1. 1 Copyright © 2016 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. Chapter 06 Lecture Outline

2. Simple Mendelian inheritance describes inheritance patterns that obey The Law of Segregation The Law of Independent Assortment As well as two other rules: Genes are passed unaltered from generation to generation (except for rare mutations) Expression of the genes in the offspring directly influences their traits Some genes violate these rules, and deviate from the expectations of simple Mendelian inheritance Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 2

3. In this lecture we will discuss inheritance patterns that do not conform to Mendelian predictions –Extranuclear inheritance Genes not in nucleus –Mitochondria –Chloroplasts These became part of the cell by endosymbiosis –Epigenetic inheritance and imprinting Genes are altered in the offspring (ex: methylation) –Maternal effect Gene expression in the mother determines traits of offspring Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 3

4. 4 Shell coiling in the water snail Lymnaea is due to maternal effect inheritance

5. Extranuclear inheritance - Traits are inherited through genes that are not in the nucleus, but are in other organelles –Also known as cytoplasmic inheritance The two most important examples are genes in –Mitochondria –Chloroplasts Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Extranuclear Inheritance 5

6. The chromosome of both mitochondria and chloroplasts is composed of a single circular double-stranded DNA Like bacteria, the chromosomes of mitochondria and chloroplasts are found in nucleoids –The nucleoid may contain many copies of the one chromosome –There may also be multiple nucleoids Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Chloroplast Genome 6 nucleoid

7. 6.2 Extranuclear Inheritance: Mitochondria  General features of mitochondrial genomes  Predicting the outcome of crosses involving genetic variation in mitochondrial genomes  How mutations in mitochondrial genes cause human diseases Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 7

8. Like chloroplasts, mitochondria contain a single circular chromosome –Contained within the nucleoid –Multiple copies of the single chromosome Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Mitochondria Genome 8

9. The main function of mitochondria –oxidative phosphorylation - produces ATP –ATP used as an energy source to drive cellular reactions The genetic material in mitochondria is referred to as mtDNA Human mtDNA –17,000 bp –Relatively few genes –rRNA and tRNA genes –13 genes that function in oxidative phosphorylation Most mitochondrial proteins are encoded by genes in the nucleus –Proteins made in cytoplasm but have a signal to direct them to mitochondria Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 9

10. tRNA Phe tRNA Val tRNA Leu tRNA Ile tRNA Gln tRNA Met tRNA Ala tRNA Trp tRNA Asn tRNA Cys tRNA Tyr tRNA Pro tRNA Thr tRNA Glu tRNA Leu tRNA Ser tRNA His tRNA Arg tRNA Gly tRNA Lys tRNA Asp tRNA Ser 12S rRNA 16S rRNA Ribosomal RNA genes Noncoding DNA ATP synthase subunit genes (2) Cytochrome c oxidase subunit genes (3) NADH dehydrogenase subunit genes (7) Cytochrome b gene Transfer RNA genes Figure 6.5 Necessary for synthesis of mitochondrial proteins Function in oxidative phosphorylation Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 10

11. Like chloroplasts, mitochondria are usually – but not always – inherited from the female parent via egg cells Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Mitochondrial Inheritance 11

12. Species with maternal inheritance may, on occasion, exhibit paternal leakage –Mitochondria provided through the sperm –Example: In the mouse 1-4 paternal mitochondria are inherited for every 100,000 maternal mitochondria per generation of offspring Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 12

13. Two mechanisms of mitochondrial disease: 1.Transmitted from mother to offspring via the egg Follow a strict maternal inheritance pattern 2.Mutations can occur in somatic cells during aging Mitochondria are especially susceptible to DNA damage from free radicals Over 200 human mitochondrial diseases discovered –Typically chronic degenerative disorders affecting cells that need high levels of ATP Nerve and muscle cells Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Human Mitochondrial Diseases 13

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15. Example: Leber’s hereditary optic neuropathy (LHON) –Affects the optic nerve –May lead to progressive loss of vision in one or both eyes –LHON is caused by mutations in several different mitochondrial genes Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 15

