CN104178572B - Sequencing data processing method and device - Google Patents
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- CN104178572B CN104178572B CN201410416250.3A CN201410416250A CN104178572B CN 104178572 B CN104178572 B CN 104178572B CN 201410416250 A CN201410416250 A CN 201410416250A CN 104178572 B CN104178572 B CN 104178572B
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Abstract
The invention provides a sequencing data processing method and device and an individual chromosome aneuploidy non-diagnosis detection method. The first-type chromosome window combined nucleic acid molecular weight value, the nucleic acid molecular weight of the corresponding window on the second-type chromosome, and the functional relationship are utilized to process the first chromosome sequencing data and perform non-diagnosis detection on the individual chromosome aneuploidy.
Description
Related application
The application is to be on April 23rd, 2010 applying date, entitled " detection method of fetal chromosomal aneuploidy "
The division of Chinese patent application 201080032859.0.
Technical field
The present invention relates to medical detection field, more particularly to the detection method of foetal chromosome aneuploidy, pass through
The nucleic acid molecules of the value of nucleic acid molecular weight of the first chromosomoid window combination corresponding window on the second chromosomoid with it
Amount, and functional relationship therebetween is detecting prenatal foetal chromosomal aneuploidy.
Background technology
Fetal aneuploidy chromosome refers to the exception of some region of amount of chromosome or chromosome.This abnormal amount
Can be abnormal height, such as No. 21 three bodies of fetus, are No. 21 chromosomes more than normal diploid fetus；Or it is different
Often low, such as Turner syndrome patient is exactly to have lacked one or part x chromosome.
Using the method for such as chorionic villus sampling (cvs) or amniotomy in tradition, obtain and separate at fetus
To cell, it is possible to use these cells carry out routine prenatal diagnosis.Although carrying out the standard of diagnosis of fetal aneuploidy in this way
Really property is higher, however, these methods are invasive, has obvious danger to mother and fetus.(tabor a,et
al.randomised controlled trial of genetic amniocentesis in4606low-risk
women.lancet1986,1:1287-1293).
Find there is acellular circulation fetus dna in Maternal plasma and serum, this provides for non-invasive prenatal diagnosis
Unlimited possibility., in pnas2008,105:20458-20463, the article on magazine is " using big for rossa w.k.chiu et al.
The method of scale high-flux sequence is carrying out the noinvasive prenatal diagnosis of aneuploid chromosome " describe profit in detail in this way
To carry out the diagnosis of noinvasive fetal aneuploidy, and to point out can farthest obtain in peripheral blood by the means of sequencing
The information of face nucleic acid molecules, particularly contained in the parent sample the extracting nucleic acid molecules from fetal chromosomal are relatively
(rossa w.k.chiu, et al.noninvasive in the case of being relatively little of for the amount of background maternal nucleic acids molecule
prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel
genomic sequencing of dna in maternalplasma.pnas,2008,105:20458-20463).Described
Method is: first extracts the nucleic acid molecules in maternal plasma, then carries out through extensive high flux second filial generation sequenator
Sequencing, obtains the positional information which item chromosome the sequence information of dna segment and sequence fall on.Dennis lo et al. base
In this essential information, then core on the chromosome (such as No. 21, No. 18, No. 13 chromosomes) having medical significance for the statistics
The amount of acid molecule and the amount from the nucleic acid molecules as background stainings body, are measured by this two, can obtain a parameter,
Then this parameter is contrasted with the one or more thresholdings built by normal sample, and then send out now with medical significance dye
This parameter of abnormal sample and multiple thresholdings are had to there is larger difference (dennis lo, et on colour solid
al.presence of fetal dna in maternal plasma and serum.lancet 1997,350:485-
487).Thus, this method can be used to detect the aneuploid of fetus.
However, this method has the limitation of itself.First it for each sample detection all rely on logical
Cross the normal control values that the sequence distributed quantity of n (n is more than 20) standard negative control sample is set up, that is, mentioned above
Thresholding.Based on these normal control values, it is only possible to analyze the situation of detected sample.That is correctly sentence to make
Disconnected, the interdependency between the measured value of each sample is obvious, because between comparative sample to be passed through and sample
The difference of value is possible to make correct judgement.
Therefore, because needing the relation being compared to each other between sample, each batch sample required by this method is adopted
Experiment condition is more strict, if experiment condition gap larger it will be difficult to obtain more believable normal control values or sample value.
This experiment condition includes sample preparation, the batch of agents useful for same and the species of early stage, and sequencing gc is partial to, system temperature etc.,
That is, the change of various experiment conditions all should control in fairly small scope, otherwise can lead between each negative control sample
The variance of value increase, or the relatively large deviation each other of the value of each negative control sample, the value of some negative sample is very
To departing from range of normal value, become outlier.In the same manner, this method also relies on the accurate of the value of sample to be detected
Property, for obtaining exact value, prepare this sample and reagent used and sequencing condition, be partial to including sequencing gc, system temperature etc., all
Should with implement as far as possible being consistent of negative control sample.Only in this way, could be ideal and believable count exception
The exception of distributed quantity on the chromosome studied for the sample, and ensure that its value is believable.
But it is ensured that the concordance of each microsystem condition is not too simple thing under the conditions of experiment and sequencing, because
For having other interference factors in experimentation, so it is not ideal or several between each sample to frequently can lead to experimental data
According to differing greatly, on the one hand, once data deficiency concordance, the credibility of its testing result also decreases, and produces false sun
Property or false-negative result；On the other hand, if data is larger due to the changing factor gap of experiment condition, more can be allowed to
Become outlier and be abandoned without.It is known that sequencing cost is current still higher, so outlier is abandoned without reason
Certainly can cause suitable waste.
More advanced at present as aforesaid examining of fetal chromosomal aneuploidy is carried out by sequence measurement
In disconnected method, the experiment condition of sample preparation or sequencing etc. is required relatively strictly, because in itself, it depends on sample
This comparison and sample between.Normal sample and exceptional sample are what there were significant differences in value to be studied, but once
When being more than the difference between exceptional sample and normal sample due to the different introduced difference of experiment condition between sample,
Arise that wrongheaded situation, reduce the credibility of inspection.
Content of the invention
The technical problem to be solved
For this situation, inventor has carried out many-sided in-depth study, finally develops a kind of sample and itself contrasts
Method, no longer made decision by the contrast between sample, but by comparing correlation from sample itself
To judge.Which eliminate the dependency to experiment condition, which provide and can be used for fetal chromosomal aneuploidy
Non-invasive detection new method, it eliminates the dependency to experiment condition.
The technology used in the present invention means
Specifically, inventor is based on sequencing data, finds that interchromosomal has the dependency of mutually corresponding nucleic acid amount,
Following methods are provided according to this dependency, the data acquisition and processing (DAP) method according to the present invention detects the non-of fetal chromosomal
Ortholoidy.
Specifically, the method for inventor includes:
1. sequencing data processing method, methods described is applied to sequencing data processing meanss, and described sequencing data processes dress
Put including sequencing unit and modeling unit, methods described includes:
(1) described modeling unit receives the sequencing data from described sequencing unit, described sequencing data include multiple just
Often the sequencing data of whole genome of individual specimen, the chromosome to be studied as object of study is defined as the first chromosomoid,
In full-length genome, remaining chromosome is defined as the second chromosomoid；
(2) all chromosomes in (1) are respectively cut into overlapped or nonoverlapping fragment, each fragment is defined as
One window；
(3) in statistics (2) nucleic acid molecules of each window of multiple normal individual sample chromosomes amount, this amount is defined as going
For value；
(4) according to the behavior value in (3), by mathematical statistics method find on the second chromosomoid in (1) with (1) in
The first chromosomoid have window or a combination thereof of strong correlation, set up the window of the first chromosomoid and found have strong phase
Closing property window or the functional relation a of a combination thereof；
(5) using the functional relation in (4) and the part with the first chromosomoid or the first chromosomoid in (4)
Have the window of the second chromosomoid of strong correlation or a behavior value of window combination, determine the first chromosomoid in (1) or
(1) scope of the normal behaviour value of the part of the first chromosomoid in.
2. sequencing data processing meanss, comprising:
Sequencing unit, described sequencing unit is used for the genome sequencing of sample, produces sequencing data, described sequencing data
Including the sequencing data of whole genome of multiple normal individual samples, the chromosome to be studied as object of study is defined as first
Chromosomoid, in full-length genome, remaining chromosome is defined as the second chromosomoid；
Modeling unit, described modeling unit is used for receiving the sequencing data from sequencing unit；By all chromosomes respectively
Cut into overlapped or nonoverlapping fragment, each fragment is defined as a window；Count the plurality of normal individual sample
The amount of the nucleic acid molecules of each window of this chromosome, this amount is defined as behavior value；According to described behavior value, by mathematical statistics method
Find the window or a combination thereof that there are strong correlation with described first chromosomoid on described second chromosomoid, set up the first kind
The window of chromosome and the functional relation a having strong correlation window or a combination thereof being found；Using described functional relation a
Window or window with the second chromosome that the described part with the first chromosomoid or the first chromosomoid has strong correlation
The behavior value of combination, determines the model of the normal behaviour value of part of described first chromosomoid or described first chromosomoid
Enclose.
3. the non-diagnostic method of detection individual chromosome aneuploidy or chromosomal section aneuploidy, comprising:
A. carry out genome sequencing in advance or simultaneously to multiple normal individual samples, using as object of study wait grind
Study carefully chromosome and be defined as the first chromosomoid, in full-length genome, remaining chromosome is defined as the second chromosomoid；
B. in advance or simultaneously using the method described in project 1 sequencing data available from a is processed, obtain first kind dye
The window of colour solid and have the window of the second chromosomoid of strong correlation or window combination with described first chromosomoid window
Functional relation and, the scope of the normal behaviour value of the part of described first chromosomoid or described first chromosomoid；
C. test individual is sequenced, and then obtains the behavior value of individuality the second chromosomoid of to be detected itself, such as
The amount of the individual nucleic acid molecules of the first chromosomoid to be detected that fruit calculates according to the functional relation in b is not in b
In the range of normal behaviour value, then can determine that the first chromosomoid of test individual is non-ortholoidy.
4. detect the non-diagnostic method of individual chromosome aneuploidy, comprising:
Full-length genome is sequenced, the chromosome to be studied as object of study is defined as the first chromosomoid, entirely
In genome, remaining chromosome is defined as the second chromosomoid；According to Equations of The Second Kind chromosome segment and first kind chromosome segment
The dependency of behavior value, founding mathematical models on full-length genome；
Test individual is carried out with genome sequencing, so obtain to be detected individual itself the first chromosomoid and the
The behavior value of two chromosomoids, if the behavior value in certain confidence level is unsatisfactory for aforementioned mathematical model, can be true
The chromosome determining test individual is aneuploidy.
5. the method for project 4, methods described includes:
Whole chromosomes are respectively cut into overlapped or nonoverlapping fragment, each fragment is defined as a window
Mouthful；
By the nucleic acid molecules of each window of chromosome from the normal individual sample of dye-free volume defect for the sequencing statistics
Amount, this amount is defined as behavior value；
According to behavior value, being found by mathematical statistics method has strong correlation with the first chromosomoid on the second chromosomoid
The window of property or a combination thereof, set up functional relation；
The amount of real nucleic acid molecules in each window of second chromosomoid in foundation functional relation and sample to be detected,
Under certain confidence level, obtain the analogue value confidence interval of the behavior value of the first chromosomoid to be studied；
By judging the relation of behavior value and its analogue value confidence interval of the first chromosomoid of detection sample, judge the
Whether one chromosomoid is abnormal.
