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SUMMARY:Evidence of non-random mutation rates suggests  a risk management 
 strategy for bacterial evolution - Nicholas Luscombe (EBI)
DTSTART:20110307T160000Z
DTEND:20110307T170000Z
UID:TALK27565@talks.cam.ac.uk
CONTACT:Florian Markowetz
DESCRIPTION:Inigo Martincorena\, Aswin SN Seshasayee & Nicholas M Luscombe
 \n\nA fundamental principle in evolutionary theory is that mutations occur
 \nrandomly with respect to their value to an organism\; natural selection\
 nthen governs whether these mutations are fixed in a population. This\nvie
 w has been challenged by long-standing theoretical models\npredicting that
  selection could modulate the rate of mutation itself.\nIndeed\, at a glob
 al level\, experimental studies have shown that the\naverage mutation rate
  of a population can vary in response to\nenvironmental changes that deman
 d greater genetic diversity. However\,\nat a local level\, our understandi
 ng of how mutation rates vary between\ndifferent sites within a genome has
  been limited by technical\ndifficulties in measuring them. As a result\, 
 single nucleotide\nsubstitutions – arguably the major form of mutation 
 – are considered\nto occur randomly. Here\, we present a general computa
 tional method for\ncalculating mutation rates that overcomes previous limi
 tations by\ncombining comparative genomic and population genetic technique
 s. In\napplying the method to 34 E. coli genomes\, we provide the most\nre
 liable estimates to date of local mutation rates at a genome-wide\nlevel. 
 Remarkably\, rates vary by more than 20-fold across 2\,663 genes\,\nand mu
 tational hot and cold spots span ~10kb. Further\, they are not\nrandomly d
 istributed with regard to their fitness effect: for the\nfirst time\, we p
 rovide firm evidence that mutation rates correlate\nwith selection strengt
 h. Contrary to previous theoretical models\,\npoint mutation rates have be
 en evolutionarily optimised to minimise\nthe risk of deleterious mutations
  among functionally important and\nhighly expressed genes\, rather than pr
 omoting mutations in those under\nstrong positive selection. Current knowl
 edge of factors influencing\nmutation rates – including transcription-co
 upled repair – do not\nexplain these observations\, indicating that addi
 tional mechanisms must\nbe involved. The findings have important implicati
 ons for our\nunderstanding of evolution and the control of mutations\; mor
 eover\,\nthey raise new questions that are immediately relevant to pathoge
 n\nevolution and human diseases.\n \n \n	\n\n 
LOCATION:Cancer Research UK Cambridge Research Institute\, Room 215
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