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Welcome to Part 3 of Bio 219. Lecturer – David Ray Contact info: Office hours – 1:00-2:00 pm MTW Office location – LSB 5102 Office phone – 293-5102 ext 31454 E-mail – [email protected] Lectures are available online at http://www.as.wvu.edu/~dray go to ‘Teaching’ link.

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Welcome to part 3 of bio 219

Welcome to Part 3 of Bio 219

Lecturer – David Ray

Contact info:

Office hours – 1:00-2:00 pm MTW

Office location – LSB 5102

Office phone – 293-5102 ext 31454

E-mail – [email protected]

Lectures are available online at

http://www.as.wvu.edu/~dray

go to ‘Teaching’ link


How genes and genomes evolve

How Genes and Genomes Evolve


Variation

Variation

  • There is obviously variation among and within taxa.

  • How does the variation arise in genomes?

  • Are there patterns to the variation?

  • How is the variation propagated?

  • What questions can be addressed using the variation?

  • What patterns exist in humans with regard to genomic variability?


Generating genetic variation

Generating Genetic Variation

  • Somatic vs. germ line cells

    • Somatic cells – “body” cells, no long term descendants, live only to help germ cells perform their function.

    • Germ cells – reproductive cells, give rise to descendants in the next generation of organisms.


Generating genetic variation1

Generating Genetic Variation

  • Somatic vs. germ line mutations

    • Somatic mutations – occur in somatic cells and will only effect those cells and their progeny, cannot not be passed on to subsequent generations of organisms.

    • Germ mutations – can be passed on to subsequent generations.


Generating genetic variation2

Generating Genetic Variation

  • Five types of change contribute to evolution.

    • Mutation within a gene

    • Gene duplication

    • Gene deletion

    • Exon shuffling

    • Horizontal transfer – rare in Eukaryotes


Generating genetic variation3

Generating Genetic Variation

  • Most changes to a genome are caused by mistakes in the normal process of copying and maintaining genomic DNA.


Generating genetic variation4

Generating Genetic Variation

  • Mutations within genes

    • Point mutations – errors in replication at individual nucleotide sites occur at a rate of about 10-10 in the human genome.

    • Most point mutations have no effect on the function of the genome – are selectively neutral.


Generating genetic variation5

Generating Genetic Variation

  • DNA duplications

    • Slipped strand mispairing

    • Unequal crossover during recombination


Generating genetic variation6

Generating Genetic Variation

  • Gene duplication allows for the acquisition of new functional genes in the genome


Generating genetic variation7

Generating Genetic Variation

  • Gene Duplication: the globin family

    • A classic example of gene duplication and evolution

    • Globin molecules are involved in carrying oxygen in multicellular organisms

    • Ancestral globin gene (present in primitive animals) was duplicated ~500 mya.

    • Mutations accumulated in both genes to differentiate them - α and β present in all higher vertebrates

    • Further gene duplications produced alternative forms in mammals and in primates


Welcome to part 3 of bio 219

Primates

Mammals


Generating genetic variation8

Generating Genetic Variation

  • Gene Duplication

    • Almost every gene in the vertebrate genome exists in multiple copies

    • Gene duplication allows for new functions to arise without having to start from scratch

    • Studies suggest the early in vertebrate evolution the entire genome was duplicated at least twice


Generating genetic variation9

Generating Genetic Variation

  • Exon Duplication

    • Duplications are not limited to entire genes

    • Proteins are often collections of distinct amino acid domains that are encoded by individual exons in a gene

    • The separation of exons by introns facilitates the duplication of exons and individual gene evolution


Generating genetic variation10

Generating Genetic Variation

  • Exon Shuffling

    • The exons of genes can sometimes be thought of as individual useful units that can be mixed and matched through exon shuffling to generate new, useful combinations


Review from last week

Review from last week

  • Overall theme – There are lots of ways to create genetic variation. Genetic variation is the basis of evolutionary change but the variation must be introduced into the germ line to contribute to evolutionary change.

  • Two cell lines in multicellular organisms

    • Somatic – short term genetic repository

    • Germ line – long term genetic repository

  • Variation that occurs in the germ line are the only ones that can contribute to evolutionary change

  • Genetic variation can be accumulated through various events

    • Mutations in genes – point mutations

    • DNA duplications – microsatellites (small), unequal crossover (large)

    • Gene and exon duplications are the major method for generating new gene functions

    • Exon shuffling can produce new gene functions by creating new combinations of functional exons/protein domains


Generating genetic variation11

Generating Genetic Variation

  • Mobile elements contribute to genome evolution in several ways

    • Exon shuffling

    • Insertion mutagenesis

    • Homologous and non-homologous recombination


Generating genetic variation12

Generating Genetic Variation

  • What are mobile elements and how do they work?

