INTRODUCTIONSeveral factors must be understood to predict the phenotype of offspring from their genotype.Includes dominant/recessive relationshipsgene interactions, sex, environmentMendelian inheritance patterns involve genes that Directly influence the outcome of an organisms traitsandObey Mendels lawsMost genes in eukaryotic species follow a Mendelian pattern of inheritanceHowever, there are many that dont

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INTRODUCTIONIn this chapter we will discuss additional (even bizarre) patterns of inheritance that deviate from a Mendelian patternMaternal effect and epigenetic inheritanceInvolve genes in the nucleusGenotype of offspring does not directly govern phenotype as predicted by MendelExtranuclear inheritance Involves genes in organelles other than the nucleusMitochondriaChloroplasts5-3

Maternal effect refers to an inheritance pattern for certain nuclear genes in which the genotype of the mother directly determines the phenotype of her offspringSurprisingly, the genotypes of the father and offspring themselves do not affect the phenotype of the offspringThis phenomenon is due to the accumulation of gene products that the mother provides to her developing eggs5-45.1 MATERNAL EFFECT

5-5The first example of a maternal effect gene was discovered in the 1920s by A. E. Boycott

He was studying morphological features of the water snail, Limnaea peregraIn this species, the shell and internal organs can be arranged in one of two directions Right-handed (dextral)Left-handed (sinistral)The dextral orientation is more common and dominant

The snails body plan curvature depends on the cleavage pattern of the egg immediately after fertilizationFigure 5.1 describes Boycotts experiment

5-6Cross and Reciprocal crossFigure 5.1A 3:1 phenotypic ratio would be predicted by a Mendelian pattern of inheritanceThe 3:1 phenotypic ratio shows up in the next generationSame genotype, but different phenotype

5-7Alfred Sturtevant later explained the incongruity with Mendelian inheritanceSnail coiling is due to a maternal effect gene that exists as dextral (D) and sinistral (d) alleles

The phenotype of the offspring depended solely on the genotype of the mother

His conclusions were drawn from the inheritance patterns of the F2 and F3 generations

5-8Figure 5.1

The dominant allele, D, caused ALL the F2 offspring to be dextralReciprocal cross

5-9Thus, in this exampleDD or Dd mothers produce dextral offspringdd mothers produce sinistral offspring

The phenotype of the progeny is determined by the mothers genotype NOT by her phenotypeThe genotypes of the father and offspring do not affect the phenotype of the offspring

The non-Mendelian inheritance pattern of maternal effect genes can be explained by the process of oogenesis in female animalsMaturing animal oocytes are surrounded by maternal cells that provide them with nutrientsThese nurse cells are diploid, whereas the oocyte becomes haploid

In the example of Figure 5.2aA female is heterozygous for the snail-coiling maternal effect geneThe haploid oocyte received the d allele in meiosis5-10

Figure 5.2a5-11They are transported to the cytoplasm of the oocyte where they persist for a significant time after the egg has been fertilizedThus influencing the early developmental stages of the embryo

Figure 5.2b5-12D gene products cause egg cleavage that promotes a right-handed body plan

5-13Figure 5.2bd gene products cause egg cleavage that promotes a left-handed body planThe sperms genotype is irrelevant because the expression of the sperms gene would be too late

5-14Figure 5.2cRemarkably, the orientation of the cleavage plane in the earliest stages of development carries through to the adult

5-15Maternal effect genes encode RNA and proteins that play important roles in the early steps of embryogenesisFor example-Cell division, Cleavage pattern, Body Axis orientationAccumulation of maternal effect gene products before fertilization allows these steps to proceed very quickly after fertilizationTherefore defective alleles in maternal gene effects tend to have a dramatic effect on the phenotype of the individualIn Drosophila, geneticists have identified several dozen maternal effect genesThese have profound effects on the early stages of development

Epigenetic inheritance refers to a pattern in which a modification occurs to a nuclear gene or chromosome that alters gene expressionHowever, the expression is not permanently changed over the course of many generationsThat is because the DNA sequence does not changeEpigenetic changes are caused by DNA and chromosomal modificationsThese can occur during oogenesis, spermatogenesis or early embryonic developmentWe will look at Dosage Compensation and Genomic Imprinting5.2 EPIGENETIC INHERITANCE5-16

The purpose of dosage compensation is to offset differences in the number of active sex chromosomes

Dosage compensation has been studied extensively in mammals, Drosophila and Caenorhabditis elegans

Depending on the species, dosage compensation occurs via different mechanismsRefer to Table 5.15-17Dosage Compensation

