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PowerPoint to accompany Genetics: From Genes to Genomes Fourth Edition Leland H. Hartwell, Leroy Hood, Michael L. Goldberg, Ann E. Reynolds, and Lee M.

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Presentation on theme: "PowerPoint to accompany Genetics: From Genes to Genomes Fourth Edition Leland H. Hartwell, Leroy Hood, Michael L. Goldberg, Ann E. Reynolds, and Lee M."— Presentation transcript:

1 PowerPoint to accompany Genetics: From Genes to Genomes Fourth Edition Leland H. Hartwell, Leroy Hood, Michael L. Goldberg, Ann E. Reynolds, and Lee M. Silver Prepared by Mary A. Bedell University of Georgia 1 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition

2 How Genes Are Regulated 2 PART V Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 Gene Regulation in Eukaryotes 16.1 Overview of Eukaryotic Gene Regulation 16.2 Control of Transcription Initiation 16.3 Chromatin Structure and Epigenetic Effects 16.4 Regulation After Transcription 16.5 A Comprehensive Example: Sex Determination in Drosophila CHAPTER OUTLINE CHAPTERCHAPTER

3 Overview of eukaryotic gene regulation Eukaryotes use complex sets of interactions Regulated interactions of large networks of genes Each gene has multiple points of regulation Themes of gene regulation in eukaryotes: Environmental adaptation in unicellular eukaryotes Maintenance of homeostasis in multicellular eukaryotes Genes are turned on or off in the right place and time Differentiation and precise positioning of tissues and organs during embryonic development Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 3

4 Compared to prokaryotes, eukaryotes have additional levels of complexity for controlling gene expression Eukaryotic genomes are larger than prokaryotic genomes Chromatin structure in eukaryotes makes DNA unavailable to transcription machinery Additional RNA processing events occur in eukaryotes In eukaryotes, transcription takes place in the nucleus and translation takes place in the cytoplasm Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 4

5 Key regulatory differences between eukaryotes and prokaryotes Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 5 Table 16.1

6 Multiple steps where production of the final gene product can be regulated in eukaryotes Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 6 Fig. 16.1

7 Control of transcription initiation Three types of RNA polymerases in eukaryotes RNA pol I – transcribes rRNA genes RNA pol II – transcribes all protein-coding genes (mRNAs) and micro-RNAs RNA pol III – transcribes tRNA genes and some small regulatory RNAs Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 7

8 RNA polymerase II transcription RNA pol II catalyzes synthesis of the primary transcript, which is complementary to the template strand of the gene Most RNA pol II transcripts undergo further processing to generate mature mRNA RNA splicing – removes introns Addition of 5' GTP cap – protects RNA from degradation Cleavage of 3' end and addition of 3' polyA tail Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 8

9 cis-acting elements: promoters and enhancers Promoters – usually directly adjacent to the gene Include transcription initiation site Often have TATA box: Allow basal level of transcription Enhancers – can be far away from gene Augment or repress the basal level of transcription Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 9 Fig. 16.2

10 Use of reporter genes to identify promoters and enhancers in eukaryotes Examples of reporter genes used in eukaryotes lacZ gene (Ch 15), blue color when X-gal used Gene for "green fluorescent protein" (GFP) Mutations in regulatory regions can be engineered and tested for effects on expression Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig. 16.3

11 trans-acting factors interact with cis-acting elements to control transcription initiation Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig Direct effects of transcription factors: Through binding to DNA Indirect effect of transcription factors: Through protein- protein interactions

12 Use of reporter genes to identify trans-acting factors in transcriptional regulation Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig. 16.5

13 Basal transcription factors Basal transcription factors assist the binding of RNA pol II to promoters (see Fig 16.6) Key components of basal factor complex: TATA box-binding protein (TBP) Bind to TATA box First of several proteins to assemble at promoter TBP-associated factors (TAFs) Bind to TBP assembled at TATA box RNA pol II associates with basal complex and initiates basal level of transcription Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 13

14 Basal factors bind to promoters of all protein-encoding genes Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig Ordered pathway of assembly at promoter: 1. TBP binds to TATA box 2. TAFs bind to TBP 3. RNA pol II binds to TAFs

