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4: Genome evolution. break. Gene Duplication. Gene Duplication - History. 1936: The first observation of a duplicated gene was in the Bar gene of Drosophila. 1950: Alpha and beta chains of hemoglobin are recognized to have been derived from gene duplication

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  1. 4: Genome evolution break

  2. Gene Duplication

  3. Gene Duplication - History 1936: The first observation of a duplicated gene was in the Bar gene of Drosophila. 1950: Alpha and beta chains of hemoglobin are recognized to have been derived from gene duplication 1970: Ohno developed a theoretical framework of gene duplication 1995: Gene duplications are studied in fully sequenced genomes

  4. Types of Genomic Duplications • Part of an exon or the entire exon is duplicated • Complete gene duplication • Partial chromosome duplication • Complete chromosome duplication • Polyploidy: full genome duplication

  5. Mechanism of Gene Duplication Genes are duplicated mainly due to unequal crossing over

  6. Mechanism of Gene Duplication If these regions are complementary, it increases the chance of unequal crossing over. For example, if both of these regions are the same repeated sequence (microsatellite, transposon, etc’…)

  7. After a Gene is Duplicated • Alternative fates: • It can die and become a pseudogene. • It can retain its original function, thus allowing the organism to produce double the amount of the derived protein. • The two copies can diverge and each one will specialize in a different function. Divergence One copy dies Identical copies

  8. Invariant repeats If the duplicated genes are identical or nearly identical, they are called invariant repeats. Many times the effect is an increase in the quantity of the derived protein, and this is why these duplications are also called “dose repetitions”. Classical examples are the genes encoding rRNAs and tRNAs needed for translation. Invariant repeats

  9. Variant repeats Some classic examples: Trypsin, the digestive enzyme and Thrombin (cleaves fibrinogen during blood clotting) were derived from a complete gene duplication. Lactalbumin, connected with lactose synthesis and Lysozyme, which degrades bacteria cell wall are also a result of an ancient gene duplication. Variant repeats

  10. 4: Genome evolution break

  11. Dose Repetition

  12. Gene duplication in mosquito as a response to insecticides Kingdom = Metazoa (humans are also Metazoa) Phylum = Arthropoda (humans are Chordata) Class = Insecta (humans are Mammalia) Order = Diptera (humans are Primates) Genus = Culex (humans are Homo) Species = pipiens (sapiens)

  13. Organophosphorous insecticides Organophosphorous insecticides (e.g., parathion and malathion) interact with many enzymes and in particlar they inhibit the acetylcholinesterase (AChE) activity in the central nervous system, inducing lethal conditions.

  14. Organophosphorous insecticides The acetylcholine is a is a neurotransmitter that, upon release from neurons, stimulates the opening of a Na+ and K+ channels. These channels regulate the function of the brain as well as the heart, lungs, and skeletal muscles. The acetylcholinesterase catalyzes the hydrolysis of acetylcholine to form inactive acetate and choline.

  15. Acetylcholinesterase Cholinergic neuron Acetyl-CoA + Choline Acetylcholine Acetylcholinesterase Postsynaptic tissue

  16. Acetylcholinesterase Cholinergic neuron Acetyl-CoA + Choline Acetylcholine Insecticide Acetylcholinesterase Postsynaptic tissue

  17. Esterases Esterases are detoxifying carboxylester hydrolase which are responsible for the resistance to organophosphorous insecticides. These enzymes are none specific.

  18. Detoxifying esterases Cholinergic neurone Acetyl-CoA + Choline Acetylcholine Insecticide Esterase Postsynaptic tissue

  19. Esterases Culex pipiens typically has 2 genes encoding esterases: Est-3 and Est-2. These genes are separated by an intergenic DNA fragment varying between 2–6 kb. Est-3 Est-2

  20. Alignment of predicted estα2 and estβ2 amino acid sequencesof Culex quinquefasciatus ~47% similarity between the two sequences [Biochem.J.(1997) 325,359-365]

  21. Esterases Resistance alleles correspond to an esterase over-production (which binds or metabolizes the insecticide) relative to basal esterase production of susceptibility alleles. Several resistance allele have been described.

  22. Esterase starch gel Different allele show 85-90% of similarity

  23. Esterases For most alleles, the over-production of esterase is the result of gene duplication. This concerns either one locus or both. A Est-3 Est-2 B 47 % of similarity A ~100 % of similarity B

  24. Nomenclature for the various resistance genes and their products at the Ester resistance locus Genetica 112–113: 287–296, 2001

  25. Esterases The duplication of the two esterase loci, explains the tight statistical association of some electromorphs, like A2 and B2. Although, A4, A2 and A1 are coded by alleles of the Est-locus , and B2 and B4 by alleles at the Est-2 locus, A1, A4-B4 and A2-B2 are considered as alleles of a single superlocus (named Ester). Independent amplifications have occurred only a few times.

  26. Esterases The level of gene duplication varies between the different alleles: EsterB1 could reach easily 100 copies in the field Ester4 has never been found above few copies. It varies also within and among populations for a given amplified allele. Why the various amplified alleles have distinct limits of amplification is unknown.

  27. Frequency of resistance allelein Montpellier (France) A1 A1 1 11 21 31 41 km 1 11 21 31 41 km A1 A1 1 11 21 31 41 km Treatment area

  28. Esterases Resistance allele has a cost for the mosquito. In absence of insecticide in the environment non resistant-mosquitoes have the best fitness.