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Dosage compensation is not well understood in some species, such as birds and fishIn birds, the sex chromosomes are theZ, a large chromosome containing many genesW, a microchromosome containing few genesMales are ZZ; females are ZWIt appears that the Z chromosome in males does not undergo condensation like one of the X chromosomes in female mammalsDifferent studies have shown variation in gene expression of some Z-linked genes in male and female birdsMay lack a general mechanism, but some compensation may occur on specific genes

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In 1949, Murray Barr and Ewart Bertram identified a highly condensed structure in the interphase nuclei of somatic cells in female cats but not in male catsThis structure became known as the Barr body (Figure 5.3a)In 1960, Susumu Ohno correctly proposed that the Barr body is a highly condensed X chromosome In 1961, Mary Lyon proposed that dosage compensation in mammals occurs by the inactivation of a single X chromosome in females5-20Dosage compensation in mammals

5-21Dosage compensation in mammalsFigure 5.3The Barr body in a human nucleusThe black and orange mosaic pattern is due to an X-linked gene that can occur as an orange or black alleleBarr body(b) A calico catCopyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Tim Davis / Photo Researchers

The mechanism of X inactivation, also known as the Lyon hypothesis, is schematically illustrated in Figure 5.45-22The example involves a white and black variegated coat color found in certain strains of miceA female mouse has inherited two X chromosomesOne from its mother that carries an allele conferring white coat color (Xb)One from its father that carries an allele conferring black coat color (XB)

Mouse withpatches ofblack andwhite fur

5-23Figure 5.4At an early stage of embryonic developmentThe epithelial cells derived from this embryonic cell will produce a patch of white furWhile those from this cell will produce a patch of black fur

During X chromosome inactivation, the DNA becomes highly compactedMost genes on the inactivated X cannot be expressed When this inactivated X is replicated during cell division-Both copies remain highly compacted and inactiveX inactivation is passed along to all future somatic cells

Another example of variegated coat color is found in calico catsRefer to Figure 5.3b

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In 1963, Ronald Davidson, Harold Nitowsky and Barton Childs set out to test the Lyon hypothesis at the cellular levelTo do so they analyzed the expression of a human X-linked geneThe gene encodes glucose-6-phosphate dehydrogenase (G-6-PD), an enzyme used in sugar metabolism5-25The Lyon Hypothesis Put to the TestExperiment 5A

Biochemists had found that individuals vary with regard to the G-6-PD enzymeThis variation can be detected when the enzyme is subjected to gel electrophoresis

One G-6-PD allele encodes an enzyme that migrates very quicklyThe fast enzymeAnother allele encodes an enzyme that migrates more slowlyThe slow enzyme

The two types of enzymes have minor differences in their structuresThese do not significantly affect G-6-PD function5-26

Figure 5.5 illustrates the mobility of G-6-PD proteins from various individuals5-27Heterozygous adult females produce both types of enzymesHemizygous males produce either the fast or the slow typeHeterozygousfemaleHemizygousmaleHemizygousmaleOriginDirection ofmigrationSlow G-6-PDFast G-6-PDCopyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

The HypothesisAccording to the Lyon hypothesis, an adult female who is heterozygous for the fast and slow G-6-PD alleles should express only one of the two alleles in any particular somatic cell and its descendants, but not both5-28Testing the HypothesisRefer to Figure 5.6

5-29Figure 5.6

The Data5-30All cellsClones11023456789Slow G-6-PDFast G-6-PDCopyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.Ronald G. Davidson, Harold M. Nitowsky, and Barton Childs. Demonstration of Two Populations of Cells in the Human Female Heterozygous for Glucose-6-PhosphateDehydrogenase Variants. PNAS. 50 (1963) f. 2, p. 484. Courtesy Harold M. Nitowsky. Reproduced with author permission.

All cellsClones11023456789Slow G-6-PDFast G-6-PDRonald G. Davidson, Harold M. Nitowsky, and Barton Childs. Demonstration of Two Populations of Cells in the Human Female Heterozygous for Glucose-6-PhosphateDehydrogenase Variants. PNAS. 50 (1963) f. 2, p. 484. Courtesy Harold M. Nitowsky. Reproduced with author permission.

