HUMAN GENOME PROJECT 101

Human Genome Program, U.S. Department of Energy, Genomics and Its Impact on Medicine and Society: A 2001 Primer, 2001

Human Genome Project Begun in 1990, the U.S. Human Genome Project is a 13-year effort coordinated by the U.S. Department of Energy and the National Institutes of Health. The project originally was planned to last 15 years, but effective resource and technological advances have accelerated the expected completion date to HGP goals are to: ■ identify all the approximately 35,000* genes in human DNA, ■ determine the sequences of the 3 billion chemical base pairs that make up human DNA, ■ store this information in databases, ■ improve tools for data analysis, ■ transfer related technologies to the private sector, and ■ address the ethical, legal, and social issues (ELSI) that may arise from the project.

Human Genome Data Derived from the Human Genome Project sequence freeze date in anticipation of data release: 22 July 2000 Release of First Draft Sequence of Human Genome : Nature 409 (6822), 15 February 2001 Science 291 (5507), 16 February 2001 Release of “Complete” Draft Sequence of Human Genome: April 2003

GENE Intragenic region exons introns interspersed repeats tandem repeats Fine Structure of Human Genomic DNA ACGTTGTGTCGCTGATTAGCTAGACCAAGATAGTTCG CTATAGGCTATAGCGATATAACCCAGGGGGGATATAT TAGGAGGAGAGATATAGGATAGATTACATGTGATATA TAGGAGAGAGAATATATAAGAGAGAGAGAGATTTTTT CTCCTGGTAAAAAGCTCGCTTAGGATTGCGCTAGATG

3.2 billion nucleotides The Human Genome How many genes?

>100,000 < 40,000

all But think of all our traits, Jim-bo! Ours?! Are you of my species?

Get lost, punk! Ouch!

The Human Genome ACGTTGTGTCGCTGATTAGCTAGACCAAGATAG TTCGCTATAGGCTATAGCGATATAACCCAGGGG GGATACGCWHENISAGENEAGENETATTAGGAG GAGAGATATAGGATAGATTACATGTGATATATA GGAGAGAGAATATATAAGAGAGAGAGAGATTTT TTCTCCTGGTAAAAAGCTCGCTTAGGATTGCGC Comparative Genomics (Alignment) Gene Prediction Experimental Discovery (Genetics)

Alignment

CTCGCTGACTCAATCGGATTATGCTAGTCG GCCCCCCCCCCCCTGAGTCAGGGGGGCTCGCTGCTGTGCTG TGACTCAATCGGATTATGCTAGTCG ATAGCCTAATAGCTGACTCAATCGGATTATGCTAGTCG ATTTTTTTGACTCAATCGGATTA CGGGGTGACTCAATCGGA AAAAATATATTGACTCAATCGGATTATGCTAGTCG GTCGTAGCTTGACTCAATCGGATTATGCTAGTCG TCATATGACTCAATCGGATTATGCTAGTCG

CTCGCTGACTCAATCGGATTATGCTAGTCG GCCCCCCCCCCCCTGAGTCAGGGGGGCTCGCTGCTGTGCTG TGACTCAATCGGATTATGCTAGTCG ATAGCCTAATAGCTGACTCAATCGGATTATGCTAGTCG ATTTTTTTGACTCAATCGGATTA CGGGGTGACTCAATCGGA AAAAATATATTGACTCAATCGGATTATGCTAGTCG GTCGTAGCTTGACGGAATCGGATTATGCTAGTCG TCATATGACTCAATCGGATTATGCTAGTCG

CTCGCTGACTCAATCGGATTATGCTAGTCG GCCCCCCCCCCCCTGAGTCAGGGGGGCTCGCTGCTGTGCTG TGACTCAATCGGATTATGCTAGTCG ATAGCCTAATAGCTGACTCAATCGGATTATGCTAGTCG ATTTTTTTGACTCAATCGGATTA CGGGGTGACTCAATCGGA AAAAATATATTGACTCAATCGGATTATGCTAGTCG GTCGTAGCTTGACGGAATCGGATTATGCTAGTCG TCATATGACTCAATCGGATTATGCTAGTCG