6. the method for project 4, including modeling procedure (1)-(4) and detecting step (5)-(8), specific as follows:
(1) full-length genome of the normal individual from dye-free volume defect is selected to be sequenced, using as object of study
Chromosome to be studied is defined as the first chromosomoid, and remaining chromosome is defined as the second chromosomoid；
(2) all chromosomes in (1) are cut into overlapped or nonoverlapping fragment, each fragment is defined as one
Individual window；
(3) amount of the nucleic acid molecules of each window of statistics multiple sample chromosomes under multiple different experimental conditions, is defined as
Behavior value；
(4) according to the behavior value in (3), by mathematical statistics method find on the second chromosomoid in (1) with (1) in
The first chromosomoid have window or a combination thereof of strong correlation, set up the window of the first chromosomoid and found have strong phase
Closing property window or the functional relation a of a combination thereof, thus complete modeling procedure；
(5) all chromosomes of the full-length genome of individual sample to be detected are sequenced, wherein as object of study
Chromosome to be studied be equally defined as the first chromosomoid, it is identical numbering corresponding with the first chromosomoid in (1)
Chromosome, remaining chromosome is as the second chromosomoid；
(6) according to the chromosome of sample to be detected in same window specification cutting (5) in (2), statistics first kind dyeing
The behavior value of body and the second chromosomoid；
(7) the behavior value of each window of the second chromosomoid in (6) is incorporated in relational expression a, sets confidence level, meter
Calculate and obtain the theoretical interval of first kind chromosome behavior value；
(8) if in (6) the behavior value not behavior value in (7) of first chromosomoid of statistics theoretical range
Interior then it is assumed that first kind chromosomal abnormality to be studied.
7. the relational expression of step (1)-(4) wherein is repeated to make in the detection of different samples to be tested by the method for project 6
With it is not necessary to all replication during each pattern detection, measuring the aneuploidy of chromosome by carrying out step (5)-(8).
Above-mentioned " scope of normal behaviour value " meaning with " behavior value theoretical interval ", be by set confidence level, will
Substitute into functional relation with the behavior value of the window of the second chromosomoid of the first chromosomoid strong correlation and calculate acquisition.
Above-mentioned " confidence interval " includes the confidence interval of each window and the confidence interval of whole chromosome.
Above-mentioned " different experimental conditions " main inclusion sequencing gc content is inconsistent, and reagent conditions are different, experiment preparation
Situations such as method has difference.
The invention provides a kind of method, the method using the single sample from anemia of pregnant woman, and according to its Chromosome number
According to judging whether fetal chromosomal is aneuploidy.By this method, invention is finally obtained one group of first chromosomoid group of windows
Close, and assume the analogue window of strong correlation with it in the second chromosomoid and combine, and correct under certain confidence level
Functional relation afterwards.By these windows and functional relation it can be determined that whether the first chromosomoid of concrete sample is
Aneuploidy.
The modeling process of the present invention once it is determined that, that is, be no longer necessary to substantial amounts of normal sample and be modeled, only need to be each
The behavior value of the second chromosomoid of itself of sample to be detected substitutes in relational expression a that modeling process determines, you can judge
Whether the first chromosomoid is normal.
The technique effect of the present invention
The method of the present invention can be used for aneuploid detection.The method of the present invention has been broken away from former method and has been controlled for strict
Relying on more by force of experiment condition, is applicable to revise by the led to outlier sample of experiment condition variation, thus reducing wave
Take.The method of the present invention can pass through sample own control, and does not rely on the value of other samples, to judging that fetal chromosomal is
No for aneuploidy provide important evidence；The risk that the method for the present invention also avoids invasive method simultaneously and leads to.The present invention
Method is based on sequencing and not only can be used to diagnose whether chromosome is aneuploidy, more can be used under unknown experiment condition or real
Test condition control bad in the case of obtained isolated sample chromosomal aneuploidy diagnosis, and can with background technology in
Method combine use, verify each other, thus improving the accuracy of inspection further, from big impact, permissible
Efficiently control the natality of the aneuploid chromosome fetus including No. 21 three bodies.In addition the method for the present invention establishes
A kind of data processing method, flexible and changeable, No. 21 chromosomes can be simulated, that is, find out consistent with the optimum behavior value of No. 21 chromosomes
Internal reference window combination it is also possible to be generalized to all chromosomes interested, such as No. 18 chromosomes, the first kind such as No. 13 chromosomes
Chromosome, or even some chromosomal fragments interested, thus increase the range of application of the method.
Brief description
Fig. 1: find in full-length genome (except the first chromosomoid to be studied) and determine and for demonstrating the present invention
The flow chart of the method that the analogue window that each window combination of one chromosomoid has extremely strong dependency combines, is designated as method 100.
Fig. 2: for demonstrate the present invention diagnose anemia of pregnant woman pregnant fetus be whether chromosomal aneuploidy method flow chart,
It is designated as method 200.
Fig. 3: the scatterplot of linear dependence between display window.Come from genomic window mark by counted to table 3
Number for the nucleic acid molecules on (chr4,642) window area value (89 behavior values xi), be numbered with from genomic window
The value (89 behavior values yi) of the nucleic acid molecules on (chr21,180) window area, using correlation analysiss statistically,
Calculate the correlation coefficient between two windows, and relation function.The r of display on figure2For 0.9724, illustrate that two window dependencys are fine.
Fig. 4: the scatterplot of linear relationship between display window.By being counted to table 3 from genomic window mark
Number for the nucleic acid molecules on (chr1,256) window area value (89 behavior values xi), be numbered with from genomic window
The value (89 behavior values yi) of the nucleic acid molecules on (chr21,180) window area, using correlation analysiss statistically,
Calculate the dependency relation coefficient r between two windows, due to correlation coefficient r2Only only have 0.6, two windows are linear as seen from the figure
Relation is bad.
Fig. 5: the scatterplot of linear dependence between display window.By being counted to table 7 from genomic window label
Value (89 behavior values xi) for the nucleic acid molecules on (chr8,710) window area, is numbered with from genomic window
The value (53 behavior values yi) of the nucleic acid molecules on (chr18,259) window area, using correlation analysiss statistically,
Calculate the correlation coefficient between two windows, and relation function.The r of display on figure2For 0.9816, illustrate that two window dependencys are fine.
Fig. 6: the scatterplot of linear relationship between display window.By being counted to table 7 from genomic window mark
Number for the nucleic acid molecules on (chr1,8) window area value (53 behavior values xi), be numbered with from genomic window
The value (53 behavior values yi) of the nucleic acid molecules on (chr18,259) window area, using correlation analysiss statistically,
Calculate the dependency relation coefficient r between two windows, due to correlation coefficient r2Only only have 0.0043, two window line as seen from the figure
Sexual intercourse is bad.
Fig. 7: the figure of the actual value of display normal sample and exceptional sample and the relation of respective analogue value confidence interval.Tool
Body shows that 4 are derived from maternal blood sample of nucleic acid, the actual value of sample 1 and sample 2 respective analogue value confidence interval it
Outward, sample is No. 21 chromosomal aneuploidies；And the actual value of sample 5 and sample 6 is within respective analogue value confidence interval,
Sample is normal.
Fig. 8: the figure of the actual value of display normal sample and exceptional sample and the relation of respective analogue value confidence interval.Aobvious
Show that 4 are derived from maternal blood sample of nucleic acid, the actual value of sample 3 and sample 4 outside respective analogue value confidence interval, sample
This is No. 21 chromosomal aneuploidies；And the actual value of sample 7 and sample 8 is within respective analogue value confidence interval, sample
Normally.
Fig. 9: the figure of the actual value of display normal sample and exceptional sample and the relation of respective analogue value confidence interval.Tool
Body shows that 4 are derived from maternal blood sample of nucleic acid, sample 1, and the actual value of sample 2 and sample 3 is in respective analogue value confidence
Within interval, sample is that No. 18 chromosomes are normal；And the actual value of sample 4 is outside respective analogue value confidence interval, it is 18
Number chromosomal aneuploidy.
Figure 10: the figure of the actual value of display normal sample and exceptional sample and the relation of respective analogue value confidence interval.
Display 2 is derived from maternal blood sample of nucleic acid, the actual value of sample 5 and sample 6 outside respective analogue value confidence interval,
Sample is No. 18 chromosomal aneuploidies.
Specific embodiment
Definition
In order to more clearly illustrate the present invention, the term using in the present invention is defined as follows.
" aneuploid chromosome " or " chromosomal aneuploidy " refers to certain chromosome with respect to normal diploid base
Because this in group chromosome has whole piece or excalation or redundancy.It is often the case that have extra item chromosome or
Item chromosome therein is lost.The most common situation of chromosomal aneuploidy is three bodies, that is, have an extra chromosome.Example
If No. 21 chromosome trisomy are exactly a kind of chromosomal abnormality finding No. 21 chromosomes of Article 3 in cell.
" biological specimen " refers to the sample comprising nucleic acid molecules interested from object (as anemia of pregnant woman), such as blood plasma,
Serum or the biological specimen containing nucleic acid molecules for the other.
" normal sample " refers to that any chromosome the abnormal maternal blood sample of aneuploid.
" nucleic acid molecules " refer to contained deoxyribonucleotide molecule in the biological specimen extracting, and herein refer to give birth to
Contain in thing sample, from the nucleic acid molecules of the 300000000 genome base pairs of people.
" nucleic acid fragment molecule " refers to that biological specimen, after the steps such as preparation, can obtain its sequence by sequencing means
Information and its positional information on genome simultaneously can represent the fragment nucleic acid molecules of nucleic acid molecules corresponding thereto.
After " unique nucleic acid molecules " refer to sequencing, information analysiss show that this nucleic acid molecules has and only on human genome
There is the position of a distribution.
" window " refers to split chromosome or chromosomal region according to artificially defined unit nucleotide sequence length
Become to have overlapping region or the fragment not having overlapping region, and each window correspond on this chromosome or chromosomal region only
One section of one, positional information is unique.
" amounts of nucleic acid molecules ", also referred to as behavior value, navigate to each chromosome according to nucleic acid fragment molecule based on sequencing concrete
Behind position, it is positioned at the bar number of the nucleic acid fragment molecule in this region obtained by statistics or can reflect that how many nucleic acid divides
Son is distributed in the value in this region, such as the bar by the nucleic acid fragment molecule that can be positioned at this region of statistics gained
Number, or it is derived from the bar number institute divided by all nucleic acid molecules being counted or partly being counted for the bar number of this region nucleic acid molecules
The ratio obtaining or the accumulated value of nucleic acid fragment molecular length etc., in a word, for an experiment sample, a certain
In window area, as long as this value can reflect the situation of the amount of the distribution in this window for the nucleic acid molecules, this value is just permissible
It is referred to as behavior value or the amount of the nucleic acid molecules from this window.
" from the amount of the nucleic acid molecules of a certain window " (the behavior value of window) refers to be based on according to nucleic acid fragment molecule
After sequencing navigates to each chromosome particular location, the bar number of the nucleic acid fragment molecule that can be positioned at this region of statistics gained
Or can reflect that how many nucleic acid molecules on earth are distributed in the value in this region, such as will can the positioning of statistics gained
In the bar number of the nucleic acid fragment molecule in this region, or from the same area nucleic acid molecules bar number counted divided by all or
A ratio that the bar number of nucleic acid molecules that part is counted is obtained or the cumulant of nucleic acid fragment molecular length etc., always
It, is for an experiment sample, as long as this value can reflect the situation of the amount of the distribution in this window for the nucleic acid molecules,
This value is just properly termed as behavior value or the amount of the nucleic acid molecules from this window.
" behavior value is consistent " refers to two behavior values, and one of behavior value changes, and another behavior value occurs simultaneously
The change of functional relation approximate expression can be used.
" actual value " refers to the amount of the nucleic acid molecules of the window from the first chromosomoid.
" the first chromosomoid " refers to all or part of nucleotide sequence of value of clinical studies, in other words medically,
Imbalance through commonly using these chromosomes to detect some abnormal symptoms.Such as No. 21 chromosome sequences, No. 18 chromosomes
Sequence, No. 13 chromosome sequences, x chromosome sequence or y chromosome sequence etc..
" the second chromosomoid " refers to remove other chromosomes of the first chromosomoid on genome, and middle finger of the present invention is concrete
Other chromosomes of the first chromosomoid to be studied are removed in enforcement.
" the first chromosomoid window combination " refers to the window combination being had overlapping or non-overlapping window to be constituted by several,
This window combination can cover the first chromosomoid all or in part.
