Chapter 8 Genome Evolution Jocelyn E Krebs Figure

Chapter 8 Genome Evolution Jocelyn E. Krebs

Figure 08. CO: A circular genome map showing shared regions between humans (outer ring) and (from inner ring outwards) chimpanzee, mouse, rat, dog, chicken, and zebrafish genomes. © Martin Krzywinski/Photo Researchers, Inc.

8. 1 Introduction Comparative genomics

8. 2 DNA Sequences Evolve by Mutation and a Sorting Mechanism • The probability of a mutation is influenced by the likelihood that the particular error will occur and the likelihood that it will be repaired (homologous and site-specific recombination). • Transversion and transition mutation • Transversion is less common and easily detected by repair system

• synonymous mutation – A change in DNA sequence in a coding region that does not alter the amino acid sequence of the polypeptide product. • silent muation • nonsynonymous mutation –A change in DNA sequence in a coding region that alters the amino acid sequence of the polypeptide product. • missense or nonsense mutation • Neutral mutation- no phenotype chance, noncoding region mutation

Genetic drift In small populations, the frequency of a mutation will change randomly and new mutations are likely to be eliminated by chance fixation –The process by which a new allele replaces the allele that was previously predominant in a population. Figure 08. 01 The fixation or loss of alleles by random genetic drift Data courtesy of Kent E. Holsinger, University of Connecticut [http: //darwin. eeb. uconn. edu]

• The frequency of a neutral mutation largely depends on genetic drift, the strength of which depends on the size of the population. • The frequency of a mutation that affects phenotype will be influenced by negative or positive selection. Data courtesy of Kent E. Holsinger, University of Connecticut [http: //darwin. eeb. uconn. edu]

8. 3 Selection Can Be Detected by Measuring Sequence Variation • The ratio of nonsynonymous to synonymous substitutions in the evolutionary history of a gene is a measure of positive or negative selection. • Ks/Ka< 1: negative selection common event • Ks/Ka>1 positive selection • Example 1) antigenic proteins of some pathogens 2) sexual selection; traits 3) MHC (2 -10)

• • Low heterozygosity of a gene may indicate recent selective events. genetic hitchhiking – The change in frequency of a genetic variant due to its linkage to a selected variant at another locus. Figure 08. 02: Nonsynonymous and synonymous variation in the Adh locus in Drosophila melanogaster (“polymorphic”) and between D. melanogaster, D. simulans, and D. yakuba (“fixed”). Adapted from J. H. Mc. Donald, J. H. and M. Kreitman, Nature 351 (1991): 652 -654.

• Comparing the rates of substitution among related species can indicate whether selection on the gene has occurred. Figure 08. 03: A higher number of nonsynonymous substitutions in lysozyme sequences in the cow/deer lineage as compared to the pig lineage. Adapted from N. H. Barton, et al. Evolution. Cold Spring Harbor Laboratory Press, 2007. Original figure appeared in J. H. Gillespie, The Causes of Molecular Evolution. Oxford University Press, 1991.

Figure 08. 04: Nucleotide diversity (pi) of the tb 1 region in domesticated maize is much lower than in wild teosinte, indicating strong selection on this locus in maize. Reproduced from R. M. Clark, et al. , Proc. Natl. Acad. Sci. USA 101 (2004): 700 -707. Copyright © 2004 National Academy of Sciences, U. S. A. Courtesy of John F. Doebley, University of Wisconsin, Madison

linkage disequilibrium – A nonrandom association between alleles at two different loci, often as a result of linkage. Figure 08. 05: The fraction of recombinants between an allele of G 6 PD and alleles at nearby loci on a human chromosome remains low. Adapted from E. T. Wang, et al. , Proc. Natl. Acad. Sci. USA 103 (2006): 135 -140.

8. 4 A Constant Rate of Sequence Divergence Is a Molecular Clock • The sequences of orthologous genes in different species vary at nonsynonymous sites (where mutations have caused amino acid substitutions) and synonymous sites (where mutation has not affected the amino acid sequence). • Synonymous substitutions accumulate ~10× faster than nonsynonymous substitutions. • Divergence • Codon bias-A higher usage of one codon in genes to encode amino acids for which there are several synonymous codons.