    • Fragments of DNA that can copy itself and insert those copies back into the genome

    • Found in most eukaryotic genomes

    • Humans – Alu (SINE); Ta, PreTa (LINEs); SVA; plus several families that are no longer active


Welcome to part 3 of bio 219

Pol III transcription

Generating Genetic Variation:

Normal SINE mobilization

Reverse transcription and insertion

1. Usually a single ‘master’ copy

2. Pol III transcription to an RNA intermediate

3. Target primed reverse transcription (TPRT) – enzymatic machinery provided by LINEs


Generating genetic variation13

Generating Genetic Variation

  • Mobile elements contribute to genome evolution in several ways

    • Exon shuffling


Welcome to part 3 of bio 219

SINE

exon 2

Generating Genetic Variation:

Exon shuffling via

SINE mobilization

exon 1

SINE

exon 2

intron

DNA copy of transcript

SINE transcription can extend past the normal stop signal

Reverse transcription creates DNA copies of both the SINE and exon 2

Reinsertion occurs elsewhere in the genome


Generating genetic variation14

Generating Genetic Variation

  • Mobile elements contribute to genome evolution in several ways

    • Exon shuffling

    • Insertion mutagenesis

      • The insertion of mobile elements can disrupt gene structure and function


Welcome to part 3 of bio 219

Generating Genetic Variation


Generating genetic variation15

Generating Genetic Variation

  • Gene expression alteration via a P-element mobilization in Drosophila


Generating genetic variation16

Generating Genetic Variation

  • Mobile elements contribute to genome evolution in several ways

    • Exon shuffling

    • Insertion mutagenesis

      • The insertion of mobile elements can disrupt gene structure and function

    • Homologous and non homologous recombination

      • 10,000 – 1,000,000 + nearly identical DNA fragments scattered throughout the genome


Generating genetic variation17

Generating Genetic Variation

Unequal crossover due to

non-homologous recombination


Generating genetic variation18

Generating Genetic Variation

  • Gene transfer can move genes between entire genomes

    • Horizontal gene transfer

    • Main problem with the development of drug resistant strains of bacteria


Welcome to part 3 of bio 219

Generating Genetic Variation

  • Bacterial conjugation


Reconstructing life s tree

Reconstructing Life’s Tree

  • Evolutionary theory predicts that organisms that are derived from a common ancestor will share genetic signatures

  • Organisms that shared an ancestor more recently will be more similar than those that shared a more distant common ancestor

  • Similarity can include sequence composition, genome organization, presence/absence of mobile elements, presence/absence of gene families, etc.


09 15 phylogen trees jpg

09_15_Phylogen.trees.jpg


09 16 ancestral gene jpg

09_16_Ancestral.gene.jpg


09 22 genetic info jpg

09_22_genetic.info.jpg


09 17 human chimp jpg

09_17_Human_chimp.jpg

Chromosome 1


Review from last time

Review from last time

  • Overall themes: Genetic variation can be introduced due to the activities and presence of mobile elements (MEs); Genetic information can be introduced into organisms through horizontal transfer.

  • MEs are fragments of DNA that can make copies of themselves and insert those copies back into the genome

    • MEs can lead to variation through exon shuffling, insertion mutagenisis, and recombination

    • Many human diseases are the result of MEs

  • Horizontal transfer can introduce genetic variation into bacteria via the process of conjugation

  • Introduction of concepts for discussion of “Reconstructing life’s tree”

    • All sorts of variation provide information on the relationships among organisms

    • Homology – derived from the same ancestral source

    • Phylogeny – a reconstruction of relationships based on observations


Reconstructing life s tree1

Reconstructing Life’s Tree

  • Basic terms

    • Homologous – derived from a common ancestral source

    • Phylogeny – a reconstruction of relationships based on observed patterns


Reconstructing life s tree2

Reconstructing Life’s Tree

  • Homologous genes can be recognized over large amounts of evolutionary time


Reconstructing life s tree3

Reconstructing Life’s Tree

  • Homologous genes can be recognized over large amounts of evolutionary time

  • Why?