" being had the analogue window (analogue window combines) of extremely strong dependency with the window of the first chromosomoid " is referred in research
In genome, it is present in the specific analogue window on other chromosomes in addition to the first chromosomoid of current research, this specific mould
Intend window and there is strong correlation with the first chromosomoid window under current research, it shows themselves in that for each
For normal biological sample, it is constantly present such a relation, in this sample, derive from the first chromosomoid window
If the amount of nucleic acid molecules change, from the analogue window (simulation having pole dependency with the first chromosomoid window
Window combination) nucleic acid molecular weight also occur to change accordingly, and a this amount changes, another amount also changes
Dependency relation can by correlation function expression formula approximate expression out.The selected square of analogue window (analogue window combination)
Method 100.
" confidence interval of chromosome behavior value to be studied " refers to by the window combination from the first chromosomoid
The amount of nucleic acid molecules and corresponding functional relation counted under certain confidence level, this first chromosomoid (dyeing
Body window) confidence interval.If relationship between expression formula is y=ax+b between two windows, now statistics gained from first
It is x that chromosomoid window has the amount of the nucleic acid molecules of pole dependency relation analogue window, can calculate and must simulate according to functional relation
Value y, can obtain corresponding confidence interval further according to knowledge of statistics.
" uneven " herein refers to be not calculated according to analogue window and functional relation by comparing actual value
Confidence interval in it is believed that the biological specimen now detecting is deposited in the first chromosomoid studied or first kind chromosomal region
Uneven.
" chr " in the present invention is the abbreviation of " chromosome ", and such as " chr18 " represents No. 18 chromosome.Chromosome is double
Coiled strand includes a normal chain, an anti-chain, and positive anti-chain is complementary, that is, chain base sequence determines, in addition a complementary strand
Base sequence also determines.Therefore, each position base occurs in pairs, and base pair is complementary: a and t is complementary, c
Complementary with g.On the chromosome of the mankind, on the basis of the base positions of normal chain, any one position all referring to a pair of base pair,
Both contained the base in normal chain, also contains the complementary base on anti-chain simultaneously, position location in the present invention, be all with
Bp is unit, i.e. base pair abbreviation (base pair).Such as chr21:150-450kbp, represents and is on No. 21 chromosomes
150000 base pairs are to the window of 450000 base pairs.To distinguish direction if, normal chain refers to 5 ' -3 ' that chain, anti-chain
It is that chain being complementary to, and direction should be 3 ' -5 '.We are generally on the basis of normal chain base positions, locate here
Base in chr21:150bp refers to, from normal chain, direction 5 ' -3 ', the 1st base starts to count, and is in No. 150 that base
Right；From minus strand, direction 3 ' -5 ', the 1st base starts to count, and is in No. 150 that base pair.
In embodiments of the invention, provide a kind of mould found and have pole dependency with the first chromosomoid window combination
The method intending window or window combination.The essence of the described method of " finding analogue window or window combination " is by novelty
Each window between the correlation analysiss of behavior value find out the mould having extremely strong dependency with the first chromosomoid window or window combination
Intend window or analogue window combination.For example, the selected analogue window combination being known as the first chromosomoid window combination
In window and its first corresponding chromosomoid window between behavior value correlation coefficient close to 1, and be obtained in that one
Individual universal functional relation, for stating the dependency relation between two window behavior values.
When the window of the first chromosomoid only finds a second chromosomoid window and has strong correlation therewith, function closes
It is the function of a single variable relational expression that formula is therebetween, if having found multiple strong correlation window, functional relation is matching
Function of many variables relational expression after optimization.
Embodiment of the present invention, there is provided following diagnostic methods, by judging the first kind from same sample
Whether the amount of the nucleic acid molecules of chromosome window combination diagnoses aneuploid chromosome, confidence interval origin in confidence interval
Come from the aforementioned dependency relation found between the behavior value of analogue window combination determining and each respective window to together decide on.
Embodiment
Below example is only used for explaining the present invention, rather than is used for limiting the scope of the invention, any and basis
The method of invention variant of equal value is included in the middle of the present invention.
Embodiment one
Step 1: obtain sequencing data needed for modeling
Select 89 normal samples, these samples are prepared under discrepant experiment condition and is sequenced.
In brief, first prepare dna library, then nucleic acid fragment molecule is connected in solexa sequence measuring joints, Ran Houfen
From purified nucleic acid fragments length 150 to 300 base pairs nucleic acid molecules.The nucleic acid molecules connecting joint can be with flow
Cell surface complementarity joint hybridizes, and under certain condition, nucleic acid molecules cluster grows, then in illumina genome
36 wheel sequencing circulations are passed through on analyzer, that is, is equivalent to the nucleic acid fragment that each nucleic acid molecules has recorded 35 base pairs.Connect
Get off the sequence information recording through a pipeline process, may finally obtain and with the human genomic sequence in ncbi be
The eland comparison result of canonical sequence.
Under study for action, for avoiding the interference of some repetitive sequences, those are in genome tandem sequence repeats and turn by inventor
The nucleic acid molecule fragment that seat repeats is rejected, and only counts the nucleic acid fragment molecule that those can navigate to genome unique positions.This
Sample is got on very well, and in all nucleic acid molecules measured and, probably only a quarter to 1/3rd nucleic acid molecules are to determine
Genome unique positions are arrived in position.The nucleic acid molecules that now these are counted are referred to as unique nucleic acid molecules, and this counts gained
The amount of unique nucleic acid molecules still represent the amount of the nucleic acid molecules being distributed in specific genome area.
This step corresponds to 110,120 steps of Fig. 1.
Step 2: set up No. 21 chromosome detection models
Flow chart according to Fig. 1 is carried out, and the process of Mathematical Models is completed by optimization for program.Computer program
Selected by different parameter, complete the searching of dependency window, find optimized parameter, set up the first chromosomoid window and the
The functional relation of two chromosomoid windows.
In 130 steps, based on sequencing, by the means of analysis of biological information, every measured nucleic acid fragment can be divided
Son navigates on the accurate location of genome.
In 140 steps, cutting window is carried out to each sample.Every chromosome constituting genome is divided into some windows
Mouth sequence.Whole gene group is cut into the window of suitable size, being equivalent to regard every chromosome as has overlay region by some
The combination of the window in domain or non-overlapping region.The base pair of about 47mega as a total of in No. 21 chromosomes, if big with 10mega
If little is a window, and the position that each window starts slides backward 1mega size, then No. 21 chromosomes correspond to 47
There is the window of the 10mega size of overlap.The length of window size that can artificially defined want and the length of windows overlay region sequence
Degree, and be also window number, produce the mapping that a pair of windows numbers the true coordinate on window each chromosome on genome.
With 300k as window size in embodiment, 150k be overlap splitter (be each window initiating terminal be front
One window initiating terminal slides backward 150k), table 1 shows 40 windows after No. 21 chromosomes of cutting.If a window pair
The window answered is numbered chr21,2, then its corresponding position on genome is chr21:150-450kbp.
Table 1
Table 1 illustrates the position by the label and window of the artificially window that No. 21 chromosomes of cutting are obtained on genome
Put coordinate, the exterior and the interior only shows 40 windows.As window is numbered (chr21,180), represent it be cutting No. 21 chromosomes after
180th window, the particular location on No. 21 chromosomes is coordinate is (chr21:26850-27150kbp), that is, be in 21
Between 26850000 base pairs of number chromosome and 27150000 base pairs.Thus, each window label represent right
Answer the mapping position of chromosome, i.e. the chromosomal region of one section of artificial cutting.
In embodiment, No. 4 chromosomes are non-first chromosomoids, if with 300k base pair size for a window,
And the mode that the position that window starts every time slides backward 150k base pair can cut into some windows in the same manner, table 2 lists two
Ten window labels and positional information on chromosome are window coordinates.Window as corresponding in window is numbered chr4,
2, then its corresponding position on genome is chr4:150-450kbp.
Table 2
Illustrate the label of the window being obtained by artificial cutting rice chromosome in table 2 and represent it in genome
On position window coordinates, only show 20 windows therein.As window is numbered (chr4,643), represent that it is cutting 4
180th window thereon after number chromosome, the particular location on No. 4 chromosomes is coordinate is (chr4:96300-
96600kbp), that is, it is between 96330000 base pairs and 96600000 base pairs of No. 4 chromosomes.
In 150 steps, the sample these prepared under the conditions of discrepant and is sequenced, based on sequencing gained information, difference
The amount of statistics this nucleic acid fragment molecule from each series of windows of various kinds.
As the window of No. 21 chromosomes, refer to the window combination of the chromosome of value of clinical studies as previously mentioned.Assume
In this window combination, the coordinate of a certain window is (chr21:89000-89200bp), illustrates that it is on No. 21 chromosomes,
And this window area starts to the 89200th base pair to terminate from the 89000th base pair, and now, record is a certain
The origin coordinates of nucleic acid fragment molecule is chr21:89100, and measured molecule fragment length is 35 base pairs, then,
The sequence location of this nucleic acid fragment molecule just within this window coordinates, then illustrates this nucleic acid fragment molecular origin
In this window area, all sequences position as counted a sample is in the bar number of the nucleic acid molecules of this window, that
This number is properly termed as the amount of the nucleic acid molecules from this window.Then this first chromosomoid window will be constituted
The amount of the nucleic acid fragment molecule of window of combination is altogether it is possible to obtain the nucleic acid from the first chromosomoid window combination
Molecular weight, it is emphasized that this first chromosomoid window combination according to circumstances can partially or entirely cover first
Chromosomoid one or many.
In 160 steps, for each window of No. 21 chromosomes, the window in whole gene group (except No. 21 chromosomes)
Analysis and the dependency of this window, select the group of windows of extremely strong dependency to retain, and determine functional relation therebetween, this
When, the single window of No. 21 chromosomes may correspond to multiple correlation windows, composition correlation window combination.If statistics gained is next
The nucleic acid molecular weight coming from the second chromosomoid window is xi, and statistics gained derives from the nucleic acid molecules of the first chromosomoid window
Measure as yi, i representative sample is numbered, then observation sample is (x1, y1), (x2, y2) ... (xn, yn). now, according to these numbers
According to, can calculate the correlation coefficient of this two groups of data square.Correlation coefficient square closer to 1, intercept close to 0, explanation
Dependency is higher.Each No. 21 chromosome and its single correlation window can determine a functional relation.
In embodiment, prepare 89 and carried out sample preparation and sequencing under the conditions of discrepant experiment condition and sequencing
Biological specimen, the amount of this nucleic acid fragment from each window area sequence of statistics various kinds respectively, that is, to each sample, it is in base
Each window because of cutting in group correspond to a behavior value.For 89 samples, in each window, there are 89 behaviors
Value.
In this embodiment, for each window of No. 21 chromosomes, simultaneously at genome (except No. 21 chromosomes)
A upper search window high with this window dependency.For convenience of description, three windows are only taken here for illustrating,
It is shown in Table 5, a window deriving from the first chromosomoid window combination, numbering is (chr21,180), and two derive from non-first
The window of chromosomoid, numbering is respectively window (chr1,256), window (chr4,642).It is shown in Table 3, shown the first row, display
Sample number, i.e. the numbering of 89 samples that this method is studied；Second row illustrates in corresponding 89 samples of sample number
The nucleic acid molecules being numbered from genomic window on (chr1,256) window of each sample value, i.e. 89 behaviors
Value, is designated as x'i, i value gets 89 from 1.The third line illustrates being derived from of each sample in corresponding 89 samples of sample number
Genomic window is numbered the value of the nucleic acid molecules on (chr4,642) window, is also 89 behavior values, is designated as xi, and i value is from 1
Get 89.Fourth line shows being numbered from genomic window of each sample in corresponding 89 samples of sample number
The value of the nucleic acid molecules on (chr21,180) window, is also 89 behavior values, is designated as yi, and i value gets 89 from 1.