Molecular clock Figure 08. 06: The rate of evolution of three types of proteins over time. The approximately constant rate of evolution of each protein type is a molecular clock. Reproduced with kind permission from Springer Science+Business Media: J. Mol. Evol. , The structure of cytochrome and the rates of molecular evolution, vol. 1, 1971, pp. 26 -45, R. E. Dickerson, fig. 3. Courtesy of Richard Dickerson, University of California, Los Angeles.

Nonsynonymous substitution (AA change) is deleterious. Thus it is eliminated by natural selection Advantageous few mutation can be accumulated fixation Random genetic drift-Fixation Divergence Replacement site vs silent site Condon bias Comparison between d and chain; 10 differences in 146 residue divergence=6. 9% 31 base pair/441 bp 11 in 330 replacement (3. 7%) vs 20 in 111 silent (32%) Theoratically, 105 mutation in nonsynonymous region.

• The evolutionary divergence between two DNA sequences is measured by the corrected percent of positions at which the corresponding nucleotides differ. • Substitutions may accumulate at a more or less constant rate after genes separate, so that the divergence between any pair of globin sequences is proportional to the time since they shared common ancestry. Figure 08. 07: Divergence of DNA sequences depends on evolutionary separation. Each point on the graph represents a pairwise comparison.

0. 12%/million years- nonsynonymous divergence Duplication 0. 1%/million years (50% nonsynonymous divergence) 500 million years Figure 08. 08: All globin genes have evolved by a series of duplications, transpositions, and mutations from a single ancestral gene.

Figure 08. 09: This tree accounts for the separation of classes of globin genes.

Figure 08. 10: An ancestral consensus sequence for a family is calculated by taking the most common base at each position.

8. 5 The Rate of Neutral Substitution Can Be Measured from Divergence of Repeated Sequences • The rate of substitution per year at neutral sites is greater in the mouse genome than in the human genome, probably because of a higher mutation rate. 2. 2 X 10 -9 vs 4. 5 X 10 -9 Figure 08. 10: An ancestral consensus sequence for a family is calculated by taking the most common base at each position.

8. 6 How Did Interrupted Genes Evolve? • A major evolutionary question is whether genes originated with introns or whether they were originally uninterrupted. • “introns late” model – The hypothesis that the earliest genes did not contain introns, and that introns were subsequently added to some genes. • Interrupted genes that correspond either to proteins or to independently functioning nonprotein-encoding RNAs probably originated in an interrupted form (the “introns early” hypothesis).

exon shuffling – The hypothesis that genes have evolved by the recombination of various exons encoding functional protein domains. A special class of introns is mobile and can insert themselves into genes. Figure 08. 11: An exon surrounded by flanking sequences that is translocated into an intron may be spliced into the RNA product.

8. 7 Why Are Some Genomes So Large? Figure 08. 12: DNA content of the haploid genome increases with morphological complexity of lower eukaryotes, but varies extensively within some groups of higher eukaryotes. • There is no clear correlation between genome size and genetic complexity. • C-value – The total amount of DNA in the genome (per haploid set of chromosomes). • C-value paradox – The lack of relationship between the DNA content (C-value) of an organism and its coding potential.

8. 7 Why Are Some Genomes So Large? • There is an increase in the minimum genome size associated with organisms of increasing complexity. • There are wide variations in the genome sizes of organisms within many taxonomic groups. Figure 08. 13: The minimum genome size found in each taxon increases from prokaryotes to mammals.

8. 8 Morphological Complexity Evolves by Adding New Gene Functions Figure 08. 15: Human genes can be classified according to how widely their homologues are distributed in other species. • In general, comparisons of eukaryotes to prokaryotes, multicellular to unicellular eukaryotes, and vertebrate animals to invertebrate animals show a positive correlation between gene number and morphological complexity as additional genes are needed with generally increased complexity.