15 Activators are transcription factors that bind to enhancers Activators are responsible for much of the variation in levels of transcription of different genes Increase levels of transcription by interacting directly or indirectly with basal factors at the promoter 3-dimensional complex of proteins and DNA (Fig. 16.7) Mechanisms of activator effects on transcription Stimulate recruitment of basal factors and RNA pol II to promoters Stimulate activity of basal factors already assembled on promoters Facilitate changes in chromatin structure Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 15

16 Binding of activators to enhancers increases transcriptional levels Low level transcription occurs when only basal factors are bound to promoter Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter When basal factors and activators are bound to DNA, rate of transcription increases Fig. 16.7

17 Domains within activators Activator proteins have two functional domains Sequence-specific DNA binding domain (Fig 16.8) Binds to enhancer Transcription-activator domain Interacts with other transcriptional regulatory proteins Some activators have a third domain (Fig 16.9) Responds to environmental signals Example - steroid hormone receptors Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 17

18 DNA-binding domains of activator proteins Interacts with major groove of DNA Specific amino acids have high-affinity binding to specific nucleotide sequence The three best-characterized motifs: Helix-loop-helix (HLH) Helix-turn-helix (HTH) Zinc finger Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig. 16.8

19 Steroid hormone receptors are activators only in the presence of specific hormones Steroid hormones don't bind to DNA but are coactivators of steroid hormone receptors In the absence of hormone, these receptors cannot bind to DNA and so cannot activate transcription In the presence of hormone, these receptors bind to enhancers for specific genes and activate their expression Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig. 16.9

20 Many activators must form dimers to function Homodimers: multimeric proteins made of identical subunits Heterodimers: multimeric proteins made of nonidentical subunits Examples - Fos and Jun, both have leucine zippers Fos forms heterodimers with Jun, but cannot form homodimers Jun can form homodimers Jun-Jun and Jun-Fos dimers bind to the same enhancer sequence, but have different affinities Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig

21 Dimerization domains make up another class of transcription factor domains Dimerization domains are specialized for polypeptide- polypeptide interactions Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig Leucine zippers are a common dimerization motif in eukaryotes Amino acid sequence twirls into an helix with leucines protruding at regular intervals

22 Repressor proteins suppress transcription initiation through different mechanisms Some repressors have no effect on basal transcription but suppress the action of activators Compete with activator for the same enhancer (Fig 16.12a) OR Block access of activator to an enhancer (Fig 16.12b) Some repressors eliminate virtually all basal transcription from a promoter Block RNA pol II access to promoter OR Bind to sequences close to promoter or distant from promoter Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 22

23 Repressor proteins that act through competition with an activator protein Repressor binds to the same enhancer sequence as the activator Has no effect on the basal transcription level Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig a

24 Repressor proteins that act through quenching an activator protein Quenchers bind to the activator but do not bind to DNA Type I: Repressor blocks the DNA-binding domain Type II: Repressor blocks the activation domain Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig b

25 The same transcription factor can play different roles in different cells Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig Example: 2 repressor in yeast Determines mating type by binding to enhancers of certain genes In haploids and /a diploids, 2 binds to enhancers of a-specific genes but not to enhancers of haploid-specific genes In /a diploids, binding specificity of 2 is altered so that it can bind to enhancers of haploid-specific genes

26 The Myc-Max mechanism can activate or repress transcription Myc identified as an oncogene Regulates transcription of genes involved in cell proliferation Doesn't have DNA binding activity on its own Max identified through its binding to Myc Max/Max homodimers and Myc/Max heterodimers bind to the same enhancers Max/Max represses transcription Myc/Max activates transcription Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 26

27 Comparative structures of Myc and Max Myc/Myc homodimers cannot form Max/Max homodimers and Myc/Max heterodimers can form Max/Max homodimers bind DNA but cannot act as activators Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig

28 Dimer structure and subunit concentrations of Myc and Max affect activation or repression Max is constitutively expressed but Myc expression is tightly regulated Max/Max acts as a repressor when Myc is not expressed Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig a

29 Dimer structure and subunit concentrations of Myc and Max affect activation or repression When Myc is present, Myc/Max heterodimers form and activate transcription Myc - Max affinity is higher than Max - Max affinity Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig b

30 Complex regulatory regions enable fine-tuning of gene expression Each gene can have many regulatory proteins In humans, ~2000 genes encode transcriptional regulatory proteins Each regulatory protein can act on many genes Each regulatory region can have dozens of enhancers Enhanceosome – multimeric complex of proteins and other small molecules that associate with an enhancer Enhancers can be bound by activators and repressors with varying affinities Different sets of cofactors and corepressors compete for binding to activators and repressors Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 30