Table 3
Research window (chr4,642) and the dependency relation of window (chr21,180) first, now observation sample be (x1,
Y1), (x2, y2) ... (xn, yn), in this embodiment, n can get 89, studies the correlation coefficient of two columns values, related
Coefficient square closer to 1, illustrate that dependency is higher, that is, when the behavior value of a window changes, another window also can be sent out
Raw corresponding variation.When correlation coefficient close to 1 when, whether linear pass can be obeyed according to the behavior that observation sample studies two windows
The behavior value of system, the window (chr4,642) that table 3 represents and window (chr21,180) obeys linear relationship, and can obtain
The expression formula of its linear equation and correlation coefficient r square.See Fig. 3, in this embodiment it can be seen that two windows, window
Mouthful (chr4,642) and window (chr21,180), behavior value there is extremely strong linear dependence, and associated expression is: y
=0.7564-0.6487, r2=0.9724.Obviously r still relatively 1, then this window (chr4,642) can be selected
As the analogue window that have extremely strong dependency corresponding with embodiment window (chr21,180).To study again window (chr1,
256) with window (chr21,180), see Fig. 4, its r2=0.6214 then it is assumed that two window behavior values are not very related, Yi Houke
Not consider this window.Like this, can go to seek with such method for the window in the first chromosomoid window combination
Obtain the extremely strong analogue window of one or more dependencys.Just only need to oneself later and know an x value, that is, only need to count derive from
What this was corresponding with embodiment window has the amount of the analogue window of extremely strong dependency it is possible to calculate one by relational expression
The analogue value or analogue value confidence interval.
As selected by table 4 discloses by method 100 process step have extremely strong dependency with first kind window combination
It is dispersed in the analogue window combination of genome other positions, in table, only show the combination being made up of 20 windows.First row shows
Show the window label on the first chromosomoid, secondary series shows its window coordinates；3rd row display and the corresponding first kind
Chromosome has the window label of the analogue window of extremely strong dependency, and the 4th row show corresponding analogue window coordinate；5th row are aobvious
Show the relational expression of window and associated analog window；The square value of the 6th row display correlation coefficient, i.e. r side's value, r square value is got over
Close to 1, illustrate that between two windows, dependency is higher, the nucleic acid molecular weight wherein deriving from a window changes, then originate
Can occur to change accordingly in another window nucleic acid molecular weight.
Table 4
| Window label | Window coordinates | Correlation window label | Correlation window coordinate | Relational expression | R square |
| Chr21,180 | Chr21:26850k～27150k | Chr4,642 | Chr4:96150k～96450k | Y=-0.64869+0.75641x | 0.9724 |
| Chr21,181 | Chr21:27000k～27300k | Chr7,782 | Chr7:117150k～117450k | Y=3.567+0.99173x | 0.9823 |
| Chr21,182 | Chr21:27150k～27450k | Chr8,430 | Chr8:64350k～64650k | Y=-1.22256+0.99396x | 0.985 |
| Chr21,183 | Chr21:27300k～27600k | Chr4,1047 | Chr4:156900k～157200k | Y=2.39720+1.10153x | 0.9874 |
| Chr21,184 | Chr21:27450k～27750k | Chr11,150 | Chr11:22350k～22650k | Y=3.17063+0.96416x | 0.987 |
| Chr21,185 | Chr21:27600k～27900k | Chr3,142 | Chr3:21150k～21450k | Y=4.58025+0.97502x | 0.9843 |
| Chr21,186 | Chr21:27750k～28050k | Chr3,509 | Chr3:76200k～76500k | Y=3.88257+0.78812x | 0.9828 |
| Chr21,187 | Chr21:27900k～28200k | Chr12,396 | Chr12:59250k～59550k | Y=-0.17406+0.95561x | 0.9776 |
| Chr21,188 | Chr21:28050k～28350k | Chr2,870 | Chr2:130350k～130650k | Y=0.01040+0.80918x | 0.9804 |
| Chr21,189 | Chr21:28200k～28500k | Chr4,324 | Chr4:48450k～48750k | Y=-3.521250.87993+x | 0.9702 |
| Chr21,190 | Chr21:28350k～28650k | Chr13,386 | Chr13:57750k～58050k | Y=4.73997+1.02240x | 0.9856 |
| Chr21,191 | Chr21:28500k28800k | Chr3,1134 | Chr3:169950k～170250k | Y=-2.48579+0.88400x | 0.9827 |
| Chr21,192 | Chr21:28650k～28950k | Chr3,1140 | Chr3:170850k～171150k | Y=-1.85926+0.99063x | 0.983 |
| Chr21,193 | Chr21:28800k～29100k | Chr7,259 | Chr7:38700k～39000k | Y=-8.27537+0.77680x | 0.9844 |
| Chr21,194 | Chr21:28950k～29250k | Chr15,320 | Chr15:47850k～48150k | Y=-2.12127+0.96872x | 0.9793 |
| Chr21,195 | Chr21:29100k～29400k | Chr4,654 | Chr4:97950k～98250k | Y=-1.65001+0.8842x | 0.9773 |
| Chr21,196 | Chr21:29250k～29550k | Chr6,648 | Chr6:97050k～97350k | Y=-1.40945+0.87820x | 0.9785 |
| Chr21,197 | Chr21:29400k～29700k | Chr7,144 | Chr7:21450k～21750k | Y=-5.49623+0.83878x | 0.9809 |
| Chr21,198 | Chr21:29550k～29850k | Chr9,27 | Chr9:3900k～4200k | Y=-0.06492+0.86796x | 0.9849 |
| Chr21,199 | Chr21:29700k～30000k | Chr2,1072 | Chr2:160650k～160950k | Y=0.08203+0.98155x | 0.9859 |
Then the analogue window having extremely strong dependency with No. 21 chromosome window combination can be combined, collectively form
Analogue window combine, further according to from analogue window or analogue window combination nucleic acid molecules amount calculate one corrected
Confidence interval, for the judgement to chromosomal aneuploidy for the method 200.
In 170 steps, because each window on No. 21 chromosomes may have multiple windows associated, so for fully making
With sequencing data, improve detection accuracy, the correlation function formula of these windows is fitted, and according to real data,
It is corrected, finally determine in No. 21 chromosomes, the functional relation of each window of strong correlation can be found on genome.
Step 3: sample to be detected is sequenced
8 anemia of pregnant woman volunteers participate in this detection, and the sample number being obtained is respectively sample 1-8.Four anemia of pregnant woman nourish
No. 21 chromosome trisomy fetuses, four anemia of pregnant woman nourish No. 21 chromosome normal fetus.Collect each maternal blood, and to carrying out
Centrifugation, takes blood plasma, then extracts nucleic acid molecules from blood plasma again, by the sequenator of illumina company to these nucleic acid molecules
Carry out extensive high-flux sequence.
The flow chart of 200 methods according to Fig. 2 is carried out, and specifically, in 210 steps, obtains biological specimen at anemia of pregnant woman.This
Biological specimen can be blood plasma or other suitable sample.This biological specimen comprises to derive from the nucleic acid of anemia of pregnant woman and fetus
Molecule.
In 220 steps, random sequencing is carried out to the nucleic acid molecules in sample.The nucleic acid fragment molecules present being sequenced entirely
A part for genome, can be positioned on each bar chromosome.Nucleic acid molecules in sample can only survey one end (as surveyed one end 35
Individual base pair) or survey two ends, or whole piece nucleic acid molecules all are measured.
Sequencing can pass through the parallel sequencer of extensive high flux, such as 454, solexa, solid system, Yi Jidan
Molecule sequencing or nano-pore sequencing etc..In one embodiment we by the solexa sequenator of illumina company come to core
Acid molecule carries out one end sequencing.
Although the rough flow of sample preparation and experiment is identical, in order to verify the suitable experiment condition of the inventive method less
Consistent situation, that is, having to experiment condition requirement is not very strict advantage, and described experiment condition is included using different
Reagent, sequencing gc is partial to inconsistent etc..Spy is divided into two groups, sample 1, sample 2, sample 5, and sample 6 is one group of experiment condition (a
Group)；Sample 3, sample 4, sample 7, sample 8 is another group of experiment condition (b group).A group, for extracting 5ml pregnant woman blood plasma, uses
Qiaamp dna micro kit (qiagen, 56304) extracts free dna, uses according to illumina/solexa Library development flow
Neb reagent builds se library, upper se36 sequencing, and b group extracts 600ul pregnant woman blood plasma and uses tianamp micro dna kit
(tiangen dp316) extracts free dna, uses enzymatics reagent to build according to illumina/solexa Library development flow
Pei library, upper se36+7 sequencing.
210,220 steps of this step such as Fig. 2.
Step 4: detection sample, the flow chart according to Fig. 2 is carried out.
In 230 steps, based on sequencing, by the means of analysis of biological information, every measured nucleic acid fragment can be divided
Son navigates on the accurate location of genome.As table 1 which show by sequencing measured by can navigate to each bar chromosome
Its starting position coordinates on this chromosome of nucleic acid fragment molecule.
After table 5 shows biological specimen sample 1 and sample 2 sequencing, some obtained nucleic acid molecules navigate to No. 4 dyeing
The positional information of front ten initiation sites on body and No. 21 chromosomes.
As can be seen from Table 5, for sample 1, it can navigate to first nucleic acid fragment on No. 21 chromosomes
The initial point position of molecule is 9797443, and that is, the starting point of this article of nucleic acid fragment molecule is located at the 9797443rd of No. 21 chromosomes
Base pair position.In the same manner, it can navigate to the initial point position of first nucleic acid fragment molecule on No. 4 chromosomes and is
19219, that is, the starting point of this article of nucleic acid fragment molecule is positioned at the 19219th base pair position of No. 4 chromosomes.
Table 5
In 240 steps, the same in model with setting up, it is window size with 300k, 150k is that overlap is to be detected to 8
All chromosomes of sample are respectively cut window.In 250 steps, based on nucleic acid fragment positional information, statistics is from No. 21 dyes
The amount of the nucleic acid fragment molecule of each window of colour solid.In 260 steps, based on nucleic acid fragment positional information, statistics derives from each sample
The amount of the nucleic acid molecules that this analogue window having strong correlation with No. 21 chromosome windows combines, and calculate according to functional relation
Go out confidence interval.In 270 steps, by the 250th step judging each sample obtained from No. 21 chromosome windows
The amount of nucleic acid fragment molecule whether in the confidence interval obtained in the 260th step of same sample it can be determined that fetus whether
There is the excessive risk of aneuploidy in No. 21 chromosomes.
Table 6: detect the result obtained by eight samples in embodiment with the inventive method
Actual value y row in table 6, are the nucleic acid molecules from each No. 21 chromosome window combination of sample of statistics gained
Amount；Count in this sample to the nucleic acid molecular weight that the analogue window that No. 21 chromosome window combination have strong correlation combines and related
Relational expression (as shown in table 4), then by a confidence interval (confidence level: 95%) obtained by knowledge of statistics.Right
For the sample of a research, when its actual value is present in calculated confidence interval it is believed that being studied
Sample be that normal probability is very big, if conversely, actual value is present in outside analogue value confidence interval, illustrate that this sample is
Normal probability very little.As sample 1, sample 2, sample 3, sample 4, their actual value derives from No. 21 chromosomals
Nucleic acid molecular weight all outside fiducial interval range, then the conclusion that obtained with this method is trisomy 21 fetus sample for them
This, this result has obtained the proof of karyotyping result.
By relatively more above-mentioned various kinds, this derives from the value of the amount of the nucleic acid fragment molecule of first kind chromosome window combination
(actual value) and the analogue value confidence interval being obtained, judges whether the fetal aneuploidy on the first chromosomoid
Chromosome or aneuploid chromosomal region.As shown in table 6 it can be seen that the actual value of No. 21 chromosome trisomy is put in the analogue value
Outside letter interval, and normal twice its actual value of body sample is within analogue value fiducial interval range.Fig. 7, display four is derived from
Maternal blood sample of nucleic acid, the actual value of sample 1 and sample 2 is on respective analogue value confidence interval it may be determined that being
No. 21 chromosomal aneuploidies；And the actual value of sample 5 and sample 6 within respective analogue value confidence interval it is believed that
Sample is normal.Fig. 8 is it is illustrated that the relation of the actual value of normal sample and exceptional sample and respective analogue value confidence interval.Display
Four are derived from maternal blood sample of nucleic acid, and the actual value of sample 3 and sample 4, can on respective analogue value confidence interval
To be defined as No. 21 chromosomal aneuploidies；And the actual value of sample 7 and sample 8 is within respective analogue value confidence interval,
It is considered that sample is normal.
