The Human Genome Project

1
The Human Genome Project

• Main reference Nature (2001) 409, 860-921
• http//www.abdn.ac.uk/gen155/lectures/hgpcore.ppt
  
• http//www.nature.com/ng/web_specials/
• Whole issue also available from Nature Genome
  Gateway
• www.nature.com/genomics/human/
• Describes the publicly funded project Celeras
  private HGP published in Science

2
Main points

• Basic genome statistics
• Genome browsers e.g. UCSC, Ensembl
• Genomic landscape
• Repeated DNA as a fossil record
• Number of genes
• Polymorphism
• Applications

3
The Strategy

• The genome sequence was a multinational
  collaboration involving 100s of scientists,
  millions of dollars, many countries
• The strategy was top-down using methods
  developed on small genomes (e.g. yeast)
• Figure 2 in the Nature paper

4
Genome statistics

• Total size 3290 Mb
• 212 Mb of heterochromatin
• Chromosomes range from 279 Mb (1) to 45 Mb (21)
  (fig 9, table 8 in paper)
• Total raw sequence 23,000 Mb
• Number of genes about 31,000
• About 30 of the genome is transcribed
• About 1.5 of the genome is protein coding

5
Repeat DNA fossils

• Genomes are full of repeated DNA sequences of
  various kinds (table 11/12)
• Each type of repeat has a single origin and has
  replicated many times within the genome,
  transposing to new sites and accumulating
  mutations
• By comparing copies of the repeat to see how much
  they have diverged, can get an idea of how old
  repeat is (fig 18)

6
Humans versus worms and flies

• Humans have only about twice as many genes as
  worms or flies (table 23)
• But human genes are subject to more alternative
  splicing (60 vs 22 average 3 different
  transcripts per gene)
• So humans probably have about 5 times as many
  proteins as worms or flies
• Complexity is not proportional to numbers of
  genes or proteins, but to the number of
  interactions they can have

7
Index of human genes and proteins

• 3 basic methods to predict genes from the genomic
  DNA
• Comparison with ESTs, mRNAs
• Homology with other known genes/proteins
• Purely computational methods based on Hidden
  Markov Models (HMMs)
• Started with predictions by Ensembl, combined
  with other information..

8
The Human Proteome

• Key database is InterPro, which combines
  information on all known protein domains
• Only 94 of the 1262 InterPro types (7) are
  vertebrate-specific - so most domains are older
  than common ancestor of all animals - new ones
  are not invented very often
• Many of these are concerned with defence/immunity
  and the nervous system
• Most novelty is generated by new protein
  architectures, combining old domains in new
  ways (fig 42/45)

9
Genome History

• Mouse and human diverged about 100Mya, so there
  is 200My of evolution between them
• Chromosome translocations are involved in the
  formation of new species
• By comparing locations in the genome of
  homologous genes, can define regions of synteny
  (fig 46)
• Breakage seems to occur randomly, but tends to be
  in gene-poor regions
• No convincing evidence for whole-genome
  duplications

10
Polymorphism

• More than a million SNPs (single nucleotide
  polymorphisms were found
• Average 1 SNP per 1.9kb or 15 SNPs per gene
• Combinations of closely linked SNP alleles form
  haplotypes
• Not all possible haplotypes are found in
  population - e.g about 4-5 per gene
  (theoretically could have 215 about 32000)
• HapMap the haplotype mapping project
• A paper (Trends in Genetics) on the subject of
  haplotype blocks

11
Applications in medicine

• Having the genome sequence, and databases of
  genes, makes it much easier to find disease genes
  by positional cloning (e.g. BRCA2 for breast
  cancer)
• Sequence reveals new drug targets e.g. a new
  type of serotonin receptor, predicted from
  sequence, shown to be a candidate for treating
  mood disorders and schizophrenia

12
Latest - the Y chromosome

• Nature paper