CN104178572A - Sequencing data processing method and device - Google Patents

Sequencing data processing method and device Download PDF

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Publication number
CN104178572A
CN104178572A CN201410416250.3A CN201410416250A CN104178572A CN 104178572 A CN104178572 A CN 104178572A CN 201410416250 A CN201410416250 A CN 201410416250A CN 104178572 A CN104178572 A CN 104178572A
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window
chromosomal
base position
karyomit
corresponding equations
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CN104178572B (en
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李英睿
李松岗
杨广霞
蒋馥蔓
张秀清
玄兆伶
陈芳
林静蓉
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BGI Shenzhen Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6881—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for tissue or cell typing, e.g. human leukocyte antigen [HLA] probes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

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

The treatment process of sequencing data and device
Related application
The application is to be on April 23rd, 2010 applying date, and name is called the division of the Chinese patent application 201080032859.0 of " detection method of fetal chromosomal aneuploidy ".
Technical field
The present invention relates to medical detection field, relate to particularly the detection method of fetal chromosomal aneuploidy, by the value of nucleic acid molecular weight and the amount of the nucleic acid molecule of its corresponding window on Equations of The Second Kind karyomit(e) of first kind karyomit(e) window combination, and funtcional relationship therebetween detects antenatal fetal chromosomal aneuploidy.
Background technology
Fetus aneuploid karyomit(e) refers to amount abnormal in karyomit(e) or chromosomal a certain region.This abnormal amount can be abnormal height, as No. 21 trisomes of fetus, be than normal diploid fetus many No. 21 karyomit(e)s; Or extremely low, as Turner syndrome patient has lacked one or part X chromosome exactly.
In tradition, use as the method for chorionic villus sampling (CVS) or amniocentesis, obtain from fetus and separate and obtain cell, can use these cells to carry out conventional antenatal diagnosis.Although it is higher to carry out in this way the accuracy of diagnosis of fetal aneuploidy, but these methods are invasive, and mother and fetus are had to obvious danger.(Tabor?A,et?al.Randomised?controlled?trial?of?genetic?amniocentesis?in4606low-risk?women.Lancet1986,1:1287-1293)。
In Maternal plasma and serum, find that there is acellular circulation foetal DNA, this provides unlimited possibility for non-invasive prenatal diagnosis.The people such as Rossa W.K.Chiu are at PNAS2008, 105:20458-20463, article on magazine " utilizes the method for extensive high-flux sequence to carry out the antenatal diagnosis of the chromosomal nothing wound of aneuploid " and describes the sharp diagnosis of carrying out in this way without wound fetus aneuploid in detail, and point out can farthest obtain by the means of order-checking the information of peripheral blood the inside nucleic acid molecule, particularly in the parent sample extracting the contained nucleic acid molecule that derives from fetal chromosomal with respect to the amount of background parent nucleic acid molecule be quite few (Rossa W.K.Chiu, et al.Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternalplasma.PNAS, 2008, 105:20458-20463).Described method is: first extract the nucleic acid molecule in maternal plasma, then check order through extensive high-throughput s-generation sequenator, the sequence information and the sequence that obtain DNA segment drop on the positional information on which item chromosome.The people such as Dennis Lo are based on this essential information, then the karyomit(e) that statistics derives from medical significance is (as No. 21, No. 18, No. 13 karyomit(e)s) on nucleic acid molecule amount and derive from the amount of chromosomal nucleic acid molecule as a setting, by these two amounts, can obtain a parameter, then this parameter and one or more thresholdings of being built by normal sample are contrasted, and then find on medical significance karyomit(e), have this parameter of abnormal sample and multiple thresholding to exist larger difference (Dennis Lo having, et 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.
But this method exists the limitation of self.First it depends on the normal control value of setting up by the sequence distributed quantity of N (N is greater than 20) standard negative control sample, the thresholding of mentioning above for the detection of each sample.Based on these normal control values, just may analyze the situation of detected sample.That is to say that, in order to make accurate judgment, the interdependent property between the value of measured each sample is obvious, just because will likely make correct judgement by the difference of the value between comparative sample and sample.
Therefore,, due to the relation that needs between sample mutually to compare, the experiment condition that the desired each batch of sample of this method adopts is comparatively strict, if experiment condition gap is larger, will be difficult to obtain comparatively believable normal control value or sample value.This experiment condition comprises the sample preparation in early stage, agents useful for same batch and kind, order-checking GC deflection, system temperatures etc., that is to say, the variation of various experiment conditions all should be controlled in quite little scope, otherwise can cause the variance of the value between each negative control sample to increase, or the relatively large deviation each other of the value of each negative control sample, the value of some negative sample even may depart from range of normal value, becomes outlier.In like manner, this method also depends on the accuracy of the value of sample to be detected, for obtaining exact value, prepares this sample and reagent and order-checking condition used, comprises order-checking GC deflection, system temperature etc., all should with implement being as far as possible consistent of negative control sample.Only in this way, comparatively ideal is also believable counts the abnormal of the distributed quantity of exceptional sample on studied karyomit(e), and ensures that its value is for believable.
But, ensure under experiment and order-checking condition that the consistence of each microsystem condition is not simple thing too, because have other interfering factors in experimentation, so tend to cause experimental data not ideal, or data difference is larger between each sample, on the one hand, once data deficiency consistence, the confidence level of its detected result also decreases, and produces false positive or false-negative result; On the other hand, if data because gap due to the changing factor of experiment condition is larger, more can make it to become outlier and be abandoned need not.As everyone knows, order-checking cost is current still higher, like this outlier is abandoned and need not naturally can be caused suitable waste.
More advanced being undertaken in the diagnostic method of fetal chromosomal aneuploidy by sequence measurement at present just as previously mentioned, requirement for experiment condition to sample preparation or order-checking etc. is stricter, because in itself, it depends on the comparison between sample and sample.Normal sample and exceptional sample are what there were significant differences in the value that will study, once but when being greater than the difference between exceptional sample and normal sample due to different the introduced difference of experiment condition between sample, just there will be wrongheaded situation, reduce the confidence level of inspection.
Summary of the invention
technical problem to be solved by this invention
For this situation, contriver has carried out many-sided deep research, finally develops a kind of method that sample self is contrasted, no longer by between sample to recently making decision, but judge by the correlation that relatively derives from sample itself.Eliminated like this dependency to experiment condition, provide like this can be used for fetal chromosomal aneuploidy without wound new detecting method, it has eliminated the dependency to experiment condition.
the technology used in the present invention means
Particularly, contriver, based on sequencing data, finds that interchromosomal has the dependency of the nucleic acid amount of mutual correspondence, provides following method according to this dependency, detects the dysploidy of fetal chromosomal according to data acquisition and processing (DAP) method of the present invention.
Particularly, contriver's method comprises:
1. sequencing data treatment process, described method is applied to sequencing data treatment unit, and described sequencing data treatment unit comprises order-checking unit and modeling unit, and described method comprises:
(1) described modeling unit receives the sequencing data from described order-checking unit, described sequencing data comprises the sequencing data of whole genome of multiple normal individual samples, karyomit(e) to be studied as research object is defined as to first kind karyomit(e), and in full genome, all the other karyomit(e)s are defined as Equations of The Second Kind karyomit(e);
(2) all karyomit(e) in (1) is cut into respectively to overlapped or nonoverlapping fragment, each fragment is defined as a window;
(3) amount of the nucleic acid molecule of the each window of multiple normal individual sample dyeing body in statistics (2), is defined as behavior value by this amount;
(4) according to the behavior value in (3), the first kind karyomit(e) with (1) of finding on the Equations of The Second Kind karyomit(e) in (1) by mathematical statistics method has window or its combination of strong correlation, the functional relation A that has strong correlation window or its combination that sets up the chromosomal window of the first kind and find;
(5) utilize and have the chromosomal window of Equations of The Second Kind of strong correlation or the behavior value of window combination with first kind karyomit(e) or the chromosomal part of the first kind in functional relation in (4) and (4), determine the scope of the normal behaviour value of the first kind karyomit(e) in (1) or the chromosomal part of the first kind in (1).
2. sequencing data treatment unit, comprising:
Order-checking unit, described order-checking unit is for the genome sequencing of sample, produce sequencing data, described sequencing data comprises the sequencing data of whole genome of multiple normal individual samples, karyomit(e) to be studied as research object is defined as to first kind karyomit(e), and in full genome, all the other karyomit(e)s are defined as Equations of The Second Kind karyomit(e);
Modeling unit, described modeling unit is for receiving the sequencing data from order-checking unit; All karyomit(e) is cut into respectively to overlapped or nonoverlapping fragment, and each fragment is defined as a window; The amount of adding up the nucleic acid molecule of the each window of described multiple normal individual sample dyeing body, is defined as behavior value by this amount; According to described behavior value, find and have the window of strong correlation or its combination, the functional relation A that has strong correlation window or its combination that sets up the chromosomal window of the first kind and find with described first kind karyomit(e) on described Equations of The Second Kind karyomit(e) by mathematical statistics method; Utilize described functional relation A and described and first kind karyomit(e) or the chromosomal part of the first kind to have the second chromosomal window of strong correlation or the behavior value of window combination, determine the scope of the normal behaviour value of described first kind karyomit(e) or the chromosomal part of the described first kind.