    • Selectively advantageous genes and sequences tend to be conserved (preserved)

    • Selectively disadvantageous genes and sequences are tend not to be passed on to offspring


Reconstructing life s tree4

Reconstructing Life’s Tree

  • Most DNA of most genomes is non-coding

    • Changes to much of this DNA are selectively neutral – cause no harm or good to the genome

    • Different portions of the genome will therefore diverge at different rates depending on their function

      The neutral regions tend to change in a clock-like fashion

    • We can estimate divergence times for certain groups


09 19 human mouse1 jpg

09_19_human_mouse1.jpg


Reconstructing life s tree5

Reconstructing Life’s Tree

  • Most DNA of most genomes is non-coding

    • Changes to much of this DNA are selectively neutral – cause no harm or good to the genome

    • Different portions of the genome will therefore diverge at different rates depending on their function

  • The neutral regions tend to change in a clock-like fashion

    • We can estimate divergence times for certain groups


Reconstructing life s tree6

Reconstructing Life’s Tree

  • The accumulation of changes can be quantified by several logical methods

    • Parsimony – the best hypothesis is the one requiring the fewest steps (i.e. Occam’s razor)

    • Distance – count the number of differences between things, the ones with the fewest numbers of differences are most closely related

    • Sequence based models – take into account what we know about the ways sequences change over time


Welcome to part 3 of bio 219

Reconstructing Life’s Tree: An example using distance

  • These slides and the sequence files used to produce them are available as a supplement on the class website:

  • DNA sequence from six taxa


Welcome to part 3 of bio 219

Sumatran orang

Bornean orang

gorilla

bonobo chimp

common chimp

human


Reconstructing life s tree an example using parsimony

ATGGCT

ATGGCT

ATGGCT

ATGGCT

CAGGCT

CAGGCT

CAGGCT

CAGGCT

AAGACG

AAGACG

AAGACG

AAGACG

CAGGCT

CAGGCT

CAGGCT

CAGGCT

AAGACT

AAGACT

AAGACT

AAGACT

A-C

T-G

G-A

G-A

A-C

T-A

Reconstructing Life’s Tree: An example using parsimony

6 steps


Reconstructing life s tree an example using parsimony1

T-G

G-A

A-C

G-A

T-A

Reconstructing Life’s Tree: An example using parsimony

ATGGCT

CAGGCT

AAGACG

AAGACT

CAGGCT

5 steps


Welcome to part 3 of bio 219

T-G

A-C

G-A

T-A

Reconstructing Life’s Tree: An example using parsimony

ATGGCT

AAGACT

AAGACG

CAGGCT

CAGGCT

4 steps


Reconstructing life s tree7

Reconstructing Life’s Tree

  • The accumulation of changes can be quantified by several logical methods

  • The accumulation of mobile elements provides a nearly perfect record of evolutionary relationships


Phylogenetic inference using sines

Phylogenetic Inference Using SINEs


Phylogenetic inference using sines1

Phylogenetic Inference Using SINEs

Species A

Species B

Species C

Species D


Resolution of the human chimp gorilla trichotomy

Resolution of the Human:Chimp:Gorilla Trichotomy

  • (H,C)G

  • (H,G)C

  • (C,G)H

  • (H,C,G)


Welcome to part 3 of bio 219

Phylogenetic Analysis

  • PCR of 133 Alu loci

    • 117 Ye5

    • 13 Yc1

    • 1 Yi6

    • 1 Yd3

    • 1 undefined subfamily

PNAS (2003) 22:12787-91


Alu elements and hominid phylogeny

Alu Elements and Hominid Phylogeny

PNAS (2003) 22:12787-91


Review from last time1

Review from last time

  • The variation that is present in genomes allows us to make determinations about the relationships among living things

  • Different parts of the genome accumulate variation at different rates depending on their function (or lack thereof)

  • The presence of different rates allows for different questions to be addressed depending on the level of divergence

  • Several methods are available to analyze variation for phylogenetic signal

    • Parsimony, distance, sequence based models

  • Patterns of mobile element insertion can be used to infer relationships among taxa


Reconstructing life s tree8

Reconstructing Life’s Tree

  • Much of the “junk” DNA is dispensible

    • The Fugu (Takifugu rubripes) genome is almost completely devoid of unnecessary sequences

    • Exon number and organization is similar to mammals

    • Compared to other vertebrates

      • Intron size (not number) is reduced

      • Intergenic regions are reduced in size

      • No mobile elements


09 21 fugu introns jpg

09_21_Fugu.introns.jpg


Reconstructing life s tree9

Reconstructing Life’s Tree

  • Using all of the available information, we can reconstruct relationships between organisms back to the earliest forms of life