8. 8 Morphological Complexity Evolves by Adding New Gene Functions Figure 08. 16: Common eukaryotic proteins are concerned with essential cellular functions. Figure 08. 17: Increasing complexity in eukaryotes is accompanied by accumulation of new proteins for transmembrane and extracellular functions.

8. 9 Gene Duplication Contributes to Genome Evolution • Most of the genes that are unique to vertebrates are concerned with the immune or nervous systems. • Duplicated genes may diverge to generate different genes, or one copy may become an inactive pseudogene. Figure 08. 18: After a globin gene has been duplicated, differences may accumulate between the copies. The genes may acquire different functions or one of the copies may become inactive. Fate of duplicated genes 1. Working as intact genes; different time, different cell type 2. Inactivated pseudogene

8. 10 Globin Clusters Arise by Duplication and Divergence • All globin genes are descended by duplication and mutation from an ancestral gene that had three exons. • The ancestral gene gave rise to myoglobin, leghemoglobin, and α and globins. Figure 08. 19: Each of the alpha- • The α- and -globin genes separated in like and beta-like globin gene the period of early vertebrate families is organized into a single evolution, after which duplications cluster that includes functional genes and pseudogenes (psi). generated the individual clusters of separate α- and -like genes.

8. 10 Globin Clusters Arise by Duplication and Divergence • nonallelic genes – Two (or more) copies of the same gene that are present at different locations in the genome (contrasted with alleles, which are copies of the same gene derived from different parents and present at the same location on the homologous chromosomes). • Once a gene has been inactivated by mutation, it may accumulate further mutations and become a pseudogene ( ), which is homologous to the active gene(s) but has no functional role.

Figure 08. 20: Different hemoglobin genes are expressed during embryonic, fetal, and adult periods of human development.

Figure 08. 21: Clusters of -globin genes and pseudogenes are found in vertebrates.

8. 11 Pseudogenes Are Nonfunctional Gene Copies Figure 08. 22: Many changes have occurred in a -globin gene since it became a pseudogene. • Processed pseudogenes result from reverse transcription and integration of m. RNA transcripts. • Nonprocessed pseudogenes result from incomplete duplication or second-copy mutation of functional genes. • Some pseudogenes may gain functions different from those of their parent genes, such as regulation of gene expression, and take on different names.

Figure 08. 23: Most human RP pseudogenes are of recent origin; many are shared with the chimpanzee but absent from rodents. Adapted from S. Balasubramanian, et al. , Genome Biol. 20 (2009): R 2.

8. 12 Genome Duplication Has Played a Role in Plant and Vertebrate Evolution • Genome duplication occurs when polyploidization increases the chromosome number by a multiple of two. • autopolyploidy – Polyploidization resulting from mitotic or meiotic errors within a species. • allopolyploidy – Polyploidization resulting from hybridization between two different but reproductively compatible species.

8. 12 Genome Duplication Has Played a Role in Plant and Vertebrate Evolution • Genome duplication events can be obscured by the evolution and/or loss of duplicates as well as by chromosome rearrangements. • Genome duplication has been detected in the evolutionary history of many flowering plants and of vertebrate animals. • 2 R hypothesis – The hypothesis that the early vertebrate genome underwent two rounds of duplication. Figure 08. 24: Genomnic Duplication Adapted from G. Blanc and K. H. Wolfe, Plant Cell 16 (2004): 1667 -1678.

8. 13 What Is The Role of Transposable Elements in Genome Evolution? • Transposable elements tend to increase in copy number when introduced to a genome but are kept in check by negative selection and transposition regulation mechanisms.

8. 14 There May Be Biases in Mutation, Gene Conversion, and Codon Usage • Mutational bias may account for a high AT content in organismal genomes. • Gene conversion bias, which tends to increase GC content, may act in partial opposition the mutational bias. • Codon bias may be a result of adaptive mechanisms that favor particular sequences, and of gene conversion bias.

Figure 08. 24: Genomnic Duplication Adapted from G. Blanc and K. H. Wolfe, Plant Cell 16 (2004): 1667 -1678.