3. the non-diagnostic method that detects individual chromosome dysploidy or karyomit(e) part dysploidy, comprising:
A. in advance or simultaneously multiple normal individual samples are carried out to genome sequencing, the karyomit(e) to be studied as research object is defined as to first kind karyomit(e), in full genome, all the other karyomit(e)s are defined as Equations of The Second Kind karyomit(e);
B. utilize in advance or simultaneously the method described in project 1 to process the sequencing data available from a, obtain the chromosomal window of the first kind and with described first kind karyomit(e) window have the chromosomal window of Equations of The Second Kind of strong correlation or the functional relation of window combination and, the scope of the normal behaviour value of described first kind karyomit(e) or the chromosomal part of the described first kind;
C. individuality to be measured is checked order, and then the chromosomal behavior value of the Equations of The Second Kind that obtains individuality to be detected itself, if the amount of the chromosomal nucleic acid molecule of the first kind of the individuality to be detected calculating according to the functional relation in b within the scope of the normal behaviour value in b, can not determine that the first kind karyomit(e) of individuality to be measured is dysploidy.
4. the non-diagnostic method that detects individual chromosome dysploidy, comprising:
Full genome is checked order, the karyomit(e) to be studied as research object is defined as to first kind karyomit(e), in full genome, all the other karyomit(e)s are defined as Equations of The Second Kind karyomit(e); According to the dependency of the behavior value of Equations of The Second Kind chromosome segment and first kind chromosome segment, on full genome, setting up mathematical model;
Individuality to be measured is carried out to genome sequencing, and then obtain individuality to be detected itself first kind karyomit(e) and the chromosomal behavior value of Equations of The Second Kind, if the behavior value in certain confidence level does not meet aforementioned mathematical model, the karyomit(e) that can determine individuality to be measured is dysploidy.
5. the method for project 4, described method comprises:
Whole karyomit(e) is cut into respectively to overlapped or nonoverlapping fragment, and each fragment is defined as a window;
Add up the amount from the nucleic acid molecule of the each window of karyomit(e) of the normal individual sample of dye-free bulk defects by order-checking, this amount is defined as to behavior value;
According to behavior value, find and have window or its combination of strong correlation with first kind karyomit(e) on Equations of The Second Kind karyomit(e) by mathematical statistics method, set up functional relation;
According to the amount of real nucleic acid molecule in the each window of Equations of The Second Kind karyomit(e) in functional relation and sample to be detected, under certain confidence level, obtain the analogue value fiducial interval of the chromosomal behavior value of the first kind to be studied;
Detect the chromosomal behavior value of the first kind of sample and the relation of its analogue value fiducial interval by judgement, judge that whether first kind karyomit(e) is abnormal.
6. the method for project 4, comprises modeling procedure (1)-(4) and detecting step (5)-(8), specific as follows:
(1) selection is checked order from the full genome of the normal individual of dye-free bulk defects, and the karyomit(e) to be studied as research object is defined as to first kind karyomit(e), and all the other karyomit(e)s are defined as Equations of The Second Kind karyomit(e);
(2) all karyomit(e)s in (1) are cut into overlapped or nonoverlapping fragment, each fragment is defined as a window;
(3) amount of statistics nucleic acid molecule of the each window of multiple sample dyeing body under multiple different experimental conditions, is defined as behavior value;
(4) according to the behavior value in (3), the first kind karyomit(e) with (1) of finding on the Equations of The Second Kind karyomit(e) in (1) by mathematical statistics method has window or its combination of strong correlation, the functional relation A that has strong correlation window or its combination that sets up the chromosomal window of the first kind and find, completes modeling procedure thus;
(5) complete genomic all karyomit(e) of the sample to individuality to be detected checks order, wherein be defined as equally first kind karyomit(e) as the karyomit(e) to be studied of research object, it is and the karyomit(e) of the corresponding identical numbering of first kind karyomit(e) in (1) that all the other karyomit(e)s are as Equations of The Second Kind karyomit(e);
(6) according to the karyomit(e) of sample to be detected in window specification cutting (5) same in (2), statistics first kind karyomit(e) and the chromosomal behavior value of Equations of The Second Kind;
(7) the behavior value of the each window of Equations of The Second Kind karyomit(e) in (6) is incorporated in relational expression A, sets confidence level, calculate the theory interval of first kind chromosome behavior value;
(8), if chromosomal behavior value of the first kind of statistics is not in the theoretical interval range of the behavior value in (7) in (6), think first kind chromosome abnormalty to be studied.
7. the method for project 6, wherein the relational expression of step (1)-(4) is reused in the detection of different samples to be tested, replication all while not needing each pattern detection, measures chromosomal dysploidy by carrying out step (5)-(8).
Above-mentioned " scope of normal behaviour value " meaning is with " the theory interval of behavior value ", is by setting confidence level, will calculating and obtain with the behavior value substitution functional relation of the chromosomal window of Equations of The Second Kind of first kind karyomit(e) strong correlation.
Above-mentioned " fiducial interval " comprises the fiducial interval of each window and the fiducial interval of whole chromosome.
Above-mentioned " different experimental conditions " mainly comprises that order-checking GC content is inconsistent, and reagent condition is different, and experiment preparation method has the situations such as difference.
The invention provides a kind of method, the method is used and derives from pregnant woman's single sample, and according to its chromosome number certificate, judges whether fetal chromosomal is dysploidy.Method thus, invention has finally obtained one group of first kind karyomit(e) window combination, and in Equations of The Second Kind karyomit(e), presents the analogue window combination of strong correlation with it, and functional relation after proofreading and correct under certain confidence level.By these windows and functional relation, can judge whether the first kind karyomit(e) of concrete sample is dysploidy.
Once modeling process of the present invention is determined, no longer need a large amount of normal samples to carry out modeling, only need, by self the chromosomal behavior value of Equations of The Second Kind substitution of each sample to be detected in the definite relational expression A of modeling process, can judge that whether first kind karyomit(e) is normal.
technique effect of the present invention
Method of the present invention can detect for aneuploid.Method of the present invention has been broken away from the more by force dependence of former method for strict control experiment condition, applicable to revising because experiment condition changes the outlier sample causing, thereby reduces waste.Method of the present invention can be passed through sample own control, and does not rely on the value of other sample, gives and judges that fetal chromosomal is whether for dysploidy provides important evidence; Method of the present invention is also avoided invasive method and the risk that causes simultaneously.The inventive method not only can be used for diagnosing based on order-checking whether karyomit(e) is dysploidy, more can be used under unknown experiment condition or situation that experiment condition control is bad under the chromosomal aneuploidy diagnosis of the isolated sample that obtains, and can with background technology in the method use that combines, checking each other, thereby further improve the accuracy of inspection, from large impact, can effectively control the natality of the aneuploid karyomit(e) fetus including No. 21 trisomes.Method of the present invention has been set up a kind of data processing method in addition, flexible and changeable, can simulate karyomit(e) No. 21, find out and No. 21 consistent internal reference window combination of chromosomal optimum behavior value, also can be generalized to all interested karyomit(e), as No. 18 karyomit(e)s, first chromosomoids such as No. 13 karyomit(e)s, even some interested chromosomal fragments, thereby the range of application of increase the method.
Brief description of the drawings
Fig. 1: be used for demonstrating the present invention and find in full genome (except first kind karyomit(e) to be studied) and determine and the each window combination of first kind karyomit(e) has the schema of the method that the analogue window of extremely strong dependency combines, be designated as method 100.
Fig. 2: be used for demonstrating the present invention diagnose pregnant woman pregnant fetus whether be the schema of the method for chromosomal aneuploidy, be designated as method 200.
Fig. 3: the scatter diagram of linear dependence between display window.Add up by his-and-hers watches 3 to come from genome window label be (chr4,642) value of the nucleic acid molecule on window area (89 behavior value xi), with be (chr21 from genome window label, 180) value of the nucleic acid molecule on window area (89 behavior value yi), utilize correlation analysis statistically, calculate the relation conefficient between two windows, and relation function.The R showing on figure 2be 0.9724, illustrate that two window dependencys are fine.
Fig. 4: the scatter diagram of linear correlationship between display window.What add up by his-and-hers watches 3 is (chr1 from genome window label, 256) value of the nucleic acid molecule on window area (89 behavior value xi), with be (chr21 from genome window label, 180) value of the nucleic acid molecule on window area (89 behavior value yi), utilize correlation analysis statistically, calculate the correlationship coefficients R between two windows, due to coefficient R 2only only have 0.6, two window linear relationships are bad as seen from the figure.
Fig. 5: the scatter diagram of linear dependence between display window.What add up by his-and-hers watches 7 is (chr8 from genome window label, 710) value of the nucleic acid molecule on window area (89 behavior value xi), with be (chr18 from genome window label, 259) value of the nucleic acid molecule on window area (53 behavior value yi), utilize correlation analysis statistically, calculate the relation conefficient between two windows, and relation function.The R showing on figure 2be 0.9816, illustrate that two window dependencys are fine.
Fig. 6: the scatter diagram of linear correlationship between display window.What add up by his-and-hers watches 7 is (chr1 from genome window label, 8) value of the nucleic acid molecule on window area (53 behavior value xi), with be (chr18 from genome window label, 259) value of the nucleic acid molecule on window area (53 behavior value yi), utilize correlation analysis statistically, calculate the correlationship coefficients R between two windows, due to coefficient R 2only only have 0.0043, two window linear relationships are bad as seen from the figure.
