CN109033752A - It is a kind of to read the long polygenes fusion detection method being sequenced based on long - Google Patents
It is a kind of to read the long polygenes fusion detection method being sequenced based on long Download PDFInfo
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Abstract
The invention discloses a kind of based on the long polygenes fusion detection method for reading long sequencing, and it includes following steps: step 1: pre-processing and compare；Step 2: establishing the candidate long database of reading；Step 3: length being read to candidate and is clustered, establishes candidate polygenes fusion ratio to coordinate sequence database；Step 4: determining that breakpoint location, building polygenes merge mutation database；Step 5: filtering polygenes merges mutation database, reduces false positive.Provided by the present invention effectively to detect polygenes fusion based on the long polygenes fusion detection method for reading long sequencing, the performance indicators such as sensitivity and positive predictive value are far superior to existing detection instrument, provide judgment basis for clinical detection disease.
Description
Technical field
The present invention relates to technical field of gene detection, and in particular to a kind of to merge detection based on the long polygenes for reading long sequencing
Method.
Background technique
The mark of Gene Fusion very universal and some types of cancer in genome.It is produced by chromosomal rearrangement
Raw, the transposition including chromosome is inserted into, and is expanded, and is overturned, and is lacked (non-equilibrium rearrangement).Gene Fusion often shows as two not
Relevant Gene Fusion is formed, and has the function of completely new or different from gene before two fusions function.One strong promoter with
The fusion of one downstream functional gene (proto-oncogene) is universal in certain cancers.Fusion occurs in vivo,
It can lead to the generation of disease.Fusion is generally existing in cancer, closely related with the occurrence and development of cancer.
It with the rapid development in recent years based on the short high throughput sequencing technologies for reading long sequencing and popularizes, high-flux sequence is
It is widely used in Gene Fusion detection: data is obtained based on the long sequencing of short reading, detect gene using the various algorithms continuously improved
Fusion.But this still has very big problem: multiple alignment caused by 1. genome repetitive sequences makes testing result uncertain；2.
The polygenes fusion of large fragment can not be detected.
Summary of the invention
The object of the present invention is to provide a kind of based on the long polygenes fusion detection method for reading long sequencing, above-mentioned existing to solve
There is the problem of technology.
In order to achieve the above objectives, the long polygenes fusion detection method being sequenced is read based on long the present invention provides a kind of,
It comprises the steps of:
Step 1: the long gene for comparing onto reference genome, obtaining reading long of reading that long sequencing obtains will be read by DNA long
Group coordinate, and only retain every and read long optimal comparison result；
Step 2: comparison result being filtered, the reading that only reservation is mutated there may be Gene Fusion is long, obtains candidate reading
Long database；
Step 3: each candidate being read to grow, according to the comparison result of its different zones segment, using area segment is compared
Coordinate sequence indicates to read length；Coordinate sequence is compared to whole region segments and carries out Cluster merging, being formed includes multiple fusion bases
Because long group of reading of candidate polygenes fusion ratio is to coordinate sequence database, wherein each fusion reads long group comprising multiple next
Reading derived from the mutation of the same Gene Fusion is long；
Step 4: each of coordinate sequence database fusion being read to grow by the candidate polygenes fusion ratio
Group determines corresponding Gene Fusion mutation；Its whole breakpoint coordinate is determined for the mutation of each Gene Fusion, is formed more
Gene Fusion mutation database.
Above-mentioned reads the long polygenes fusion detection method being sequenced based on long, wherein in step 1, the comparison passes through
The processing of Last alignment algorithm.
Above-mentioned reads the long polygenes fusion detection method being sequenced based on long, wherein in step 1, before being compared also
It is pre-processed including step, the pretreatment is converted into fastq first will to read the long data of original reading that long sequencing obtains by DNA long
After file, then it is removed by filtration low-quality reading length.
It is above-mentioned based on the long polygenes fusion detection method for reading long sequencing, wherein in step 2, it is described there may be
The reading of Gene Fusion mutation is long to refer to that the reading for comparing coordinate there are 2 or more region segments is long.
