Phenomenon where one gene controls several functions or has more than one effect Example: Porphyria variegate Affected several members of European Royal families, including King George III Varied illnesses and quirks appeared to be different unrelated disorders McGraw-Hill Education.

5-18 Chapter 3 Marfan Syndrome is Pleiotropic Columbia University, ho/AP Images McGraw-Hill Education. 5-19 Chapter 3 Genetic Heterogeneity Different genes can produce identical phenotypes.

Hearing loss132 autosomal recessive forms Osteogenesis imperfectaAt least two different genes involved Alzheimers diseaseAt least four different genes involved Genes may encode enzymes that catalyze the same biochemical pathway, or different proteins that are part of the pathway. McGraw-Hill Education. 5-20

Chapter 3 Many Routes to Blindness McGraw-Hill Education. 5-21 Chapter 3 Phenocopy Trait that appears inherited but is caused by the environment May have symptoms that resemble an inherited trait or occur within families Examples:

Exposure to teratogens Thalidomide causes limb defects similar to inherited phocomelia Infection AIDS virus can be passed from mother to child, looking like it is inherited McGraw-Hill Education. 5-22

Chapter 3 The Human Genome Sequence Adds Perspective Revealed that complications to Mendelian inheritance are more common than originally thought Terms like epistasis and genetic heterogeneity are beginning to overlap and blur Example: Marfan syndrome Interactions between genes also underlie penetrance and expressivity

Example: Huntington disease McGraw-Hill Education. 5-23 Chapter 3 Table 5.1 Factors That Alter SingleGene Phenotypic Ratios (1 of 2) Phenomenon Effect on Phenotype Example Lethal alleles

A phenotypic class does not survive to reproduce. Achondroplasia Multiple alleles Many variants or degrees of a phenotype are possible. Cystic fibrosis Incomplete dominance A heterozygotes phenotype is intermediate between those of the two homozygotes.

Familial hypercholesterolemia Codominance A heterozygotes phenotype is distinct from and not intermediate between those of the two homozygotes. ABO blood types Epistasis One gene masks or otherwise affects anothers phenotype. Bombay phenotype

Penetrance Some individuals with a particular genotype do not have the associated phenotype. Polydactyly Expressivity A genotype is associated with a phenotype of varying intensity. Polydactyly McGraw-Hill Education.

5-24 Chapter 3 Table 5.1 Factors That Alter SingleGene Phenotypic Ratios (2 of 2) Phenomenon Effect on Phenotype Example Pleiotrophy The Phenotype includes many symptoms, with different subsets in different individuals. Marfan syndrome

Phenocopy An environmentally caused condition has symptoms and a recurrence pattern similar to those of a known inherited trait. Infection Genetic heterogeneity Genotypes of different genes cause the same phenotype. Osteogenesis imperfecta McGraw-Hill Education.

5-25 Chapter 3 Mitochondrion (1 of 2) Organelle providing cellular energy Contains small circular DNA called mtDNA37 genes without noncoding sequences No crossing over and little DNA repair High exposure to free radicals Mutation rate is greater than nuclear DNA McGraw-Hill Education. 5-26

Chapter 3 Mitochondrion (2 of 2) Mitochondrial genes are transmitted from mother to all of her offspring. McGraw-Hill Education. 5-27 Chapter 3 Mitochondrial DNA Cell typically has thousands of mitochondria, and each has numerous

copies of its mini chromosome. McGraw-Hill Education. 5-28 Chapter 3 Mitochondrial Disorders Mitochondrial genes encode proteins that participate in protein synthesis and energy production Several diseases result from mutations in mtDNA Examples:

Mitochondrial myopathiesWeak and flaccid muscles Leber optical atrophyImpaired vision Ooplasmic transfer technique can enable woman to avoid transmitting a mitochondrial disorder McGraw-Hill Education. 5-29 Chapter 3 Appearance of Skeletal Muscle Fibers in Mitochondrial Disease

Courtesy of Alan Pestronk, MD McGraw-Hill Education. 5-30 Chapter 3 Heteroplasmy (1 of 2) Condition where the mtDNA sequence is not the same in all copies of the genome Mitochondrion will have different alleles for the same gene At each cell division, the mitochondria are

distributed at random into daughter cells If an oocyte is heteroplasmic, differing number of copies of a mutant mtDNA may be transmitted Phenotype reflects the proportion of mitochondria bearing the mutation McGraw-Hill Education. 5-31 Chapter 3 Heteroplasmy (2 of 2) McGraw-Hill Education.