Fig. 7: the figure that shows the relation of the actual value of normal sample and exceptional sample and analogue value fiducial interval separately.From maternal blood sample of nucleic acid, sample 1 is with the actual value of sample 2 outside analogue value fiducial interval separately in 4 of concrete demonstrations, and sample is No. 21 chromosomal aneuploidies; And sample 5 with the actual value of sample 6 within analogue value fiducial interval separately, sample is normal.
Fig. 8: the figure that shows the relation of the actual value of normal sample and exceptional sample and analogue value fiducial interval separately.Show that 4 from maternal blood sample of nucleic acid, sample 3 is with the actual value of sample 4 outside analogue value fiducial interval separately, and sample is No. 21 chromosomal aneuploidies; And sample 7 with the actual value of sample 8 within analogue value fiducial interval separately, sample is normal.
Fig. 9: the figure that shows the relation of the actual value of normal sample and exceptional sample and analogue value fiducial interval separately.Specifically show that 4 from maternal blood sample of nucleic acid, sample 1, sample 2 is with the actual value of sample 3 within analogue value fiducial interval separately, and sample is that No. 18 karyomit(e)s are normal; And the actual value of sample 4 is outside analogue value fiducial interval separately, be No. 18 chromosomal aneuploidies.
Figure 10: the figure that shows the relation of the actual value of normal sample and exceptional sample and analogue value fiducial interval separately.Show that 2 from maternal blood sample of nucleic acid, sample 5 is with the actual value of sample 6 outside analogue value fiducial interval separately, and sample is No. 18 chromosomal aneuploidies.
Embodiment
definition
In order more clearly to set forth the present invention, the term definition using is in the present invention as follows.
" aneuploid karyomit(e) " or " chromosomal aneuploidy " refer to that certain karyomit(e) exists whole piece or excalation or redundancy with respect to this karyomit(e) in normal diploid gene group.Normal conditions are to have extra item chromosome or item chromosome wherein to lose.The common situations of chromosomal aneuploidy is trisome, has an extra karyomit(e).For example, No. 21 karyomit(e) trisomes are found No. 21 chromosomal a kind of chromosome abnormalties of Article 3 exactly in cell.
" biological specimen " refers to the sample that comprises interested nucleic acid molecule that derives from object (as pregnant woman), as blood plasma, and serum or other biological specimen that contains nucleic acid molecule.
" normal sample " refers to and do not occur that any karyomit(e) has the abnormal maternal blood sample of aneuploid.
" nucleic acid molecule " refers to deoxyribonucleotide molecule contained in the biological specimen of extraction, here refers to contain in biological specimen, derives from the nucleic acid molecule of people's 300,000,000 genome base pairs.
" nucleic acid fragment molecule " refers to that biological specimen is after the steps such as preparation, can be obtained its sequence information and the positional information on genome thereof and can be represented the fragment nucleic acid molecule of nucleic acid molecule corresponding thereto by order-checking means.
After " Unique nucleic acid molecule " refers to order-checking, information analysis shows that this nucleic acid molecule has and only have the position of a distribution on human genome.
" window " refers to the fragment that the unit nucleotide sequence length of karyomit(e) or the artificial definition of chromosomal region basis can be divided into overlapping region or there is no overlapping region, and each window corresponding on this karyomit(e) or chromosomal region unique one section, positional information is unique.
" amount of nucleic acid molecule ", also claim behavior value, navigate to after each karyomit(e) particular location based on order-checking according to nucleic acid fragment molecule, statistics and the nucleic acid fragment molecule that is positioned at this region number or can reflect the value that has how many nucleic acid molecule to be distributed in this region, such as by the number of the nucleic acid fragment molecule that can be positioned at this region of statistics gained, or added up or number obtained the ratio of nucleic acid molecule that part is added up or the accumulated value of nucleic acid fragment molecular length etc. divided by all from the number of this region nucleic acid molecule, in a word, for an experiment sample, in a certain window area, as long as this value can reflect the situation of nucleic acid molecule in the amount of the distribution of this window, this value just can be called behavior value or derive from the amount of the nucleic acid molecule of this window.
(the behavior value of window) refers to according to nucleic acid fragment molecule and navigates to after each karyomit(e) particular location based on order-checking " to derive from the amount of the nucleic acid molecule of a certain window ", the number of the nucleic acid fragment molecule that can be positioned at this region of statistics gained or can be reflected to the end and have how many nucleic acid molecule to be distributed in the value in this region, such as by the number of the nucleic acid fragment molecule that can be positioned at this region of statistics gained, or added up or number obtained the ratio of nucleic acid molecule that part is added up or the semi-invariant of nucleic acid fragment molecular length etc. divided by all from the number of the same area nucleic acid molecule, in a word, for an experiment sample, as long as this value can reflect the situation of nucleic acid molecule in the amount of the distribution of this window, this value just can be called behavior value or derive from the amount of the nucleic acid molecule of this window.
" behavior value is consistent " refers to two behavior values, and one of them behavior value changes, and the variation of functional relation approximate expression occurs to use another behavior value simultaneously.
" actual value " refers to the amount of the nucleic acid molecule that derives from the chromosomal window of the first kind.
" first kind karyomit(e) " refers to all or part of nucleotide sequence that clinical study is worth, and medically, detects some abnormal symptom through conventional these chromosomal imbalances in other words.For example No. 21 chromosome sequences, No. 18 chromosome sequences, No. 13 chromosome sequences, X chromosome sequence or Y chromosome sequence etc.
" Equations of The Second Kind karyomit(e) " refers on genome and removes chromosomal other karyomit(e)s of the first kind, in the concrete enforcement of middle finger of the present invention, remove chromosomal other karyomit(e)s of the first kind to be studied.
" first kind karyomit(e) window combination " refers to by several window combination overlapping or that zero lap window forms, and this window combination can cover first kind karyomit(e) all or in part.
" there is the analogue window (analogue window combination) of extremely strong dependency with the chromosomal window of the first kind " and refer in research genome, be present in the specific analogue window on other karyomit(e) except the first kind karyomit(e) of current research, first kind karyomit(e) window under this specific analogue window and current research exists strong correlation, it shows as: for each normal biological sample wherein, always exist so a kind of relation, if deriving from the amount of the nucleic acid molecule of first kind karyomit(e) window in this sample changes, deriving from first kind karyomit(e) window has the nucleic acid molecular weight of the analogue window (analogue window combination) of utmost point dependency that corresponding variation also occurs, and a this amount change another correlationship of also changing of amount can be by related function expression formula approximate expression out.The selected square method 100 of analogue window (analogue window combination).
" fiducial interval of chromosome behavior value to be studied " refer to the amount of the nucleic acid molecule by deriving from the chromosomal window combination of the first kind and the functional relation corresponding with it calculate under certain confidence level, the fiducial interval of this first kind karyomit(e) (karyomit(e) window).If relationship between expression formula is y=ax+b between two windows, now adding up deriving from of gained, to have the amount of the nucleic acid molecule of utmost point correlationship analogue window with first kind karyomit(e) window be x, analogue value y can be calculated to obtain according to functional relation, more corresponding fiducial interval can be obtained according to knowledge of statistics.
" imbalance " here refers to by actual value relatively not in the fiducial interval calculating according to analogue window and functional relation, thinks that the biological specimen now detecting exists imbalance at studied first kind karyomit(e) or first kind chromosomal region.
" Chr " in the present invention is the abbreviation of " karyomit(e) ", and for example " Chr18 " represents karyomit(e) No. 18.Karyomit(e) duplex chain comprises a normal chain, an anti-chain, and positive anti-chain is complementary, and a chain base sequence is determined, and the base sequence of an other complementary strand is also determined.Therefore, each position base wherein occurs in pairs, and base pair is complementary: A and T complementation, C and G complementation.On the mankind's karyomit(e), taking the base position of normal chain as benchmark, any one position all refers to a pair of base pair, both comprised the base in normal chain, also comprised the complementary base on anti-chain simultaneously, position location in the present invention, all taking bp as unit, i.e. base pair abbreviation (base pair).For example chr21:150-450kbp, represents on No. 21 karyomit(e)s the window to 450000 base pairs in 150000 base pairs.If the direction of differentiation, normal chain refers to that chain of 5 '-3 ', and anti-chain is and that chain of its complementation, and direction should be 3 '-5 '.We are taking normal chain base position as benchmark conventionally, refer in the base of chr21:150bp here, and from normal chain, direction 5 '-3 ', the 1st base starts number, in that base pair of No. 150; From minus strand, direction 3 '-5 ', the 1st base starts number, in that base pair of No. 150.
In embodiments of the invention, provide a kind of searching and first kind karyomit(e) window combination to have the analogue window of utmost point dependency or the method for window combination.The essence of the method for described " finding analogue window or window combination " is to find out by the correlation analysis of behavior value between each window of novelty the analogue window or the analogue window combination that have extremely strong dependency with first kind karyomit(e) window or window combination.For example, selected can being called is that the window in the analogue window combination of first kind karyomit(e) window combination and the behavior value relation conefficient between its corresponding first kind karyomit(e) window are close to 1, and can obtain a general functional relation, be used for explaining the correlationship between two window behavior values.
In the time that the chromosomal window of the first kind only finds an Equations of The Second Kind karyomit(e) window to have strong correlation with it, functional relation is the function of a single variable relational expression between the two, if while having found multiple strong correlation window, functional relation is the multivariate function relational expression after matching is optimized.