  29. Geographic distribution of resistance allele Genetica 112–113: 287–296, 2001

  30. Esterases The level of gene duplication varies between the different alleles: EsterB1 could reach easily 100 copies in the field Ester4 has never been found above few copies. It varies also within and among populations for a given amplified allele. Why the various amplified alleles have distinct limits of amplification is unknown.

  31. Gene Duplication in Aphids as a response for insecticide. Same story than the mosquitoes

  32. Few Words About Aphids Kingdom=Metazoa (humans are also metazoa) Phylum=Arthropoda (humans are Chordata) Class=Insecta (humans are Mammalia) Order=Hemiptera (humans are Primates) Genus=Myzus (humans are Homo) Species=persicae (sapiens) Around 4,000 species, ~250 are pests.

  33. Few Words About Aphids The Myzus persicae likes…lettuce. In fact, it is the most important aphid pest on lettuce

  34. E4 & FE4 Myzus persicae has 2 genes encoding esterases E4 and FE4, which are responsible for the resistance to organophosphorous insecticides. These genes show 99% identity in nucleotide sequences, both have exactly the same exon-intron structure (same size and same positions).

  35. Many copies of E4 and FE4 Resistance strains of the aphid were found to contain multiple copies of E4 and FE4. The sequences of all copies are 100% identical. It is believed that this duplication occurred within the last 50 years, with the introduction of the selective agent.

  36. Take home message I: Increase in gene number can occur quite rapidly under selection pressure.

  37. Take home message II: Mutations of gene duplication are not the limiting step (in evolution). It is selection that counts most.

  38. 4: Genome evolution break

  39. Duplications of RNA-specifying genes

  40. Ribosome Ribosome is a complex of proteins and RNA (called rRNA) on which proteins are built, based on the information in the mRNA. Ribosomes are always composed of two units – big and small.

  41. Ribosome In prokaryotes the entire ribosome is 70S, and is composed of a 50S large subunit, and a 30S small subunit. In eukaryotes the entire ribosome is 80S, and is composed of a 60S large subunit and a 40S small subunit. Each subunit contain different rRNA. The S value is the sedimentation coefficient in ultracentrifuge.

  42. rRNA There are also ribosomal genes coded by the mitochondrial genome. In fact, the mitochondrial ribosome is coded by both nuclear and mitochondrial genes.

  43. Comparison of ribosome structure in Bacteria, Eukaryotes, and Mitochondria 16S, 18S are the most commonly used genes in phylogenetic analysis

  44. Eukaryotic rRNA genes • 28S, 5.8S, and 18S rRNAs are encoded by a single transcription unit (45S) separated by 2 internally transcribed spacers (ITS) and bounded by externally transcribed spacers (ETS). ETS ITS 1 ITS 2 ETS 18S 28S 5.8 S

  45. 18S 18S 18S 18S 28S 28S 28S 28S Human rRNA genes • In Human the 45S rDNA is organized into 5 clusters (each has 30-40 repeats) • These clusters are located on chromosomes 13, 14, 15, 21, and 22. • These clusters are transcribed by the RNA polymerase I.

  46. Human rRNA genes • 5SrRNA genes occurs in tandem arrays and there are about ~200-300 true 5S genes and many dispersed pseudogenes. • In human there are two gene cluster on chromosome 1 (in dogs there is a single gene cluster). • 5S rRNA is transcribed by RNA polymerase III.

  47. Correlation between the number of rRNA genes and the genome size Numbers of rRNA and tRNA genes per haploid genome in various organisms __________________________________________________________________________ Genome Source Number of Number of Approximate rRNA sets tRNA genesa genome size (bp) __________________________________________________________________________ Human mitochondrion 1 22 2  104 Nicotiana tabacum chloroplast 2 37 2  105 Escherichia coli 7 ~ 100 4  106 Neurospora crassa ~ 100 ~ 2,600 2  107 Saccharomyces cerevisiae ~ 140 ~ 360 5  107 Caenorhabditis elegans ~ 55 ~ 300 8  107 Tetrahymena thermophila 1 ~ 800c 2  108 Drosophila melanogaster 120-240 590-900 2  108 Physarum polycephalum 80-280 ~ 1,050 5  108 Euglena gracilis 800-1,000 ~ 740 2  109 Human ~ 300 ~ 1,300 3  109 Rattus norvegicus 150-170 ~ 6,500 3  109 Xenopus laevis 500-760 6,500-7,800 8  109 __________________________________________________________________________

  48. Correlation between number of rRNA genes and genome size: an exception Numbers of rRNA and tRNA genes per haploid genome in various organisms __________________________________________________________________________ Genome Source Number of Approximate rRNA sets genome size (bp) __________________________________________________________________________ Human mitochondrion 1 2  104 Nicotiana tabacum chloroplast 2 2  105 Escherichia coli 7 4  106 Neurospora crassa ~ 100 2  107 Saccharomyces cerevisiae ~ 140 5  107 Caenorhabditis elegans ~ 55 8  107 Tetrahymena thermophila 1 2  108 Drosophila melanogaster 120-240 2  108 Physarum polycephalum 80-280 5  108 Euglena gracilis 800-1,000 2  109 Human ~ 300 3  109 Rattus norvegicus 150-170 3  109 Xenopus laevis 500-760 8  109 __________________________________________________________________________ The general pattern: bigger genomes  more genes to transcribed  more rRNA needed.

  49. 4: Genome evolution break

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