Above-mentioned reads the long polygenes fusion detection method being sequenced based on long, wherein in step S3, to whole region pieces
Section compare coordinate sequence carry out Cluster merging detailed process are as follows: for arbitrary two strip areas segment compare coordinate sequence a and
B, and the region segments of a compare coordinate quantity and are greater than b, if comparing coordinate b (i) for each of b region segments, exist
The difference of left wing's coordinate of existence domain segment comparison coordinate a (j+i) or a (j-i) and b (i) and the difference of right flank coordinate are equal in a
Less than 10, then by b and a Cluster merging to one group；Wherein, b (i) indicates that ith zone segment compares coordinate, and 1≤i≤b in b
Region segments compare coordinate sum；A (j+i) indicates that jth+i region segments compare coordinate, and the region 1≤j+i≤a in a
Segment compares coordinate sum；A (j-i) indicates that jth-i region segments compare coordinate, and 1≤j-i≤a region segments ratio in a
To coordinate sum.
Above-mentioned reads the long polygenes fusion detection method being sequenced based on long, wherein in step S3, each fusion is read
Long group needs 2 or more region segments to compare coordinate sequence support.
Above-mentioned reads the long polygenes fusion detection method being sequenced based on long, wherein the detection method further includes step 5:
Calculate the probability value of each Gene Fusion mutation in polygenes fusion mutation database；If the probability value of Gene Fusion mutation
More than or equal to the desired value of Gene Fusion mutation, then the Gene Fusion is mutated and is sorted out according to Gene Fusion type, and protected
Polygenes fusion mutation database is stayed in, is otherwise abandoned.
Above-mentioned reads the long polygenes fusion detection method being sequenced based on long, wherein in step S5, the Gene Fusion class
Type includes transposition, insertion, amplification, reverse, missing and polygenic mutation.
Above-mentioned reads the long polygenes fusion detection method being sequenced based on long, wherein in step S5, the probability value is used
Hidden Ma Erfu chain model algorithm is calculated.
Above-mentioned reads the long polygenes fusion detection method being sequenced based on long, wherein in step S5, the desired value is root
According to the breakpoint quantity of Gene Fusion mutation, the degrees of fusion energy value and sequencing error rate of breakpoint coordinate, hidden Ma Erfu chain mould is used
Type algorithm is calculated.
Compared with the existing technology, the invention has the following advantages:
The long long sequencing of reading can detecte DNA long fragment/RNA molecule, to directly obtain fusion overall length, easily judge
Position of fusion.So compared with high-flux sequence, it is long to read long sequencing in terms of detecting Gene Fusion with huge advantage.
The new polygenes fusion detection method based on the long long sequencing technologies of reading provided by the present invention, has high sensitivity
And the advantages of positive predictive value, it is suitble to merge using DNA fragmentation detection polygenes, polygenes fusion can be detected, effectively to face
Bed detection disease provides judgment basis.
Specific embodiment
Below by way of specific embodiment, the invention will be further described, these embodiments are merely to illustrate the present invention,
It is not limiting the scope of the invention.
Using document " Nanopore sequencing detects structural variants in cancer "
(Alexis L.Norris etc., DOI:http: //dx.doi.org/10.1080/15384047.2016.1139236) is provided
Fusion data set is as a kind of test object based on the long polygenes fusion detection method for reading long sequencing provided by the invention.
The present invention provides a kind of based on the long polygenes fusion detection method for reading long sequencing, and it includes following steps:
Step 1: pretreatment and comparison: will first read the long data of original reading that long sequencing obtains by DNA long and be converted into fastq
After file (format of Fusion data set is fastq file, therefore no longer needs to carry out data conversion step herein), then pass through filtering
Low-quality reading length is removed, low quality reads the long no fixed standard of definition, it should the survey according to different microarray datasets, the batch
The factors such as sequence quality, the long average length of reading are customized；Last is the software dedicated for long sequence alignment, passes through Last ratio
It to algorithm by the long comparison to reference genome of filtered reading, obtains reading long genomic coordinates, and only retains every reading length
Optimal comparison result；People has 23 chromosomes, and the Human Genome Project obtains the base of every chromosome by sequencing
(ACTG) sequence information is announced out as with reference to genome, descendant is facilitated to study；In general, not according to announcement
Same version, is broadly divided into GRCH37 and GRCH38.Last comparison result refers to, each that sequencing obtains is read length and is compared respectively
To genome is referred to, its genomic coordinates are obtained, all reading long genomic coordinates is last comparison result.