Embodiment of the present invention, following diagnostic method is provided, whether the amount that derives from the nucleic acid molecule of the first kind karyomit(e) window combination of same sample by judgement diagnoses aneuploid karyomit(e) in fiducial interval, and the correlationship that fiducial interval origin comes between behavior value and each respective window of the definite analogue window of aforementioned searching combination determines jointly.
Embodiment
Following embodiment is only used for explaining the present invention, instead of is used for limiting the scope of the invention, and the variant of method equivalence any and of the present invention is all included in the middle of the present invention.
Embodiment mono-
Step 1: obtain the required sequencing data of modeling
Select 89 normal samples, these samples are prepared under discrepant experiment condition and checked order.
In brief, first prepare DNA library, then nucleic acid fragment molecule is connected in Solexa sequence measuring joints, then separation and purification nucleic acid fragment length is at the nucleic acid molecule of 150 to 300 base pairs.The nucleic acid molecule that connects joint can be hybridized with flow cell surface complementarity joint, under certain condition, nucleic acid molecule cluster growth is then taken turns order-checking circulation by 36 on Illumina Genome Analyzer, is equivalent to each nucleic acid molecule and has recorded the nucleic acid fragment of 35 base pairs.Next the sequence information recording, through a Pipeline process, finally can obtain the ELAND comparison result taking the human genomic sequence in NCBI as canonical sequence.
Under study for action, for avoiding the interference of some tumor-necrosis factor glycoproteinss, contriver rejects those in the nucleic acid molecule fragment that genome series connection repeats and swivel base repeats, and only adds up those and can navigate to the nucleic acid fragment molecule of the unique position of genome.So in fact, measure in the nucleic acid molecule that come all, probably only having 1/4th to 1/3rd nucleic acid molecule is to navigate to the unique position of genome.Now these nucleic acid molecule of being added up are called Unique nucleic acid molecule, and the amount of the Unique nucleic acid molecule of this statistics gained still represents the amount of the nucleic acid molecule that is distributed in genome specific region.
This step is corresponding to 110,120 steps of Fig. 1.
Step 2: set up karyomit(e) detection model No. 21
Carry out according to the schema of Fig. 1, the process of Mathematical Models is completed by optimization for program.Computer program is selected by different parameters, completes the searching of dependency window, finds optimized parameter, sets up the functional relation of first kind karyomit(e) window and Equations of The Second Kind karyomit(e) window.
In 130 steps, based on order-checking, can every measured nucleic acid fragment molecule be navigated on genomic accurate location by the means of analysis of biological information.
In 140 steps, each sample is cut to window.Genomic formation every karyomit(e) is divided into some series of windows.Whole genome is cut into the window of suitable size, be equivalent to regard every karyomit(e) as had the window in overlapping region or zero lap region by some combination.As altogether the have an appointment base pair of 47Mega of No. 21 karyomit(e), if taking 10Mega size as a window, and the position that each window starts slides backward 1Mega size, and No. 21 karyomit(e) correspondences 47 windows that have overlapping 10Mega size.Can artificially define the length of window size wanted and the length of windows overlay region sequence, and be also window number, produce pair of windows and number the mapping of window true coordinate on each karyomit(e) on genome.
In embodiment, taking 300k as window size, 150k is overlap splitter (initiating terminal that is each window is that previous window initiating terminal slides backward 150k), and table 1 has shown 40 windows that cut after No. 21 karyomit(e)s.If a window label corresponding to window is chr21,2, the position on genome of its correspondence is chr21:150-450kbp.
Table 1
Table 1 has been shown label and the position coordinates of window on genome of the window obtaining by No. 21 karyomit(e)s of artificial cutting, only shows 40 windows in table.If window label is (chr21,180), represent that it is the 180th window after No. 21 karyomit(e)s of cutting, particular location on No. 21 karyomit(e)s is that coordinate is (chr21:26850-27150kbp), between No. 21 chromosomal 26850000 base pairs and 27150000 base pairs.Thus, each window label is representing the mapping position of institute homologue, i.e. the chromosomal region of one section of artificial cutting.
In embodiment, No. 4 karyomit(e)s are a non-first kind karyomit(e), if taking 300k base pair size as a window, and the position that each window starts slides backward the mode of 150k base pair and in like manner can cut into some windows, table 2 is listed 20 window labels and the positional information on karyomit(e) is window coordinates.If a window label corresponding to window is chr4,2, the position on genome of its correspondence is chr4:150-450kbp.
Table 2
In table 2, show the label by No. 4 window that karyomit(e) obtains of artificial cutting and represented the window coordinates of its position on genome, only shown 20 windows wherein.If window label is (chr4,643), represent that it is the 180th window thereon after No. 4 karyomit(e)s of cutting, particular location on No. 4 karyomit(e)s is that coordinate is (chr4:96300-96600kbp), between No. 4 chromosomal 96330000 base pairs and 96600000 base pairs.
In 150 steps, the sample that these are prepared and checked order under discrepant condition, based on order-checking gained information, adds up respectively various kinds and originally derives from the amount of the nucleic acid fragment molecule of each series of windows.
As No. 21 chromosomal windows, refer to as previously mentioned the chromosomal window combination that clinical study is worth.The coordinate of supposing a certain window in this window combination is (chr21:89000-89200bp), illustrate that it is on No. 21 karyomit(e)s, and this window area finishes since 89200 base pairs of the 89000th base pair to the, and now, the origin coordinates of a certain nucleic acid fragment molecule recording is chr21:89100, and measured molecule fragment length is 35 base pairs, so, the sequence location of this nucleic acid fragment molecule is just within these window coordinates, illustrate that this nucleic acid fragment molecule derives from this window area, as the number of the nucleic acid molecule of all sequences position that can add up a sample in this window, this number can be called the amount of the nucleic acid molecule that derives from this window so.Then by the amount of the nucleic acid fragment molecule of the window of this first kind karyomit(e) window combination of formation altogether, just can obtain deriving from the nucleic acid molecular weight of first kind karyomit(e) window combination, be stressed that this first kind karyomit(e) window combination according to circumstances covers to a part or whole part first kind karyomit(e) one or many here.
In 160 steps, for No. 21 chromosomal each window, window analysis on whole genome (except No. 21 karyomit(e)s) and the dependency of this window, select the group of windows of extremely strong dependency to retain, and determine functional relation therebetween, at this moment, No. 21 chromosomal single windows may corresponding multiple correlation windows, the combination of composition correlation window.If the nucleic acid molecular weight that derives from Equations of The Second Kind karyomit(e) window of statistics gained is Xi, the nucleic acid molecular weight that statistics gained derives from first kind karyomit(e) window is Yi, i representative sample numbering, observation sample is (X1, Y1), (X2, Y2) ... (Xn, Yn). now, according to these data, can calculate these two groups of data relation conefficient square.Relation conefficient square more approach 1, intercept, close to 0, illustrates that dependency is higher.Each No. 21 karyomit(e) correlation window single with it can be determined a functional relation.
In embodiment, 89 biological specimens that carry out sample preparation and order-checking under discrepant experiment condition and order-checking condition are prepared, add up respectively various kinds and originally derive from the amount of the nucleic acid fragment of each window area sequence, to each sample, its each window cutting on genome corresponding a behavior value.For 89 samples, in each window, there are 89 behavior values.
In this embodiment, for No. 21 chromosomal each window, simultaneously at the upper search of genome (except a No. 21 karyomit(e)s) window high with this window dependency.For convenience of description, only get three windows here and be used for explanation, in table 5, one derives from the window of first kind karyomit(e) window combination, is numbered (chr21,180), two derive from the chromosomal window of the non-first kind, and numbering is respectively window (chr1,256), window (chr4,642).In table 3, shown in the first row, show sample number, the numbering of 89 samples that present method is studied; The second row has been shown the value for the nucleic acid molecule on (chr1,256) window from genome window label of the each sample in 89 samples corresponding to sample number, i.e. 89 behavior values, are designated as X'i, and i value gets 89 from 1.The third line has been shown the value for the nucleic acid molecule on (chr4,642) window from genome window label of the each sample in 89 samples corresponding to sample number, is also 89 behavior values, is designated as xi, and i value gets 89 from 1.What fourth line was shown each sample in 89 samples corresponding to sample number is the value of the nucleic acid molecule on (chr21,180) window from genome window label, is also 89 behavior values, is designated as yi, and i value gets 89 from 1.
Table 3
First study the correlationship of window (chr4,642) and window (chr21,180), now observation sample is (X1, Y1), (X2, Y2) ... (Xn, Yn), in this embodiment, n can get 89, the relation conefficient of research two columns values, relation conefficient square more approach 1, illustrate that dependency is higher,, in the time that the behavior value of a window changes, also can there is corresponding variation in another window.In the time that relation conefficient approaches 1, whether the behavior that can study two windows according to observation sample obeys linear relationship, window (the chr4 that table 3 is expressed, 642) with window (chr21,180) behavior value is obeyed linear relationship, and can obtain the expression formula of its linear equation and coefficient R square.See Fig. 3, in this embodiment, can find out two windows, window (chr4,642) and window (chr21,180), behavior value exist extremely strong linear dependence, and correlated expression formula is: y=0.7564-0.6487, R 2=0.9724.Obviously R still relatively approaches 1, and this window (chr4,642) can be selected as the analogue window that has extremely strong dependency corresponding with embodiment window (chr21,180).Study again window (chr1,256) and window (chr21,180), see Fig. 4, its R 2=0.6214, think that two window behavior values are not very relevant, can not consider this window later.Like this, can go to seek to obtain the extremely strong analogue window of one or more dependencys by such method for the window in first kind karyomit(e) window combination.Just only need oneself to know an X value later, only need to add up the amount that derives from this analogue window of having extremely strong dependency corresponding with embodiment window, just can calculate an analogue value or analogue value fiducial interval by relational expression.
