CN106407746A - Method and device for acquiring mutational sites of genes corresponding to respiratory system - Google Patents
Method and device for acquiring mutational sites of genes corresponding to respiratory system Download PDFInfo
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Abstract
The invention provides a method and a device for acquiring mutational sites of genes corresponding to a respiratory system, and relates to the technical field of biological information. The method comprises the following steps: carrying out data comparison on a plurality of short sequence and reference genome of genes to be tested to obtain the initial mutational site information of the genes to be tested; according to the initial mutational site information, deleting mutational sites which do not meet a preset reservation condition in a plurality of initial mutational sites, wherein the mutational sites, in the genes to be tested, obtained after deletion are taken as sites to be tested; comparing the sites to be tested with a plurality of mutational sites of the genes corresponding to the respiratory system in a respiratory system gene bank; and when the mutational site of which the position and mutation basic group are the same as the site to be tested exists in the respiratory system gene bank, obtaining the site mutation condition of the genes corresponding to the respiratory system in the genes to be tested. According to the method and the device, the mutation condition of a plurality of mutational sites relevant to the respiratory system in the mutational sites in the genes to be tested can be obtained.
Description
Technical field
The application is related to technical field of biological information, in particular to a kind of mutation of the corresponding gene of respiratory system
The acquisition methods in site and device.
Background technology
Development with medical science, genomics and high throughput sequencing technologies and maturation, precisely medical (Precision
Medicine) also apply in countries in the world, become new medical model.Precisely medical treatment is by individual people's gene, environment and life
The prevention from suffering from the diseases that custom difference is taken into account and the therapy disposed, according to everyone hereditary information, personalized, precision
Go formulate medical treatment and health management scheme.
And everyone genetic background is distinguishing, in the process it is necessary to determine everyone genome or
The catastrophe of some genes being associated with corresponding organ or position, further according to this base mutation situation to allow to
Analysis contrast, determines final ill possibility, to specify medical treatment and health management scheme accordingly.
Respiratory disorder is respiratory disease, and the incidence of disease of respiratory disorder is higher, such as pulmonary emphysema, bronchial astehma, lung
Fibrosis etc. are disease occurred frequently.
Incidence due to respiratory disorder has certain contacting with gene, the position of the corresponding gene of respiratory system
Point base mutation situation is different, and the incidence of different respiratory disorders of respiratory system and incidence probability may be made different.Then,
Accurate medical model, the base mutation situation according to the corresponding gene of respiratory system and the combination pair of other information can be utilized
The incidence of respiratory disorder and probability are predicted, and are a kind of effective precautionary approach so that respiratory disorder is carried out with prevention.
The existing determination to respiratory system gene point mutation situation, obtains testing gene typically by chemical mode
The gene loci of a certain specified location base mutation situation, this acquisition modes obtain mutational site limited amount, lead to
The catastrophe of some or certain several bases often can only be obtained it is impossible to determine corresponding with respiratory system in testing gene simultaneously
The catastrophe of as much as possible multiple variant sites of gene, makes subsequently to combine the disease condition to respiratory disorder for the other information
Predict the outcome and be likely to occur relatively large deviation.
Content of the invention
In view of this, the embodiment of the present application provides a kind of acquisition methods in the mutational site of the corresponding gene of respiratory system
And device, by by multiple changes of the variant sites of testing gene and the corresponding gene of respiratory system in respiratory system gene pool
Ectopic sites are compared, it is hereby achieved that the base of multiple variant sites of the corresponding gene of the respiratory system in testing gene
Catastrophe, to improve the problems referred to above.
To achieve these goals, the technical scheme that the application adopts is as follows：
A kind of acquisition methods in the mutational site of the corresponding gene of respiratory system, methods described includes：By testing gene
Multiple short sequences and reference gene group carry out comparing, obtain the preliminary variant sites information of testing gene, described preliminary change
Ectopic sites information includes the mutating alkali yl of multiple preliminary variant sites and the positional information of each preliminary variant sites；According to
Described preliminary variant sites information, the variant sites being unsatisfactory for default reserve in the plurality of preliminary variant sites are deleted
Remove, the variant sites in the described testing gene obtaining after deleting are as site to be checked；By described site to be checked and breathing system
Multiple variant sites of the corresponding gene of respiratory system in system gene pool are compared, and described respiratory system gene pool includes
The mutating alkali yl of each variant sites of the corresponding gene of respiratory system and each variant sites position；When described to be checked
There are and mutating alkali yl identical variant sites identical with position in described respiratory system gene pool in site, obtain described to be measured
The site mutation situation of the corresponding gene of respiratory system in gene.
A kind of acquisition device in the mutational site of the corresponding gene of respiratory system, described device includes：Comparing module, is used for
The multiple short sequence of testing gene and reference gene group are carried out comparing, obtains the preliminary variant sites letter of testing gene
Breath, described preliminary variant sites information includes the mutating alkali yl of multiple preliminary variant sites and each preliminary variant sites
Positional information；Filtering module, for according to described preliminary variant sites information, being unsatisfactory in the plurality of preliminary variant sites
The variant sites of default reserve are deleted, and the variant sites in the described testing gene obtaining after deleting are as position to be checked
Point；Comparison module, for by multiple changes of described site to be checked and the corresponding gene of respiratory system in respiratory system gene pool
Ectopic sites are compared, and described respiratory system gene pool includes the mutation of each variant sites of the corresponding gene of respiratory system
Base and each variant sites position；Mutation acquisition module, when presence and described respiratory system in described site to be checked
In gene pool, position is identical and mutating alkali yl identical variant sites, corresponding for obtaining respiratory system in described testing gene
The site mutation situation of gene.