Step 2: establishing the candidate long database of reading: Last comparison result is filtered, only there may be genes to melt for reservation
The reading for closing mutation is long, obtains the candidate long database of reading；It is described there may be the reading of Gene Fusion mutation it is long refer to there are 2 with
On region segments compare coordinate (segment-alignment) reading it is long；If a reading is long to have one or more fusions
Site, it may appear that the different zones segment (segment) on the reading is long is compared to different zones coordinate on genome
(alignment), and these area coordinates are not that continuously, then the reading is long there are 2 or more region segments comparison coordinate, are answered
The reservation.If only one long region segments of a reading compare coordinate, abandon.
Step 3: length being read to candidate and is clustered, establishes candidate polygenes fusion ratio to coordinate sequence database: to each
Item candidate reads length, and according to the comparison result of its different zones segment, using area segment compares coordinate sequence and indicates to read length；To complete
The region segments in portion compare coordinate sequence and carry out Cluster merging, form the candidate polygenes for reading long group comprising multiple fusions and melt
Composition and division in a proportion is to coordinate sequence database, and wherein the long group of each fusion reading is comprising multiple from the mutation of the same Gene Fusion
Reading it is long；Each fusion reads long group and 2 or more region segments comparison coordinate sequences is needed to support；The same Gene Fusion
Mutation can be sequenced repeatedly, so the reading length from the mutation of the same Gene Fusion should be merged, it is subsequent to facilitate
Analysis.
Fusion is mutated, different genetic fragments links together, that is, discontinuous gene coordinate is connected to one
It rises.For example, chr1:30000-50000 indicates No. 1 the 30000 to 50000th base sequence of chromosome.If chr1:
A segment chr8:7000-7800 is inserted at 40000, then the mutation should be expressed as chr1:30000-40000；chr8:
7000-7800；chr1:40001-50000.A certain item reads length and just measures the region, and 1-500bp is compared to chr1:
38501-40000,501-1300bp are compared to chr8:7000-7800,1301-2000bp and are compared to chr1:40001-
40700.It can be converted into region segments according to the comparison result for reading long upper different zones and compare coordinate sequence: chr1:30000-
40000；chr8:7000-7800；chr1:40001-50000.
The detailed process that coordinate sequence carries out Cluster merging is compared to whole region segments are as follows: for the arbitrary area Liang Tiao
Domain segment compares coordinate sequence a and b, and the region segments of a compare coordinate quantity and are greater than b, if for the region each of b
Segment compares coordinate b (i), and existence domain segment compares coordinate a (j+i) or a (j-i) and is overlapped with b (i) height in a, such as a
(j+i) or the difference of left wing's coordinate of a (j-i) and b (i) and the difference of right flank coordinate are respectively less than 10, then close b and a cluster
And to one group；Wherein, b (i) indicates that ith zone segment compares coordinate in b, and 1≤i≤b region segments comparison coordinate is total
Number；A (j+i) indicates that jth+i region segments compare coordinate in a, and 1≤j+i≤a region segments compare coordinate sum；a
(j-i) indicate that jth-i region segments compare coordinate in a, and 1≤j-i≤a region segments compare coordinate sum.A so-called left side
Wing coordinate and right flank coordinate refer to: for region segments: chr1:40000-5000, left wing's coordinate are chr1:40000, right flank
Coordinate is chr1:50000.
Step 4: determining that breakpoint location, building polygenes merge mutation database: by the candidate polygenes fusion ratio
Long group is read to each of coordinate sequence database fusion and determines corresponding Gene Fusion mutation；For each base
Because fusion mutation determines its whole breakpoint coordinate, forms polygenes and merge mutation database；In original continuous genetic fragment
Break and alien gene segment links together, the position for interrupting connection again is breakpoint.For example, being compared for region segments
Coordinate sequence: chr1:30000-40000；chr8:7000-7800；Chr1:40001-50000, breakpoint coordinate are chr1:
40000.It is read in long group in the same fusion, reads length comprising many items.Because there are sequencing error, for each breakpoint
Coordinate, every to read long value inconsistent, general by being averaged or the method for mode obtains exact breakpoint coordinate.