As table 4 announced by method 100 process steps selected have the analogue window combination that is dispersed in other position of genome of extremely strong dependency with first kind window combination, in table, only show the combination being formed by 20 windows.First row shows the window label being positioned on first kind karyomit(e), and secondary series shows its window coordinates; The 3rd row show the window label that has the analogue window of extremely strong dependency with corresponding first kind karyomit(e), and the 4th row show corresponding analogue window coordinate; The relational expression of the 5th row display window and relevant analogue window; The 6th row show the square value of relation conefficient, i.e. R side's value, and R square value more approaches 1, illustrates that between two windows, dependency is higher, and the nucleic acid molecular weight that wherein derives from a window changes, and derives from another window nucleic acid molecular weight corresponding variation can occur.
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 can will there is the analogue window of extremely strong dependency to combine with No. 21 karyomit(e) window combination, the combination of common formation analogue window, calculate to obtain a corrected fiducial interval, the judgement for method 200 to chromosomal aneuploidy according to the amount of the nucleic acid molecule that derives from analogue window or analogue window combination again.
In 170 steps, because the each window on No. 21 karyomit(e)s may have multiple windows associated, institute thinks abundant use sequencing data, improve detection accuracy, the related function relational expression of these windows is carried out to matching, and according to real data, proofread and correct, in final definite No. 21 karyomit(e)s, can on genome, find the functional relation of each window of strong correlation.
Step 3: to sample order-checking to be detected
8 pregnant woman volunteers participate in this detection, and the sample number obtaining is respectively sample 1-8.Four pregnant woman nourish karyomit(e) trisome fetus No. 21, and four pregnant woman nourish karyomit(e) normal fetus No. 21.Collect each maternal blood, and centrifugal to carrying out, get blood plasma, and then extract nucleic acid molecule from blood plasma, by the sequenator of Illumina company, these nucleic acid molecule are carried out to extensive high-flux sequence.
Carry out according to the schema of 200 methods of Fig. 2, particularly, in 210 steps, obtain biological specimen from pregnant woman.This biological specimen can be blood plasma or other suitable sample.This biological specimen is comprising the nucleic acid molecule that derives from pregnant woman and fetus.
In 220 steps, the nucleic acid molecule in sample is carried out to random sequencing.The nucleic acid fragment molecule being sequenced is representing a whole genomic part, can be positioned on each karyomit(e).Nucleic acid molecule in sample can only be surveyed one end (as surveyed 35 of one end base pair) or survey two ends, or whole piece nucleic acid molecule is all measured.
Order-checking can be checked order by the parallel sequenator of extensive high-throughput, as 454, Solexa, and SOLiD system, and single-molecule sequencing or nanoporous order-checking etc.We carry out one end order-checking by the solexa sequenator of Illumina company to nucleic acid molecule in one embodiment.
Although the general flow process of sample preparation and experiment is identical, in order to verify that the inventive method is applicable to the not too consistent situation of experiment condition, having requirement for experiment condition is not very strict advantage, and described experiment condition comprises the reagent that use is different, and order-checking GC deflection is inconsistent etc.Spy is divided into two groups, sample 1, and sample 2, sample 5, sample 6 is one group of experiment condition (A group); Sample 3, sample 4, sample 7, sample 8 is another group experiment condition (B group).A group is for extracting 5ml pregnant woman blood plasma, use QIAamp DNA Micro kit (QIAGEN, 56304) extract dissociative DNA, building storehouse flow process according to Illumina/Solexa uses NEB reagent to build SE library, upper SE36 order-checking, B group extracts 600ul pregnant woman blood plasma and uses TIANamp Micro DNA Kit (Tiangen DP316) to extract dissociative DNA, builds storehouse flow process and uses Enzymatics reagent to build PEI library, upper SE36+7 order-checking according to Illumina/Solexa.
This step is as 210,220 steps of Fig. 2.
Step 4: detect sample, carry out according to the schema of Fig. 2.
In 230 steps, based on order-checking, can every measured nucleic acid fragment molecule be navigated on genomic accurate location by the means of analysis of biological information.As table 1, it has shown by checking order and measured can navigate to its zero position coordinate on this karyomit(e) of each chromosomal nucleic acid fragment molecule.
Table 5 has shown that some nucleic acid molecule that obtain after biological specimen sample 1 and sample 2 order-checkings navigate to the positional information of front ten initiation sites on No. 4 karyomit(e)s and No. 21 karyomit(e)s.
As can be seen from Table 5, for sample 1, its initial point position that can navigate to No. 21 Article 1 nucleic acid fragment molecules on karyomit(e) is 9797443, and the starting point of this article of nucleic acid fragment molecule is positioned at chromosomal the 9797443rd base pair position No. 21.In like manner, its initial point position that can navigate to No. 4 Article 1 nucleic acid fragment molecules on karyomit(e) is 19219, and the starting point of this article of nucleic acid fragment molecule is positioned at chromosomal the 19219th base pair position No. 4.
Table 5
In 240 steps, with set up model in the same, with 300k be window size, 150k is that overlap cuts respectively window to all karyomit(e)s of 8 samples to be detected.In 250 steps, based on nucleic acid fragment positional information, statistics derives from the amount of the nucleic acid fragment molecule of No. 21 each windows of karyomit(e).In 260 steps, based on nucleic acid fragment positional information, what statistics derived from each sample has the amount of the nucleic acid molecule of the analogue window combination of strong correlation with No. 21 karyomit(e) windows, and calculates fiducial interval according to functional relation.In 270 steps, by judging in the fiducial interval whether amount of the nucleic acid fragment molecule that derives from No. 21 karyomit(e) windows that the 250th step of each sample obtains obtain in the 260th step of same sample, can judge that whether fetus exists the excessive risk of dysploidy at No. 21 karyomit(e).
Table 6: by eight results that sample obtains in the inventive method detection embodiment
Actual value Y row in table 6 are nucleic acid molecular weights that derive from No. 21 karyomit(e) window combination of each sample of statistics gained; Add up in this sample the nucleic acid molecular weight and the correlationship expression formula (as shown in table 4) that have the analogue window combination of strong correlation with No. 21 karyomit(e) window combination, then the fiducial interval (confidence level: 95%) obtaining by knowledge of statistics.For the sample of a research, within its actual value is present in the fiducial interval calculating time, can think that studied sample is that normal possibility is very large, otherwise, if actual value is present in outside analogue value fiducial interval, illustrate that this sample is that normal possibility is very little.As sample 1, sample 2, sample 3, sample 4, the nucleic acid molecular weight that their actual value derives from No. 21 chromosomals all outside fiducial interval range, the conclusion obtaining by present method for they be trisomy 21 fetus sample, this result has obtained the proof of karyotyping result.
Originally the value (actual value) and the analogue value fiducial interval obtaining that derive from the amount of the nucleic acid fragment molecule of first kind karyomit(e) window combination by more above-mentioned various kinds, judge whether to exist fetus aneuploid karyomit(e) or aneuploid chromosomal region on first kind karyomit(e).As shown in table 6, can see that the actual value of No. 21 karyomit(e) trisomes is outside analogue value fiducial interval, and normal its actual value of twice sample body is within analogue value fiducial interval range.Fig. 7, shows that four from maternal blood sample of nucleic acid, and sample 1 on analogue value fiducial interval separately, can be defined as chromosomal aneuploidy with the actual value of sample 2 No. 21; And the actual value of sample 5 and sample 6 is within analogue value fiducial interval separately, can think that sample is normal.Fig. 8, illustrates the relation of the actual value of normal sample and exceptional sample and analogue value fiducial interval separately.Show that four from maternal blood sample of nucleic acid, sample 3 on analogue value fiducial interval separately, can be defined as chromosomal aneuploidy with the actual value of sample 4 No. 21; And the actual value of sample 7 and sample 8 is within analogue value fiducial interval separately, can think that sample is normal.
Embodiment bis-
step 1: obtain the required sequencing data of modeling
Select 53 normal samples, these samples are prepared under discrepant experiment condition and checked order.
This step is corresponding to 110,120 steps of Fig. 1.
step 2: set up karyomit(e) detection model No. 21
Carry out according to the schema of Fig. 1, the process of Mathematical Models is completed by optimization for program.Computer program is selected by different parameters, completes the searching of dependency window, finds optimized parameter, sets up the functional relation of first kind karyomit(e) window and Equations of The Second Kind karyomit(e) window.
In 130 steps, based on order-checking, can every measured nucleic acid fragment molecule be navigated on genomic accurate location by the means of analysis of biological information.
In 140 steps, each sample is cut to window.Genomic formation every karyomit(e) is divided into some series of windows.In embodiment, taking 300k as window size, 150k is overlap splitter (initiating terminal that is each window is that previous window initiating terminal slides backward 150k).
In 150 steps, the sample that these are prepared and checked order under discrepant condition, based on order-checking gained information, adds up respectively various kinds and originally derives from the amount of the nucleic acid fragment molecule of each series of windows.