Our own genome

Our Own Genome

  • The human genome is large and complex

    • 23 pairs of chromosomes

    • ~3.2 x 109 (3.2 billion) nucleotide pairs

    • Human genome composition


09 26 noncoding jpg

09_26_noncoding.jpg


09 25 chromosome22 jpg

09_25_Chromosome22.jpg


Our own genome1

Our Own Genome

  • Nuclear genome

    • 3300 Mb

    • 23 (XX) or 24 (XY) linear chromosomes

    • 30-35,000 genes

    • 1 gene/40kb

    • Introns

    • 3% coding

    • Repetitive DNA sequences (45%)


Our own genome2

Our Own Genome

  • The human genome is large and complex

    • 23 pairs of chromosomes

    • ~3.2 x 109 (3.2 billion) nucleotide pairs

    • Human genome composition

    • The human genome project was one of the largest undertakings in human history


Our own genome3

Our Own Genome

  • Progress in human genome sequencing

    • Hierarchical vs. whole genome shotgun (WGS) sequencing

    • Repetitive DNA represents a significant problem for WGS sequencing in particular


10 09 shotgun sequenc jpg

10_09_Shotgun.sequenc.jpg


08 03 jpg

08_03.jpg


Our own genome4

Our Own Genome

  • Progress in human genome sequencing

    • Hierarchical vs. whole genome shotgun (WGS) sequencing

    • Repetitive DNA represents a significant problem for WGS sequencing in particular


10 10 repetit sequence jpg

10_10_Repetit.sequence.jpg


Our own genome5

Our Own Genome

  • Progress in human genome sequencing

    • Hierarchical vs whole genome shotgun sequencing

    • Repetitive DNA represents a significant problem for WGS sequencing in particular

    • Landmark papers in Nature and Science (2001)

      • Venter et al Science 16 February 2001; 291: 1304-1351

      • Lander et al Nature 409 (6822): 860-921


Our own genome6

Our Own Genome

  • A typical high-throughput genomics facility


Our own genome7

Our Own Genome

  • Exploring and exploiting the genome sequences

  • BLAST/BLAT and other tools

    • BLAST - Basic local alignment search tool

      • Input a sequence and find matches to human or other organisms

    • publication information

    • DNA and protein sequence (if applicable)


Our own genome8

Our Own Genome

  • Exploring and exploiting the genome sequences

  • BLAST/BLAT and other tools

    • BLAT – BLAST-like alignment tool

      • A “genome browser”

      • Genomes available :

        • human, chimp, rhesus monkey, dog, cow, mouse, opossum, rat, chicken, Xenopus, Zebrafish, Tetraodon, Fugu, nematode (x3), Drosophila (x10), Apis (x3), Saccharomyces (yeast), SARS

      • example: chr6:121,387,504-121,720,836


Our own genome9

Our Own Genome

  • BLAT can be used to make direct comparisons between our genome and others.

Query sequence - Callithrix

Human ortholog


Our own genome10

Our Own Genome

  • Comparisons with other genomes inform us about our own

    • Important genes and regulatory sequences can easily be identified if they are conserved between genomes


Our own genome11

Our Own Genome

  • Human variation

    • ~0.1% difference in nucleotide sequence between any two individual humans

    • Translates to about 3 million differences in the genome

    • Most of these differences are Single Nucleotide Polymorphisms (SNPs)

    • We can use these differences to investigate human variation, population structure and evolution


Our own genome12

Our Own Genome

  • Human evolution

    • Coalescence analyses (mtDNA and Y chromosome)

    • Mutiregional vs. Out of Africa

      • Predictions of the Multiregional Hypothesis

        • Equal diversity in human subpopulations

        • No obvious root to the human tree

      • Predictions of the Out of Africa Hypothesis

        • Higher diversity in African subpopulations

        • Root of the human tree in Africa


Population relationships based on 100 autosomal alu elements

Population Relationships Based on 100 Autosomal Alu Elements

Africa

Asia

Europe

S. India


Our own genome13

Our Own Genome

  • Human evolution

    • Higher diversity in African subpopulations

      • Insulin minisatellite Table 12.6 in text

      • 22 divergent lineages exist in the human population

      • All are found in Africa. Only 3 are found outside of Africa.


Our own genome14

Our Own Genome

  • Interpreting the information generated by the human genome project

    • The complexity of genome function makes interpretation difficult

    • Ex. What are the regulatory sequences?

    • Ex. Exons can be spliced together in different ways in different tissues


09 30 alt splice rna jpg

09_30_alt.splice.RNA.jpg


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