31 Different enhancers for the string gene in Drosophila are used in different cell types Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig Cells in different parts of Drosophila embryos go through the 14 th mitosis at different times The string gene product activates the 14 th mitosis Different activators for string are expressed at different times in different tissues

32 Chromatin structure and epigenetic effects Chromatin structure can affect transcription Nucleosomes can sequester promoters and make them inaccessible to RNA polymerase and transcription factors Histone modification and DNA methylation Chromatin remodeling and hypercondensation Epigenetic changes – changes in chromatin structure that are inherited from one generation to the next DNA sequence is not altered Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 32

33 Chromatin reduces transcription Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig

34 Effects of chromatin structure on transcription: Histone modification and DNA methylation N-terminal tails of histones H3 and H4 can be modified Methylation, acetylation, phosphorylation, and ubiquitination Can affect nucleosome interaction with other nucleosomes and with regulatory proteins Can affect higher-order chromatin structure DNA methylation occurs at C5 of cytosine in a CpG dinucleotide Associated with gene silencing Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 34

35 Determining methylation state of DNA using two restriction enzymes and Southern blotting HpaII and MspI have the same recognition sequence (CCGG), but different sensitivity to DNA methylation Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig HpaII doesn't cut if 2 nd C is methylated Methylation doesn't affect MspI cutting

36 Chromatin remodeling can expose the promoter Nucleosomes can be repositioned of removed by chromatin remodeling complexes After remodeling, DNA at promoters and enhancers becomes more accessible to transcription factors Can be assayed using DNase digestion (DNase hypersensitive sites) Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig

37 The SWl-SNF remodeling complex One of best-studied remodeling complexes Uses energy from ATP hydrolysis to alter nucleosome positioning Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig

38 Hypercondensation of chromatin results in silencing of transcription Examples of heterochromatin – inactive X chromosome, centromeres, telomeres Heterochromatin has methylation of CpG dinucleotides and methylation of lysine in histone H3 tails Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig

39 Gene silencing by the SIR complex in yeast Gene for 2 repressor is at the MAT (mating type) locus HML and HMR are copies of MAT locus but are silenced by SIR complex Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter SIR mutations cause sterility because HML and HMR genes not silenced and both and a- specific genes are expressed Fig

40 Genomic imprinting results from transcriptional silencing Genomic imprinting – expression of a gene depends on whether it was inherited from the mother or father Occurs with some genes of mammals Epigenetic effect (no change in DNA sequence) Paternally imprinted gene is transcriptionally silenced if it was transmitted from the father Maternal allele is expressed Maternally imprinted gene is transcriptionally silenced if it was transmitted from the mother Paternal allele is expressed Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 40

41 In mice, deletion of Igf2 causes a mutant phenotype only when transmitted by father Maternal imprinting of Igf2 gene Maternally-inherited Igf2 allele is silenced Igf2 deletion heterozygotes have normal phenotype if the mutant allele was inherited from the mother Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig a

42 Methylation of complementary strands of DNA in genomic imprinting Epigenetic state can be maintained across cell generations through the action of DNA methylases Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig b

43 Insulators limit the chromatin region over which an enhancer can operate An insulator that binds CTCF is involved in reciprocal imprinting of the Igf2 and H19 genes Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig.16.23c Methylation of the H19 promoter and the insulator occurs in spermatogenesis A methylase is essential for imprinting of the H19 gene

44 The resetting of genomic imprints during meiosis Epigenetic imprints remain throughout the lifespan of the mammal In germ cells, epigenetic imprints are reset at each generation During meiosis, imprints are erased and new ones are set Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig d

45 Genomic imprinting and human disease Examples: two syndromes associated with small deletions in chromosome 15 At least two genes within this region are differently imprinted Praeder-Willi syndrome occurs when the deletion is inherited from the father Angelman syndrome occurs when the deletion is inherited from the mother Affected individuals have mental retardation and development disorders Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 45

46 Inheritance patterns of disorders resulting from mutations in imprinted genes These pedigrees may appear to be instances of incomplete penetrance, but are distinctly different Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig e

47 Regulation after transcription Posttranscriptional regulation can occur at any step At the level of RNA Splicing, stability, and localization Example – alternative splicing of mRNA Generates more diversity of proteins Common feature in eukaryotes At the level of protein Synthesis, stability, and localization Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 47