In 160 steps, for No. 18 chromosomal each window, window analysis on whole genome (except No. 21 karyomit(e)s) and the dependency of this window, select the group of windows of extremely strong dependency to retain, and determine functional relation therebetween, at this moment, if No. 18 corresponding multiple correlation windows of chromosomal single window, the combination of composition correlation window.
In embodiment bis-, 53 biological specimens that carry out sample preparation and order-checking under discrepant experiment condition and order-checking condition are prepared, add up respectively various kinds and originally derive from the amount of the nucleic acid fragment of each window area sequence, to each sample, its each window cutting on genome corresponding a behavior value.For 53 samples, in each window, there are 53 behavior values.As shown in table 7, choose 3 windows, come from respectively (chr18,259), (chr1,8), (chr8,710).Shown in the first row, show sample number, the numbering of 53 samples studying in the present embodiment; The second row has been shown the value for the nucleic acid molecule on (chr1,8) window from genome window label of the each sample in 53 samples corresponding to sample number, i.e. 53 behavior values, are designated as X'i, and i value gets 53 from 1.The third line has been shown the amount (53 behavior values) that is (chr18,259) nucleic acid molecule from genome window label of the each sample in 53 samples corresponding to sample number, is designated as xi, and i value gets 53 from 1.What fourth line was shown each sample in 53 samples corresponding to sample number is the amount (53 behavior values) of (chr18,259) nucleic acid molecule from genome window label, is designated as yi, and i value gets 53 from 1.
Table 7
First study window (chr8,710) with window (chr18,259) correlationship, now observation sample is (X1, Y1), (X2, Y2), (Xn, Yn), in this embodiment, n can get 53, study the relation conefficient of two columns values, obtain window (chr8,710) and exist strong correlation with the behavior value of window (chr18,259), and correlated expression formula is: y=-9.18452+0.98295x, R 2=0.9816, see Fig. 5.Obviously R 2still relatively approach 1, this window (chr8,710) can be selected as the window that has strong correlation corresponding with embodiment window (chr18,259).Study again window (chr1,8) and window (chr8,259), see Fig. 6, its R 2=0.004344, think that two window behavior values are uncorrelated, can not consider this window later.So, can be at the upper selected one or more windows strong with No. 18 karyomit(e) dependencys of genome (except No. 18 karyomit(e)s).Just only need a known X value later, only need to add up the amount that derives from this analogue window of having extremely strong dependency corresponding with embodiment window, just can calculate a fiducial interval by functional relation.
As table 8 announced by method 100 flow processs selected above step selected have the window combination that is dispersed in other position of genome of extremely strong dependency with No. 18 karyomit(e), in figure, only show wherein 20 windows.First row demonstration is positioned at the window label on karyomit(e) No. 18, and secondary series shows its window coordinates; The 3rd row show the label that has the window of strong correlation with corresponding No. 18 karyomit(e)s, and the 4th row show corresponding window coordinates; The relational expression of the 5th row display window and correlation window; The 6th row show the square value of relation conefficient, i.e. R 2.
Table 8
Window label Window coordinates Correlation window Correlation window coordinate Relational expression R is flat
[0156]?
? ? 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 karyomit(e) window combination, then calculate to obtain a corrected fiducial interval, the judgement for method 200 to chromosomal aneuploidy according to the amount of the nucleic acid molecule that derives from each window.
step 3: to sample order-checking to be detected
6 pregnant woman volunteers participate in this detection, and the sample number obtaining is respectively sample 1-6.Collect each maternal blood, and centrifugal to carrying out, get blood plasma, and then extract nucleic acid molecule from blood plasma, by the sequenator of Illumina company, these nucleic acid molecule are carried out to extensive high-flux sequence.
Carry out according to the schema of 200 methods of Fig. 2, particularly, in 210 steps, obtain biological specimen from pregnant woman.This biological specimen can be blood plasma or other suitable sample.This biological specimen is comprising the nucleic acid molecule that derives from pregnant woman and fetus.
In 220 steps, the nucleic acid molecule in sample is carried out to random sequencing.The nucleic acid fragment molecule being sequenced is representing a whole genomic part, can be positioned on each karyomit(e).In embodiment, we carry out one end order-checking by the solexa sequenator of Illumina company to nucleic acid molecule.
Spy is divided into two groups, sample 1, and sample 2, sample 4 is one group of experiment condition (A group); Sample 3, sample 5, sample 6 is another group experiment condition (B group).A group is for extracting 5ml pregnant woman blood plasma, use QIAamp DNA Micro kit (QIAGEN, 56304) extract dissociative DNA, building storehouse flow process according to Illumina/Solexa uses NEB reagent to build SE library, upper SE36 order-checking, B group extracts 600ul pregnant woman blood plasma and uses TIANamp Micro DNA Kit (Tiangen DP316) to extract dissociative DNA, builds storehouse flow process and uses Enzymatics reagent to build PEI library, upper SE36+7 order-checking according to Illumina/Solexa.
This step is as 210,220 steps of Fig. 2.
step 4: detect sample
Carry out according to the schema of Fig. 2.
In 230 steps, based on order-checking, can every measured nucleic acid fragment molecule be navigated on genomic accurate location by the means of analysis of biological information.As table 1, it has shown by checking order and measured can navigate to its zero position coordinate on this karyomit(e) of each chromosomal nucleic acid fragment molecule.
In 240 steps, with set up model in the same, with 300k be window size, 150k is that overlap cuts respectively window to all karyomit(e)s of 6 samples to be detected.
In 250 steps, based on nucleic acid fragment positional information, statistics derives from the amount of the nucleic acid fragment molecule of No. 18 each windows of karyomit(e).
In 260 steps, based on nucleic acid fragment positional information, what statistics derived from each sample has the amount of the nucleic acid molecule of the window combination of strong correlation with No. 18 karyomit(e) windows, and calculates fiducial interval according to functional relation.
In 270 steps, by judging in the fiducial interval whether amount of the nucleic acid fragment molecule that derives from No. 21 karyomit(e) windows that the 250th step of each sample obtains obtain in the 260th step of same sample, can judge that whether fetus exists the excessive risk of dysploidy at No. 18 karyomit(e).
Table 9: by eight results that sample obtains in the inventive method detection embodiment
Actual value (secondary series) in table 9 is the nucleic acid molecular weight that derives from No. 18 karyomit(e) window combination of each sample of statistics gained; Add up in this sample the nucleic acid molecular weight and the related function expression formula (as shown in table 8) that have the analogue window combination of strong correlation with No. 18 karyomit(e) window combination, then the fiducial interval (confidence level: 95%) obtaining by knowledge of statistics.For the sample of a research, within its actual value is present in the fiducial interval calculating time, can think that studied sample is that normal possibility is very large, otherwise, if actual value is present in outside analogue value fiducial interval, illustrate that these sample right and wrong are euploid very risky.As sample 4, sample 5, sample 6, their actual value derives from the nucleic acid molecular weight of No. 21 chromosomals all outside fiducial interval range, the conclusion obtaining by present method for they be No. 18 chromosomal aneuploidy fetus samples, this result has obtained the proof of karyotyping result.
Originally the value (actual value) and the analogue value fiducial interval obtaining that derive from the amount of the nucleic acid fragment molecule of first kind karyomit(e) window combination by more above-mentioned various kinds, judge whether to exist fetus aneuploid karyomit(e) or aneuploid chromosomal region on first kind karyomit(e).As shown in table 9, can see that the actual value of No. 18 karyomit(e) trisomes is outside analogue value fiducial interval, and normal its actual value of twice sample body is within analogue value fiducial interval range.Fig. 9 and Figure 10, show that 6 from maternal blood sample of nucleic acid, sample 1, the actual value of sample 2 and sample 3 is within analogue value fiducial interval separately, can think that sample is normal, and sample 4, sample 5 outside fiducial interval separately, thinks that No. 18 chromosomal aneuploidy risks are very high with the actual value of sample 6.

Claims (14)

1. sequencing data treatment process, described method is applied to sequencing data treatment unit, and described sequencing data treatment unit comprises order-checking unit and modeling unit, and described method comprises:
(1) described modeling unit receives the sequencing data from described order-checking unit, described sequencing data comprises the sequencing data of whole genome of multiple normal individual samples, karyomit(e) to be studied as research object is defined as to first kind karyomit(e), and in full genome, all the other karyomit(e)s are defined as Equations of The Second Kind karyomit(e);
(2) all karyomit(e) in (1) is cut into respectively to overlapped or nonoverlapping fragment, each fragment is defined as a window;
(3) amount of the nucleic acid molecule of the each window of multiple normal individual sample dyeing body in statistics (2), is defined as behavior value by this amount;
(4) according to the behavior value in (3), the first kind karyomit(e) with (1) of finding on the Equations of The Second Kind karyomit(e) in (1) by mathematical statistics method has window or its combination of strong correlation, the functional relation A that has strong correlation window or its combination that sets up the chromosomal window of the first kind and find;
(5) utilize and have the chromosomal window of Equations of The Second Kind of strong correlation or the behavior value of window combination with first kind karyomit(e) or the chromosomal part of the first kind in functional relation in (4) and (4), determine the scope of the normal behaviour value of the first kind karyomit(e) in (1) or the chromosomal part of the first kind in (1).
2. the process of claim 1 wherein that described functional relation can be an equation or multiple equational group.
3. the process of claim 1 wherein that described functional relation is function of a single variable formula or multivariate function formula.