The acquisition methods in mutational site of the corresponding gene of respiratory system and device that the embodiment of the present application provides, are obtaining
In the case of the variant sites of testing gene, by the variant sites of testing gene with respiratory system pair in respiratory system gene pool
Multiple variant sites of the gene answered are compared, and respiratory system gene pool includes each change of the corresponding gene of respiratory system
The mutating alkali yl of ectopic sites and each variant sites position.When presence and respiratory system gene pool middle position in testing gene
Put identical and mutating alkali yl identical variant sites and dash forward it may be determined that there is the corresponding gene of respiratory system in this testing gene
Become.
Because respiratory system gene pool includes the multiple variant sites related to respiratory system, then this programme can determine
The multiple variant sites related to respiratory system in testing gene, and the concrete base mutation situation of the plurality of variant sites.
For enabling the above-mentioned purpose of the application, feature and advantage to become apparent, preferred embodiment cited below particularly, and coordinate
Appended accompanying drawing, is described in detail below.
Brief description
Purpose, technical scheme and advantage for making the embodiment of the present application are clearer, below in conjunction with the embodiment of the present application
In accompanying drawing, the technical scheme in the embodiment of the present application is clearly and completely described it is clear that described embodiment is
Some embodiments of the present application, rather than whole embodiments.Based on the embodiment in the application, those of ordinary skill in the art
The every other embodiment being obtained under the premise of not making creative work, broadly falls into the scope of the application protection.
Fig. 1 shows the structural representation of the computer that the embodiment of the present application provides；
Fig. 2 shows the acquisition methods in the mutational site of the corresponding gene of respiratory system that the application first embodiment provides
A kind of flow chart；
Fig. 3 shows the acquisition methods in the mutational site of the corresponding gene of respiratory system that the application first embodiment provides
Part steps flow chart；
Fig. 4 shows the acquisition device in the mutational site of the corresponding gene of respiratory system that the application second embodiment provides
Functional block diagram；
Fig. 5 shows the acquisition device in the mutational site of the corresponding gene of respiratory system that the application second embodiment provides
Gene pool set up the functional block diagram of module；
Fig. 6 shows the acquisition device in the mutational site of the corresponding gene of respiratory system that the application second embodiment provides
Filtering module functional block diagram；
Fig. 7 shows the acquisition device in the mutational site of the corresponding gene of respiratory system that the application second embodiment provides
Comparing module functional block diagram.
Specific embodiment
Below in conjunction with accompanying drawing in the embodiment of the present application, the technical scheme in the embodiment of the present application is carried out clear, complete
Ground description is it is clear that described embodiment is only some embodiments of the present application, rather than whole embodiments.Generally exist
The assembly of the embodiment of the present application described and illustrated in accompanying drawing can be arranged with various different configurations and design herein.Cause
This, be not intended to limit claimed the application's to the detailed description of the embodiments herein providing in the accompanying drawings below
Scope, but it is merely representative of the selected embodiment of the application.Based on embodiments herein, those skilled in the art are not doing
The every other embodiment being obtained on the premise of going out creative work, broadly falls into the scope of the application protection.
It should be noted that：Similar label and letter represent similar terms in following accompanying drawing, therefore, once a certain Xiang Yi
It is defined in individual accompanying drawing, then do not need it to be defined further and explains in subsequent accompanying drawing.Meanwhile, the application's
In description, term " first ", " second " etc. are only used for distinguishing description, and it is not intended that indicating or hint relative importance.
As shown in figure 1, being the block diagram of the application computer 100.Described computer 100 includes respiratory system and corresponds to
The acquisition device 200 in the mutational site of gene, memory 101, storage control 102, processor 103, Peripheral Interface 104,
Input-output unit 105 and other.
Described memory 101, storage control 102, processor 103, Peripheral Interface 104 and input-output unit 105
Each element is directly or indirectly electrically connected with each other, to realize transmission or the interaction of data.For example, these elements mutually it
Between can realize being electrically connected with by one or more communication bus or holding wire.The mutation position of the corresponding gene of described respiratory system
The acquisition device 200 of point includes at least one and can be stored in described memory 101 in the form of software or firmware (firmware)
In or be solidificated in the software function module in the operating system (operating system, OS) of described computer 100.Described place
Reason device 103 is used for executing in memory 101 the executable module of storage, the mutation position of the corresponding gene of for example described respiratory system
Software function module or computer program that the acquisition device 200 of point includes.
Wherein, memory 101 may be, but not limited to, random access memory (Random Access Memory,
RAM), read-only storage (Read Only Memory, ROM), programmable read only memory (Programmable Read-Only
Memory, PROM), erasable read-only memory (Erasable Programmable Read-Only Memory, EPROM),
Electricallyerasable ROM (EEROM) (Electric Erasable Programmable Read-Only Memory, EEPROM) etc..
Wherein, memory 101 is used for storage program, and described processor 103, after receiving execute instruction, executes described program, aforementioned
The method performed by computer 100 of the stream process definition that the embodiment of the present application any embodiment discloses can apply to processor
In 103, or realized by processor 103.
Processor 103 is probably a kind of IC chip, has the disposal ability of signal.Above-mentioned processor 103 can
To be general processor, including central processing unit (Central Processing Unit, abbreviation CPU), network processing unit
(Network Processor, abbreviation NP) etc.；Can also be digital signal processor (DSP), special IC (ASIC),
Ready-made programmable gate array (FPGA) or other PLDs, discrete gate or transistor logic, discrete hard
Part assembly.Can realize or execute disclosed each method in the embodiment of the present application, step and logic diagram.General processor
Can be microprocessor or this processor 103 can also be any conventional processor etc..
