Genetics: From Genes to Genomes 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 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition

20 Evolution at the Molecular Level CHAPTER OUTLINE PART VI Beyond the Individual Gene and Genome CHAPTER Evolution at the Molecular Level CHAPTER OUTLINE 20.1 The Origin of Life on Earth 20.2 The Evolution of Genomes 20.3 The Organization of Genomes 20.4 A Comprehensive Example: Rapid Evolution in the Immune Response and in HIV Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Charles Darwin's theory of evolution "On the Origin of Species by Means of Natural Selection" Published in 1859, based on 5 years of collecting specimens from around the globe Three principles: Variation exists among individuals of a population Variant forms of traits can be inherited Some variant traits confer an increased chance of surviving and reproducing Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

The origin of life on earth Self-replicating molecules may have led to the complexity of cells The first step in life had to fulfill three requirements: Encode information by variation of letters in strings of a simple digital alphabet Fold in three dimensions to create molecules capable of self-replication and other functions Expand the population of successful molecules through selective self-replication Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

The RNA world 1980s, Thomas Cech discovered ribozymes - RNA that can catalyze chemical reactions RNA satisfies all three requirements of the first replicator: linear strings encode information, folds into a 3-dimensional molecular machine, reproduces itself Intrinsic disadvantages of RNA Relatively unstable Limited capability for 3-dimensional folding compared to proteins No record of intermediates between an RNA world and cell complexities Fig 20.1 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Evolution of living organisms 4.5 billion yrs ago − coalescence of planet earth 4.2 billion yrs ago − emergence of informational RNA 3.7 billion yrs ago − life began 3.5 billion yrs ago − oldest fossilized cells (see Fig 20.2) 1.4 billion yrs ago − emergence of eukaryotes Symbiotic incorporation of single-celled organisms into other single-celled organisms Complex compartmentalization of cell interior (nucleus) 1 billion yrs ago − ancestors of plants and animals diverged 0.57 billion yrs ago − explosive appearance of multicellular animals (metazoans) and plants Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Living organisms evolved into three kingdoms The length of the branches is proportional to the times of species divergence Fig 20.3 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

The Burgess shale of southeastern British Columbia One of the most amazing finds in paleontology! Enormous diversity in body plans – many are extinct but some still exist Punctuated evolution – short periods of explosive change All basic body plans of metazoans are represented Fig 20.4 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

The evolution of humans 35 million yrs ago − humans arose from a common ancestor to most contemporary primates 6 million yrs ago – divergence of humans and chimpanzees from a common ancestor Fig 20.5 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Similarities between chimps and humans Genomes are 99% similar Karyotypes are nearly the same (see Fig 12.11) No significant differences in gene function Differences between species may have been caused by only a few thousand isolated genetic changes Species-specific differences probably occurred because of alterations in regulatory sequences Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

DNA alterations form the basis of genomic evolution New mutations provide a continuous source of variation Replacement of individual nucleotides in coding regions: Synonymous – substitutions have no effect on encoded amino acid Nonsynonymous – substitutions cause change in amino acid or premature termination codon Order and types of transcription factor binding sites in gene promoters can be altered Mutations can be deleterious, neutral, or favorable Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Classification of mutations according to effect Neutral mutations are not affected by the agents of selection Survive or disappear from a population by genetic drift Synonymous mutations can produce minute advantage or disadvantage Availability of different tRNAs and tRNA-synthetases? Deletions and insertions almost certainly have an effect Mutations with only deleterious effects disappear because of negative selection Mutations with advantageous effects will increase in the population because of positive selection May become fixed in the population Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Gene regulatory networks may dominate developmental evolution Sea urchins and sea stars diverged ~ 500 million yrs ago But, they share some basic gene networks (Fig 20.6b) Fig 20.6a Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Gene regulatory networks in sea urchins and in sea stars Rewiring of a gene regulatory network can encode enormous phenotype change Fig 20.6b Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

An increase in genome size generally correlates with evolution of complexity Duplication and diversification of genomic regions Can occur at random throughout genome Sizes range from a few nucleotides to the entire genome Can occur through transposition or unequal crossing- over Either the original or copy of the gene can accumulate mutations Acquisition of repetitive sequences – can make up more than 50% of a genome Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Transposition may occur through excising and reinserting the DNA segment Fig 20.7a Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Transposition events that produce duplications Transposition through an RNA intermediate Transposition through a DNA intermediate Fig 20.7b Fig 20.7c Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Transposition through direct movement of a DNA sequence After transposition occurs in a germ cell, the new copy of the transposon may become fixed in the next generation Fig 20.8 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Duplications resulting from unequal crossing- over Also referred to as "illegitimate recombination" Mediated by sequence similarity between related sequences located close to each other After the initial duplication, subsequent rounds of unequal crossing over can occur readily Fig 20.9 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Duplicated genes can evolve into pseudogenes or evolve new functions Pseudogenes – nonfunctional genes that results from random mutations in a duplicated gene Loss of regulatory function, substitutions at critical amino acids, premature termination, frame-shift mutation, altered splicing patterns Accumulate mutations at a fast pace New functions can arise in a duplicated gene Random mutations provide selective advantage to the organism The new gene usually has a novel pattern of expression Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Evolutionary histories are diagrammed in phylogenetic trees Molecular clock – provides a good estimate of time of divergence because rate of evolution is constant across all lineages Phylogenetic tree illustrates relatedness of homologous gene or proteins Nodes are taxonomic units Branch lengths represent time that has elapsed Fig 20.10 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Four levels of gene duplication have fueled evolution of complex genomes At each level, diversification and selection can occur Exons duplicate or shuffle Entire genes duplicate to create multigene families Multigene families duplicate to produce gene superfamilies Entire genome duplicates to double the number of copies of every gene and gene families Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Duplications create multigene families and gene superfamilies Hierarchical generation of greater amounts of new information at each level Fig 20.11 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