16. 6.4 Epigenetics: Imprinting  Definition of epigenetic inheritance and genomic imprinting  Predicting the outcome of crosses involving imprinted genes  The molecular mechanism of imprinting Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 16

17. Modification to a gene that changes gene expression, but is not permanent over the course of generations –May permanently affect the life of an individual –Not a change in the DNA sequence itself Epigenetic changes can be inherited, but may not follow Mendelian inheritance –DNA and chromosomal modifications can occur during gametogenesis or early embryonic development X-chromosome inactivation is an example Another example is genomic imprinting Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Epigenetic Inheritance 17

18. Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Genomic Imprinting Genomic imprinting - expression of a gene depends on whether it is inherited from the male or the female parent –Several mammalian genes are imprinted –Biological significance not always clear Phenotypes controlled by imprinted genes have a non- Mendelian pattern of inheritance –Offspring express either the maternally-inherited or the paternally-inherited allele but not both –This is termed monoallelic expression 18

19. Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Example: Igf-2 in mice –Igf-2 encodes a growth hormone called insulin-like growth factor 2 Functional Igf-2 gene is necessary for normal size –Imprinting causes expression of the paternal allele but not the maternal allele The paternal allele is transcribed into RNA The maternal allele is not transcribed –Igf-2 - is a mutant allele that makes a defective protein This causes a mouse to be dwarf But only if inherited from the father 19

20. Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Figure 6.7 lgf2 lgf2 – Normal offspring (Only the lgf2 allele is expressed in somatic cells of this heterozygous offspring.) Denotes an allele that is silent in the offspring Denotes an allele that is expressed in the offspring lgf2 lgf2 – Dwarf offspring lgf2 – (mother’s genotype) xx (Only the lgf2 – allele is expressed in somatic cells of this heterozygous offspring.) © Courtesy of Dr. Argiris Efstratiadis. lgf2 (father’s genotype) lgf2 (mother’s genotype) lgf2 – (father’s genotype) 20

21. Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Imprinting can be divided into three stages 1.Establishment of the imprint during gametogenesis 2.Maintenance of the imprint during embryogenesis and in the adult somatic cells 3.Erasure and reestablishment of the imprint in the germ cells 21

22. Transcribed allele Silenced allele Egg lgf2 Sperm lgf2 Eggs carry silenced alleles Sperm carry expressed alleles Erasure and reestablishment During gametogenesis, the imprint is erased. The female mouse produces eggs in which the gene is silenced. The male produces sperm in which the gene can be transcribed into mRNA. Somatic cell EggSperm lgf2 Somatic cell Establishment of the imprint In this example, imprinting occurs during gametogenesis in the lgf2 gene, which exists in the lgf2 allele from the male and the lgf2 – allele from the female. This imprinting occurs so that only the paternal allele is expressed. Maintenance of the imprint After fertilization, the imprint pattern is maintained throughout development. In this example, the maternal lgf2 – allele will not be expressed in the somatic cells. Note that the offspring on the left is a female and the one on the right is a male; both are normal in size. lgf2 – Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Figure 6.8 22

23. Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Genomic imprinting is permanent in the somatic cells of one animal –However, it can be altered from generation to generation Genomic imprinting occurs in several species including mammals, insects and plants It may involve –A single gene –A part of a chromosome –An entire chromosome –Even all the chromosomes from one parent 23

24. Imprinting involves methylation of specific regions of DNA Genomic imprinting must involve a marking process that is reversible –Methylation of DNA bases Imprinting Control Regions (ICRs) –Located near the imprinted genes –Methylated either in the oocyte or sperm but not both –Contain transcription factor binding sites 24

25. Original zygote Early oocyteEarly spermatocyte Original zygote Maintenance methylation occurs in all somatic cells Erasure (demethylation) Maintenance methylation occurs in all somatic cells EggsSperm De novo methylation Erasure (demethylation) No methylation Formation of gametes CH 3 3 3 Female cellsMale cells CH 3 CH 3 3 3 Maternal chromosome Somatic cell Paternal chromosome Maternal chromosome Paternal chromosome Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. CH 3 Figure 6.9 Female gametes have unmethylated ICR Male gametes have methylated ICR 25