4. the first kind karyomit(e) the process of claim 1 wherein is selected from chromosome sequence No. 21, No. 18 chromosome sequences, No. 13 chromosome sequences, X chromosome sequence and Y chromosome sequence or its fragment sequence.
5. the method for claim 1, described multiple normal individual samples are to select from the multiple samples under different experimental conditions.
6. sequencing data treatment unit, comprising:
Order-checking unit, described order-checking unit is for the genome sequencing of sample, produce sequencing data, described sequencing data comprises the sequencing data of whole genome of multiple normal individual samples, karyomit(e) to be studied as research object is defined as to first kind karyomit(e), and in full genome, all the other karyomit(e)s are defined as Equations of The Second Kind karyomit(e);
Modeling unit, described modeling unit is for receiving the sequencing data from order-checking unit; All karyomit(e) is cut into respectively to overlapped or nonoverlapping fragment, and each fragment is defined as a window; The amount of adding up the nucleic acid molecule of the each window of described multiple normal individual sample dyeing body, is defined as behavior value by this amount; According to described behavior value, find and have the window of strong correlation or its combination, the functional relation A that has strong correlation window or its combination that sets up the chromosomal window of the first kind and find with described first kind karyomit(e) on described Equations of The Second Kind karyomit(e) by mathematical statistics method; Utilize described functional relation A and described and first kind karyomit(e) or the chromosomal part of the first kind to have the second chromosomal window of strong correlation or the behavior value of window combination, determine the scope of the normal behaviour value of described first kind karyomit(e) or the chromosomal part of the described first kind.
7. the non-diagnostic method that detects individual chromosome dysploidy or karyomit(e) part dysploidy, comprising:
A. in advance or simultaneously multiple normal individual samples are carried out to genome sequencing, the karyomit(e) to be studied as research object is defined as to first kind karyomit(e), in full genome, all the other karyomit(e)s are defined as Equations of The Second Kind karyomit(e);
B. utilize in advance or simultaneously the arbitrary described method of claim 1-5 to process the sequencing data available from a, obtain the chromosomal window of the first kind and with described first kind karyomit(e) window have the chromosomal window of Equations of The Second Kind of strong correlation or the functional relation A of window combination and, the scope of the normal behaviour value of described first kind karyomit(e) or the chromosomal part of the described first kind;
C. individuality to be measured is checked order, and then the chromosomal behavior value of the Equations of The Second Kind that obtains individuality to be detected itself, if the amount of the chromosomal nucleic acid molecule of the first kind of the individuality to be detected calculating according to the functional relation A in b within the scope of the normal behaviour value in b, can not determine that the first kind karyomit(e) of individuality to be measured is dysploidy.
8. the method for claim 7, cuts into full sample to be checked genome karyomit(e) and the consistent window of parameter in normal sample.
9. the method for claim 8, wherein said parameter is selected from window size and overlap size.
10. the method for claim 9, window size is wherein selected from 300kb and 500kb, and corresponding overlap size is respectively 150kb and 250kb.
The method of 11. claims 10, in the time that window is 300kb, overlap is 150kb, wherein has extremely strong dependency window combination to be selected from following window combination:
In the time that the chromosomal window of the first kind is No. 21 chromosomal base position window that is 14400k-14700k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 13 chromosomal base position is 37050k-37350k;
In the time that the chromosomal window of the first kind is No. 21 chromosomal base position window that is 14550k-14850k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 88050k-88350k;
In the time that the chromosomal window of the first kind is No. 21 chromosomal base position window that is 14700k-15000k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 16500k-16800k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 14850k-15150k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 16500k-16800k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 15000k-15300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 144300k-144600k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 15150k-15450k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 144300k-144600k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 15300k-15600k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 145050k-145350k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 15450k-15750k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 17 chromosomal base position is 56400k-56700k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 15600k-15900k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 21750k-22050k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 15750k-16050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 8 chromosomal base position is 105150k-105450k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 15900k-16200k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 50850k-51150k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 16050k-16350k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 77850k-78150k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 16200k-16500k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 112800k-113100k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 16350k-16650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 83250k-83550k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 16500k-16800k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 76200k-76500k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 16650k-16950k, the window that the base position that its corresponding Equations of The Second Kind karyomit(e) window is Chromosome 9 is 74850k-75150k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 16800k-17100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 50700k-51000k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 16950k-17250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 138600k-138900k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 17100k-17400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 8 chromosomal base position is 77100k-77400k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 17250k-17550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 138450k-138750k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 17700k-18000k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 111750k-112050k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 18000k-18300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 36150k-36450k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 18150k-18450k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 119250k-119550k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 18300k-18600k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 450k-750k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 18450k-18750k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 69300k-69600k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 18600k-18900k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 69450k-69750k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 18750k-19050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 62400k-62700k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 18900k-19200k,
Its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 62250k-62550k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 19050k-19350k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 135300k-135600k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 19200k-19500k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 103350k-103650k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 19350k-19650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 125550k-125850k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 19500k-19800k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 85350k-85650k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 19650k-19950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 166650k-166950k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 19800k-20100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 13 chromosomal base position is 67350k-67650k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 19950k-20250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 167250k-167550k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 20100k-20400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 62400k-62700k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 20250k-20550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 62400k-62700k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 20400k-20700k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 12150k-12450k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 20550k-20850k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 125550k-125850k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 20700k-21000k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 118050k-118350k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 20850k-21150k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 81750k-82050k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 21000k-21300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 112650k-112950k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 21150k-21450k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 81750k-82050k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 21300k-21600k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 83250k-83550k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 21450k-21750k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 84450k-84750k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 21600k-21900k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 84450k-84750k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 21750k-22050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 82650k-82950k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 21900k-22200k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 141150k-141450k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 22050k-22350k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 51450k-51750k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 22200k-22500k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 51450k-51750k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 22500k-22800k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 135150k-135450k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 22650k-22950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 105300k-105600k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 22800k-23100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 184950k-185250k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 22950k-23250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 141000k-141300k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 23100k-23400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 141600k-141900k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 23250k-23550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 82350k-82650k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 26700k-27000k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 8 chromosomal base position is 93450k-93750k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 26850k-27150k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 13 chromosomal base position is 46800k-47100k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 31200k-31500k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 47100k-47400k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 31350k-31650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 18 chromosomal base position is 41100k-41400k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 31500k-31800k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 87600k-87900k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 31650k-31950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 15 chromosomal base position is 60300k-60600k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 31950k-32250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 38850k-39150k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 32100k-32400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 13 chromosomal base position is 97650k-97950k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 32250k-32550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 169500k-169800k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 32400k-32700k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 8 chromosomal base position is 20850k-21150k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 32550k-32850k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 1500k-1800k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 33000k-33300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 18 chromosomal base position is 71550k-71850k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 33150k-33450k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 52350k-52650k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 33300k-33600k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 18 chromosomal base position is 52350k-52650k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 33600k-33900k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 24600k-24900k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 33750k-34050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that the chromosomal base of o.11 position is 84900k-85200k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 33900k-34200k, its corresponding Equations of The Second Kind karyomit(e) window is the window that the chromosomal base of o.11 position is 120300k-120600k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 34050k-34350k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 165450k-165750k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 34200k-34500k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 45600k-45900k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 34350k-34650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 105300k-105600k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 34500k-34800k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 21 chromosomal base position is 24750k-25050k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 34650k-34950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 60450k-60750k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 34800k-35100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 157950k-158250k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 34950k-35250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 157950k-158250k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 35100k-35400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 8100k-8400k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 35250k-35550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 72600k-72900k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 35400k-35700k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 83550k-83850k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 35550k-35850k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 73500k-73800k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 35700k-36000k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 56100k-56400k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 35850k-36150k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 174150k-174450k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 36000k-36300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 15 chromosomal base position is 58950k-59250k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 36150k-36450k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 17 chromosomal base position is 15000k-15300k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 36300k-36600k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 157950k-158250k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 36600k-36900k, its corresponding Equations of The Second Kind karyomit(e) window is the window that the chromosomal base of o.11 position is 12150k-12450k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 36750k-37050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 15 chromosomal base position is 77100k-77400k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 36900k-37200k, its corresponding Equations of The Second Kind karyomit(e) window is the window that the chromosomal base of o.11 position is 120150k-120450k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 37050k-37350k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 37500k-37800k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 37200k-37500k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 42600k-42900k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 37350k-37650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 186150k-186450k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 37500k-37800k, the window that the base position that its corresponding Equations of The Second Kind karyomit(e) window is Chromosome 9 is 20100k-20400k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 37650k-37950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 54900k-55200k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 37800k-38100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 15 chromosomal base position is 78750k-79050k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 37950k-38250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 118350k-118650k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 38100k-38400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 93450k-93750k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 38250k-38550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 66150k-66450k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 38400k-38700k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 30300k-30600k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 38550k-38850k, the window that the base position that its corresponding Equations of The Second Kind karyomit(e) window is Chromosome 9 is 100800k-101100k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 38700k-39000k, the window that the base position that its corresponding Equations of The Second Kind karyomit(e) window is Chromosome 9 is 96600k-96900k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 38850k-39150k, its corresponding Equations of The Second Kind karyomit(e) window is the window that the chromosomal base of o.11 position is 130650k-130950k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 39000k-39300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 1050k-1350k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 39150k-39450k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 169800k-170100k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 39300k-39600k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 43200k-43500k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 39450k-39750k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 25650k-25950k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 39750k-40050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 173700k-174000k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 39900k-40200k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 29550k-29850k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 40200k-40500k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 104700k-105000k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 40350k-40650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that the chromosomal base of o.11 position is 92100k-92400k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 40500k-40800k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 18 chromosomal base position is 70650k-70950k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 40650k-40950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 13950k-14250k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 40800k-41100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 8 chromosomal base position is 9900k-10200k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 40950k-41250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 18 chromosomal base position is 40650k-40950k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 41100k-41400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 8 chromosomal base position is 9750k-10050k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 41250k-41550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 20 chromosomal base position is 22350k-22650k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 41400k-41700k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 16 chromosomal base position is 55350k-55650k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 41550k-41850k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 15 chromosomal base position is 99750k-100050k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 41700k-42000k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 170700k-171000k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 41850k-42150k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 