Human Genetics: Chapter 5 - Beyond Mendel's Laws PDF

Because learning changes everything.® Chapter 05 Beyond Mendel’s Laws HUMAN GENETICS Concepts and Applications Fourteenth Edition Ricki Lewis © McGraw Hill LLC. All rights reserved. No reproduction or distribution without the prior written consent of McGraw Hill LLC.  Learni...

Because learning changes everything.® Chapter 05 Beyond Mendel’s Laws HUMAN GENETICS Concepts and Applications Fourteenth Edition Ricki Lewis © McGraw Hill LLC. All rights reserved. No reproduction or distribution without the prior written consent of McGraw Hill LLC.  Learning Outcomes 1 1. Explain the effect of lethal alleles on Mendelian ratios. 2. State how DNA structure underlies multiple gene variants. 3. Distinguish among complete dominance, incomplete dominance, and codominance. 4. Distinguish epistasis from interactions of alleles of the same genes. 5. Describe how penetrance, expressivity, and pleiotropy affect gene expression. 6. Explain how a phenocopy can appear to be inherited. © McGraw Hill 2  Learning Outcomes 2 1. Describe the mode of inheritance of a mitochondrial trait. 2. Explain how mitochondrial DNA differs from DNA in the nucleus. 3. Loading… Explain how inheritance of linked traits differs from inheritance of genes on different chromosomes. 4. Discuss the basis of linkage in meiosis. 5. Explain how linkage is used to derive genetic maps. © McGraw Hill 3  When Gene Expression Appears to Alter Mendelian Ratios Mendel’s traits showed two distinct forms Most genes do not exhibit simple inheritance This chapter considers three general phenomena that seem to be exceptions to Mendel’s laws, but are actually not Gene expression, mitochondrial inheritance, and linkage. In several circumstances, phenotypic ratios appear to contradict Mendel’s laws, but they do not. © McGraw Hill 4  Lethal Alleles 1 Lethal genotype causes death before the individual can reproduce. Removes an expected progeny class following a specific cross Loading… Double dose of a dominant allele may be lethal. Example Achondroplastic dwarfism Caused by a gain-of-function mutation in a gene (FGFR3) that normally inhibits growth of the long bones of arms and legs © McGraw Hill 5  Lethal Alleles 2 Kevin Winter/Getty Images © McGraw Hill 6  Lethal Alleles 3 Access the text alternative for slide images. © McGraw Hill 7  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. An individual with two different mutant recessive alleles for same gene is a compound heterozygote. © McGraw Hill 8  Different dominance Relationships: Incomplete Dominance Heterozygous phenotype is intermediate 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 Example: Hair follicle development EDAR gene acts in developing hair follicles. “G” allele common in East Asian ancestry European and African ancestry have “A” allele rather than “G” allele GG = thick hair, AA = very thin hair, AG = hair with diameter in between other two phenotypes © McGraw Hill 9  Incomplete Dominance Access the text alternative for slide images. © McGraw Hill 10  Different dominance Relationships: Codominance Heterozygous phenotype results from the expression of both alleles. ABO gene encodes a cell surface glycoprotein. I A allele produces A antigen. Loading… I B allele produces B antigen. i (I O ) allele does not produce antigens. Alleles I A and I B are codominant, and both are completely dominant to i. © McGraw Hill 11  ABO Blood Types Illustrate Codominance Access the text alternative for slide images. © McGraw Hill 12  Offspring from Parents with Blood Type A and Blood Type B Access the text alternative for slide images. © McGraw Hill 13  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 R B C All hh genotypes have the phenotype of type O, although the A B O blood group can be anything (A, B, A B, or O) © McGraw Hill 14  Penetrance and Expressivity Two terms describe the degrees of expression of a single gene. 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 15  Pleiotropy Phenomenon where one gene controls several functions or has more than one effect Can be difficult to trace through families because people with different subsets of symptoms may appear to have different diseases Example: Marfan syndrome A defect in an elastic connective tissue protein called fibrillin. The symptoms are lens dislocation, long limbs, spindly fingers, and a caved-in chest. The most serious symptom is a weakening in the aorta, which can suddenly burst. © McGraw Hill 16  Genetic Heterogeneity Different genes can produce identical phenotypes. Genes may encode enzymes that catalyze the same biochemical pathway, or different proteins that are part of the pathway. Examples: Osteogenesis imperfecta—At least 18 genetically distinct forms are recognized Retinal dystrophies—Caused by mutations in more than 270 genes © McGraw Hill 17  Many Routes to Blindness Access the text alternative for slide images. © McGraw Hill 18  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 19  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 20  Summary Table 5.1 Factors That Alter Single-Gene Phenotypic Ratios Phenomenon Effect on Phenotype Example Lethal alleles A phenotypic class does not survive to reproduce. Achondroplasia Multiple Many variants or degrees of a phenotype are possible. Cystic fibrosis alleles Incomplete A heterozygote’s phenotype is intermediate between those Familial dominance of the two homozygotes. hypercholesterolemia Codominance A heterozygote’s phenotype is distinct from and not ABO blood types intermediate between those of the two homozygotes. Epistasis One gene masks or otherwise affects another’s phenotype. Bombay phenotype Penetrance Some individuals with a particular genotype do not have the Polydactyly associated phenotype. Expressivity A genotype is associated with a phenotype of varying Polydactyly intensity. Pleiotropy The phenotype includes many symptoms, with different Marfan syndrome subsets in different individuals. Phenocopy An environmentally caused condition has