rearrangementType: Determine the type of rearrangement supported by each...

In cancer-genomics/trellis: Somatic structural variant analysis

Determine the type of rearrangement supported by each improper read pair

Description

Determine the type of rearrangement supported by each improper read pair

Usage

rearrangementType(object)

Arguments

object

a Rearrangement

Details

Rearrangements are typed by the following criteria for read 1 (R1) and read 2 (R2):

1. strand of R1 and R2

2. orientation of R1 and R2 (e.g., R1 < R2)

3. whether R1 and R2 are on different chromosomes

4. whether R1 and R2 have an aberrant separation

Deletions: A deletion results in a single new sequence junction. There are two orientations of a R1 and R2 that support this junction: R1+ < R2- and R1- > R2+. The former R1+ < R2- is the sequenced + strand DNA fragment, while the latter R1- > R2+ is the sequenced - strand. These orientations are the expected orientations in unrearranged genomes, except that the distance between R1 and its mate is larger than expected (> 10kb).

Amplicons: For purpose of downstream analyses, we only type intra-chromosomal amplicons that are replicated at the same site in the genome and without any changes to the strand orientation. Illustration:

 Reference:
        1  2  3     4 5 6    7 8 9
  +5' ------------|--------|-------------
  -3' ------------|--------|-------------

 Tumor
        1  2  3     4 5 6    4 5 6   7 8 9
  +5' ------------|--------X-------|---------
  -3' ------------|--------X-------|---------
 

Note that only 'X' is a new sequence junction not seen in the reference. Characteristics of 'X' are R1+ > R2- (+ fragment) and R1- < R2+ (- fragment). The amplicon could also insert further downstream:

 Tumor 
        1  2  3     4 5 6    7 8 9   4 5 6
  +5' ------------|--------|-------X---------
  -3' ------------|--------|-------X---------

 or further upstream:

 Tumor 
        4  5  6     1 2 3    4 5 6   7 8 9
  +5' ------------X--------|-------|---------
  -3' ------------X--------|-------|---------

In each case, the rearrangement junctions given by 'X' would be identified by R1+ > R2 - and R1- < R2+.

Inter-chromosomal translocations: For translocations, positional orientation is determined by chromosome number and not genomic position. WLOG, we consider chr1 to be less than chr2 and chr22 to be less that chrX. In the case of an unbalanced translocation, a single rearrangement junction will be identified by the improper read pairs.

Reference   (-- chr1, == chr2)
  
     chr1  1 2 3   4 5 6   chr2  20 21 22   23  24  25
5' + ------------|------   ===============|==============
3' - ------------|------   ===============|==============

Tumor

      chr1  1 2 3   23 24 25 
5' + ------------|========== 
3' - ------------|==========

Read orientations R1+ < R2- and R1- > R2+ are consistent with the fusion of the two positive strands and the two negative strands, respectively. If the translocation is balanced, we would also observe

Tumor
     chr2  20 21 22   4 5 6
5' + ==============|--------
3' - ==============|--------

with R1+ > R2- and R1- < R2+. Hence, there are four distinct read pair orientations for a balanced tranlocation. For the purpose of assessing gene fusions, we treat all translocations as if they are balanced even if we do not observe all 4 possible orientations. An inversion translocation is typed and analyzed as an inversion.

Inversions:

An intrachromosomal inversion:

Reference:  (-- positive strand,  == negative strand)

      1 2 3   4 5 6     7 8 9
5'+  ------>|-------->|------->
3'-  <======|<========|<=======

Tumor (inversion)

      1 2 3   6 5 4    7 8 9
5'+  ------>X=======>X------->
3'-  <======X<-------X<=======

Again, X's denote the new sequence junctions formed as a result of the inversion. The left-most X's are supported by R1+ < R2+ (the top strand in the diagram) and R1+ > R1+ (bottom strand). The right-most X's are supported by R1- < R2- (top strand) and R1- > R2- (bottom strand).

An inversion can also involve a translocation.

Value

a data.frame with colnames 'type' and 'percent'

Note

Type amp1,amp3 would never be identified because the junction does not involve an aberrant separation between read pairs.

cancer-genomics/trellis documentation built on Feb. 2, 2023, 7:04 p.m.