The Human Genome Project

Public: International Human Genome Sequencing Consortium (aka HUGO)

Private: Celera Genomics, Inc. (aka TIGR)

The HGP1st proposed in 1986

In addition to humans, the effort included E. coli, yeast, C. elegans, Drosophila, and mouse

Funded in 1988Estimated cost: $3 billion Final cost: $2.6 billionGot underway in 1990

1st genome sequenced in 1995 (TIGR)

Yeast sequenced in 1996

E. coli sequenced in 1997

C. elegans sequenced in 1998

Drosophila sequenced in 2000 (Celera)

The Human Sequence

The genome was sequenced about 4 times over

Contained errors and gaps

The finished sequence, released in April of 2003, was sequenced 8 times over, had 1 error in 10,000 bases and did not contain significant gaps

Gaps can exist:1) within unfinished sequence clones2) between sequenced BACs3) between mapped BACs

Human draft sequence released in Jan. 2001 (HUGO & Celera)

The “Typical” Human Gene

Size of exons 145 bp

# of exons 8.8

Size of introns 3,365 bp

Size of 3’ UTR 770 bp

Size of 5’ UTR 300 bp

Coding sequence size 1,340 bp

CDS 447 aa

Genomic extent 27 kb

The Number of Human Genes

0

20,000

40,000

60,000

80,000

100,000

120,000

140,000

Earlyestimates

Laterestimates

Draft sequence

Final sequence

# of Genes in Other Organisms

0

5000

10000

15000

20000

25000

M. g E. c S. c D. m C. e H. s A. t

Orthologs of Human Proteins

Where did the prokaryotic orthologs come from?

One possibility is horizontal transfer

41 genes may have been transferred in this way

For example: MAOs, monoamine oxidases

These enzymes deactivate neurotransmittersAnother possibility is the loss of these genes over time so that most eukaryotes lack them

Functional Categories of Proteins

Families of Transcription Factors

Some surprises from the HGP Not every gene has its own promoter Not every gene encodes a protein The number of genes in our genome

Promoters: a number of adjacent genes are transcribed simultaneously. These genes were shown to share a promoter, much like prokaryotes control gene expression.

Genes that do not encode proteins tRNA rRNA snRNAs (small nuclear RNAs) snoRNAs (small nucleolar RNAs) ncRNAs (non-coding RNAs)These are untranslated genes such as the

let-7 gene in C. elegans. It encodes a 21-base RNA that binds to another gene

How Can We Have So Few Genes? Combinatorial Control

Alternate Splicing

We are not just 1.5 times as complex as flies, even though we have about 1.5 times the number of genes.

If each gene has 2 states: on or off, then

there are 213,600 different combinations in Drosophila but 221,000 different combinations in humans.

Epigenetic Control