Various input/output devices are coupled to processor 103 and memory 101 by described Peripheral Interface 104.At some
In embodiment, Peripheral Interface 104, processor 103 and storage control 102 can be realized in one single chip.Other one
In a little examples, they can be realized by independent chip respectively.
Input-output unit 105 is used for being supplied to user input data realizes interacting of user and described computer.Described
Input-output unit may be, but not limited to, digital independent device, mouse and keyboard etc..
It should be understood that the structure shown in Fig. 1 be only illustrate, computer 100 can also include more more than shown in Fig. 1 or
Less assembly, or there are the configurations different from shown in Fig. 1.Each assembly shown in Fig. 1 can using hardware, software or its
Combination is realized.
First embodiment
The embodiment of the present application provides a kind of acquisition methods in the mutational site of the corresponding gene of respiratory system, for obtaining
The base mutation situation of the variant sites of the gene related to respiratory system in testing gene.Refer to Fig. 2, the method includes：
Step S110：The multiple short sequence of testing gene and reference gene group are carried out comparing, obtains testing gene
Preliminary variant sites information, described preliminary variant sites information includes the mutating alkali yl of multiple preliminary variant sites and every
The positional information of individual preliminary variant sites.
First, obtain the multiple short sequence of testing gene, this short sequence can be exported by second generation microarray dataset.Will
The short sequence of testing gene and reference gene group are compared.As if testing gene is human gene, this reference gene group is then
Mankind's reference gene group.
Certainly, this comparison process can include repeatedly comparing and the process such as duplicate removal, the multiple change of the inclusion after being compared
The preliminary variant sites information of ectopic sites.
Specifically, as shown in figure 3, in the present embodiment, the comparing in this step is to obtain preliminary variant sites letter
The process of breath can include：
Step S111：The multiple short sequence of described testing gene and reference gene group are compared first, is obtained SAM lattice
The comparison result of formula.
The short sequence of testing gene and reference gene group are carried out comparing, this comparison process can utilize existing ratio
Software is carried out, such as Bowtie2, it is possible to obtain the comparison result of SAM form, be stored with the comparison result of this SAM form ratio
Comparison information to rear acquisition.It should be understood that in the comparison result of this SAM form, including each alkali in testing gene
The information of base, such as positional information.
Certainly, the representation of specifically used comparison software and comparison result is not intended as limiting in the present embodiment
System, can compare the multiple short sequence of testing gene and reference gene group and obtain the comparison information representing comparison result
It is advisable.
Step S112：Duplicate removal is carried out to described comparison result, makes contrast arrive the short sequence of a position of reference gene group
Number is less than or equal to 1.
In the comparison result that step S111 obtains, there are a certain proportion of repetitive sequence and result, for example, contrast with reference to base
Same position because of group may have multiple short sequences, then, in this step, comparison result is carried out duplicate removal.
In the present embodiment, it is possible to use software Picard carries out duplicate removal work.Specifically, using can be Picard
MarkDuplicate instrument duplicate removal, obtain bam form duplicate removal result.
Step S113：Comparing result after duplicate removal is carried out with local anharmonic ratio to (local multiple alignment).
The short sequence compared to reference gene group due to obtaining is difficult to accurately compare highly similar repetition
Region, then the repeat region in genome be readily available false-positive variant sites, such as false-positive SNPs.It is appreciated that
, false-positive variant sites are the variant sites of comparison result mistake.In order to reduce false positive variant sites quantity and
Ratio, in the present embodiment, carries out local anharmonic ratio pair to the comparing result after duplicate removal.
Specifically, this local anharmonic ratio can be using in GATK to (local multiple alignment)
IndelRealigner is carried out, obtain bam form anharmonic ratio to after comparison result.This comparison process typically has three steps,
A. detect suspicious, need to carry out the region of anharmonic ratio pair；B. anharmonic ratio pair is carried out to these suspicious regions；C. repair in anharmonic ratio
To during lose mate pairing information.
Step S114：Recalculate local anharmonic ratio to after comparison result in base mass fraction.
In step S111 during aforementioned processing, each single base can be endowed in data processing
One mass fraction (Quality scores), for reflecting the confidence level of nucleotides that corresponding base is observed.
Mass fraction due to obtaining during aforementioned processing does not have preferably to contact with wrong genotyping result possibility
Get up, simultaneously the mass fraction of single base, do not contact with other specification phase example, different surveys such as in same sample
Sequence platform, different sequencing circulations, different libraries etc. are contacted.
Therefore, in this step in S114, the mass fraction of each base is connected with each factor in sequencing procedure
System, recalculates to the mass fraction of each base, generates new mass fraction, for judging that each base whether may be used
Letter.
Specifically, in the present embodiment, it is possible to use GATK carries out empirical quality score
Recalibration, obtains the result of bam form.
Step S115：According to described base mass fraction, to local anharmonic ratio to after comparing result carry out SNP and indel
Analysis, obtains preliminary variant sites information.
According to the base mass fraction recalculating acquisition, local anharmonic ratio is carried out to the comparison result obtaining SNP and
The preliminary interpretation of indel, carries out SNP and indel parting to it, to obtain the variant sites information including multiple variant sites,
, as preliminary variant sites information, multiple variant sites that this includes are as preliminary variant sites for this variant sites information.Permissible
Understand, in this preliminary variant sites information, include the mutating alkali yl of multiple preliminary variant sites, and each becomes dystopy
Point position.In the present embodiment, for SNP and indel it is preferred that in the present embodiment, variant sites are only variant sites
SNP.