Gene Prediction

TTCGCTATAGGCTATAGCGATATAACCCAGGGGGGATACGCTATTAGGAG GAGAGAATATAAAGGATAGATTACATGTGATATATGGAGAGAGAATATAT AAGAGAGAGAGAGATTTTTTCTCCTGGTAAAAAGCTCGCTTATGGATTGC GCTTCGCTATAGGCTATAGCGATATAACCCAGGGGGGATACGCTATTAGG AGGAGAGATATAGGATAGATTACATGTGATATATAGGAGAGAGAATATAT AAGAGAGAGAGAGATTTTTTCTCCTGGTAAAAAGCTCGCTTAGGATTGCG CTTCGCTATAGGCTATGCGATATAACCCAGGGGGGATACGCTATTAGGAG GAGAGATATAGGATAGATTACATGTGATATATAGGAGAGAGAATATATAA GAGAGAGAGAGATTTTTTCTCCTGGTAAAAAGCTCGCTTAGGATTGCGCT TCGCTATAGGCTATAGCGATATGACCCAGGGGGGATACGCTATTAGGAGG AGAGATATAGGATAGATTACATGTGATATATAGGAGAGAGAATATATAAG AGAGAGAGAGATTTTTTCTCCTGGTAAAAAGCTCGCTTAGGATTGCGCTT CGCTATAGGCTATAGCGATATAACCCAGGGGGGATATGATATTAGGAGGA GAGATATAGGATAGATTACATGTGATATATAGGAGAGAGAAATAATATAA GAGAGAGAGATTTTTTCTCCTGGTAAAAAGCTCGCTTAGGATTGCGC

GENE Intragenic region exonsintrons interspersed repeats tandem repeats Gene Prediction Algorithms based on consensus nucleotide sequences of tata boxes and start codons stop codons splice junctions CpG islands

Comparative Gross Results from Model Genome Projects

Humans have about 35,000 genes! You were right. So what’s new!

Human Genes

Surprising Findings = !! !! Only 35,000 genes most genes in euchromatin GC/AT patchiness !! Gene density higher & intron size smaller in GC-rich patches !! 1.4% translated, 28% transcribed !! Origins of genes

Some Origins of Human Genes Most from distant evolutionary past (basic metabolism, transcription, translation,repli- cation fixed since appearance of bacteria and yeast) Only 94/1278 families vertebrate-specific 740 are nonprotein-encoding RNA genes many derive from partial genomes of viruses and virus-like elements—genomic fossils some acquired directly from bacteria (rather than by evolution from bacteria)

Genomic Fossils

Genomic Fossils (also known as Molecular Fossils) interspersed repeats generated by integration of transposable elements or retrotransposable RNAs active contemporary modifier of some vertebrate genomes (mouse) formerly active modifier of human genome some as prevalent as 1.5 million copies

Alu Elements Type of Short Interspersed Nuclear Element (SINE) transcribed by RNA polymerase III 3’ oligo dA-rich tail found only in primates 1,500,000 copies derived from 7SL RNA gene dimer-like structure most retroposition occurred 40 mya

Reverse Transcription Essential for Retroposition and Proliferation of Retroelements Converts primed RNAs into cDNAs catalyzed by RNA-dependent DNA pol »(reverse transcriptase) pol encoded by retroviruses and active LINEs Retroviral genomic RNA Alu RNA LINE RNA

Alu Subfamily Structure (millions of years) Oldest [J] Intermediate [S] Youngest [Y] JoJb (65) S (50) Sq Sp Sx Sc Sg Y (25) Yb8 Ya5Ya8 450,000 copies 50,000 copies Alu Elements as Genomic Fossils

Alu Subfamily Structure PS [J]: Primate-Specific. Abundant in all primates mya: Early Prosimian (strepsirhini) Lorise or galago

AS [S]: Anthropoid-Specific (haplorhini) mya One mutation difference than PS. Alu Subfamily Structure

CS[S]: Catarrhine-specific. Nine mutations arising mya: Platyrrhines (FN) (Marmoset) Catarrhine (DFN) (Macaque) macaque Alu Subfamily Structure

HS [Y]: Human-specific. Five or more additional mya: Almost exclusively Hominids Alu Subfamily Structure

Master Gene Model of Retroposition P. Deininger, M. Batzer, Trends in Genetics 8:307, Master mutation 1. Amplification TIME (m.y.) COPY NUMBER 3’5’ 3’ 5’

Alu Subfamily Structure (millions of years) Oldest [J] Intermediate [S] Youngest [Y] JoJb (65) S (50) Sq Sp Sx Sc Sg Y (25) Yb8 Ya5Ya8 450,000 copies 50,000 copies Alus as Genomic Fossils

What’s New About Old Fossils? In the Human Genome Comprise nearly 50% of genome 50% more Alu elements than were predicted by molecular biology scarce in highly-regulated regions (detrimental?) enriched in GC regions (beneficial?) little activity, but little scouring occur frequently within exons contribute to formation of genes encoding novel proteins

3.2 billion bases 28% transcribed <1.4% encodes protein 50% repeats Only ~35,000 genes! FEATURES The Human Genome not many modern protein families

Humans have about 35,000 genes! Well, then… How can you explain human complexity?