Interpreting the Data5-31All nine clones expressed one of the two types of G-6-PD enzyme, not bothThese epithelial cells were used to generate the nine clones (as described in steps 2 to 4)The heterozygous woman produced both types of G-6-PD enzymesClones 2, 3, 5, 6, 9 & 10 expressed only the slow typeClones 4, 7 & 8 expressed only the fast type

These results are consistent with the hypothesis thatX inactivation has already occurred in any given epithelial cellANDThis pattern of inactivation is passed to all of the cells progeny

5-32Interpreting the Data

X Inactivation in Mammals Depends on Xic, Xist, Tsix and XceResearchers have found that mammalian cells can count their X chromosomes and allow only one of them to remain activeAdditional X chromosomes are converted to Barr bodies5-33Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

PhenotypeSex Chromosome CompositionNumber of Barr bodiesNormal femaleXX1Normal maleXY0Turner syndrome (female)X00Triple X syndrome (female)XXX2Klinefelter syndrome (male)XXY1

The genetic control of inactivation is not entirely understood at the molecular levelHowever, a short region on the X chromosome termed the X-inactivation center (Xic) plays a critical roleFor inactivation to occur, each X chromosome must have a Xic region (Figure 5.7)The Xic region contains a gene named Xist (for X-inactive specific transcript)The Xist gene is only expressed on the inactive X chromosomeIt does not encode a proteinIt codes for a long RNA, which coats the inactive X chromosomeOther proteins will then bind and promote chromosomal compaction into a Barr body5-34

A gene designated Tsix also plays a role in chromosome choiceIt is located in the Xic region, overlaps Xist, and is expressed in the opposite direction of XistTsix is Xist spelled backwardsIt is expressed only during early embryonic developmentIt encodes an RNA complementary to Xist RNA

X chromosomes carrying a Tsix mutant are preferentially inactivated in females5-35

Figure 5.75-36Promotes compactionPrevents compaction

The process of X inactivation can be divided into three stagesInitiationOne of the X chromosomes is targeted for inactivationSpreadingThe chosen X chromosome is inactivatedMaintenanceThe inactivated X chromosome is maintained as such during future cell divisions

Refer to Figure 5.85-37

Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.5-38Figure 5.8The Barr body is replicated and both copies remain compacted

A few genes on the inactivated X chromosome are expressed in the somatic cells of adult female mammalsThese genes escape the effects of X inactivationThey includeXistPseudoautosomal genesDosage compensation in this case is unnecessary because these genes are located on both the X and Y chromosomesUp to a quarter of X genes in humans may escape full inactivationThe mechanism is not understoodMay involve loosening of chromatin in specific regions5-39

5.3 GENOMIC IMPRINTINGGenomic imprinting is a phenomenon in which a segment of DNA is marked and the effect is maintained throughout the life of the organism inheriting the marked DNA

Imprinted genes follow a non-Mendelian pattern of inheritanceDepending on how the genes are marked, the offspring expresses either the maternally-inherited or the paternally-inherited alleleNot bothThis is termed monoallelic expression5-40

Lets consider the following example in mice:The Igf-2 gene encodes a growth hormone called insulin-like growth factor 2A functional Igf-2 gene is necessary for a normal size

Imprinting results in the expression of the paternal but not the maternal alleleThe paternal allele is transcribed into RNAThe maternal allele is not transcribed

Igf-2- is a loss-of-function allele that does not express a functional Igf-2 proteinThis may cause a mouse to be dwarf depending on whether it inherits the mutant allele from its father or from its motherRefer to Figure 5.95-41

5-42Figure 5.9Normal SizeNormal SizeDwarfDwarfReciprocal cross-Genotypes are identical

At the cellular level, imprinting is an epigenetic process that can be divided into three stages

1)Establishment of the imprint during gametogenesis2) Maintenance of the imprint during embryogenesis and in the adult somatic cells3) Erasure and reestablishment of the imprint in the germ cells

These stages are described in Figure 5.10The example also considers the imprinting of the Igf2 gene5-43

5-44Figure 5.10Both male and female mice express the Igf2 in their somatic cellsMale mouse transmits transcriptionally active allelesFemale mouse transmits transcriptionally inactive allelesTranscribed into mRNA in the somatic cells of offspring; But half yield defective proteins

Thus genomic imprinting is permanent in the somatic cells of an animalHowever, the marking of alleles can be altered from generation to generationGenomic imprinting occurs in several species including insects, mammals and flowering plants

It may involve A single geneA part of a chromosomeAn entire chromosomeEven all the chromosomes from one parentIt can be used for X inactivation in some species5-45