Step 5: filtering polygenes merges mutation database, reduces false positive: being calculated using hidden Ma Erfu chain model algorithm
Polygenes merges the probability value p of each Gene Fusion mutation in mutation database；If the probability value p of Gene Fusion mutation is big
In the desired value E for being equal to Gene Fusion mutation, then the Gene Fusion is mutated and is sorted out according to Gene Fusion type, and retained
Mutation database is merged in polygenes, is otherwise abandoned.The desired value E is the breakpoint quantity being mutated according to Gene Fusion, breakpoint
The factors such as the degrees of fusion energy value of coordinate and sequencing error rate are calculated using hidden Ma Erfu chain model algorithm, are not
One single threshold value.The degrees of fusion energy value of breakpoint coordinate, which refers to two genetic fragment fractures and reconnects fusion, to be required to consume
The energy taken；The Chemical bond energy of two fusion segment junctions is the degrees of fusion energy value of breakpoint coordinate.One fusion is prominent
Become and contain many features, each feature value has a probability distribution；The different characteristic value meter being mutated according to one
Probability of happening is calculated, by big data training, Gene Fusion is formed and is mutated model of expected value.Some specific fusion is mutated, it should
Model provides lowest threshold.Lower than the threshold determination, the fusion can not occur.The Gene Fusion type includes transposition, inserts
Enter, expand, overturning, lacking and polygenic mutation.
Fusion data set is detected respectively using 3 fusion detection instruments (lumpy, sniffles and nanosv),
For compared with the method for the present invention carries out performance.This 3 tools are the common tool of detection fusion.Comparative indices are as follows: sensitive
Degree and positive predictive value, Calculation of Sensitivity formula are as follows: (TP/TF) * 100, positive predictive value calculation formula are as follows: (TP/ (TP+
FP))*100.Wherein TP represents the quantity of the fusion mutation correctly detected, and TF represents all fusion mutation quantity, and FP represents vacation
The quantity of positive fusion mutation.
Fusion data set contains 18 samples, reads long 550-600bp, averagely reads long 573bp, and minimum fusion mutation is dense
Degree is 1%.Positive predictive value and the detection of inspiration degree are calculated separately to each sample, method provided by the invention is to Fusion data
Concentrate the testing result of 18 samples as shown in table 1:
Testing result of the method provided by the invention of table 1. to 18 samples in Fusion data set
The result shows that the positive predictive value mean value of method provided by the invention reaches 100%, sensitivity mean value reaches
100%.
Performance (sensitivity average value and positive predictive value average value) ratio based on Fusion data set difference detection method
Relatively as shown in table 2:
Table 2. is compared based on the performance of Fusion data set difference detection method
| Measurement index | The method of the present invention | lumpy | sniffles | Nanosv |
| Sensitivity average value/% | 100 | 61.76 | 76.47 | 44.12 |
| Positive predictive value average value/% | 100 | 43.87 | 40.5 | 45.15 |
As shown in Table 2, in 4 kinds of detection methods, method sensitivity average value and positive predictive value provided by the invention are flat
Mean value is all optimal, and significantly surmounts remaining 3 kinds of method.
It is read in conclusion the detection performance based on Fusion data set relatively shows that the present invention provides one kind based on long
The polygenes fusion detection method of long sequencing can effectively detect polygenes fusion, the performance indicators such as sensitivity and positive predictive value
Better than existing detection instrument.
It is discussed in detail although the contents of the present invention have passed through above preferred embodiment, but it should be appreciated that above-mentioned
Description is not considered as limitation of the present invention.After those skilled in the art have read above content, for of the invention
A variety of modifications and substitutions all will be apparent.Therefore, protection scope of the present invention should be limited to the appended claims.
