1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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