Specifically, in this step, can be to be analyzed using the Unified Genotyper of GATK.Because complete
After becoming the parting of SNPs, employ a lot of data filtering parameter logistic according to being filtered again, with further control data quality,
So in this step standard minimum confidence thresholds is both configured to zero.It should be understood that
SNPs represents the plural form of SNP.
Certainly, the preliminary interpretation process of this SNP and indel can also be carried out, in the present embodiment not in other ways
As limit or other, the such as HaplotypeCaller of GATK is carried out.
In this step, it is possible to obtain include the vcf file of preliminary variant sites information, the preliminary change in this vcf file
Ectopic sites information includes each variant sites obtaining in step s 110 and the corresponding positional information of each variant sites,
Certainly, other are also included, here is not added with repeating.
Step S120：According to described preliminary variant sites information, will be unsatisfactory for presetting in the plurality of preliminary variant sites
The variant sites of reserve are deleted, and the variant sites in the described testing gene obtaining after deleting are as site to be checked.
In step s 110, it would still be possible to there is false sun in the preliminary variant sites in the preliminary variant sites information of acquisition
Property variant sites, then, this step is filtered further to preliminary variant sites, delete wherein false positive possibility higher
Variant sites, the variant sites in result after to delete as the variant sites in this testing gene, make finally to obtain
Variant sites are more accurate.It should be understood that delete after result in further comprises each variant sites positional information and
Other information, will not be described here.
Specifically, in this step, following one or more can be included and delete the variation being unsatisfactory for default reserve
The mode in site：
Mode one：Remove in the plurality of preliminary variant sites, the number of allele is more than the change dystopy of predetermined threshold value
Point.
Allele is more than the variant sites of predetermined threshold value, is that the possibility of false positive variant sites is higher, it is carried out
Remove.In the present embodiment, this predetermined threshold value can value according to actual needs, due to comprising more than more than 1 allele
Site just there is higher Genotyping mistake it is preferred that this predetermined threshold value value can be 1.
When predetermined threshold value value is 1, that is, in the multiple preliminary variant sites removing acquisition, there is more than 1 allele
Variant sites.
Mode two：Delete in the plurality of preliminary variant sites, positioned at each insertion and deletion (indel) upstream span or
The base number that all variant sites in person's span downstream, described upstream span and span downstream include is predetermined number.
Because the short sequence for comparing is often exported by two generations direction finding platform, and the short sequence of two generation microarray datasets exists
It is more prone to the comparison of mistake near the region of insertion and deletion (indel), and the local anharmonic ratio in above-mentioned processing procedure is not to
This mistake can be completely eliminated.Then, all variant sites in insertion and deletion upstream span or span downstream are deleted, with
Reduce the possibility of false positive results.
The base number that this upstream span and span downstream include is predetermined number, this predetermined number can by user according to
Actual demand determines, is not restricted in the present embodiment, and, the predetermined number of upstream span and span downstream can phase
Same or different.
In the present embodiment, the base number that scope includes above is had to be preferably 5, the base number that span downstream includes is excellent
Elect 5 as.That is, all indel in preliminary variant sites are determined, for each indel, by its upstream 5bp (5 bases)
Within all variant sites delete, or all variant sites within 5bp downstream are deleted.
Certainly, in the present embodiment, can only delete in variant sites or the span downstream in the upstream span of indel
Variant sites it is also possible to the variant sites in the upstream span of indel and the variant sites in span downstream are all deleted.
Preferably, in the present embodiment, in the upstream span for insertion and deletion (indel) of deletion or span downstream
All SNPs.
Mode three：By in the plurality of preliminary variant sites, the variant sites being spaced default base number each other are deleted
Remove.
In this step, variant sites close to each other are deleted, will each other distance less than the variation of certain value
Site is deleted.
In the present embodiment, this default base number is not intended as limiting, and can set according to actual needs.
Preferably, this default base number is 4, if there is the variation that the base number being spaced each other is less than 4
Site, is deleted.That is, deleting the variant sites within upstream each other or downstream 5bp.
Preferably, in this step, the SNPs for being spaced default base number each other of deletion.
Mode four：By in the plurality of preliminary variant sites, corresponding GQ (Genotype quality) value is less than default
The variant sites of GQ threshold value are deleted.
GQ (Genotype quality) is a posterior probability (the phred-scaled probabilities) value,
For each site, GQ value is not possible of truth in order to represent this site in the genotypic results of current acquisition
Property, that is, represent obtain in this genotype of this site there is a possibility that.Calculation is：
GQ value=- 10*log10 (P [error]), wherein, P [error] represents that corresponding site is not the general of truth
Rate.
Preferably, in the present embodiment, default GQ threshold value is 20.Empirical tests, when GQ threshold value is 20, theoretic mistake
Rate is 1%.
Mode five：By in the plurality of preliminary variant sites, corresponding MQ (Mapping quality) value is less than default MQ
The variant sites of threshold value are deleted.
MQ represents the selectivity (uniqueness) in aligned sequences.When same short sequence can compare same
During genome zones of different, the alignment score of the first best comparison area (the first best alignment)
The alignment score of (alignment's score) and the second best comparison area (the second best alignment), two
Person's difference is bigger, shows that the selectivity comparing is better, the value of MQ is higher.
In this embodiment it is believed that it is false sun that MQ value has higher possibility less than the variant sites of default MQ threshold value
Property, it is deleted.
