Genome Projects Maps Human Genome Mapping Human Genome Sequencing Landmarks in Sequencing Comparative Genomics The Tree and Our Place on It

Genome Projects: Maps Cytogenetic maps Restriction maps Low resolution (each band = several Mb) Chromosome banding Restriction maps Rare-cutting restriction enzymes Resolution - Several hundred kb Clone contig maps Overlapping YAC/cosmid clones Resolution – 10s of kb to several hundred

Genome Projects: Maps STS maps EST maps DNA sequence Sequence tagged site PCR of known sequence to identify location Resolution – 1 – 10s of kb EST maps Sequence cDNAs and locate on other physical maps Resolution ~90 kb DNA sequence Resolution – 1 bp

Genome Projects: Maps Progress in human gene mapping Slow when compared to Drosophila and mouse Speed increased when non-coding markers began being used in conjunction with familial patterns of linkage

Genome Projects: Sequencing Landmarks in genome sequencing

Genome Projects: Sequencing Progress in human genome sequencing Hierarchical vs. whole genome shotgun sequencing Precision and accuracy Repetitive DNA

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Genome Projects: Sequencing Progress in human genome sequencing Hierarchical vs whole genome shotgun sequencing 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

Genome Projects: Sequencing A typical high-throughput genomics facility

Genome Projects: Sequencing 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)

Genome Projects: Sequencing BLAST/BLAT and other tools BLAT – BLAST-like alignment tool A “genome browser” Genomes available: human, chimp, dog, cow, mouse, opossum, rat, chicken, Xenopus, Zebrafish, Tetraodon, Fugu, nematode (x3), Drosophila (x5), Apis (x3), Saccharomyces (yeast). Off-slide show example: chr6:121,387,504-121,720,836

Genome Projects: BLAT BLAT and other tools Off-slide show example: chr6:121,387,504-121,720,836 STS and RH markers Known genes (alternative splices of genes) Conservation with other genomes Known single nucleotide polymorphisms (SNPs) Repetitive DNA

Our Place in the Tree of Life: Genome Evolution Endosymbiont hypothesis

Our Place in the Tree of Life: Genome Evolution Gene duplication Acquisition of novel functions

Our Place in the Tree of Life: Genome Evolution Gene duplication Paralogous chromosome segments Ancient genome duplications Hox gene clusters

Our Place in the Tree of Life: Genome Evolution Concerted evolution – members of a sequence of families in a species evolve together so that they maintain high similarities among themselves while diverging from members of other species via gene conversion example primate photoreceptors

X-linked pigment genes Primate ancestor X-linked pigment gene Divergence NWM Gene duplication X-linked pigment gene OW primates X-linked pigment genes

If duplication occurred before human-OWM split, divergence between genes should be comparable (~7.1%) Baboon divergence of exons 4 and 5 b/t genes = 11% Human divergence of exons 4 and 5 b/t genes = 8% Baboon divergence of intron 4 b/t genes = 0.5% Human divergence of intron 4 b/t genes = 0.0%

Our place in the tree of life Exon duplication and shuffling Examples May be mediated by mobile elements

Our Place in the Tree of Life: Genome Evolution Mammalian phylogeny

Our Place in the Tree of Life: Genome Evolution Conservation between mouse and man Limited to subchromosomal regions Variable rates of amino acid sequence divergence

Our Place in the Tree of Life: Genome Evolution Human evolution Determining our place in the tree Cytogenetic analysis Gene content analysis Sequence analysis Intron and exon sequences, mtDNA sequences SINE analysis

Phylogenetic Inference Using SINEs

Phylogenetic Inference Using SINEs Species A Species B Species C Species D

Resolution of the Human:Chimp:Gorilla Trichotomy (H,C)G (H,G)C (C,G)H (H,C,G)

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 PNAS (2003) 22:12787-91

Our Place in the Tree of Life: Genome Evolution 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 Africa Asia Europe S. India

Europe Low diversity 0.1 0.1 0.6 Africa High diversity 0.3 0.3 0.9 Australia Low diversity

Our Place in the Tree of Life: Genome Evolution 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.