5-32 Chapter 3 Mitochondrial DNA Reveals Past mtDNA provides a powerful forensic tool used to: Link suspects to crimes Identify war dead Support or challenge historical records

ExampleIdentification of the son of Marie Antoinette and Louis XVI mtDNA is likely to survive extensive damage and cells have many copies of it McGraw-Hill Education. 5-33 Chapter 3 Linkage (1 of 3) Genes that are close on the same chromosome are said to be linked. Linked genes do not assort independently in meiosis.

Usually inherited together when the chromosome is packaged into a gamete Do not produce typical Mendelian ratios McGraw-Hill Education. 5-34 Chapter 3 Linkage (2 of 3) McGraw-Hill Education.

5-35 Chapter 3 Linkage (3 of 3) McGraw-Hill Education. 5-36 Chapter 3 Recombination Chromosomes recombine during crossing over in prophase I of meiosis. New combinations of alleles are created. Parental chromosomes have the original

configuration. Recombinant chromosomes have new combinations of alleles. McGraw-Hill Education. 5-37 Chapter 3 Crossing Over Disrupts Linkage McGraw-Hill Education. 5-38 Chapter 3

Allele Configuration Is Important CisTwo dominant or two recessive alleles are on each chromosome. TransOne dominant and one recessive allele are on each chromosome. McGraw-Hill Education. 5-39 Chapter 3 Frequency of Recombination (1 of 2) Correlation between cross over frequency and gene distance is used to construct linkage maps.

McGraw-Hill Education. 5-40 Chapter 3 Frequency of Recombination (2 of 2) Based on percentage of meiotic divisions that result in breakage of linkage between parental alleles Proportional to the distance between the two genes recombining McGraw-Hill Education. 5-41

Chapter 3 Linkage versus Nonlinkage (Independent Assortment) McGraw-Hill Education. 5-42 Chapter 3 Linkage Maps Diagram indicating the relative distance between genes 1% recombination = 1 map unit = 1 centimorgan (cM) Map distances are additive McGraw-Hill Education.

5-43 Chapter 3 Linkage Disequilibrium (LD) Nonrandom association between DNA sequences Inherited together more often than would be predicted from their frequency Human genome consists of many LD blocks where alleles stick together Interspersed with areas where crossing over is

prevalent McGraw-Hill Education. 5-44 Chapter 3 Solving Linkage Problems Genes for Nail-patella syndrome (N) and the ABO blood type (I) are 10 map units apart on chromosome 9. Greg and Susan each have Nail-patella syndrome. Greg has type A and Susan type B blood. What is the probability that their child has normal nail and knees and type O blood?

McGraw-Hill Education. 5-45 Chapter 3 Inheritance of Nail-Patella Syndrome ni sperm would have to fertilize the ni oocyte Using the product rule, the probability of a child with nnii genotype is 0.45 0.05 = 0.025 or 2.25% McGraw-Hill Education. 5-46 Chapter 3

Genetic Markers DNA sequences that serve as landmarks near genes of interest Were used starting in 1980 in linkage mapping Used in genome-wide association studies McGraw-Hill Education. 5-47 Chapter 3 LOD Score Indicates the tightness of linkage between a marker and a gene of interest Likelihood that particular cross over frequency data suggests linkage rather than inheritance by

chance LOD scores of 3 or higher signifies linkage Observed data are 1000 times more likely to be due to linkage than chance McGraw-Hill Education. 5-48 Chapter 3 Haplotype (1 of 2) Set of DNA sequences inherited on one chromosome due to linkage disequilibrium Make it possible to track specific chromosome

segments in pedigrees Disruptions of a marker sequence indicate cross over sites McGraw-Hill Education. 5-49 Chapter 3 Haplotype (2 of 2) McGraw-Hill Education. 5-50

End of Presentation McGraw-Hill Education. All rights reserved. Authorized only for instructor use in the classroom. No reproduction or further distribution permitted without the prior written consent of McGraw-Hill Education. 5-51

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