Preferably, in the present embodiment, default MQ threshold value value is 30.Empirical tests, when MQ value is 30, P [error]=
0.001, arrive current location with respect to comparing, the possibility comparing another position is up to 0.1%.
In embodiments of the present invention, mode one is optional executive mode to mode five, that is, in this step, can adopt it
In a certain mode, certain several ways or all of mode.When carrying out being unsatisfactory for the change of reservation conditions using various ways
During the deletion of ectopic sites, the execution sequence between this various ways is not intended as limiting.Certainly, this various ways can also be parallel
Execution.
In addition, in this step 120, when there being various ways to be performed serially, follow-up step can be in preceding step
On the basis of execute.For example, if the number of the plurality of preliminary variant sites allelic of removal of executive mode one is more than in advance
If in the variant sites of threshold value, and mode three, default base will be spaced in the plurality of preliminary variant sites each other
The variant sites of number are deleted, and first carry out mode one, then executive mode three.Then in mode three, deletion can be mode
It is spaced the variant sites of default base number each other in variant sites after one process.
After step S120 carries out to preliminary variant sites deleting and filters, variant sites in the final result of acquisition are as treating
The site to be checked of cls gene, can be represented with vcf formatted file.
Step S130：Multiple changes by described site to be checked and the corresponding gene of respiratory system in respiratory system gene pool
Ectopic sites are compared, and described respiratory system gene pool includes the mutation of each variant sites of the corresponding gene of respiratory system
Base and each variant sites position.
In embodiments of the present invention, initially set up respiratory system gene pool, this respiratory system gene pool includes breathing system
Unite the mutating alkali yl of each variant sites of corresponding gene and each variant sites position.
This respiratory system gene pool step S130 relatively before set up.Specifically, this sets up process can be, obtain
COSMIC gene database, the clivar database of NCBI, other international and domestic each big authority's academic journal magazine, genetic tests
In the gene database that company and relevant government department announce, the gene loci information related to respiratory system.Main acquisition
Be the base mutation situation of each variant sites including the corresponding gene of respiratory system and each variant sites institute is in place
The described gene loci information put.
Certainly, the data source obtaining gene loci information can also be other, is not intended as in the present embodiment limiting.
Further, each change dystopy of the corresponding gene of respiratory system can also be included in the gene loci information of acquisition
The impact to protein function for every kind of mutating alkali yl of point, that is, get the base of certain variant sites by normal base mutation to
Which kind of impact current mutating alkali yl, can produce to the function of corresponding protein.
Certainly, in the present embodiment, can also include in the gene loci information of acquisition：The corresponding base in each mutational site
Write a Chinese character in simplified form because of name, gene name full name, coordinate in human genome for this site, corresponding histoorgan type, gene are dashed forward
Become type, the normal gene base in this site, whether this kind of mutation in this site of clinical research causes a disease, original mutation finds
Crowd, the sex of original mutation patient carrier, the age of original mutation patient carrier, in the source of original mutation record
One or more.
Again by described gene loci information with a low credibility in preset standard and mistake gene loci information deletion,
The gene loci information obtaining forms described respiratory system gene pool.
In the present embodiment, include following at least one less than the gene loci information of preset standard：
1) the gene loci information getting from the very poor periodical of non-SCI periodical or reputation in the field of business, reputation is very in the industry for this
The periodical of difference can be that factor of influence is less than the periodical being unsatisfactory under the periodical of certain value or other judgment criteria requiring；2) record
In the original of this gene loci information, sample size used is less than certain value so that being not enough to draw the conclusion of science
's；3) in the original recording this gene loci, this gene loci is not the most important gene loci finding in document,
This most important gene loci can be in the result getting front 10% site.
The gene loci information of mistake includes following at least one：1) this gene loci information described in the database obtaining
Original substantially do not have been reported that this site；2) record in the original of this gene loci, this gene loci
Result is statistically non-significant.
Certainly, the criterion of preset standard and gene loci information errors, is not intended as limiting in the present embodiment,
Can be determined according to actual conditions.
Further, because the gene studies related to respiratory system is constantly carried out, the gene related to respiratory system
The catastrophe of variant sites can be in renewal, and might not there are all breathings in current respiratory system gene pool
The variant sites catastrophe of the related gene of system, then, in embodiments of the present invention, also includes every preset time period pair
Described respiratory system database is updated.
Specific renewal process can be, every preset time period, acquisition is up-to-date to be published in internal authority scholarly journal, such as
The research paper related to respiratory system delivered on Nature, Nature Genetics etc., in the research paper that will obtain
The new gene loci information related to respiratory system, deletion wherein with a low credibility in preset standard and mistake gene position
Point information, is added in respiratory system database to realize updating.
After obtaining respiratory system gene pool, by site to be checked and the corresponding gene of respiratory system in respiratory system database
Multiple variant sites be compared.
In the present embodiment, this comparison procedure can directly be carried out behind the acquisition site to be checked of step S120, also may be used
To be to be carried out by user's triggering.I.e. after the inquiry request receiving user's triggering, execute the comparison in this step S130.
Alternatively, it is also possible to be, one or more of site to be checked obtaining in user input step S120, step S130
The middle site to be checked by user input is entered with multiple variant sites of the corresponding gene of respiratory system in respiratory system gene pool
Row compares.
