Download presentation
Presentation is loading. Please wait.
Published byIris Pierce Modified over 8 years ago
1
Evolutionary Genome Biology Gabor T. Marth, D.Sc. Department of Biology, Boston College marth@bc.edu
2
Lecture overview 1. Inter-species evolution and comparative genomics 2. Intra-species evolution, population genomics, and human origins
3
1. Inter-species evolution and comparative genomics Initial sequencing and comparative analysis of the mouse genome Mouse Genome Sequencing Consortium Nature 420, 520-562. 2002
4
Questions of Evolutionary Biology What are the taxological relationships between living organisms (which organisms are more or less closely related to each other)? How do genes evolve? How do genomes evolve? How do comparisons with other organisms help us understand our own genome?
5
Mechanisms of molecular evolution
6
DNA sequence evolution: mutations
7
Phylogenetic relationships (1) Higgs and Attwood, Bioinformatics and Molecular Evolution, Blackwell Publishing Multiple alignment of mammalian mitochondrial small subunit rRNA sequences
8
Phylogenetic relationships (2) Higgs and Attwood, Bioinformatics and Molecular Evolution, Blackwell Publishing Jukes-Cantor distance matrix for mammalian mitochondrial small subunit rRNA sequences
9
Phylogenetic relationships (3) Higgs and Attwood, Bioinformatics and Molecular Evolution, Blackwell Publishing Phylogenetic tree constructed from mammalian mitochondrial small subunit rRNA sequences
10
Gene structure evolution: duplications
11
Gene duplication – paralogs Lander et al. Initial sequencing and analysis of the human genome, Nature, 2001
12
Evolution of chromosome organization
13
Synteny Initial sequencing and comparative analysis of the mouse genome Mouse Genome Sequencing Consortium Nature 420, 520-562. 2002
14
Gene classes across organisms Lander et al. Initial sequencing and analysis of the human genome, Nature, 2001
15
Gene conservation across organisms Lander et al. Initial sequencing and analysis of the human genome, Nature, 2001
16
Comparative genomics helps gene annotations
17
2. Intra-species evolution, population genomics, and human origins
18
Questions about human evolution How do we discover / assess genetic variations? What is the level of diversity across humans? How can we model the ancestral and mutation processes? What do phylogenetic analyses of human mitochondrial sequences tell us about human origins and dispersal? Does mitochondrial DNA give us the full picture? What do we learn from model-fitting analysis of nuclear DNA? A single wave of out-of-Africa migration or multiple waves?
19
Human genetic diversity polymorphism density along chromosomes varies widely average polymorphism rate between a pair of human chromosomes: 1 SNP in 1,300 bp of sequence
20
What explains heterogeneity? G+C nucleotide content CpG di-nucleotide content recombination rate functional constraints 3’ UTR5.00 x 10 -4 5’ UTR4.95 x 10 -4 Exon, overall4.20 x 10 -4 Exon, coding3.77 x 10 -4 synonymous 366 / 653 non-synonymous287 / 653 Variance is so high that these quantities are poor predictors of nucleotide diversity in local regions hence random processes are likely to govern the basic shape of the genome variation landscape (random) genetic drift
21
The origin of genetic variations sequence variations are the result of mutation events TAAAAAT TAACAAT TAAAAAT TAACAAT TAAAAATTAACAAT TAAAAAT MRCA mutations are propagated down through generations and determine present-day variation patterns
22
Recombination messes up phylogenies acggttatgtaga accgttatgtaga acggttatgtaga accgttatgtaga because of recombination, DNA sequences may not have a unique common ancestor, hence phylogenetic analysis may not apply
23
What does mtDNA say about human origins? However, the mitochondrion is only a single locus (~16kb, short on the scale of the 3Gb human genome) Campbell and Heyer. Genomics, Proteomics, Bioinformatics. Cummings.
24
What does nuclear DNA say? Because of recombination, phylogenetic analysis is not feasible (there is not a unique tree that can explain the ancestry of DNA sequences) Instead, one uses statistical “genetic analysis” i.e. one examines the statistical properties of the possible ancestries that produced the nucleotide sequences observed in individuals
25
Polymorphism data 1. marker density (MD): distribution of number of SNPs in pairs of sequences “rare” “common” 2. allele frequency spectrum (AFS): distribution of SNPs according to allele frequency in a set of samples Clone 1 Clone 2# SNPs AL00675AL009828 AS81034AK430010 CB00341AL432342 SNPMinor alleleAllele count A/GA1 C/TT9 A/GG3
26
Population genetic models past present stationaryexpansioncollapse MD (simulation) AFS (direct form) history bottleneck
27
Data fitting: polymorphism density best model is a bottleneck shaped population size history present N 1 =6,000 T 1 =1,200 gen. N 2 =5,000 T 2 =400 gen. N 3 =11,000 Marth et al. PNAS 2003 our conclusions from the marker density data are confounded by the unknown ethnicity of the public genome sequence we looked at allele frequency data from ethnically defined samples
28
Data fitting: allele frequency present N1=20,000 T1=3,000 gen. N2=2,000 T2=400 gen. N3=10,000 model consensus: bottleneck bottleneck ~ 3,000 generations (or 100,000 years) ago
29
Data from other human populations European data African data bottleneck modest but uninterrupted expansion Marth et al. Genetics 2004
30
What nuclear DNA tells us Recent African OriginMultiregional our results
Similar presentations
© 2024 SlidePlayer.com Inc.
All rights reserved.