title: Historic, demographic, and genetic evidence for increased population frequencies of CCR5Delta32 mutation in Croatian Island isolates after lethal 15th century epidemics.
abstract: OBJECTIVE
  To assess the frequency of 32 base pair deletion in CCR5 (CCR5Delta32), which has been shown to confer resistance to HIV infection in a homozygous form, in 10 isolated island communities of Dalmatia, Croatia, with different histories of exposure to epidemics during and since the medieval period.
  
  
  METHODS
  In 2002, DNA analysis of 100 randomly selected individuals from each of the 10 isolated communities of 5 Croatian islands (Susak, Rab, Vis, Lastovo, and Mljet) showed high levels of 3-generational endogamy, indicating limited gene flow. Five of the communities were decimated by epidemics of unknown cause between 1449-1456, while the other 5 villages remained unaffected. Genotyping of the CCR5 gene was performed using the polymerase chain reaction method with primers flanking the region containing 32-bp deletion.
  
  
  RESULTS
  The frequency of CCR5Delta32 in the 5 villages affected by the epidemic was 6.1-10.0%, and 1.0-3.8% in the 5 unaffected villages. The Delta32 mutation was found in 71 of 916 alleles among the individuals from the affected villages (7.5%), and in 24 of 968 alleles in unaffected villages (2.5%, chi(2)=27.3, P<10-6). A previous study in 303 random Croatian blood donors showed the frequency of the CCR5 Delta32 of 7.1% in the general population. The difference remained significant after correcting for population structure using both STRAT and STRUCTURE software and the genomic control test, to ensure results do not arise from the background genetic differences.
  
  
  CONCLUSIONS
  Our results and historical evidence, suggest that the mid-15th century epidemic could have acted as a selection pressure for the CCR5Delta32 mutation.
authors.affiliation: Andrija Stampar School of Public Health, School of Medicine, University of Zagreb, Rockefellerova 4, 10000 Zagreb, Croatia. zrinka23@yahoo.com
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Biloglav
authors.forename: Lina
authors.initials: L
authors.lastname: Zgaga
authors.forename: Mladen
authors.initials: M
authors.lastname: Smoljanović
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.forename: Ozren
authors.initials: O
authors.lastname: Polasek
authors.forename: Ivana
authors.initials: I
authors.lastname: Kolcić
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.forename: Tatijana
authors.initials: T
authors.lastname: Zemunik
authors.forename: Vesna
authors.initials: V
authors.lastname: Boraska
authors.forename: Vesela
authors.initials: V
authors.lastname: Torlak
authors.forename: Rosanda
authors.initials: R
authors.lastname: Mulić
authors.forename: Darko
authors.initials: D
authors.lastname: Ropac
authors.forename: Ivica
authors.initials: I
authors.lastname: Grković
authors.forename: Diana
authors.initials: D
authors.lastname: Rudan
authors.forename: Smiljana
authors.initials: S
authors.lastname: Ristić
authors.forename: Maja
authors.initials: M
authors.lastname: Barbalić
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
mesh_terms: D017523:Croatia / Q000453:epidemiology; D003710:Demography; D005787:Gene Frequency; D005828:Genetics, Population; D005843:Geography; D015658:HIV Infections / Q000235:genetics; D049668:History, 15th Century; D049669:History, 16th Century; D049670:History, 17th Century; D049671:History, 18th Century; D049691:History, Medieval; D006801:Humans; D010930:Plague / Q000453:epidemiology / Q000235:genetics / Q000266:history*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D019713:Receptors, CCR5 / Q000235:genetics*
chemical_list: D019713:Receptors, CCR5