Alternatively, it is also possible to be, user directly obtains the related variant sites of respiratory system from respiratory system gene pool.Tool
Body, user by input-output unit input gene name, site genome the information such as coordinate.Defeated receiving user
After the information entering, the information according to user input makes a look up in respiratory system gene pool, by lookup result, such as gene name
The various information such as word, site coordinate, base mutation type are shown.If finding user input in respiratory system gene pool
Information, then prove that the corresponding gene loci of this input information is related to respiratory system, and there is base mutation.It should be understood that
The position in the coordinate as site in genome for the site.
Step S140：When presence and mutating alkali yl identical with position in described respiratory system gene pool in described site to be checked
Identical variant sites, obtain the site mutation situation of the corresponding gene of respiratory system in described testing gene.
When comparative result is, exist in site to be checked and identical variant sites in respiratory system database, then can root
Determine in this testing gene, there is the site of the corresponding gene of respiratory system according to this identical variant sites in respiratory system database
Mutation, and catastrophe is consistent with this identical variant sites in respiratory system database.Thus it is possible in acquisition testing gene
There are the variant sites of which gene related to respiratory system and specifically dashing forward of each variant sites related with respiratory system
Change situation, which base mutation which position this catastrophe includes in is which base.
It should be understood that the position that identical variant sites refer to variant sites is identical and base mutation situation is identical, that is, exist
Same position has identical mutating alkali yl it is believed that being to become dystopy with identical in respiratory system database in site to be checked
Point.I.e. related to the respiratory system gene of the corresponding gene of respiratory system.
Then, related personnel can be according to the site mutation feelings of the corresponding gene of respiratory system in the testing gene obtaining
Under condition, and other information, such as every kind of catastrophe of respiratory system related gene, possible disease condition, determines this base to be measured
Respiratory system disease condition because of corresponding object.
Further, in the present embodiment, can also be according to the position of the corresponding gene of respiratory system in described testing gene
Every kind of mutating alkali yl of each variant sites of the corresponding gene of respiratory system in point mutation situation, and respiratory system database
Impact to protein function, determines the impact of the mutations on protein function of each variant sites in described testing gene, from
And can determine which protein function related to respiratory system of the corresponding object of testing gene (as corresponding people) is subject to
Which impact impact, receive.So that skilled addressee can according to the impact of protein function, in conjunction with other information,
As protein function changes interactively with organ concrete function etc., judge the respiratory disorder of the corresponding object of this testing gene
Ill probability and may be suffered from which respiratory disorder.
Certainly, the catastrophe including every kind of variant sites in embodiments of the present invention or directly is to breathing disease
The pathogenic situation of disease, the impact such as to bronchial astehma potentially include pathogenic, may cause a disease, hazards, not know, have conflict
Result of study, optimum, the wherein pathogenic situation of certain certain mutating alkali yl of position is hazards, shows that there is this kind this position
The probability that the object of mutating alkali yl suffers from bronchial astehma is very high, should be noted to prevent.
Second embodiment
Present embodiments provide a kind of acquisition device 200 in the mutational site of the corresponding gene of respiratory system, refer to figure
4, this device 200 includes：
Comparing module 210, for the multiple short sequence of testing gene and reference gene group are carried out comparing, acquisition is treated
The preliminary variant sites information of cls gene, described preliminary variant sites information includes the mutating alkali yl of multiple preliminary variant sites
And the positional information of each preliminary variant sites.
Filtering module 220, for according to described preliminary variant sites information, pre- by being unsatisfactory in multiple preliminary variant sites
If the variant sites of reserve are deleted, the variant sites in the described testing gene obtaining after deleting are as site to be checked.
Comparison module 230, for by described site to be checked and the corresponding gene of respiratory system in respiratory system gene pool
Multiple variant sites be compared, described respiratory system gene pool include the corresponding gene of respiratory system each become dystopy
The mutating alkali yl of point and each variant sites position.
Mutation acquisition module 240, when in described site to be checked exist identical with position in described respiratory system gene pool and
Mutating alkali yl identical variant sites, for obtaining the site mutation feelings of the corresponding gene of respiratory system in described testing gene
Condition.
Further, also include in respiratory system gene pool the corresponding gene of respiratory system each variant sites every kind of
The impact to protein function for the mutating alkali yl, the mutation acquisition module 240 in the present embodiment is additionally operable to according to described testing gene
The site mutation situation of the corresponding gene of middle respiratory system, the mutation determining each variant sites in described testing gene is to albumen
The impact of matter function.
Further, in the present embodiment, as shown in figure 4, also including gene pool to set up module 250, for setting up breathing system
System gene pool, described gene pool is set up module 250 and is included：Data capture unit 251, for obtain COSMIC gene database,
The gene loci information related to respiratory system in the clivar database of NCBI, described gene loci information includes breathing system
Unite the mutating alkali yl of each variant sites of corresponding gene and each variant sites position.Data deletes unit 252,
For by described gene loci information with a low credibility in preset standard and mistake gene loci information deletion, acquisition
Gene loci information forms described respiratory system gene pool.
Further, as shown in figure 5, this gene pool sets up module 250 also includes updating block 253, for every default
Time period is updated to described respiratory system gene pool.
Further, as shown in fig. 6, in the present embodiment, filtering module 220 includes one or more of：First deletes
Except unit 221, for removing in the plurality of preliminary variant sites, the number of allele is more than the change dystopy of predetermined threshold value
Point.Second deletion unit 222, for deleting in the plurality of preliminary variant sites, positioned at the upstream span of each insertion and deletion
Or the base number that all variant sites in span downstream, described upstream span and span downstream include is predetermined number.