Genomic imprinting must involve a marking process

At the molecular level, the imprinting of several genes is known to involve an imprinting control region (ICR) located near the imprinted geneThe ICR is methylated either in the oocyte or spermNot bothThe ICR contains binding sites for one or more transcription factors that regulate the imprinted geneFor most genes, methylation causes inhibition of transcriptionImprinting and DNA Methylation5-46

5-47Figure 5.11Both parents inherit one methylated and one unmethylated gene, which is maintained in somatic cellsMethylation is removed in gamete forming cellsBoth parents inherit one methylated and one unmethylated gene, which is maintained in somatic cellsMethylation is removed in gamete forming cellsHaploid female gametes transmit an unmethylated DMRHaploid male gametes transmit a methylated DMRMethylation in male gamete cells only

To date, imprinting has been identified in dozens of mammalian genes5-48Genomic imprinting can influence human diseases.

Imprinting plays a role in the inheritance of certain human diseases such as Prader-Willi syndrome (PWS) and Angelman syndrome (AS)PWS is characterized by Reduced motor functionObesitySmall hands and feet

AS is characterized by Hyperactivity and thinnessUnusual seizuresRepetitive symmetrical muscle movements Mental deficiencies

Most commonly, PWS and AS involve a small deletion in chromosome 15If it is inherited from the mother, it leads to ASIf it is inherited from the father, it leads to PWS5-49

Researchers have discovered that this region contains closely linked but distinct genesThese are maternally or paternally imprinted5-50AS results from the lack of expression of a single gene, UBE3AUBE3A encodes a protein that regulates protein degradation The paternal copy is silencedPWS results (most likely) from the lack of expression of a single gene, designated SNRNP SNRNP encodes a small nuclear ribonucleoprotein polypeptide N which is part of a complex that controls gene splicing The maternal copy is silenced

5-51Figure 5.12DeletioninheritedfrommotherDeletioninheritedfromfather

Extranuclear inheritance refers to inheritance patterns involving genetic material outside the nucleus The two most important examples are due to genetic material within organellesMitochondria and chloroplastsThese organelles are found in the cytoplasmTherefore, extranuclear inheritance is also termed cytoplasmic inheritance5.4 EXTRANUCLEAR INHERITANCE5-52

The genetic material of mitochondria and chloroplasts is located in a region called the nucleoidRefer to Figure 5.13The genome is composed of a single circular chromosome containing double-stranded DNANote: A nucleoid can contain several copies of the chromosomeAn organelle can contain more than one nucleoid

Chloroplasts tend to have more nucleoids per organelle than mitochondriaRefer to Table 5.35-53

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Besides variation in copy number, the sizes of organellar genomes also vary greatly among different speciesThere is a 400-fold variation in the size of mitochondrial genomesThere is also a substantial variation in size of chloroplast genomes

In general, mitochondrial genomes areFairly small in animals Intermediate in size in fungi and protistsFairly large in plantsAlthough plants and algae can show substantial variation in size5-55

The main function of mitochondria is oxidative phosphorylationA process used to generate ATP (adenosine triphosphate)Oxygen is consumed during ATP synthesisATP is used as an energy source to drive cellular reactions

The genetic material in mitochondria is referred to as mtDNAThe human mtDNA consists of only 17,000 bp (Figure 5.15)It carries relatively few genesrRNA and tRNA genes13 polypeptides that function in oxidative phosphorylation

Note: Most mitochondrial proteins are encoded by genes in the nucleusThese proteins are made in the cytoplasm, then transported into the mitochondria5-56

Ribosomal RNA genesNoncoding DNAATP synthase subunit genes (2)Cytochrome c oxidase subunit genes (3)NADH dehydrogenase subunit genes (7)Cytochrome b geneTransfer RNA genes5-57Figure 5.14Function in oxidative phosphorylationtRNAPhetRNAValtRNALeutRNAIletRNAGlntRNAMettRNAAlatRNATrptRNAAsntRNACystRNATyrtRNAProtRNAThrtRNAGlutRNALeutRNASertRNAHistRNAArgtRNAGlytRNALystRNAAsptRNASer12S rRNA16S rRNACopyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

The main function of chloroplasts is photosynthesis

The genetic material in chloroplasts is referred to as cpDNAIt is typically about 10 times larger than the mitochondrial genome of animal cells

The cpDNA of tobacco plant consists of 156,000 bpIt carries between 110 and 120 different genesrRNA and tRNA genesMany polypeptides that are required for photosynthesis

As with mitochondria, many chloroplast proteins are encoded by genes in the nucleusThese proteins contain chloroplast-targeting signals that direct them from the cytoplasm into the chloroplast5-58

