PMID- 27590916
OWN - NLM
STAT- MEDLINE
DCOM- 20170911
LR  - 20181113
IS  - 1471-2164 (Electronic)
IS  - 1471-2164 (Linking)
VI  - 17
IP  - 1
DP  - 2016 Sep 2
TI  - An analytical workflow for accurate variant discovery in highly divergent 
      regions.
PG  - 703
LID - 10.1186/s12864-016-3045-z [doi]
LID - 703
AB  - BACKGROUND: Current variant discovery methods often start with the mapping of 
      short reads to a reference genome; yet, their performance deteriorates in genomic 
      regions where the reads are highly divergent from the reference sequence. This is 
      particularly problematic for the human leukocyte antigen (HLA) region on 
      chromosome 6p21.3. This region is associated with over 100 diseases, but variant 
      calling is hindered by the extreme divergence across different haplotypes. 
      RESULTS: We simulated reads from chromosome 6 exonic regions over a wide range of 
      sequence divergence and coverage depth. We systematically assessed combinations 
      between five mappers and five callers for their performance on simulated data and 
      exome-seq data from NA12878, a well-studied individual in which multiple public 
      call sets have been generated. Among those combinations, the number of known SNPs 
      differed by about 5 % in the non-HLA regions of chromosome 6 but over 20 % in the 
      HLA region. Notably, GSNAP mapping combined with GATK UnifiedGenotyper calling 
      identified about 20 % more known SNPs than most existing methods without a 
      noticeable loss of specificity, with 100 % sensitivity in three highly 
      polymorphic HLA genes examined. Much larger differences were observed among these 
      combinations in INDEL calling from both non-HLA and HLA regions. We obtained 
      similar results with our internal exome-seq data from a cohort of chronic 
      lymphocytic leukemia patients. CONCLUSIONS: We have established a workflow 
      enabling variant detection, with high sensitivity and specificity, over the full 
      spectrum of divergence seen in the human genome. Comparing to public call sets 
      from NA12878 has highlighted the overall superiority of GATK UnifiedGenotyper, 
      followed by GATK HaplotypeCaller and SAMtools, in SNP calling, and of GATK 
      HaplotypeCaller and Platypus in INDEL calling, particularly in regions of high 
      sequence divergence such as the HLA region. GSNAP and Novoalign are the ideal 
      mappers in combination with the above callers. We expect that the proposed 
      workflow should be applicable to variant discovery in other highly divergent 
      regions.
FAU - Tian, Shulan
AU  - Tian S
AD  - Division of Biomedical Statistics and Informatics, Department of Health Sciences 
      Research, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
FAU - Yan, Huihuang
AU  - Yan H
AD  - Division of Biomedical Statistics and Informatics, Department of Health Sciences 
      Research, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
FAU - Neuhauser, Claudia
AU  - Neuhauser C
AD  - Informatics Institute, University of Minnesota, Minneapolis, MN, 55455, USA.
FAU - Slager, Susan L
AU  - Slager SL
AD  - Division of Biomedical Statistics and Informatics, Department of Health Sciences 
      Research, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA. 
      Slager.Susan@mayo.edu.
LA  - eng
GR  - U01 CA118444/CA/NCI NIH HHS/United States
GR  - UL1 TR000135/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20160902
PL  - England
TA  - BMC Genomics
JT  - BMC genomics
JID - 100965258
RN  - 0 (HLA Antigens)
SB  - IM
MH  - Algorithms
MH  - Chromosome Mapping
MH  - Computational Biology/methods
MH  - Computer Simulation
MH  - Exome
MH  - *Genetic Variation
MH  - *Genome, Human
MH  - Genomics/*methods/standards
MH  - HLA Antigens/genetics
MH  - High-Throughput Nucleotide Sequencing
MH  - Humans
MH  - INDEL Mutation
MH  - Leukemia, Lymphocytic, Chronic, B-Cell/genetics
MH  - Polymorphism, Single Nucleotide
MH  - Reproducibility of Results
MH  - *Workflow
PMC - PMC5010666
OTO - NOTNLM
OT  - Alignment algorithm
OT  - Chronic lymphocytic leukemia
OT  - Exome sequencing
OT  - Human leukocyte antigen
OT  - Variant calling
EDAT- 2016/09/04 06:00
MHDA- 2017/09/12 06:00
PMCR- 2016/09/02
CRDT- 2016/09/04 06:00
PHST- 2016/05/18 00:00 [received]
PHST- 2016/08/25 00:00 [accepted]
PHST- 2016/09/04 06:00 [entrez]
PHST- 2016/09/04 06:00 [pubmed]
PHST- 2017/09/12 06:00 [medline]
PHST- 2016/09/02 00:00 [pmc-release]
AID - 10.1186/s12864-016-3045-z [pii]
AID - 3045 [pii]
AID - 10.1186/s12864-016-3045-z [doi]
PST - epublish
SO  - BMC Genomics. 2016 Sep 2;17(1):703. doi: 10.1186/s12864-016-3045-z.