Embodiment two
Step 1: obtain sequencing data needed for modeling
Select 53 normal samples, these samples are prepared under discrepant experiment condition and is sequenced.
This step corresponds to 110,120 steps of Fig. 1.
Step 2: set up No. 21 chromosome detection models
Flow chart according to Fig. 1 is carried out, and the process of Mathematical Models is completed by optimization for program.Computer program
Selected by different parameter, complete the searching of dependency window, find optimized parameter, set up the first chromosomoid window and the
The functional relation of two chromosomoid windows.
In 130 steps, based on sequencing, by the means of analysis of biological information, every measured nucleic acid fragment can be divided
Son navigates on the accurate location of genome.
In 140 steps, cutting window is carried out to each sample.Every chromosome constituting genome is divided into some windows
Mouth sequence.With 300k as window size in embodiment, 150k be overlap splitter (be each window initiating terminal be front
One window initiating terminal slides backward 150k).
In 150 steps, the sample these prepared under the conditions of discrepant and is sequenced, based on sequencing gained information, difference
The amount of statistics this nucleic acid fragment molecule from each series of windows of various kinds.
In 160 steps, for each window of No. 18 chromosomes, the window in whole gene group (except No. 21 chromosomes)
Analysis and the dependency of this window, select the group of windows of extremely strong dependency to retain, and determine functional relation therebetween, this
When, if the single window of No. 18 chromosomes corresponds to multiple correlation windows, composition correlation window combination.
In embodiment two, prepare 53 and carried out sample preparation and sequencing under the conditions of discrepant experiment condition and sequencing
Biological specimen, respectively statistics various kinds this derive from each window area sequence nucleic acid fragment amount, that is, to each sample, its
On genome, each window of cutting correspond to a behavior value.For 53 samples, in each window, there are 53 row
For value.As shown in table 7, choose 3 windows, be respectively from (chr18,259), (chr1,8), (chr8,710).Shown first
OK, sample number, the numbering of 53 being studied in the present embodiment sample are shown；It is corresponding that second row illustrates sample number
The value of the nucleic acid molecules being numbered from genomic window on (chr1,8) window of each sample in 53 samples, that is, 53
Individual behavior value, is designated as x'i, and i value gets 53 from 1.The third line illustrates each sample in corresponding 53 samples of sample number
The amount (53 behavior values) being numbered (chr18,259) nucleic acid molecules from genomic window, be designated as xi, i value is got from 1
53.Fourth line show being numbered from genomic window of each sample in corresponding 53 samples of sample number (chr18,
259) amount (53 behavior values) of nucleic acid molecules, is designated as yi, i value gets 53 from 1.
Table 7
Research window (chr8,710) and the dependency relation of window (chr18,259) first, now observation sample be (x1,
Y1), (x2, y2) ... (xn, yn), in this embodiment, n can get 53, study the correlation coefficient of two columns values, obtain
Window (chr8,710) has strong correlation with the behavior value of window (chr18,259), and associated expression is: y=-
9.18452+0.98295x,r2=0.9816, see Fig. 5.Obviously r2Still relatively 1, then this window (chr8,710) can
To select as the window that have strong correlation corresponding with embodiment window (chr18,259).Study window (chr1,8) again
With window (chr8,259), see Fig. 6, its r2=0.004344, then it is assumed that two window behavior values are uncorrelated, can not consider later
This window.So, can be upper selected one or more strong with No. 18 chromosome dependencys in genome (except No. 18 chromosomes)
Window.Just only need to a known x value, that is, only needing to count corresponding with embodiment window has pole from this later
The amount of the analogue window of strong correlation is it is possible to calculate a confidence interval by functional relation.
As selected by table 8 discloses by method 100 flow process selected by previous step have extremely strong phase with No. 18 chromosomes
The window combination being dispersed in genome other positions of closing property, in figure only shows wherein 20 windows.First row shows positioned at 18
Window label on number chromosome, secondary series shows its window coordinates；3rd row display has strong phase with corresponding No. 18 chromosomes
The label of the window of closing property, the 4th row show corresponding window coordinates；5th row display window and the relationship expression of correlation window
Formula；The square value of the 6th row display correlation coefficient, i.e. r2.
Table 8
| Window label | Window coordinates | Correlation window | Correlation window coordinate | Relational expression | R puts down |
| Label | Side | ||||
| chr18,161 | chr18:24000k-24300k | chr4:839 | chr4:125700k-126000k | Y=7.30271+0.85427x | 0.9743 |
| chr18,162 | chr18:24150k-24450k | chr12:535 | chr12:80100k-80400k | Y=9.31993+0.74859x | 0.9761 |
| chr18,163 | chr18:24300k-24600k | chr17:322 | chr17:48150k-48450k | Y=6.97596+1.02492x | 0.9766 |
| chr18,164 | chr18:24450k-24750k | chr11:176 | chr11:26250k-26550k | Y=9.80116+0.95142x | 0.9798 |
| chr18,165 | chr18:24600k-24900k | chr6:418 | chr6:62550k-62850k | Y=9.77007+0.84016x | 0.9801 |
| chr18,166 | chr18:24750k-25050k | chr14:318 | chr14:47550k-47850k | Y=9.75245+1.28307x | 0.9764 |
| chr18,167 | chr18:24900k-25200k | chr9:68 | chr9:10050k-10350k | Y=7.68479+0.76466x | 0.9742 |
| chr18,168 | chr18:25050k-25350k | chr3:563 | chr3:84300k-84600k | Y=6.40314+1.04416x | 0.9747 |
| chr18,169 | chr18:25200k-25500k | chr4:473 | chr4:70800k-71100k | Y=5.29067+0.75633x | 0.9787 |
| chr18,170 | chr18:25350k-25650k | chr7:795 | chr7:119100k-119400k | Y=9.60467+0.83662x | 0.9545 |
| chr18,171 | chr18:25500k-25800k | chr7:795 | chr7:119100k-119400k | Y=8.01835+0.87421x | 0.959 |
| chr18,172 | chr18:25650k-25950k | chr2:243 | chr2:36300k-36600k | Y=7.85285+1.00613x | 0.9755 |
| chr18,173 | chr18:25800k-26100k | chr7:969 | chr7:145200k-145500k | Y=7.75868+0.98071x | 0.9757 |
| chr18,174 | chr18:25950k-26250k | chr2:838 | chr2:125550k-125850k | Y=7.97381+1.17329x | 0.9697 |
| chr18,175 | chr18:26100k-26400k | chr21:111 | chr21:24000k-24314k | Y=9.34115+0.77231x | 0.9811 |
| chr18,176 | chr18:26250k-26550k | chr3:641 | chr3:96000k-96300k | Y=8.868+1.098x | 0.9762 |
| chr18,177 | chr18:26400k-26700k | chr3:640 | chr3:95850k-96150k | Y=8.18252+1.09904x | 0.9746 |
| chr18,178 | chr18:26550k-26850k | chr4:410 | chr4:61350k-61650k | Y=8.84273+0.94808x | 0.9779 |
| chr18,179 | chr18:26700k-27000k | chr13:620 | chr13:92850k-93150k | Y=9.99595+0.87685x | 0.9745 |
| chr18,180 | chr18:26850k-27150k | chr5:599 | chr5:89700k-90000k | Y=9.27220+1.14163x | 0.976 |
Then can will there is the window combination of extremely strong dependency with No. 18 chromosome window combination, further according to deriving from
The amount of the nucleic acid molecules of each window calculates to obtain a corrected confidence interval, for method 200, chromosomal aneuploidy is sentenced
Disconnected.
Step 3: sample to be detected is sequenced
6 anemia of pregnant woman volunteers participate in this detection, and the sample number being obtained is respectively sample 1-6.Collect each anemia of pregnant woman
Peripheral blood, and to being centrifuged, take blood plasma, then extract nucleic acid molecules from blood plasma again, by the sequencing of illumina company
Instrument carries out extensive high-flux sequence to these nucleic acid molecules.
The flow chart of 200 methods according to Fig. 2 is carried out, and specifically, in 210 steps, obtains biological specimen at anemia of pregnant woman.This
Biological specimen can be blood plasma or other suitable sample.This biological specimen comprises to derive from the nucleic acid of anemia of pregnant woman and fetus
Molecule.
In 220 steps, random sequencing is carried out to the nucleic acid molecules in sample.The nucleic acid fragment molecules present being sequenced entirely
A part for genome, can be positioned on each bar chromosome.In embodiment, we are surveyed by the solexa of illumina company
Sequence instrument to carry out one end sequencing to nucleic acid molecules.
Spy is divided into two groups, sample 1, sample 2, and sample 4 is one group of experiment condition (a group)；Sample 3, sample 5, sample 6 is another
One group of experiment condition (b group).A group is extraction 5ml pregnant woman blood plasma, using qiaamp dna micro kit (qiagen, 56304)
Extract free dna, use neb reagent to build se library, upper se36 sequencing according to illumina/solexa Library development flow, b group is taken out
600ul pregnant woman blood plasma is taken to use tianamp micro dna kit (tiangen dp316) to extract free dna, according to
Illumina/solexa Library development flow uses enzymatics reagent to build pei library, upper se36+7 sequencing.
210,220 steps of this step such as Fig. 2.
Step 4: detection sample
Flow chart according to Fig. 2 is carried out.
In 230 steps, based on sequencing, by the means of analysis of biological information, every measured nucleic acid fragment can be divided
Son navigates on the accurate location of genome.As table 1 which show by sequencing measured by can navigate to each bar chromosome
Its starting position coordinates on this chromosome of nucleic acid fragment molecule.
In 240 steps, the same in model with setting up, it is window size with 300k, 150k is that overlap is to be detected to 6
All chromosomes of sample are respectively cut window.
In 250 steps, based on nucleic acid fragment positional information, statistics is divided from the nucleic acid fragment of each window of No. 18 chromosomes
The amount of son.
In 260 steps, based on nucleic acid fragment positional information, statistics is had with No. 18 chromosome windows from each sample
The amount of the nucleic acid molecules of the window combination of strong correlation, and calculate confidence interval according to functional relation.
In 270 steps, the nucleic acid from No. 21 chromosome windows that obtained by the 250th step judging each sample
The amount of fragments molecules whether in the confidence interval obtained in the 260th step of same sample it can be determined that whether fetus 18
There is the excessive risk of aneuploidy in number chromosome.
Table 9: detect the result obtained by eight samples in embodiment with the inventive method
Actual value (secondary series) in table 9, is the core from each No. 18 chromosome window combination of sample of statistics gained
Acid molecule amount；Count the nucleic acid molecular weight that the analogue window having strong correlation with No. 18 chromosome window combination in this sample combines
And correlation function expression formula (as shown in table 8), then by a confidence interval obtained by knowledge of statistics (confidence level:
95%).For the sample of a research, when its actual value is present in calculated confidence interval, can recognize
Sample by being studied is that normal probability is very big, if conversely, actual value is present in outside analogue value confidence interval, illustrating
This sample is non-euploid very risky.As sample 4, sample 5, sample 6, their actual value derives from No. 21 chromosomes
All outside fiducial interval range, then the conclusion being obtained with this method is No. 18 chromosomes for them to the nucleic acid molecular weight of combination
Aneuploidy fetus sample, this result has obtained the proof of karyotyping result.
