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Structural  variation  in  the  genome  of  Monozygotic  Twins

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                             Structural  variation  in  the  genome  of  Monozygotic  Twins  

Ravi  Chandra  Dasari  

The   cell   dedicates   a   lot   of   energy   for   maintaining   its   genomic   integrity,   but   no   system   is   perfect.   For   thousands  of  years  the  human  life  expectancy  was  relatively  stagnant.  The  genetic  stability  in  humans   was  not  tested  beyond  a  certain  age  limit.  But  in  the  past  century,  the  life  expectancy  has  increased  by   almost  20  years  in  many  developed  countries  due  to  the  leaps  in  modern  medicine.  Such  sudden  change   in  the  increase  in  human  lifespan  has  put  the  cells  under  considerable  strain  for  maintaining  its  genetic   integrity.   The   incapacity   to   deal   with   these   changes   is   thought   to   have   led   to   many   genetic   defects,   which  were  often  passed  on  through  generations.  These  genetic  instabilities  and  variations  have  led  to  a   growth  in  various  diseases  and  disorders  in  humans  in  recent  decades.  

Currently  “ageing”  is  one  of  the  least  understood  biological  phenomenons.  Many  studies  are  currently   underway  to  explain  the  genetic  and  epigenetic  mechanisms  underlying  the  ageing  process  in  humans.  It   is  popularly  believed  that  ageing  causes  an  accumulation  of  rearrangements  in  the  genome,  which  lead   to  irreparable  damage,  diseases  or  even  fatality.  It  has  also  been  recently  found  that  all  the  cells  in  the   body  arising  from  a  single  fertilized  event  do  not  have  the  same  genetic  composition,  as  was  previously   assumed,  and  is  referred  as  ‘somatic  mosaicism’.  Due  to  mosaicism  a  small  percentage  of  somatic  cells   in  the  body  have  a  slightly  different  genomic  content  then  the  rest  of  the  cells.    

Monozygotic   twin’s   are   an   excellent   model   for   studying   genetic   variations   occurring   throughout   the   lifetime  of  a  human  being.  As  we  know,  the  genetic  makeup  of  the  twins  is  theoretically  the  same,  as   they  arise  from  the  same  zygote.  We  have  selected  monozygotic  twin  pairs,  which  are  either  discordant   in   their   phenotype   (one   twin   healthy   and   the   other   being   affected   by   asthma   or   other   autoimmune   disease)  and/or  at  two  different  ages.  Our  aim  was  to  try  to  relate  a  phenotypic  difference  among  twins   to  a  genotype  change.  Moreover  we  investigated  the  quantity  and  the  localization  of  genetic  changes   that  occur  over  time,  by  comparing  two  populations  of  twins  differing  in  their  age  (namely  one  “young”  

and   one   “old”).   We   wanted   to   demonstrate   that   the   human   genome   accumulates   structural   rearrangements  with  age.    

Copy   Number   Variation   Analysis   (CNVs)   using   arrays   from   manufacturers   like   Illumina   BeadChip   and   Roche   NimbleGen   were   used   to   compare   the   genomes   of   these   pairs   of   MZ   twins.   The   aim   was   to   confirm  if  the  aberrations  shown  by  Illumina  would  also  be  reciprocated  on  Nimblegen  arrays,  where   both   these   platforms   are   independent.   Initially   we   worked   on   18   SNP   probes,   which   showed   point   mutation   in   one   of   the   twin   when   compared   to   other.   Later   we   went   after   larger   genetic   rearrangements,  which  were  shown  by  multiple  patients  at  the  same  loci  by  Illumina  arrays  and  then   confirmed  further  by  Nimblegen.  We  studied  20  such  loci  with  apparent  large  aberrations  (500bp-­‐8kb)   by  cloning  and  sequencing  techniques.  

Degree  project  in  biology,  Master  of  science  (2  years),  2011  

Department  of  Immunology,  Genetics  and  Pathology  (IGP),  Uppsala  University   Supervisors:  Geeta  Pakalapati  and  Jan  P.  Dumanski  

 

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