Claims (10)
1. a kind of based on the long polygenes fusion detection method for reading long sequencing, which is characterized in that it includes following steps:
Step 1: the long genome seat for being sequenced in the long comparison to reference genome of obtained reading, obtaining reading long will be read by DNA long
Mark, and only retain every and read long optimal comparison result；
Step 2: comparison result being filtered, the reading that only reservation is mutated there may be Gene Fusion is long, obtains candidate reading long number
According to library；
Step 3: each candidate being read to grow, according to the comparison result of its different zones segment, using area segment compares coordinate
Sequence indicates to read length；Coordinate sequence is compared to whole region segments and carries out Cluster merging, is formed and is read comprising multiple fusions
The candidate polygenes fusion ratio of long group is to coordinate sequence database, and wherein the long group of each fusion reading is derived from comprising multiple
The reading of the same Gene Fusion mutation is long；
Step 4: it is true that long group being read to each of coordinate sequence database fusion by the candidate polygenes fusion ratio
Fixed corresponding Gene Fusion mutation；Its whole breakpoint coordinate is determined for the mutation of each Gene Fusion, forms polygenes
Merge mutation database.
2. as described in claim 1 based on the long polygenes fusion detection method for reading long sequencing, which is characterized in that in step 1,
The comparison is handled by Last alignment algorithm.
3. as described in claim 1 based on the long polygenes fusion detection method for reading long sequencing, which is characterized in that in step 1,
It further include step pretreatment before being compared, the pretreatment is long first will to read the original reading that long sequencing obtains by DNA long
After data conversion is at fastq file, then it is removed by filtration low-quality reading length.
4. as described in claim 1 based on the long polygenes fusion detection method for reading long sequencing, which is characterized in that in step 2,
The reading being mutated there may be Gene Fusion is long to refer to that the reading for comparing coordinate there are 2 or more region segments is long.
5. as described in claim 1 based on the long polygenes fusion detection method for reading long sequencing, which is characterized in that step S3
In, the detailed process that coordinate sequence carries out Cluster merging is compared to whole region segments are as follows: for arbitrary two strip areas piece
Section compares coordinate sequence a and b, and the region segments of a compare coordinate quantity and are greater than b, if for each of b region segments
It compares coordinate b (i), existence domain segment compares the difference of left wing's coordinate of coordinate a (j+i) or a (j-i) and b (i) in a
And the difference of right flank coordinate is respectively less than 10, then by b and a Cluster merging to one group；Wherein, b (i) indicates ith zone segment in b
Coordinate is compared, and 1≤i≤b region segments compare coordinate sum；A (j+i) indicates that jth+i region segments compare seat in a
Mark, and 1≤j+i≤a region segments compare coordinate sum；A (j-i) indicates that jth-i region segments compare coordinate, and 1 in a
The region segments of≤j-i≤a compare coordinate sum.
6. as described in claim 1 based on the long polygenes fusion detection method for reading long sequencing, which is characterized in that step S3
In, each fusion reads long group and 2 or more region segments comparison coordinate sequences is needed to support.
7. as described in claim 1 based on the long polygenes fusion detection method for reading long sequencing, which is characterized in that the detection side
Method further includes step 5: calculating the probability value of each Gene Fusion mutation in polygenes fusion mutation database；As fruit gene melts
The probability value for closing mutation is more than or equal to the desired value of Gene Fusion mutation, then the Gene Fusion is mutated according to Gene Fusion type
Sorted out, and be retained in polygenes fusion mutation database, is otherwise abandoned.
8. as claimed in claim 7 based on the long polygenes fusion detection method for reading long sequencing, which is characterized in that step S5
In, the Gene Fusion type includes transposition, insertion, amplification, reverse, missing and polygenic mutation.
9. as claimed in claim 7 based on the long polygenes fusion detection method for reading long sequencing, which is characterized in that step S5
In, the probability value is calculated using hidden Ma Erfu chain model algorithm.
10. as claimed in claim 9 based on the long polygenes fusion detection method for reading long sequencing, which is characterized in that step S5
In, the desired value be according to Gene Fusion mutation breakpoint quantity, breakpoint coordinate degrees of fusion energy value and sequencing error rate,
It is calculated using hidden Ma Erfu chain model algorithm.
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