48 Expression of the Sxl mRNA in early Drosophila development Sex lethal (Sxl) gene encodes a protein required for female- specific development (see Comprehensive example) In early embryos, Sxl is transcribed only in females Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig a

49 Differential RNA splicing of Sxl mRNA during Drosophila development Later in development, Sxl gene is transcribed in both sexes Sxl protein regulates alternative splicing of its own mRNA Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig b

50 Some small RNAs are responsible for RNA interference (RNAi) Specialized RNAs that prevent expression of specific genes through complementary base pairing Small (21 – 30 nt) RNAs Micro-RNAs (miRNAs) and small interfering RNAs (siRNAs) First miRNAs (lin-4 and let-7) identified in C. elegans Nobel prize to A. Fire and C. Mello in 2006 Posttranscriptional mechanisms for gene regulation mRNA stability and translation May also affect chromatin structure Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 50

51 Primary transcripts containing miRNA Most miRNAs are transcribed by RNA polymerase II from noncoding DNA regions that generate short dsRNA hairpins Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig a

52 miRNA processing Drosha excises stem-loop from primary miRNA (pri-miRNA) to generate pre-miRNA of ~ 70 nt Dicer processes pre-miRNA to a mature duplex miRNA One strand is incorporated into miRNA-induced silencing complex (RISC) Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig

53 Two ways that miRNAs can down-regulate expression of target genes When complementarity is perfect: Target mRNA is degraded Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter When complementarity is imperfect: Translation of mRNA target is repressed Fig

54 siRNAs detect and destroy foreign dsRNAs Two biological sources of dsRNAs that are precursors of siRNAs (pri-RNAs) Transcription of both strands of an endogenous genomic sequence Arise from exogenous virus pri-RNAs are processed by Dicer siRNA pathway targets dsRNAs for degradation siRNAs are very useful experimental tools to selectively knock down expression of target genes To study function of a gene, dsRNAs for that gene can be introduced into cells Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 54

55 Posttranslational modifications of proteins Ubiquitination – covalent attachment of ubiquitin to other proteins targets those proteins for degradation by the proteosome Cascades of phosphorylation and dephosphorylation Transmission of signals across the cell membrane to the nucleus (discussed more in Chapter 17) Sensitization – tissues exposed to hormones for long periods of time lose ability to respond to the hormone Example: binding of epinephrine to β-adrenergic receptors on surface of heart muscle cells (see Fig 16.28) Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 55

56 Phosphorylation and desensitization of β-adrenergic receptor Phosphorylation of receptor has no effect on its binding to epinephrine, but blocks its downstream functions Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig

57 Computer analyses can reveal regulatory mechanisms Can translate open reading frames into in silico proteins Recognize motifs within proteins e.g. Zinc-finger domains or sites for posttranslational modification Phlyogenetic footprinting – compare noncoding DNA sequences of closely related species Sequences that are conserved may have important functions in gene regulation ChIP technology – see Chapter 10 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 57

58 A comprehensive example of gene regulation: Sex determination in Drosophila In Drosophila, ratio of X chromosomes to autosomal chromosomes (X:A ratio) determines sex, fertility, and viability X:A ratio influences sex through three independent pathways: Male vs female appearance and behavior Development of germ cells as eggs or sperm Dosage compensation – males have increased transcription of X-linked genes Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 16 58

59 Sex-specific traits in Drosophila Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig

60 How chromosomal constitution affects phenotype in Drosophila Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Table 16.2

61 Drosophila mutations that affect the two sexes differently *Sx fl is a recessive mutation of Sex lethal **Sxl ML is a dominant mutation of Sex lethal Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Table 16.3

62 The X:A ratio regulates transcription of the Sxl gene Several HLH transcription factors are key regulators of sex determination X-linked genes are "numerator elements" Autosomal genes are "denominator elements" Numerator/denominator determines ratio of HLH homodimers and heterodimers Only the homodimer activates transcription of Sxl Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig

63 The Sxl protein triggers a cascade of splicing of transformer (tra) and double-sex (dsx) mRNAs Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig Sxl protein regulates splicing of tra mRNA Tra protein regulates splicing of dsx mRNA

64 Dsx-F is a transcriptional activator and Dsx-M is a transcriptional repressor Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig

65 The Tra protein regulates splicing of fruitless (fru) mRNA Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter Fig


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