PMID- 28846675
OWN - NLM
STAT- MEDLINE
DCOM- 20170918
LR  - 20181113
IS  - 1553-7358 (Electronic)
IS  - 1553-734X (Print)
IS  - 1553-734X (Linking)
VI  - 13
IP  - 8
DP  - 2017 Aug
TI  - HLA class I haplotype diversity is consistent with selection for frequent 
      existing haplotypes.
PG  - e1005693
LID - 10.1371/journal.pcbi.1005693 [doi]
LID - e1005693
AB  - The major histocompatibility complex (MHC) contains the most polymorphic genetic 
      system in humans, the human leukocyte antigen (HLA) genes of the adaptive immune 
      system. High allelic diversity in HLA is argued to be maintained by balancing 
      selection, such as negative frequency-dependent selection or heterozygote 
      advantage. Selective pressure against immune escape by pathogens can maintain 
      appreciable frequencies of many different HLA alleles. The selection pressures 
      operating on combinations of HLA alleles across loci, or haplotypes, have not 
      been extensively evaluated since the high HLA polymorphism necessitates very 
      large sample sizes, which have not been available until recently. We aimed to 
      evaluate the effect of selection operating at the HLA haplotype level by 
      analyzing HLA A~C~B~DRB1~DQB1 haplotype frequencies derived from over six million 
      individuals genotyped by the National Marrow Donor Program registry. In contrast 
      with alleles, HLA haplotype diversity patterns suggest purifying selection, as 
      certain HLA allele combinations co-occur in high linkage disequilibrium. Linkage 
      disequilibrium is positive (Dij'>0) among frequent haplotypes and negative 
      (Dij'<0) among rare haplotypes. Fitting the haplotype frequency distribution to 
      several population dynamics models, we found that the best fit was obtained when 
      significant positive frequency-dependent selection (FDS) was incorporated. 
      Finally, the Ewens-Watterson test of homozygosity showed excess homozygosity for 
      5-locus haplotypes within 23 US populations studied, with an average Fnd of 
      28.43. Haplotype diversity is most consistent with purifying selection for HLA 
      Class I haplotypes (HLA-A, -B, -C), and was not inferred for HLA Class II 
      haplotypes (-DRB1 and-DQB1). We discuss our empirical results in the context of 
      evolutionary theory, exploring potential mechanisms of selection that maintain 
      high linkage disequilibrium in MHC haplotype blocks.
FAU - Alter, Idan
AU  - Alter I
AD  - Department of Mathematics, Bar-Ilan University, Ramat Gan, Israel.
FAU - Gragert, Loren
AU  - Gragert L
AUID- ORCID: 0000-0002-5945-6518
AD  - National Marrow Donor Program, Minneapolis, Minnesota, United States of America.
AD  - Department of Pathology and Laboratory Medicine, Tulane University School of 
      Medicine, New Orleans, Louisiana, United States of America.
FAU - Fingerson, Stephanie
AU  - Fingerson S
AD  - National Marrow Donor Program, Minneapolis, Minnesota, United States of America.
FAU - Maiers, Martin
AU  - Maiers M
AD  - National Marrow Donor Program, Minneapolis, Minnesota, United States of America.
FAU - Louzoun, Yoram
AU  - Louzoun Y
AUID- ORCID: 0000-0003-1714-6148
AD  - Department of Mathematics, Bar-Ilan University, Ramat Gan, Israel.
LA  - eng
PT  - Journal Article
DEP - 20170828
PL  - United States
TA  - PLoS Comput Biol
JT  - PLoS computational biology
JID - 101238922
RN  - 0 (Histocompatibility Antigens Class I)
SB  - IM
MH  - Alleles
MH  - Computational Biology
MH  - Genetic Variation/genetics
MH  - Haplotypes/*genetics
MH  - Histocompatibility Antigens Class I/*genetics
MH  - Humans
MH  - Linkage Disequilibrium
MH  - *Models, Genetic
MH  - Selection, Genetic/*genetics
PMC - PMC5590998
COIS- The authors have declared that no competing interests exist.
EDAT- 2017/08/29 06:00
MHDA- 2017/09/19 06:00
PMCR- 2017/08/01
CRDT- 2017/08/29 06:00
PHST- 2016/04/12 00:00 [received]
PHST- 2017/07/20 00:00 [accepted]
PHST- 2017/09/08 00:00 [revised]
PHST- 2017/08/29 06:00 [pubmed]
PHST- 2017/09/19 06:00 [medline]
PHST- 2017/08/29 06:00 [entrez]
PHST- 2017/08/01 00:00 [pmc-release]
AID - PCOMPBIOL-D-16-00592 [pii]
AID - 10.1371/journal.pcbi.1005693 [doi]
PST - epublish
SO  - PLoS Comput Biol. 2017 Aug 28;13(8):e1005693. doi: 10.1371/journal.pcbi.1005693. 
      eCollection 2017 Aug.