26. Significance is not well understood Imprinting found in multiple mammalian genes –Sometimes female alleles are active; sometimes the male alleles –Refer to Table 6.6 David Haig hypothesis –Confers a reproductive advantage –Males want their offspring to have rapid growth –Females must balance rapid growth with saving resources for herself and future offspring Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Biological Significance of Imprinting 26

27. Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Table 6.6 27

28. 6.5 Maternal Effect  Definition of maternal effect  Predicting the outcome of crosses for genes that exhibit a maternal effect pattern of inheritance  The molecular mechanism of maternal effect inheritance Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 28

29. Maternal effect – Only the genotype of the mother controls phenotype of offspring –Genotype of father has no effect –Genotype of offspring has no effect –Controlled by nuclear genes Phenomenon is due to the accumulation of gene products that the mother provides to her developing eggs Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Maternal Effect Inheritance 29

30. Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Example: Coiling in the snail, Lymnaea The first example of a maternal effect gene Discovered in the 1920s by Arthur Boycott Two different directions in which the shell and internal organs can twist Right-handed (dextral) - more common and dominant Left-handed (sinistral) Reciprocal crosses and crosses of the of the F 1 s demonstrated a non-Mendelian pattern of inheritance Even though twist is controlled by a nuclear gene 30

31. x x x Parental generation F 1 generation ddDD Dd All dextral 1 DD : 2 Dd : 1 dd 3 dextral : 1 sinistral All dextral Cross to each other Males and females DDdd Dd All sinistral Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. F 2 generation F 3 generation Reciprocal cross Figure 6.10 A Mendelian pattern of inheritance would predict 3:1 dextral to sinistral But here we see all dextral 31

32. Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Alfred Sturtevant proposed that coiling is controlled by a maternal effect gene Phenotypes controlled by the genotype of the mother Not the genotype of father or offspring He proposed one gene with two alleles D and d Dd mothers produce dextral offspring even if the offspring are dd dd mothers produce sinistral offspring even if the offspring are Dd 32

33. x x x Parental generation F 1 generation ddDD Dd All dextral 1 DD : 2 Dd : 1 dd 3 dextral : 1 sinistral All dextral Cross to each other Males and females DDdd Dd All sinistral Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. F 2 generation F 3 generation Figure 6.10 The dominant allele, D, caused ALL the F 2 offspring to be dextral F 1 mothers are Dd Explains this 3:1 ratio F 2 mothers include 3 with the D allele and 1 with the d allele Reciprocal cross 33

34. Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display The non-Mendelian inheritance pattern of maternal effect genes can be explained by the process of oogenesis –Maturing animal oocytes are surrounded by maternal cells that provide them with nutrients –These nurse cells are diploid, whereas the oocyte becomes haploid In the example of Figure 6.11a –A female Dd is heterozygous for the snail-coiling maternal effect gene –The haploid oocyte received just the d allele in meiosis 34

35. EggNurse cells Dd (a) Transfer of gene products from nurse cells to egg The nurse cells express mRNA and/or protein from genes of the d allele (red) and the D allele (green) and transfer those products to the egg. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Figure 6.11a Gene products in oocyte are based on genotype of mother Transported to cytoplasm of oocyte and persist after fertilization Influence early developmental stages of the embryo 35

36. Figure 6.11b 36

37. Mitotic spindle (c) An explanation of coiling direction at the cellular level Dextral Sinistral Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 37 Figure 6.11c

38. Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Maternal effect genes encode RNA and proteins that play important roles in the early steps of embryogenesis –Example - cell division, cleavage pattern, body axis Accumulation before fertilization allows development to proceed very quickly after fertilization Therefore defective alleles in maternal effect genes tend to have a dramatic effect on the phenotype of the individual –In Drosophila, geneticists have identified several dozen maternal effect genes Profound effects on the early stages of development 38