Carl Correns discovered that pigmentation in Mirabilis jalapa (the four oclock plant) shows a non-Mendelian pattern of inheritance Leaves could be green, white or variegated (with both green and white sectors)

5-59Maternal InheritanceCorrens determined that the pigmentation of the offspring depended solely on the maternal parent and not at all on the paternal parentThis is termed maternal inheritancedifferent than maternal effectRefer to Figure 5.15

5-60Figure 5.15

5-61In this example, maternal inheritance occurs because the chloroplasts are transmitted only through the cytoplasm of the eggThe pollen grains do not transmit chloroplasts to the offspring

The phenotype of leaves can be explained by the types of chloroplasts found in leaf cellsGreen phenotype is the wild-typeDue to normal chloroplasts that can make green pigmentWhite phenotype is the mutantDue to a mutation that prevents the synthesis of the green pigmentA cell can contain both types of chloroplastsA condition termed heteroplasmyIn this case, the leaf would start out all green

5-62Figure 5.16 provides a cellular explanation for the variegated phenotype in Mirabilis jalapa

Consider a fertilized egg that inherited two types of chloroplastGreen and whiteAs the plant grows, the chloroplasts are irregularly distributed to daughter cellsSometimes, a cell may receive only white chloroplastsSuch a cell will continue to divide and produce a white sectorCells that contain only green chloroplasts or a combination of green and white will ultimately produce green sectors

5-63Figure 5.16

The pattern of inheritance of mitochondria and chloroplasts varies among different speciesHeterogamous speciesProduce two kinds of gametesFemale gamete LargeProvides most of the cytoplasm to the zygoteMale gamete SmallProvides little more than a nucleusIn these species, organelles are typically (but not always) inherited from the motherTable 5.4 describes various inheritance patterns5-64The Pattern of Inheritance of Organelles

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Species with maternal inheritance may, on occasion, exhibit paternal leakageThe paternal parent occasionally provides mitochondria through the spermIn the mouse, for example, 1-4 paternal mitochondria are inherited for every 100,000 maternal mitochondria per generation of offspring5-66The Pattern of Inheritance of Organelles

Occurs in two waysHuman mtDNA is transmitted from mother to offspring via the cytoplasm of the eggTherefore, the transmission of human mitochondrial diseases follows a strict maternal inheritance patternMitochondrial mutations may occur in somatic cellsAccumulate as a person agesMitochondria are very susceptible to DNA damageHigh oxygen consumption leads to free radicalsMitochondrial DNA has very limited repair abilities

Over 200 human mitochondrial diseases have been identifiedThese are typically chronic degenerative disorders affecting cells requiring high levels of ATP such as nerve and muscle cellsSee Table 5.5

5-67Human Mitochondrial Diseases

5-68Human Mitochondrial Diseases

Heteroplasmy is an important factor in mitochondrial diseaseCells can contain a mixed population of mitochondriaSome may carry disease causing mutation while others do notAs cells divide some cells may receive a high ratio of mutant to normal mitochondriaDisease may occur when the ratio of mutant to normal mitochondria exceeds a threshold valueSymptoms may vary widely within a given family5-69Human Mitochondrial Diseases

The endosymbiosis theory describes the evolutionary origin of mitochondria and chloroplastsThese organelles originated when bacteria took up residence within a primordial eukaryotic cell chloroplasts originated as cyanobacteriummitochondria originated as Gram-negative nonsulfur purple bacteriaDuring evolution, the characteristic of the intracellular bacterial cell gradually changed to that of the organelleThe endosymbiotic origin of organelles is supported by several observationsThese includeOrganelles have circular chromosomes (like bacteria)Organelle genes are more similar to bacterial genes than to those found within the nucleus5-70The Endosymbiosis Theory

5-71Figure 5.17The eukaryotic cell was now able to undergo photosynthesisThe eukaryotic cell was now able to synthesize greater amounts of ATPThe bacterial cells may have gained a more stable environment with more nutrients

During the evolution of eukaryotic species, most genes originally found in the bacterial genome have been lost or transferred to the nucleusCertain genes in nucleus are more similar in sequence to known bacterial genesAbout 1500 genes transferred to nuclear genomeMost gene transfer occurred early in chloroplast and mitochondrial evolutionThe gene transfer has primarily been unidirectionalFrom the organelles to the nucleusIn addition, gene transfer can occur between organellesBetween two mitochondria, two chloroplasts or a mitochondrion and a chloroplastThe biological benefits of gene transfer remain unclear5-72The Endosymbiosis Theory

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