Comparative Analysis of Recombination Hotspots in Humans and Chimpanzees

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Comparative Analysis of Recombination Hotspots in
Humans and Chimpanzees
Instructor Yao-Ting Huang
Bioinformatics Laboratory, Department of Computer
Science Information Engineering, National Chung
Cheng University.
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Recombination Hotspots

• Recombination (or cross over) are known to
  cluster in 1-2 kb short regions in the human
  genome called recombination hotspots.
• The recombination rates in these hotspots are at
  least 10 times higher than the background rate.
• Recombination hotspots are existed every 60-200
  kb.

Recombination hot spots
Haplotype blocks
Chromosome
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Recombination Patterns

• The various recombination rates in the human
  genome are speculated due to evolutionary force
  (Nature, 2006).
• Genes involved with DNA and RNA metabolism are
  often within regions of haplotype blocks.
• Genes involved immune responses and
  neurophysiological processes are often in regions
  of recombination hotspots.

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Methods for Measuring Recombination Rates

• Collection of large pedigrees
• Kong et al. A high-resolution recombination map
  of the human genome, Nature Genetics, 2002.
• Sperm typing
• Clark, et al. Combining sperm typing and linkage
  disequilibrium analyses reveals differences in
  selective pressures or recombination rates across
  human populations, Genetics, 2007.
• However, these approaches are not practical to
  detect hotspots in a genome-wide scale.

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Inference of Recombination

• Alternatively, recombination rates can be
  inferred by linkage disequilibrium (LD) using
  Single Nucleotide Polymorphisms (SNPs).
• We estimate the amount of recombination needed to
  produce the observed LD under a certain model.

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An Example of Phylogenetic Network Implying
Recombination
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Related Works of Inferring Recombination Hotspots
in Humans

• Hudson, R. R. and Kaplan, M. L. Statistical
  Properties of the number of Recombination Events
  in the history of a sample of DNA sequences.
  Genetics, 1985.
• Simon R. M. and Robert C. G. Bounds on the
  Minimum Number of Recombination Events in a
  Sample History. Genetics, 2002.
• Li and Stephenes, Modeling linkage disequilibrium
  and identifying recombination hotspots using
  single nucleotide polymorphisms, Genetics, 2003.
• Vineet and Vikas,The Number of Recombination
  Events in a Sample History Conflict Graph and
  Lower Bounds. IEEE Transaction on Computational
  Biology and Bioinformatics, 2004.
• Dana, et al. Evidence for substantial fine-scale
  variation in recombination rates across the human
  genome, Nature Genetics, 2004.

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Recombination Patterns Across Different Species

• A larger-scale study of recombination patterns
  between human and chimpanzee.
• Susan, et al. Fine-scale recombination patterns
  differ between chimpanzees and humans, Nature
  Genetics, 2005.
• A total of 14 Mb regions in human and chimpanzee
  are examined.

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Data Collection

• Data collection in Human
• 14 Mb of two regions on chromosome 21.
• 23 Africans, 24 Han Chinese, and 24 European
  Americans.
• 11,642 SNPs are genotyped with an average spacing
  of 1.2 kb.
• Data collection in Chimpanzee
• 14 Mb homologous regions (on chromosome 22).
• 8 central chimpanzees, whereas 5 are wild-born.
• 30,611 SNPs with an average spacing of 440 bp are
  discovered.

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Division into Windows

• The 14 Mb regions are divided into 70-kb windows,
  with a 20-kb overlap.
• SNPs are discarded if minor alleles frequencies
  are lt5 in human or singletons in chimp.
• SNPs with more than 75 missing data are
  discarded.
• Windows with ?20 SNPs are considered.

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Estimation of Recombination Rates

• Assume there exists only one hotspot in each
  window, PHASE 2.1.1 is used to obtain
• the background recombination rate,
• the location of hotspot, and
• the relative intensity of hotspot recombination
  rate (?).?1 no recombination variation
  ?gt10 potential recombination hotspot.
• Li and Stephenes, Modeling linkage disequilibrium
  and identifying recombination hotspots using
  single nucleotide polymorphisms, Genetics, 2003.