The basic structure of a gene Fig 20.12 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Domains in antibody proteins Discrete exons can encode the structural and functional domains of a protein Duplication of exons, can create tandem functional domains Fig 20.13 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

The tissue plasminogen activator gene evolved from shuffling of three genes New proteins with different combinations of functions can be created by exon shuffling Fig 20.14 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Duplications of entire gene can create multigene families Multigene family – set of genes descended by duplication and diversification from one ancestral gene Fig 20.15 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Unequal crossing over can expand and contract gene numbers in multigene families Fig 20.16 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Intergenic gene conversion can increase variation in members of a multigene family Alternative outcome to unequal crossing-over Allows transfer of information from one gene to another Fig 20.17 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Increasing the number of alleles through gene conversion Major histocompatibility complex (MHC) of mice – a pseudogene family was the reservoir of genetic information to produce a dramatic increase in variation Fig 20.18 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Concerted evolution can lead to gene homogeneity Fig 20.19 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Evolution of gene superfamilies Gene superfamily – large set of related genes that is divisible into smaller families Genes in each family are more closely related to each other than to other members of the superfamily Repeated gene duplication events followed by divergence Globin gene superfamily – three branches in all vertebrates Two multigene families (β-like genes and α-like genes) and a single myoglobin gene Hox gene superfamily – four branches in mice, only one in Drosophila Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Evolution of the mouse globin superfamily Fig 20.20 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Evolution of the Hox gene superfamily of mouse and Drosophila Fig 20.21 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Repetitive “nonfunctional” DNA families constitute nearly one-half of the genome Many repetitive nonfunctional DNA families consist of retroviral elements that have integrated into the host Provirus can be active or inactive Long INterspersed Elements – LINE family "Selfish DNA", encodes reverse transcriptase Very old family, exists in many organisms May have been source material for retroviruses Short INterspersed Elements – SINE family (e.g. Alu element in humans) Does not encode reverse transcriptase Evolved from small cellular RNAs Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Creation of a LINE gene family Fig 20.22 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Creation of a SINE gene family SINEs depend on availability of reverse transcriptase encoded by other elements (LINEs or retroviruses) Fig 20.23 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

The potential selective advantage of selfish elements SINEs and LINEs have had profound impacts on whole- genome evolution Catalyze unequal homologous crossover events These duplication events can initiate formation of multigene families Some evolved regulatory functions – can act as enhancers or promoters Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Simple sequence repeats (SSRs) Tandem, nonfunctional repeats scattered throughout mammalian genomes Vary in size of repeating units (2 – 100s of nucleotides) Microsatellites, minisatellites, and macrosatellites Very useful molecular markers for genome analysis and genotyping (Chapter 11) Highly susceptible to unequal crossing-over and are highly polymorphic in size Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

Centromeres and telomeres contain many repeat sequences Centromeres – tandem arrays of noncoding sequences that interact with mitotic and meiotic spindle fibers e.g. Human alphoid DNA – 171 bp repeat that extends > 1 Mb on either side of centromere in each chromosome Each repeat is < 200 bp in length Increase efficiency and/or accuracy of chromosome segregation Telomeres – tandem arrays of noncoding sequences that are at ends of all mammalian chromosomes Arrays are 5 – 10 kb in length Each repeat is 6 bp in length Essential role in maintaining chromosome length Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

A comprehensive example: Rapid evolution in the immune response and in HIV Evolutionary battle at the molecular level between the AIDS virus and cells of the immune system After viral infection, virus-specific immune response ensues that can destroy the pathogen HIV has a high mutation rate and is able to diversity and amplify itself via selection Speed of viral evolution is faster than the immune response Effective triple-drug therapies act to reduce the rate of viral replication Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20

The immune response Differentiated B cells secrete antibodies that destroy or neutralize antigens Expanded numbers of memory T cells and B cells allow a rapid response to the 2nd encounter with an antigen Fig 20.24 Copyright © The McGraw-Hill Companies, Inc. Permission required to reproduce or display Hartwell et al., 4th edition, Chapter 20