3rd deletion unit 223, for by the plurality of preliminary variant sites, being spaced the change dystopy of default base number each other
Point deletion.4th deletion unit 224, for by the plurality of preliminary variant sites, corresponding GQ value is less than default GQ threshold value
Variant sites delete.5th deletion unit 225, for by the plurality of preliminary variant sites, corresponding MQ value is less than pre-
If the variant sites of MQ threshold value are deleted.
In this example, refer to Fig. 7, comparing module 210 can include：Comparing unit 211, for by described base to be measured
The multiple short sequence of cause and reference gene group are compared first, obtain the comparison result of SAM form；Duplicate removal unit 212, is used for
Duplicate removal is carried out to described comparison result, makes the short sequence number that a position of reference gene group is arrived in contrast be less than or equal to 1；Weight
Comparing unit 213, for carrying out local anharmonic ratio pair to the comparing result after duplicate removal；Computing unit 214, is used for recalculating locally
Anharmonic ratio to after comparison result in base mass fraction；Just sentence unit 215, for according to described base mass fraction, to this
Ground anharmonic ratio to after comparing result carry out SNP and indel analysis, obtain preliminary variant sites information.
In sum, the acquisition methods in mutational site of the corresponding gene of respiratory system provided in an embodiment of the present invention and dress
Put, behind the site to be measured obtaining testing gene, by multiple changes of site to be measured and corresponding gene in respiratory system gene pool
Ectopic sites are compared, it is hereby achieved that related to respiratory system multiple change dystopys in the variant sites in this testing gene
The catastrophe of point, for the judgement of the possible disease condition of assisted breathing system disease.
It should be noted that each embodiment in this specification is all described by the way of going forward one by one, each embodiment weight
Point explanation is all difference with other embodiment, between each embodiment identical similar partly mutually referring to.
For device class embodiment, due to itself and embodiment of the method basic simlarity, so description is fairly simple, related part ginseng
See that the part of embodiment of the method illustrates.
It should be understood that disclosed apparatus and method are it is also possible to pass through in several embodiments provided herein
Other modes are realized.Device embodiment described above is only schematically, for example, the flow chart in accompanying drawing and block diagram
Show the device of multiple embodiments according to the application, the architectural framework in the cards of method and computer program product,
Function and operation.At this point, each square frame in flow chart or block diagram can represent the one of a module, program segment or code
Part, a part for described module, program segment or code comprises holding of one or more logic function for realizing regulation
Row instruction.It should also be noted that at some as in the implementation replaced, the function of being marked in square frame can also be to be different from
The order being marked in accompanying drawing occurs.For example, two continuous square frames can essentially execute substantially in parallel, and they are sometimes
Can execute in the opposite order, this is depending on involved function.It is also noted that it is every in block diagram and/or flow chart
The combination of the square frame in individual square frame and block diagram and/or flow chart, can be with the special base of the function of execution regulation or action
System in hardware to be realized, or can be realized with combining of computer instruction with specialized hardware.
In addition, each functional module in each embodiment of the application can integrate one independent portion of formation
Divide or modules individualism is it is also possible to two or more modules are integrated to form an independent part.
If described function realized using in the form of software function module and as independent production marketing or use when, permissible
It is stored in a computer read/write memory medium.Based on such understanding, the technical scheme of the application is substantially in other words
Partly being embodied in the form of software product of part that prior art is contributed or this technical scheme, this meter
Calculation machine software product is stored in a storage medium, including some instructions with so that a computer equipment (can be individual
People's computer, server 100, or network equipment etc.) execution each embodiment methods described of the application all or part step
Suddenly.And aforesaid storage medium includes：USB flash disk, portable hard drive, read-only storage (ROM, Read-Only Memory), deposit at random
Access to memory (RAM, Random Access Memory), magnetic disc or CD etc. are various can be with the medium of store program codes.
It should be noted that herein, such as first and second, another or the like relational terms be used merely to an entity or
Person's operation is made a distinction with another entity or operation, and not necessarily requires or imply that between these entities or operation, presence is appointed
What this actual relation or order.And, term " inclusion ", "comprising" or its any other variant are intended to non-row
The comprising of his property, so that including a series of process of key elements, method, article or equipment not only include those key elements, and
And also include other key elements of being not expressly set out, or also include intrinsic for this process, method, article or equipment institute
Key element.In the absence of more restrictions, the key element being limited by sentence "including a ..." is it is not excluded that including institute
Also there is other identical element in process, method, article or the equipment of stating key element.
The foregoing is only the preferred embodiment of the application, be not limited to the application, for the skill of this area
For art personnel, the application can have various modifications and variations.All within spirit herein and principle, made any repair
Change, equivalent, improvement etc., should be included within the protection domain of the application.It should be noted that：Similar label and letter exist
Representing similar terms in figure below, therefore, once being defined in a certain Xiang Yi accompanying drawing, being then not required in subsequent accompanying drawing
It is defined further and to be explained.
The above, the only specific embodiment of the application, but the protection domain of the application is not limited thereto, and any
Those familiar with the art, in the technical scope that the application discloses, can readily occur in change or replacement, all should contain
Cover within the protection domain of the application.Therefore, the protection domain of the application should described be defined by scope of the claims.
Claims (10)
1. a kind of acquisition methods in the mutational site of the corresponding gene of respiratory system are it is characterised in that methods described includes：
The multiple short sequence of testing gene and reference gene group are carried out comparing, obtains the preliminary variant sites of testing gene
Information, described preliminary variant sites information includes mutating alkali yl and each preliminary variant sites of multiple preliminary variant sites
Positional information；
According to described preliminary variant sites information, the variant sites of default reserve will be unsatisfactory in multiple preliminary variant sites
Delete, the variant sites in the described testing gene obtaining after deleting are as site to be checked；
Described site to be checked is compared with multiple variant sites of the corresponding gene of respiratory system in respiratory system gene pool
Relatively, described respiratory system gene pool include the mutating alkali yl of each variant sites of the corresponding gene of respiratory system and each
Variant sites position；
When in described site to be checked, presence is identical with position in described respiratory system gene pool and mutating alkali yl identical becomes dystopy
Point, obtains the site mutation situation of the corresponding gene of respiratory system in described testing gene.
