Genomics

1
Genomics

• An introduction

2
Aims of genomics I

• Establishing integrated databases being far
  from merely a storage
• Linking genomic and expressed gene sequences

cDNA
3
Aims of genomics II

• Describing every gene
• function/expression data/relationships/phenotype
• 3-d structure and features (introns/exons,
  domains, repeats)
• similarities to other genes
• Characterize sequence diversity in population

4
Genomics can be

• Structural
• where it is?
• Functional
• what it does?
• DNA microarrays
• Comparative
• finding important fragments

5
Mapping genomes

• Past
• Genetic mapsDistance between simple markers
  expressed in units of recombination
• Cytological mapsStained chromosomes, observable
  under microscope
• Present
• Physical mapsDistance between nucleotides
  expressed in bases
• Comparative mapCorresponding genes detection
  Regulatory sequence detection

6
Genome sizes
Organism DNA length Genes
Mycoplasma genitalium 0.5 Mb 470
Deinococcus radiodurans 3 Mb in 4-10 copies! 3 200
Escherichia coli 4.5 Mb 4 400
Saccharomyces cerevisiae 12 Mb 6 200
Caenorhabditis elegans 97 Mb 22 000
Drosophila melanogaster 120 Mb 18 000
Homo sapiens 3200 Mb 32 000
7
Genetic differences among humans

• Goals
• Genetic diseases
• Identifying criminals
• Methods
• Genetic markers (fingerprints) and DNA sequence.
  Repeats
• Microsatellites (repeats of 1-12 nucleotides)
• Minisatellites (gt 12)
• Other types of variation
• Genome rearrangements
• Single nucleotide mutations

8
Microsatellites and disease

• Huntingtons disease
• Huntingtin gene of unknown (!) function
• Repeats 6-35 normal 36-120 disease

• Friedrich ataxia disease
• GAA repeat in non-coding (intron) region
• Repeats 7-34 normal 35 up disease
• Repeat expansion reduces expression of frataxin
  gene

9
SNP - Single Nucleotide Polymorphism

• Definition
• SNP and phenotype
• Occurrence in genome
• Rarity of most SNPs (agrees with neutral
  molecular evolutionary theory)
• SNPs in human population
• High variance in genome!
• Detection of SNPs Hybridization

Inter-genic regions Coding regions
Every 1400bp Every 1430bp
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Sickle cell anemia
Sickle looks like this

• SNP on Beta Globin gene, which is recessive
• 2 faulty copies red blood cells change shape
  under stress - anemia
• 1 faulty copy red blood cells change shape under
  heavy stress but gives resistance to malaria
  parasite

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SNPs and haplotypes

• Passengers and their evolutionary vehicles

12
SNP - Phase inference

• In the data from sequencing the genome the origin
  of SNP is scrambled

Possibility 1
Possibility 2
...CTGACGGT...
...CTGACAGT...
chromosome
...CTTACAGT...
...CTTACGGT...
chromosome

• Which SNPs are on the same chromosome (are in
  phase)?

13
SNP phase inferenceDetermining the parent of
origin for each SNP

• In this case

GG
TA
Phase inference the reason why many SNPs
sequencing is done for child and two parents.
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Linkage Disequilibrium, introHow hard is it to
break a chromosome

• An allele/trait/SNP A and a are on the same
  position in genome (locus), thus on a single
  chromosome an individual can have either of them
  but not both
• fA - frequency of occurrences of trait A in
  population
• fa 1- fA
• fB, fb 1 - fB are frequency occurrences of B
  and b
• Probabilities of occurences of both traits on the
  same chromosomefABfAbfaBfab
• LD and genomic recombination

15
Linkage Disequilibrium, calculation

• When these alleles are not correlated we expect
  them to occur together by chance alone fAB fA
  fB fAb fA fb faB fa fB fab fa fb
• But if A and B are occurring together more often
  (disequilibrium state), we can write fAB fA fB
  D fAb fA fb - D faB fa fB - D fab fa
  fb D
• where D is called the measure of disequlibrium
• Of course from definitions above we have D fAB
  - fA fB

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How can we use it?

• Phase inference tells us how SNPs are organized
  on chromosome
• Linkage disequilibrium measures the correlation
  between SNPs

17
Back to SNPs
Daly et al (2001), Figure 1
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Haplotypes - vehicles for SNPs

• Daly et al (2001) were able to infer offspring
  haplotypes largely from parents. They say that
  it became evident that the region could be
  largely decomposed into discrete haplotype
  blocks, each with a striking lack of diversity
• The haplotype blocks
• Up to 100kb
• 5 or more SNPs For example, this block shows
  just two distinct haplotypes accounting for 95
  of the observed chromosomes

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Haplotypes on the genome fragment

1. Observed haplotypes with dotted lines wherever
   probability of switching to another line is gt 2
2. Percent of explanation by haplotypes
3. Contribution of specific haplotypes

20
Another genetic testDoes haplotypes exist?

• Each row represents an SNP
• Blue dot major
• yellow minor
• Each column represents a single chromosome
• The 147 SNPs are divided into 18 blocks defined
  by black lines.
• The expanded box on the right is an SNP block of
  26 SNPs over 19kb of genomic DNA. The 4 most
  common of 7 different haplotypes include 80 of
  the chromosomes, and can be distinguished with 2
  SNPs

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How much SNPs we can ignore?

• and still predict haplotypes with high accuracy?

22
Literature

• Gibson, Muse A Primer of Genome Science
• N Patil et al . Blocks of limited haplotype
  diversity revealed by high-resolution scanning of
  human chromosome 21 Science 294 20011719-1723.
• M J Daly et al . High-resolution haplotype
  structure in the human genome Nat. Genet. 29
  2001 229-232.