PMID- 29848293
OWN - NLM
STAT- MEDLINE
DCOM- 20190429
LR  - 20190429
IS  - 1471-2105 (Electronic)
IS  - 1471-2105 (Linking)
VI  - 19
IP  - 1
DP  - 2018 May 30
TI  - Improved accuracy assessment for 3D genome reconstructions.
PG  - 196
LID - 10.1186/s12859-018-2214-2 [doi]
LID - 196
AB  - BACKGROUND: Three dimensional (3D) genome spatial organization is critical for 
      numerous cellular functions, including transcription, while certain 
      conformation-driven structural alterations are frequently oncogenic. Genome 
      conformation had been difficult to elucidate but the advent chromatin 
      conformation capture assays, notably Hi-C, has transformed understanding of 
      chromatin architecture and yielded numerous biological insights. Although most of 
      these findings have flowed from analysis of proximity data produced by these 
      assays, added value in generating 3D reconstructions has been demonstrated, 
      deriving, in part, from superposing genomic features on the reconstruction. 
      However, advantages of 3D structure-based analyses are clearly conditional on the 
      accuracy of the attendant reconstructions, which is difficult to assess. 
      Proponents of competing reconstruction algorithms have evaluated their accuracy 
      by recourse to simulation of toy structures and/or limited fluorescence in situ 
      hybridization (FISH) imaging that features a handful of low resolution probes. 
      Accordingly, new methods of reconstruction accuracy assessment are needed. 
      RESULTS: Here we utilize two recently devised assays to develop methodology for 
      assessing 3D reconstruction accuracy. Multiplex FISH increases the number of 
      probes by an order of magnitude and hence the number of inter-probe distances by 
      two orders, providing sufficient information for structure-level evaluation via 
      mean-squared deviations (MSD). Crucially, underscoring multiplex FISH 
      applications are large numbers of coordinate-system aligned replicates that 
      provide the basis for a referent distribution for MSD statistics. Using this 
      system we show that reconstructions based on Hi-C data for IMR90 cells are 
      accurate for some chromosomes but not others. The second new assay, genome 
      architecture mapping, utilizes large numbers of thin cryosections to obtain a 
      measure of proximity. We exploit the planarity of the cryosections - not used in 
      inferring proximity - to obtain measures of reconstruction accuracy, with 
      referents provided via resampling. Application to mouse embryonic stem cells 
      shows reconstruction accuracies that vary by chromosome. CONCLUSIONS: We have 
      developed methods for assessing the accuracy of 3D genome reconstructions that 
      exploit features of recently advanced multiplex FISH and genome architecture 
      mapping assays. These approaches can help overcome the absence of gold standards 
      for making such assessments which are important in view of the considerable 
      uncertainties surrounding 3D genome reconstruction.
FAU - Segal, Mark R
AU  - Segal MR
AD  - Division of Bioinformatics, Department of Epidemiology and Biostatistics, UCSF, 
      16th Street, San Francisco, 94158, USA. mark.segal@ucsf.edu.
FAU - Bengtsson, Henrik L
AU  - Bengtsson HL
AD  - Division of Bioinformatics, Department of Epidemiology and Biostatistics, UCSF, 
      16th Street, San Francisco, 94158, USA.
LA  - eng
GR  - R01 GM109457/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180530
PL  - England
TA  - BMC Bioinformatics
JT  - BMC bioinformatics
JID - 100965194
SB  - IM
MH  - Animals
MH  - Chromosomes, Mammalian
MH  - Data Accuracy
MH  - *Genome
MH  - Genomics/*methods
MH  - In Situ Hybridization, Fluorescence
MH  - Mice
MH  - Molecular Conformation
PMC - PMC5977474
OTO - NOTNLM
OT  - Chromatin conformation capture
OT  - Genome architecture mapping
OT  - Multiplex FISH
OT  - Principal components analysis
OT  - Procrustes alignment
COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not applicable. COMPETING INTERESTS: 
      The authors declare that they have no competing interests. PUBLISHER'S NOTE: 
      Springer Nature remains neutral with regard to jurisdictional claims in published 
      maps and institutional affiliations.
EDAT- 2018/06/01 06:00
MHDA- 2019/04/30 06:00
PMCR- 2018/05/30
CRDT- 2018/06/01 06:00
PHST- 2017/12/19 00:00 [received]
PHST- 2018/05/21 00:00 [accepted]
PHST- 2018/06/01 06:00 [entrez]
PHST- 2018/06/01 06:00 [pubmed]
PHST- 2019/04/30 06:00 [medline]
PHST- 2018/05/30 00:00 [pmc-release]
AID - 10.1186/s12859-018-2214-2 [pii]
AID - 2214 [pii]
AID - 10.1186/s12859-018-2214-2 [doi]
PST - epublish
SO  - BMC Bioinformatics. 2018 May 30;19(1):196. doi: 10.1186/s12859-018-2214-2.