By relatively more above-mentioned various kinds, this derives from the value of the amount of the nucleic acid fragment molecule of first kind chromosome window combination
(actual value) and the analogue value confidence interval being obtained, judges whether the fetal aneuploidy on the first chromosomoid
Chromosome or aneuploid chromosomal region.As shown in table 9 it can be seen that the actual value of No. 18 chromosome trisomy is put in the analogue value
Outside letter interval, and normal twice its actual value of body sample is within analogue value fiducial interval range.Fig. 9 and Figure 10 is it is shown that 6
Individual from maternal blood sample of nucleic acid, sample 1, the actual value of sample 2 and sample 3 respective analogue value confidence interval it
Interior it is believed that sample is normal, and sample 4, the actual value of sample 5 and sample 6 is outside respective confidence interval it is believed that No. 18
Chromosomal aneuploidy risk is very high.
Claims (6)
1. it is applied to detect the sequencing data processing system of individual chromosome aneuploidy, comprising:
(1) full-length genome of the normal individual sample from dye-free volume defect is sequenced, using treating as object of study
Research chromosome is defined as the first chromosomoid, and remaining chromosome is defined as the second chromosomoid；
(2) all chromosomes in (1) are respectively cut into overlapped or nonoverlapping fragment, each fragment is defined as one
Window；
(3) amount of the nucleic acid molecules of each window of statistics multiple normal individual sample chromosomes under multiple different experimental conditions, will
This amount is defined as behavior value；
(4) according to the behavior value in (3), contaminating with the described first kind on described second chromosomoid is found by mathematical statistics method
Colour solid has window or a combination thereof of strong correlation, set up the window of the first chromosomoid and found have strong correlation window or
The functional relation a of a combination thereof；
(5) all chromosomes of the full-length genome of individual sample to be detected are sequenced, wherein treating as object of study
Research chromosome is equally defined as the first chromosomoid, and it is and the corresponding identical volume of the first chromosomoid in sequencing unit 1
Number chromosome, remaining chromosome is as the second chromosomoid；
(6) cut the chromosome of described sample to be detected according to window specification same in (2), statistics the first chromosomoid and the
The behavior value of two chromosomoids；
(7) the behavior value of each window of the second chromosomoid of described sample to be detected is incorporated in functional relation a, setting is put
Letter level, is calculated the theoretical interval of the first kind chromosome behavior value of described sample to be detected.
2. the non-diagnostic method of detection individual chromosome aneuploidy or chromosomal section aneuploidy, comprising:
A. the system described in claim 1 is utilized to obtain the individual behavior value of the first chromosomoid to be detected and to be detected
The theoretical interval of the first kind chromosome behavior value of body；
B. the described individual behavior value of the first chromosomoid to be detected and described the first individual chromosomoid to be detected are compared
The theoretical interval of behavior value, if the behavior value of described the first individual chromosomoid to be detected is not in described individuality to be detected
It is determined that the first individual chromosomoid to be detected is non-ortholoidy in the theoretical interval of the behavior value of the first chromosomoid.
3. the method for claim 2, when window is for 300kb, overlap is 150kb, wherein has extremely strong dependency window combination
Selected from following window combination:
When the window that the base positions that the window of the first chromosomoid is No. 21 chromosome are 14400k-14700k, it is right
The the second chromosomoid window answered is the window for 37050k-37350k for the base positions of No. 13 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 21 chromosome are 14550k-14850k, it is right
The the second chromosomoid window answered is the window for 88050k-88350k for the base positions of No. 5 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 21 chromosome are 14700k-15000k, it is right
The the second chromosomoid window answered is the window for 16500k-16800k for the base positions of No. 12 chromosome；
The window of the first chromosomoid be No. 21 chromosome base positions be 14850k-15150k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 16500k-16800k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 15000k-15300k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 144300k-144600k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 15150k-15450k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 144300k-144600k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 15300k-15600k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 145050k-145350k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 15450k-15750k window when, its correspondence
The second chromosomoid window be No. 17 chromosome base positions be 56400k-56700k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 15600k-15900k window when, its correspondence
The second chromosomoid window be No. 3 chromosome base positions be 21750k-22050k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 15750k-16050k window when, its correspondence
The second chromosomoid window be No. 8 chromosome base positions be 105150k-105450k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 15900k-16200k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 50850k-51150k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 16050k-16350k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 77850k-78150k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 16200k-16500k window when, its correspondence
The second chromosomoid window be rice chromosome base positions be 112800k-113100k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 16350k-16650k window when, its correspondence
The second chromosomoid window be No. 5 chromosome base positions be 83250k-83550k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 16500k-16800k window when, its correspondence
The second chromosomoid window be No. 3 chromosome base positions be 76200k-76500k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 16650k-16950k window when, its correspondence
The second chromosomoid window be Chromosome 9 base positions be 74850k-75150k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 16800k-17100k window when, its correspondence
The second chromosomoid window be No. 5 chromosome base positions be 50700k-51000k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 16950k-17250k window when, its correspondence
The second chromosomoid window be rice chromosome base positions be 138600k-138900k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 17100k-17400k window when, its correspondence
The second chromosomoid window be No. 8 chromosome base positions be 77100k-77400k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 17250k-17550k window when, its correspondence
The second chromosomoid window be rice chromosome base positions be 138450k-138750k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 17700k-18000k window when, its correspondence
The second chromosomoid window be No. 7 chromosome base positions be 111750k-112050k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 18000k-18300k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 36150k-36450k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 18150k-18450k window when, its correspondence
The second chromosomoid window be rice chromosome base positions be 119250k-119550k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 18300k-18600k window when, its correspondence
The second chromosomoid window be No. 3 chromosome base positions be 450k-750k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 18450k-18750k window when, its correspondence
The second chromosomoid window be No. 6 chromosome base positions be 69300k-69600k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 18600k-18900k window when, its correspondence
The second chromosomoid window be No. 6 chromosome base positions be 69450k-69750k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 18750k-19050k window when, its correspondence
The second chromosomoid window be rice chromosome base positions be 62400k-62700k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 18900k-19200k window when,
Its corresponding second chromosomoid window is the window for 62250k-62550k for the base positions of rice chromosome；
The window of the first chromosomoid be No. 21 chromosome base positions be 19050k-19350k window when, its correspondence
The second chromosomoid window be rice chromosome base positions be 135300k-135600k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 19200k-19500k window when, its correspondence
The second chromosomoid window be No. 5 chromosome base positions be 103350k-103650k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 19350k-19650k window when, its correspondence
The second chromosomoid window be No. 7 chromosome base positions be 125550k-125850k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 19500k-19800k window when, its correspondence
The second chromosomoid window be No. 3 chromosome base positions be 85350k-85650k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 19650k-19950k window when, its correspondence
The second chromosomoid window be No. 3 chromosome base positions be 166650k-166950k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 19800k-20100k window when, its correspondence
The second chromosomoid window be No. 13 chromosome base positions be 67350k-67650k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 19950k-20250k window when, its correspondence
The second chromosomoid window be No. 3 chromosome base positions be 167250k-167550k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 20100k-20400k window when, its correspondence
The second chromosomoid window be rice chromosome base positions be 62400k-62700k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 20250k-20550k window when, its correspondence
The second chromosomoid window be rice chromosome base positions be 62400k-62700k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 20400k-20700k window when, its correspondence
The second chromosomoid window be No. 7 chromosome base positions be 12150k-12450k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 20550k-20850k window when, its correspondence
The second chromosomoid window be No. 7 chromosome base positions be 125550k-125850k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 20700k-21000k window when, its correspondence
The second chromosomoid window be No. 7 chromosome base positions be 118050k-118350k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 20850k-21150k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 81750k-82050k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 21000k-21300k window when, its correspondence
The second chromosomoid window be rice chromosome base positions be 112650k-112950k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 21150k-21450k window when, its correspondence
The second chromosomoid window be rice chromosome base positions be 81750k-82050k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 21300k-21600k window when, its correspondence
The second chromosomoid window be No. 5 chromosome base positions be 83250k-83550k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 21450k-21750k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 84450k-84750k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 21600k-21900k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 84450k-84750k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 21750k-22050k window when, its correspondence
The second chromosomoid window be No. 3 chromosome base positions be 82650k-82950k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 21900k-22200k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 141150k-141450k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 22050k-22350k window when, its correspondence
The second chromosomoid window be No. 5 chromosome base positions be 51450k-51750k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 22200k-22500k window when, its correspondence
The second chromosomoid window be No. 5 chromosome base positions be 51450k-51750k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 22500k-22800k window when, its correspondence
The second chromosomoid window be rice chromosome base positions be 135150k-135450k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 22650k-22950k window when, its correspondence
The second chromosomoid window be No. 5 chromosome base positions be 105300k-105600k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 22800k-23100k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 184950k-185250k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 22950k-23250k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 141000k-141300k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 23100k-23400k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 141600k-141900k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 23250k-23550k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 82350k-82650k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 26700k-27000k window when, its correspondence
The second chromosomoid window be No. 8 chromosome base positions be 93450k-93750k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 26850k-27150k window when, its correspondence
The second chromosomoid window be No. 13 chromosome base positions be 46800k-47100k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 31200k-31500k window when, its correspondence
The second chromosomoid window be No. 6 chromosome base positions be 47100k-47400k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 31350k-31650k window when, its correspondence
The second chromosomoid window be No. 18 chromosome base positions be 41100k-41400k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 31500k-31800k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 87600k-87900k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 31650k-31950k window when, its correspondence
The second chromosomoid window be No. 15 chromosome base positions be 60300k-60600k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 31950k-32250k window when, its correspondence
The second chromosomoid window be No. 6 chromosome base positions be 38850k-39150k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 32100k-32400k window when, its correspondence
The second chromosomoid window be No. 13 chromosome base positions be 97650k-97950k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 32250k-32550k window when, its correspondence
The second chromosomoid window be No. 5 chromosome base positions be 169500k-169800k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 32400k-32700k window when, its correspondence
The second chromosomoid window be No. 8 chromosome base positions be 20850k-21150k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 32550k-32850k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 1500k-1800k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 33000k-33300k window when, its correspondence
The second chromosomoid window be No. 18 chromosome base positions be 71550k-71850k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 33150k-33450k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 52350k-52650k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 33300k-33600k window when, its correspondence
The second chromosomoid window be No. 18 chromosome base positions be 52350k-52650k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 33600k-33900k window when, its correspondence
The second chromosomoid window be rice chromosome base positions be 24600k-24900k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 33750k-34050k window when, its correspondence
The second chromosomoid window be o.11 chromosome base positions be 84900k-85200k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 33900k-34200k window when, its correspondence
The second chromosomoid window be o.11 chromosome base positions be 120300k-120600k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 34050k-34350k window when, its correspondence
The second chromosomoid window be No. 6 chromosome base positions be 165450k-165750k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 34200k-34500k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 45600k-45900k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 34350k-34650k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 105300k-105600k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 34500k-34800k window when, its correspondence
The second chromosomoid window be No. 21 chromosome base positions be 24750k-25050k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 34650k-34950k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 60450k-60750k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 34800k-35100k window when, its correspondence
The second chromosomoid window be No. 6 chromosome base positions be 157950k-158250k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 34950k-35250k window when, its correspondence
The second chromosomoid window be No. 6 chromosome base positions be 157950k-158250k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 35100k-35400k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 8100k-8400k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 35250k-35550k window when, its correspondence
The second chromosomoid window be No. 5 chromosome base positions be 72600k-72900k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 35400k-35700k window when, its correspondence
The second chromosomoid window be rice chromosome base positions be 83550k-83850k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 35550k-35850k window when, its correspondence
The second chromosomoid window be No. 3 chromosome base positions be 73500k-73800k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 35700k-36000k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 56100k-56400k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 35850k-36150k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 174150k-174450k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 36000k-36300k window when, its correspondence
The second chromosomoid window be No. 15 chromosome base positions be 58950k-59250k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 36150k-36450k window when, its correspondence
The second chromosomoid window be No. 17 chromosome base positions be 15000k-15300k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 36300k-36600k window when, its correspondence
The second chromosomoid window be No. 6 chromosome base positions be 157950k-158250k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 36600k-36900k window when, its correspondence
The second chromosomoid window be o.11 chromosome base positions be 12150k-12450k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 36750k-37050k window when, its correspondence