2. method according to claim 1 is it is characterised in that also include respiratory system pair in described respiratory system gene pool
The impact to protein function for the every kind of mutating alkali yl of each variant sites of the gene answered,
Methods described also includes：
According to the site mutation situation of the corresponding gene of respiratory system in described testing gene, determine each in described testing gene
The impact of the mutations on protein function of variant sites.
3. method according to claim 1 is it is characterised in that described by described site to be checked and respiratory system gene pool
In the corresponding gene of respiratory system multiple variant sites be compared before, also include setting up respiratory system gene pool, institute
State and set up respiratory system gene pool and include：
The gene loci information related to respiratory system, institute in acquisition COSMIC gene database, the clivar database of NCBI
State the mutating alkali yl of each variant sites and each the change dystopy that gene loci information includes the corresponding gene of respiratory system
Point position；
By in described gene loci information with a low credibility in preset standard and mistake gene loci information deletion, acquisition
Gene loci information forms described respiratory system gene pool.
4. method according to claim 3 is it is characterised in that also include：
Every preset time period, described respiratory system gene pool is updated.
5. method according to claim 1 is it is characterised in that described will be unsatisfactory for default guarantor in multiple preliminary variant sites
The variant sites deletion staying condition includes one or more of：
Remove in the plurality of preliminary variant sites, the number of allele is more than the variant sites of predetermined threshold value；
Delete in the plurality of preliminary variant sites, all in the upstream span or span downstream of each insertion and deletion
The base number that variant sites, described upstream span and span downstream include is predetermined number；
By in the plurality of preliminary variant sites, the variant sites being spaced default base number each other are deleted；
By in the plurality of preliminary variant sites, the variant sites that corresponding GQ value is less than default GQ threshold value are deleted；
By in the plurality of preliminary variant sites, the variant sites that corresponding MQ value is less than default MQ threshold value are deleted.
6. method according to claim 1 is it is characterised in that the described multiple short sequence by testing gene and reference gene
Group carries out comparing, and the preliminary variant sites information obtaining testing gene includes：
The multiple short sequence of described testing gene and reference gene group are compared first, is obtained the comparison result of SAM form；
Duplicate removal is carried out to described comparison result, so that the short sequence number of contrast a to position of reference gene group is less than or equal to
1；
Local anharmonic ratio pair is carried out to the comparing result after duplicate removal；
Recalculate local anharmonic ratio to after comparison result in base mass fraction；
According to described base mass fraction, to local anharmonic ratio to after comparing result carry out SNP and indel analysis, obtain preliminary
Variant sites information.
7. method according to claim 1 is it is characterised in that described variant sites are SNP.
8. a kind of acquisition device in the mutational site of the corresponding gene of respiratory system is it is characterised in that described device includes：
Comparing module, for the multiple short sequence of testing gene and reference gene group are carried out comparing, obtains testing gene
Preliminary variant sites information, described preliminary variant sites information includes the mutating alkali yl of multiple preliminary variant sites and every
The positional information of individual preliminary variant sites；
Filtering module, for according to described preliminary variant sites information, being unsatisfactory for default reservation in multiple preliminary variant sites
The variant sites of condition are deleted, and the variant sites in the described testing gene obtaining after deleting are as site to be checked；
Comparison module, for by multiple changes of described site to be checked and the corresponding gene of respiratory system in respiratory system gene pool
Ectopic sites are compared, and described respiratory system gene pool includes the mutation of each variant sites of the corresponding gene of respiratory system
Base and each variant sites position；
Mutation acquisition module, when presence and mutating alkali yl identical with position in described respiratory system gene pool in described site to be checked
Identical variant sites, for obtaining the site mutation situation of the corresponding gene of respiratory system in described testing gene.
9. device according to claim 8 sets up module it is characterised in that also including gene pool, for setting up breathing system
System gene pool, described gene pool is set up module and is included：
Data capture unit is related to respiratory system in the clivar database of COSMIC gene database, NCBI for obtaining
Gene loci information, described gene loci information includes the mutation alkali of each variant sites of the corresponding gene of respiratory system
Base and each variant sites position；
Data delete unit, for by described gene loci information with a low credibility in preset standard and mistake gene position
Point information deletion, the gene loci information of acquisition forms described respiratory system gene pool.
10. device according to claim 8 is it is characterised in that described filtering module includes one or more of：
First deletion unit, for removing in the plurality of preliminary variant sites, the number of allele is more than predetermined threshold value
Variant sites；
Second deletion unit, for deleting in the plurality of preliminary variant sites, positioned at each insertion and deletion upstream span or
The base number that all variant sites in person's span downstream, described upstream span and span downstream include is predetermined number；
3rd deletion unit, for by the plurality of preliminary variant sites, being spaced the variation of default base number each other
Site is deleted；
4th deletion unit, for by the plurality of preliminary variant sites, corresponding GQ value is less than the variation of default GQ threshold value
Site is deleted；
5th deletion unit, for by the plurality of preliminary variant sites, corresponding MQ value is less than the variation of default MQ threshold value
Site is deleted.
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