symptoms and a Infection recurrence pattern similar to those of a known inherited trait. Genetic © McGraw Hill Genotypes of different genes cause the same phenotype. Osteogenesis imperfecta 21  heterogeneity Mitochondrion 1 Organelle providing cellular energy Contains small circular DNA called mtDNA A “mini-chromosome” that contains 37 genes The inheritance patterns and mutation rates for mitochondrial genes differ from those for genes in the nucleus. Mitochondrial genes are maternally inherited. © McGraw Hill 22  Mitochondrion 2 Mitochondrial genes are transmitted from mother to all of her offspring. Access the text alternative for slide images. © McGraw Hill 23  Mitochondrial DNA 1 Cell typically has thousands of mitochondria And each has numerous copies of its mini chromosome. Access the text alternative for slide images. © McGraw Hill 24  Mitochondrial DNA 2 DNA in the mitochondria differs functionally from DNA in the nucleus in several ways MtDNA does not cross over. It mutates faster than DNA in the nucleus. Fewer types of DNA repair and DNA-damaging oxygen free radicals are produced in the energy reactions. Mitochondrial genes are not wrapped in proteins. Mitochondrial genes are not “interrupted” by DNA sequences that do not encode protein. Mitochondria with different alleles for the same gene can reside in the same cell. © McGraw Hill 25  Mitochondrial Disorders Mitochondrial genes encode proteins involved in protein synthesis and energy production Several diseases result from mutations in mtDNA Examples: Mitochondrial myopathies—Weak and flaccid muscles Leber optical atrophy—Impaired vision Theoretically, a woman with a mitochondrial disease can avoid transmitting it to her children If her mitochondria can be replaced with healthy mitochondria from a donor. © McGraw Hill 26  Heteroplasmy 1 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 27  Heteroplasmy 2 Access the text alternative for slide images. © McGraw Hill 28  Mitochondrial DNA Reveals Past mtDNA provides a powerful forensic tool used to: Link suspects to crimes Identify war dead Loading… Support or challenge historical records Example—Identification 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 29  Linkage 1 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 30  Linkage 2 Access the text alternative for slide images. © McGraw Hill 31  Linkage 3 Access the text alternative for slide images. © McGraw Hill 32  Recombination Chromosomes recombine during crossing over in prophase 1 of meiosis. New combinations of alleles are created. Parental chromosomes have the original configuration. Recombinant chromosomes have new combinations of alleles. © McGraw Hill 33  Crossing Over Disrupts Linkage Access the text alternative for slide images. © McGraw Hill 34  Allele Configuration Is Important Cis—Two dominant or two recessive alleles are on each chromosome. Trans—One dominant and one recessive allele are on each chromosome. Access the text alternative for slide images. © McGraw Hill 35  Frequency of Recombination 1 Correlation between cross over frequency and gene distance is used to construct linkage maps. Access the text alternative for slide images. © McGraw Hill 36  Frequency of Recombination 2 The frequency of a crossover between any two linked genes is inferred from the proportion of offspring from a cross that are recombinant. Frequency of recombination is based on the percentage of meiotic divisions that break the linkage between two parental alleles. Proportional to the distance between the two genes recombining The probability that genes on opposite ends of a chromosome cross over approaches the probability that, they would independently assort—about 50%. © McGraw Hill 37  Linkage versus Nonlinkage (Independent Assortment) Access the text alternative for slide images. © McGraw Hill 38  Linkage Maps Diagram indicating the relative distance between genes 1% recombination = 1 map unit = 1 centimorgan (cM) Map distances are additive Access the text alternative for slide images. © McGraw Hill 39  Linkage Disequilibrium (LD) Nonrandom association between DNA sequences Inherited together more often than would be predicted from their frequency Human genome consists of many L D blocks where alleles stick together Interspersed with areas where crossing over is prevalent L D blocks, called haplotypes, are used to track genes in populations. © McGraw Hill 40  Solving Linkage Problems Nail-patella syndrome is a rare autosomal dominant disease that causes underdeveloped nails and painful arthritis in knee and elbow joints Genes for Nail-patella syndrome (N) and the A B O 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 & knees and type O blood? © McGraw Hill 41  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% Access the text alternative for slide images. © McGraw Hill 42  Genetic Markers DNA sequences that serve as landmarks near genes of interest These markers need not encode proteins that cause a phenotype. DNA sequence differences that alter where a DNA cutting enzyme cuts Differing numbers of short repeated sequences of DNA with no obvious function Single sites where the base varies among individuals. © McGraw Hill 43  LOD Score The “logarithm of the odds” 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 L O D scores of 3 or higher signifies linkage Observed data are 1000 times more likely to be due to linkage than chance © McGraw Hill 44  Haplotype 1 Genetic markers are still used to distinguish parts of chromosomes. Groups of linked genes that are always inherited together and not separated by crossing over are termed haplotypes Make it possible to track specific chromosome segments in pedigrees Disruptions of a marker sequence indicate cross over sites © McGraw Hill 45  Haplotype 2 Access the text alternative for slide images. © McGraw Hill 46  End of Main Content Because learning changes everything.® www.mheducation.com © McGraw Hill LLC. All rights reserved. No reproduction or distribution without the prior written consent of McGraw Hill LLC.