The second chromosomoid window be No. 15 chromosome base positions be 77100k-77400k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 36900k-37200k window when, its correspondence
The second chromosomoid window be o.11 chromosome base positions be 120150k-120450k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 37050k-37350k window when, its correspondence
The second chromosomoid window be No. 3 chromosome base positions be 37500k-37800k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 37200k-37500k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 42600k-42900k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 37350k-37650k window when, its correspondence
The second chromosomoid window be rice chromosome base positions be 186150k-186450k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 37500k-37800k window when, its correspondence
The second chromosomoid window be Chromosome 9 base positions be 20100k-20400k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 37650k-37950k window when, its correspondence
The second chromosomoid window be No. 3 chromosome base positions be 54900k-55200k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 37800k-38100k window when, its correspondence
The second chromosomoid window be No. 15 chromosome base positions be 78750k-79050k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 37950k-38250k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 118350k-118650k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 38100k-38400k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 93450k-93750k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 38250k-38550k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 66150k-66450k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 38400k-38700k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 30300k-30600k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 38550k-38850k window when, its correspondence
The second chromosomoid window be Chromosome 9 base positions be 100800k-101100k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 38700k-39000k window when, its correspondence
The second chromosomoid window be Chromosome 9 base positions be 96600k-96900k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 38850k-39150k window when, its correspondence
The second chromosomoid window be o.11 chromosome base positions be 130650k-130950k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 39000k-39300k window when, its correspondence
The second chromosomoid window be No. 6 chromosome base positions be 1050k-1350k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 39150k-39450k window when, its correspondence
The second chromosomoid window be No. 5 chromosome base positions be 169800k-170100k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 39300k-39600k window when, its correspondence
The second chromosomoid window be No. 3 chromosome base positions be 43200k-43500k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 39450k-39750k window when, its correspondence
The second chromosomoid window be No. 6 chromosome base positions be 25650k-25950k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 39750k-40050k window when, its correspondence
The second chromosomoid window be No. 5 chromosome base positions be 173700k-174000k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 39900k-40200k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 29550k-29850k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 40200k-40500k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 104700k-105000k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 40350k-40650k window when, its correspondence
The second chromosomoid window be o.11 chromosome base positions be 92100k-92400k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 40500k-40800k window when, its correspondence
The second chromosomoid window be No. 18 chromosome base positions be 70650k-70950k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 40650k-40950k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 13950k-14250k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 40800k-41100k window when, its correspondence
The second chromosomoid window be No. 8 chromosome base positions be 9900k-10200k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 40950k-41250k window when, its correspondence
The second chromosomoid window be No. 18 chromosome base positions be 40650k-40950k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 41100k-41400k window when, its correspondence
The second chromosomoid window be No. 8 chromosome base positions be 9750k-10050k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 41250k-41550k window when, its correspondence
The second chromosomoid window be No. 20 chromosome base positions be 22350k-22650k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 41400k-41700k window when, its correspondence
The second chromosomoid window be No. 16 chromosome base positions be 55350k-55650k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 41550k-41850k window when, its correspondence
The second chromosomoid window be No. 15 chromosome base positions be 99750k-100050k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 41700k-42000k window when, its correspondence
The second chromosomoid window be No. 5 chromosome base positions be 170700k-171000k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 41850k-42150k window when, its correspondence
The second chromosomoid window be No. 16 chromosome base positions be 48000k-48300k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 42000k-42300k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 0k-300k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 42150k-42450k window when, its correspondence
The second chromosomoid window be No. 16 chromosome base positions be 48000k-48300k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 42300k-42600k window when, its correspondence
The second chromosomoid window be No. 17 chromosome base positions be 73200k-73500k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 42450k-42750k window when, its correspondence
The second chromosomoid window be No. 17 chromosome base positions be 73050k-73350k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 42600k-42900k window when, its correspondence
The second chromosomoid window be o.11 chromosome base positions be 17550k-17850k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 42750k-43050k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 120750k-121050k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 42900k-43200k window when, its correspondence
The second chromosomoid window be o.11 chromosome base positions be 69300k-69600k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 43200k-43500k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 240450k-240750k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 43350k-43650k window when, its correspondence
The second chromosomoid window be No. 21 chromosome base positions be 38100k-38400k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 43500k-43800k window when, its correspondence
The second chromosomoid window be No. 16 chromosome base positions be 83850k-84150k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 43650k-43950k window when, its correspondence
The second chromosomoid window be No. 16 chromosome base positions be 3450k-3750k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 43800k-44100k window when, its correspondence
The second chromosomoid window be No. 3 chromosome base positions be 46800k-47100k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 43950k-44250k window when, its correspondence
The second chromosomoid window be No. 17 chromosome base positions be 70950k-71250k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 44100k-44400k window when, its correspondence
The second chromosomoid window be No. 7 chromosome base positions be 156900k-157200k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 44250k-44550k window when, its correspondence
The second chromosomoid window be No. 5 chromosome base positions be 1350k-1650k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 44400k-44700k window when, its correspondence
The second chromosomoid window be No. 19 chromosome base positions be 1950k-2250k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 44550k-44850k window when, its correspondence
The second chromosomoid window be Chromosome 9 base positions be 136350k-136650k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 44700k-45000k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 219900k-220200k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 44850k-45150k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 219900k-220200k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 45000k-45300k window when, its correspondence
The second chromosomoid window be No. 7 chromosome base positions be 750k-1050k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 45150k-45450k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 239550k-239850k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 45300k-45600k window when, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 238950k-239250k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 45450k-45750k window when, its correspondence
The second chromosomoid window be No. 20 chromosome base positions be 61050k-61350k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 45600k-45900k window when, its correspondence
The second chromosomoid window be No. 7 chromosome base positions be 1950k-2250k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 45750k-46050k window when, its correspondence
The second chromosomoid window be Chromosome 9 base positions be 135000k-135300k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 45900k-46200k window when, its correspondence
The second chromosomoid window be No. 19 chromosome base positions be 38700k-39000k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 46050k-46350k window when, its correspondence
The second chromosomoid window be Chromosome 9 base positions be 139800k-140100k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 46200k-46500k window when, its correspondence
The second chromosomoid window be No. 7 chromosome base positions be 750k-1050k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 46350k-46650k window when, its correspondence
The second chromosomoid window be No. 5 chromosome base positions be 1350k-1650k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 46500k-46800k window when, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 46350k-46650k window；
The window of the first chromosomoid be No. 21 chromosome base positions be 46650k-46950k window when, its correspondence
The second chromosomoid window be No. 8 chromosome base positions be 1650k-1950k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 1050k-1350k, its correspondence
The second chromosomoid window be rice chromosome base positions be 178050k-178350k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 1200k-1500k, its correspondence
The second chromosomoid window be No. 3 chromosome base positions be 6450k-6750k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 1350k-1650k, its correspondence
The second chromosomoid window be No. 7 chromosome base positions be 125700k-126000k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 1500k-1800k, its correspondence
The second chromosomoid window be No. 13 chromosome base positions be 53550k-53850k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 1650k-1950k, its correspondence
The second chromosomoid window be No. 3 chromosome base positions be 177450k-177750k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 1800k-2100k, its correspondence
The second chromosomoid window be rice chromosome base positions be 122250k-122550k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 1950k-2250k, its correspondence
The second chromosomoid window be No. 6 chromosome base positions be 18900k-19200k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 2100k-2400k, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 32400k-32700k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 2250k-2550k, its correspondence
The second chromosomoid window be No. 6 chromosome base positions be 9600k-9900k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 2400k-2700k, its correspondence
The second chromosomoid window be No. 5 chromosome base positions be 130650k-130950k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 2550k-2850k, its correspondence
The second chromosomoid window be No. 6 chromosome base positions be 48000k-48300k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 4200k-4500k, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 192450k-192750k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 4350k-4650k, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 145800k-146100k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 4650k-4950k, its correspondence
The second chromosomoid window be rice chromosome base positions be 107550k-107850k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 4800k-5100k, its correspondence
The second chromosomoid window be No. 12 chromosome base positions be 38100k-38400k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 4950k-5250k, its correspondence
The second chromosomoid window be No. 2 chromosome base positions be 39000k-39300k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 5100k-5400k, its correspondence
The second chromosomoid window be No. 6 chromosome base positions be 164550k-164850k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 9000k-9300k, its correspondence
The second chromosomoid window be No. 8 chromosome base positions be 91050k-91350k window；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 16800k-17100k, it is right
The the second chromosomoid window answered is the window for 39150k-39450k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 16950k-17250k, it is right
The the second chromosomoid window answered is the window for 32850k-33150k for the base positions of o.11 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 17100k-17400k, it is right
The the second chromosomoid window answered is the window for 19950k-20250k for the base positions of Chromosome 9；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 17250k-17550k, it is right
The the second chromosomoid window answered is the window for 39600k-39900k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 17400k-17700k, it is right
The the second chromosomoid window answered is the window for 80850k-81150k for the base positions of No. 6 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 18450k-18750k, it is right
The the second chromosomoid window answered is the window for 64350k-64650k for the base positions of No. 17 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 18600k-18900k, it is right
The the second chromosomoid window answered is the window for 19500k-19800k for the base positions of No. 3 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 21750k-22050k, it is right
The the second chromosomoid window answered is the window for 148350k-148650k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 21900k-22200k, it is right
The the second chromosomoid window answered is the window for 13800k-14100k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 22800k-23100k, it is right
The the second chromosomoid window answered is the window for 120150k-120450k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 23250k-23550k, it is right
The the second chromosomoid window answered is the window for 153450k-153750k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 23550k-23850k, it is right
The the second chromosomoid window answered is the window for 15450k-15750k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 24000k-24300k, it is right
The the second chromosomoid window answered is the window for 125700k-126000k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 24150k-2450k, it is right
The the second chromosomoid window answered is the window for 80100k-80400k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 24300k-24600k, it is right
The the second chromosomoid window answered is the window for 48150k-48450k for the base positions of No. 17 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 24450k-24750k, it is right
The the second chromosomoid window answered is the window for 26250k-26550k for the base positions of o.11 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 24600k-24900k, it is right
The the second chromosomoid window answered is the window for 62550k-62850k for the base positions of No. 6 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 24750k-25050k, it is right
The the second chromosomoid window answered is the window for 47550k-47850k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 24900k-25200k, it is right
The the second chromosomoid window answered is the window for 10050k-10350k for the base positions of Chromosome 9；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 25050k-25350k, it is right
The the second chromosomoid window answered is the window for 84300k-84600k for the base positions of No. 3 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 25200k-25500k, it is right
The the second chromosomoid window answered is the window for 70800k-71100k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 25350k-25650k, it is right
The the second chromosomoid window answered is the window for 119100k-119400k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 25500k-25800k, it is right
The the second chromosomoid window answered is the window for 119100k-119400k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 25650k-25950k, it is right
The the second chromosomoid window answered is the window for 51300k-51600k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 25800k-26100k, it is right
The the second chromosomoid window answered is the window for 145200k-145500k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 25950k-26250k, it is right
The the second chromosomoid window answered is the window for 125550k-125850k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 26100k-26400k, it is right
The the second chromosomoid window answered is the window for 16500k-16800k for the base positions of No. 21 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 26250k-26550k, it is right
The the second chromosomoid window answered is the window for 96000k-96300k for the base positions of No. 3 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 26400k-26700k, it is right
The the second chromosomoid window answered is the window for 95850k-96150k for the base positions of No. 3 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 26550k-26850k, it is right
The the second chromosomoid window answered is the window for 61350k-61650k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 26700k-27000k, it is right
The the second chromosomoid window answered is the window for 92850k-93150k for the base positions of No. 13 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 26850k-27150k, it is right
The the second chromosomoid window answered is the window for 89700k-90000k for the base positions of No. 5 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 27000k-27300k, it is right