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Conserved Hotspots in Human and Chimp

• We want to know the distribution of recombination
  hotspots between humans and chimpanzees.

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Mapping Hotspots between Human and Chimpanzee

• Each chimpanzee SNP with surrounding 24 bases are
  BLAST-aligned to the human genome.
• Only SNPs with a unique perfect match are kept.
• Two chimpanzee SNPs flanked the edge of the
  hotspot are taken.
• The average distance between the location of
  these two SNPs on chimpanzee and human are
  computed.
• We add this average distance to the chimpanzee
  genome position to determine the location of the
  chimpanzee hotspot in humans.

Remapped hotspot in human
Human
Chimpanzee
Hotspot in chimp
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Conserved Hotspots in Human and Chimp

• Only 3 out of the 39 chimp hotspots (8) are
  overlapped with those in human.

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Simulation Validation

• Even if all hotspots in chimpanzee are presented
  in human, we may not detect them all as shared.
• For each hotspot in chimpanzee, they simulate a
  corresponding hotspot in human.
• The hotspot is uniformly distributed from 10 kb
  to 60 kb in a 70-kb window using the same
  recombination rate.
• In 100 simulations, average 72 of these
  simulated hotspots are detected as shared, well
  above the observed 8.
• We can reject the hypothesis that all hotspots in
  the chimpanzee are also present in the human (P lt
  0.01).

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Simulation Validation

• In each simulation we can compute the of
  hotspots detected as shared.
• 1 0.68
• 2 0.9
• 3 0.72
• 100 0.45
• These values will approximate to a normal
  distribution if we generate sufficient simulated
  data sets.

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The Normal Distribution

• A continuous random variable X is said to have a
  normal distribution, if its p.d.f. is as follows
• and is commonly denoted by

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Simulation Validation

• In each simulation we can compute the of
  hotspots detected as shared.
• 1 0.68
• 2 0.9
• 3 0.72
• 100 0.45
• We then compute the mean and variance of these
  data.
• Mean 0.72, variance 1.2

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Linear Transformation of the Normal Distribution

• We transform the observed value (8) into
  standard normal distribution.
• The expected value and variance of adistribution
  are µ and s2, respectively.
• is N(0,1), if Y is N(µ, s2).

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Simulation Validation

• Even if all hotspots in chimpanzee are presented
  in human, we may not detect them all as shared.
• For each hotspot in chimpanzee, they simulate a
  corresponding hotspot in human.
• The hotspot is uniformly distributed from 10 kb
  to 60 kb in a 70-kb window using the same
  recombination rate.
• In 100 simulations, average 72 of these
  simulated hotspots are detected as shared, well
  above the observed 8.
• We can reject the hypothesis that all hotspots in
  the chimpanzee are also present in the human (P lt
  0.01).

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Simulation Validation

• Could we reject the hypothesis that all hotspots
  are independently distributed in human and
  chimpanzee?
• They randomly distributed the human hotspots,
  preserve their length, and determine how many of
  chimp hotspots still overlapped with them.
• In 1000 simulations, average 13 of human
  hotspots are still overlapped with chimp
  hotspots.
• We can not reject this hypothesis (P 0.9,
  compared with observed 8).

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Conservation of Total Recombination Rates

• The total recombination rates (background rate
  plus the hotspot rate) may be still conserved in
  these two species.
• They measure the correlation of total
  recombination rates in 210 pairs of 50-kb
  windows.
• The result indicates that total recombination
  rates are poorly correlated in these two species.
• r20.216, P0.002.
• 100 simulated pairs of windows with same rate
  suggest that r2 should be 0.69, well above 0.216.

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Conservation of Background Recombination Rates

• They examined the correlation of the background
  recombination rates in those pairs of 50-kb
  windows.
• The result indicates that background
  recombination rates are also poorly correlated in
  these two species
• r20.276, Plt0.001.
• 100 simulated pairs of windows with same rate
  suggest that r2 should be 0.77.

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Concluding Remarks

• The recombination hotspots are not conserved in
  humans and chimpanzees.
• Overall recombination rates are only weakly
  conserved in humans and chimpanzees.