The the second chromosomoid window answered is the window for 25050k-25350k for the base positions of No. 17 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 27150k-27450k, it is right
The the second chromosomoid window answered is the window for 88050k-88350k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 28650k-28950k, it is right
The the second chromosomoid window answered is the window for 92400k-92700k for the base positions of No. 6 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 28800k-29100k, it is right
The the second chromosomoid window answered is the window for 52050k-52350k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 28950k-29250k, it is right
The the second chromosomoid window answered is the window for 138300k-138600k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 29100k-29400k, it is right
The the second chromosomoid window answered is the window for 144450k-144750k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 29250k-29550k, it is right
The the second chromosomoid window answered is the window for 115200k-115500k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 29550k-29850k, it is right
The the second chromosomoid window answered is the window for 92250k-92550k for the base positions of No. 6 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 29700k-30000k, it is right
The the second chromosomoid window answered is the window for 62250k-62550k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 29850k-30150k, it is right
The the second chromosomoid window answered is the window for 84900k-85200k for the base positions of No. 8 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 30000k-30300k, it is right
The the second chromosomoid window answered is the window for 82650k-82950k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 30150k-30450k, it is right
The the second chromosomoid window answered is the window for 93600k-93900k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 30300k-30600k, it is right
The the second chromosomoid window answered is the window for 103950k-104250k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 32700k-33000k, it is right
The the second chromosomoid window answered is the window for 77100k-77400k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 33900k-34200k, it is right
The the second chromosomoid window answered is the window for 76200k-76500k for the base positions of Chromosome 9；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 34800k-35100k, it is right
The the second chromosomoid window answered is the window for 106350k-106650k for the base positions of No. 8 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 35550k-35850k, it is right
The the second chromosomoid window answered is the window for 35400k-35700k for the base positions of No. 15 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 36450k-36750k, it is right
The the second chromosomoid window answered is the window for 145050k-145350k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 36600k-36900k, it is right
The the second chromosomoid window answered is the window for 103050k-103350k for the base positions of No. 13 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 36750k-37050k, it is right
The the second chromosomoid window answered is the window for 83250k-83550k for the base positions of No. 5 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 36900k-37200k, it is right
The the second chromosomoid window answered is the window for 34650k-34950k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 37800k-38100k, it is right
The the second chromosomoid window answered is the window for 93300k-93600k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 38400k-38700k, it is right
The the second chromosomoid window answered is the window for 50100k-50400k for the base positions of No. 6 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 38550k-38850k, it is right
The the second chromosomoid window answered is the window for 83100k-83400k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 38700k-39000k, it is right
The the second chromosomoid window answered is the window for 106350k-106650k for the base positions of No. 8 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 38850k-39150k, it is right
The the second chromosomoid window answered is the window for 141000k-141300k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 39000k-39300k, it is right
The the second chromosomoid window answered is the window for 64050k-64350k for the base positions of No. 5 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 39150k-39450k, it is right
The the second chromosomoid window answered is the window for 69450k-69750k for the base positions of No. 6 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 39300k-39600k, it is right
The the second chromosomoid window answered is the window for 105150k-105450k for the base positions of Chromosome 9；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 39450k-39750k, it is right
The the second chromosomoid window answered is the window for 29400k-29700k for the base positions of o.11 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 39600k-39900k, it is right
The the second chromosomoid window answered is the window for 88950k-89250k for the base positions of No. 5 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 39750k-40050k, it is right
The the second chromosomoid window answered is the window for 71550k-71850k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 39900k-40200k, it is right
The the second chromosomoid window answered is the window for 163200k-163500k for the base positions of No. 3 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 44850k-45150k, it is right
The the second chromosomoid window answered is the window for 112950k-113250k for the base positions of No. 6 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 45000k-45300k, it is right
The the second chromosomoid window answered is the window for 32850k-33150k for the base positions of o.11 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 48600k-48900k, it is right
The the second chromosomoid window answered is the window for 76800k-77100k for the base positions of No. 3 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 48750k-49050k, it is right
The the second chromosomoid window answered is the window for 40800k-41100k for the base positions of o.11 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 49350k-49650k, it is right
The the second chromosomoid window answered is the window for 38850k-39150k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 49650k-49950k, it is right
The the second chromosomoid window answered is the window for 39900k-40200k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 49800k-50100k, it is right
The the second chromosomoid window answered is the window for 130350k-130650k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 49950k-50250k, it is right
The the second chromosomoid window answered is the window for 106350k-106650k for the base positions of No. 5 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 50100k-50400k, it is right
The the second chromosomoid window answered is the window for 87150k-87450k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 50250k-50550k, it is right
The the second chromosomoid window answered is the window for 79350k-79650k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 52350k-52650k, it is right
The the second chromosomoid window answered is the window for 70950k-71250k for the base positions of No. 16 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 55950k-56250k, it is right
The the second chromosomoid window answered is the window for 103800k-104100k for the base positions of No. 13 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 56100k-56400k, it is right
The the second chromosomoid window answered is the window for 172650k-172950k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 56250k-56550k, it is right
The the second chromosomoid window answered is the window for 10050k-10350k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 56400k-56700k, it is right
The the second chromosomoid window answered is the window for 90150k-90450k for the base positions of No. 8 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 56550k-56850k, it is right
The the second chromosomoid window answered is the window for 126750k-127050k for the base positions of No. 6 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 57750k-58050k, it is right
The the second chromosomoid window answered is the window for 79350k-79650k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 57900k-58200k, it is right
The the second chromosomoid window answered is the window for 101700k-102000k for the base positions of No. 3 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 60000k-60300k, it is right
The the second chromosomoid window answered is the window for 77700k-78000k for the base positions of No. 13 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 60150k-60450k, it is right
The the second chromosomoid window answered is the window for 126450k-126750k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 60300k-60600k, it is right
The the second chromosomoid window answered is the window for 167100k-167400k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 60450k-60750k, it is right
The the second chromosomoid window answered is the window for 123300k-123600k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 60600k-60900k, it is right
The the second chromosomoid window answered is the window for 34800k-35100k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 60750k-61050k, it is right
The the second chromosomoid window answered is the window for 145950k-146250k for the base positions of No. 3 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 60900k-61200k, it is right
The the second chromosomoid window answered is the window for 93900k-94200k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 61050k-61350k, it is right
The the second chromosomoid window answered is the window for 116550k-116850k for the base positions of No. 8 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 61200k-61500k, it is right
The the second chromosomoid window answered is the window for 27000k-27300k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 61350k-61650k, it is right
The the second chromosomoid window answered is the window for 85950k-86250k for the base positions of No. 3 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 61500k-61800k, it is right
The the second chromosomoid window answered is the window for 81600k-81900k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 61650k-61950k, it is right
The the second chromosomoid window answered is the window for 89700k-90000k for the base positions of o.11 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 61800k-62100k, it is right
The the second chromosomoid window answered is the window for 83700k-84000k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 61950k-62250k, it is right
The the second chromosomoid window answered is the window for 81600k-81900k for the base positions of No. 13 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 62100k-62400k, it is right
The the second chromosomoid window answered is the window for 78450k-78750k for the base positions of No. 8 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 62250k-62550k, it is right
The the second chromosomoid window answered is the window for 96150k-96450k for the base positions of No. 3 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 62400k-62700k, it is right
The the second chromosomoid window answered is the window for 91050k-91350k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 62550k-62850k, it is right
The the second chromosomoid window answered is the window for 72900k-73200k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 62700k-63000k, it is right
The the second chromosomoid window answered is the window for 73650k-73950k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 62850k-63150k, it is right
The the second chromosomoid window answered is the window for 193200k-193500k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 63000k-63300k, it is right
The the second chromosomoid window answered is the window for 181350k-181650k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 63150k-63450k, it is right
The the second chromosomoid window answered is the window for 84150k-84450k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 63300k-63600k, it is right
The the second chromosomoid window answered is the window for 157500k-157800k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 63450k-63750k, it is right
The the second chromosomoid window answered is the window for 21750k-22050k for the base positions of No. 5 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 63600k-63900k, it is right
The the second chromosomoid window answered is the window for 80850k-81150k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 63750k-64050k, it is right
The the second chromosomoid window answered is the window for 110250k-110550k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 63900k-64200k, it is right
The the second chromosomoid window answered is the window for 110250k-110550k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 64050k-64350k, it is right
The the second chromosomoid window answered is the window for 87150k-87450k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 64200k-64500k, it is right
The the second chromosomoid window answered is the window for 12300k-12600k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 64350k-64650k, it is right
The the second chromosomoid window answered is the window for 111600k-111900k for the base positions of No. 3 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 64500k-64800k, it is right
The the second chromosomoid window answered is the window for 9900k-10200k for the base positions of Chromosome 9；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 64650k-64950k, it is right
The the second chromosomoid window answered is the window for 85050k-85350k for the base positions of No. 3 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 64800k-65100k, it is right
The the second chromosomoid window answered is the window for 72600k-72900k for the base positions of No. 6 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 64950k-65250k, it is right
The the second chromosomoid window answered is the window for 92100k-92400k for the base positions of No. 6 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 65100k-65400k, it is right
The the second chromosomoid window answered is the window for 117450k-117750k for the base positions of No. 5 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 65250k-65550k, it is right
The the second chromosomoid window answered is the window for 113400k-113700k for the base positions of No. 6 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 65400k-65700k, it is right
The the second chromosomoid window answered is the window for 181500k-181800k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 65700k-66000k, it is right
The the second chromosomoid window answered is the window for 137100k-137400k for the base positions of No. 5 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 65850k-66150k, it is right
The the second chromosomoid window answered is the window for 174600k-174900k for the base positions of No. 3 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 66450k-66750k, it is right
The the second chromosomoid window answered is the window for 145800k-146100k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 66600k-66900k, it is right
The the second chromosomoid window answered is the window for 27300k-27600k for the base positions of No. 21 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 66750k-67050k, it is right
The the second chromosomoid window answered is the window for 123300k-123600k for the base positions of No. 6 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 66900k-67200k, it is right
The the second chromosomoid window answered is the window for 181950k-182250k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 67050k-67350k, it is right
The the second chromosomoid window answered is the window for 13800k-14100k for the base positions of No. 8 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 67200k-67500k, it is right
The the second chromosomoid window answered is the window for 81000k-81300k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 67350k-67650k, it is right
The the second chromosomoid window answered is the window for 162150k-162450k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 67500k-67800k, it is right
The the second chromosomoid window answered is the window for 85050k-85350k for the base positions of No. 7 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 67650k-67950k, it is right
The the second chromosomoid window answered is the window for 52050k-52350k for the base positions of No. 2 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 67800k-68100k, it is right
The the second chromosomoid window answered is the window for 30900k-31200k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 67950k-68250k, it is right
The the second chromosomoid window answered is the window for 39450k-39750k for the base positions of No. 12 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 68100k-68400k, it is right
The the second chromosomoid window answered is the window for 68400k-68700k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 68550k-68850, it is right
The the second chromosomoid window answered is the window for 88350k-88650k for the base positions of No. 5 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 68700k-69000, it is right
The the second chromosomoid window answered is the window for 87300k-87600k for the base positions of rice chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 68850k-69150, it is right
The the second chromosomoid window answered is the window for 70350k-70650k for the base positions of No. 6 chromosome；
When the window that the base positions that the window of the first chromosomoid is No. 18 chromosome are 69000k-69300, it is right
The the second chromosomoid window answered is the window for 85950k-86250k for the base positions of No. 7 chromosome.
4. the method for claim 2, wherein said individual sample to be detected is from the biology containing the dna of fetus for the anemia of pregnant woman
Sample.
5. the method for claim 4, wherein said is selected from blood plasma, blood from the biological specimen containing the dna of fetus for the anemia of pregnant woman
Clearly, urine and saliva.
6. the method for claim 4, wherein said takes off selected from cervix uteri from the biological specimen containing the dna of fetus for the anemia of pregnant woman
Fall cell and cervix uteri flushing liquor.
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| CN105316420A (en) * | 2015-12-01 | 2016-02-10 | 钦州市妇幼保健院 | Kit for rapidly detecting numbers of human chromosomes 13 and 18 by virtue of single-tube four-color dual relative fluorescence quantitative PCR technique |
| CN108920899B (en) * | 2018-06-10 | 2022-02-08 | 杭州迈迪科生物科技有限公司 | Single exon copy number variation prediction method based on target region sequencing |
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