16 chromosomal base position is 48000k-48300k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 42000k-42300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 0k-300k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 42150k-42450k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 16 chromosomal base position is 48000k-48300k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 42300k-42600k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 17 chromosomal base position is 73200k-73500k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 42450k-42750k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 17 chromosomal base position is 73050k-73350k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 42600k-42900k, its corresponding Equations of The Second Kind karyomit(e) window is the window that the chromosomal base of o.11 position is 17550k-17850k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 42750k-43050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 120750k-121050k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 42900k-43200k, its corresponding Equations of The Second Kind karyomit(e) window is the window that the chromosomal base of o.11 position is 69300k-69600k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 43200k-43500k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 240450k-240750k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 43350k-43650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 21 chromosomal base position is 38100k-38400k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 43500k-43800k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 16 chromosomal base position is 83850k-84150k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 43650k-43950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 16 chromosomal base position is 3450k-3750k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 43800k-44100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 46800k-47100k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 43950k-44250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 17 chromosomal base position is 70950k-71250k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 44100k-44400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 156900k-157200k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 44250k-44550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 1350k-1650k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 44400k-44700k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 19 chromosomal base position is 1950k-2250k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 44550k-44850k, the window that the base position that its corresponding Equations of The Second Kind karyomit(e) window is Chromosome 9 is 136350k-136650k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 44700k-45000k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 219900k-220200k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 44850k-45150k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 219900k-220200k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 45000k-45300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 750k-1050k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 45150k-45450k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 239550k-239850k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 45300k-45600k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 238950k-239250k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 45450k-45750k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 20 chromosomal base position is 61050k-61350k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 45600k-45900k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 1950k-2250k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 45750k-46050k, the window that the base position that its corresponding Equations of The Second Kind karyomit(e) window is Chromosome 9 is 135000k-135300k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 45900k-46200k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 19 chromosomal base position is 38700k-39000k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 46050k-46350k, the window that the base position that its corresponding Equations of The Second Kind karyomit(e) window is Chromosome 9 is 139800k-140100k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 46200k-46500k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 750k-1050k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 46350k-46650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 1350k-1650k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 46500k-46800k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 46350k-46650k;
When the chromosomal window of the first kind is No. 21 chromosomal base position window that is 46650k-46950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 8 chromosomal base position is 1650k-1950k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 1050k-1350k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 178050k-178350k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 1200k-1500k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 6450k-6750k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 1350k-1650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 125700k-126000k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 1500k-1800k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 13 chromosomal base position is 53550k-53850k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 1650k-1950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 177450k-177750k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 1800k-2100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 122250k-122550k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 1950k-2250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 18900k-19200k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 2100k-2400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 32400k-32700k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 2250k-2550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 9600k-9900k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 2400k-2700k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 130650k-130950k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 2550k-2850k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 48000k-48300k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 4200k-4500k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 192450k-192750k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 4350k-4650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 145800k-146100k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 4650k-4950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 107550k-107850k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 4800k-5100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 38100k-38400k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 4950k-5250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 39000k-39300k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 5100k-5400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 164550k-164850k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 9000k-9300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 8 chromosomal base position is 91050k-91350k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 16800k-17100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 39150k-39450k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 16950k-17250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that the chromosomal base of o.11 position is 32850k-33150k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 17100k-17400k, the window that the base position that its corresponding Equations of The Second Kind karyomit(e) window is Chromosome 9 is 19950k-20250k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 17250k-17550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 39600k-39900k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 17400k-17700k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 80850k-81150k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 18450k-18750k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 17 chromosomal base position is 64350k-64650k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 18600k-18900k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 19500k-19800k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 21750k-22050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 148350k-148650k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 21900k-22200k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 13800k-14100k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 22800k-23100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 120150k-120450k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 23250k-23550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 153450k-153750k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 23550k-23850k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 15450k-15750k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 24000k-24300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 125700k-126000k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 24150k-2450k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 80100k-80400k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 24300k-24600k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 17 chromosomal base position is 48150k-48450k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 24450k-24750k, its corresponding Equations of The Second Kind karyomit(e) window is the window that the chromosomal base of o.11 position is 26250k-26550k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 24600k-24900k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 62550k-62850k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 24750k-25050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 47550k-47850k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 24900k-25200k, the window that the base position that its corresponding Equations of The Second Kind karyomit(e) window is Chromosome 9 is 10050k-10350k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 25050k-25350k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 84300k-84600k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 25200k-25500k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 70800k-71100k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 25350k-25650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 119100k-119400k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 25500k-25800k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 119100k-119400k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 25650k-25950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 51300k-51600k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 25800k-26100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 145200k-145500k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 25950k-26250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 125550k-125850k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 26100k-26400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 21 chromosomal base position is 16500k-16800k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 26250k-26550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 96000k-96300k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 26400k-26700k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 95850k-96150k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 26550k-26850k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 61350k-61650k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 26700k-27000k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 13 chromosomal base position is 92850k-93150k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 26850k-27150k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 89700k-90000k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 27000k-27300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 17 chromosomal base position is 25050k-25350k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 27150k-27450k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 88050k-88350k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 28650k-28950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 92400k-92700k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 28800k-29100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 52050k-52350k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 28950k-29250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 138300k-138600k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 29100k-29400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 144450k-144750k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 29250k-29550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 115200k-115500k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 29550k-29850k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 92250k-92550k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 29700k-30000k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 62250k-62550k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 29850k-30150k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 8 chromosomal base position is 84900k-85200k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 30000k-30300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 82650k-82950k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 30150k-30450k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 93600k-93900k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 30300k-30600k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 103950k-104250k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 32700k-33000k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 77100k-77400k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 33900k-34200k, the window that the base position that its corresponding Equations of The Second Kind karyomit(e) window is Chromosome 9 is 76200k-76500k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 34800k-35100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 8 chromosomal base position is 106350k-106650k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 35550k-35850k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 15 chromosomal base position is 35400k-35700k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 36450k-36750k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 145050k-145350k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 36600k-36900k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 13 chromosomal base position is 103050k-103350k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 36750k-37050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 83250k-83550k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 36900k-37200k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 34650k-34950k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 37800k-38100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 93300k-93600k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 38400k-38700k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 50100k-50400k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 38550k-38850k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 83100k-83400k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 38700k-39000k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 8 chromosomal base position is 106350k-106650k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 38850k-39150k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 141000k-141300k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 39000k-39300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 64050k-64350k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 39150k-39450k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 69450k-69750k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 39300k-39600k, the window that the base position that its corresponding Equations of The Second Kind karyomit(e) window is Chromosome 9 is 105150k-105450k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 39450k-39750k, its corresponding Equations of The Second Kind karyomit(e) window is the window that the chromosomal base of o.11 position is 29400k-29700k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 39600k-39900k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 88950k-89250k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 39750k-40050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 71550k-71850k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 39900k-40200k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 163200k-163500k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 44850k-45150k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 112950k-113250k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 45000k-45300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that the chromosomal base of o.11 position is 32850k-33150k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 48600k-48900k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 76800k-77100k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 48750k-49050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that the chromosomal base of o.11 position is 40800k-41100k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 49350k-49650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 38850k-39150k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 49650k-49950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 39900k-40200k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 49800k-50100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 130350k-130650k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 49950k-50250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 106350k-106650k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 50100k-50400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 87150k-87450k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 50250k-50550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 79350k-79650k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 52350k-52650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 16 chromosomal base position is 70950k-71250k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 55950k-56250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 13 chromosomal base position is 103800k-104100k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 56100k-56400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 172650k-172950k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 56250k-56550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 10050k-10350k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 56400k-56700k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 8 chromosomal base position is 90150k-90450k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 56550k-56850k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 126750k-127050k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 57750k-58050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 79350k-79650k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 57900k-58200k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 101700k-102000k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 60000k-60300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 13 chromosomal base position is 77700k-78000k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 60150k-60450k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 126450k-126750k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 60300k-60600k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 167100k-167400k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 60450k-60750k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 123300k-123600k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 60600k-60900k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 34800k-35100k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 60750k-61050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 145950k-146250k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 60900k-61200k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 93900k-94200k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 61050k-61350k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 8 chromosomal base position is 116550k-116850k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 61200k-61500k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 27000k-27300k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 61350k-61650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 85950k-86250k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 61500k-61800k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 81600k-81900k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 61650k-61950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that the chromosomal base of o.11 position is 89700k-90000k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 61800k-62100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 83700k-84000k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 61950k-62250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 13 chromosomal base position is 81600k-81900k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 62100k-62400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 8 chromosomal base position is 78450k-78750k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 62250k-62550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 96150k-96450k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 62400k-62700k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 91050k-91350k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 62550k-62850k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 72900k-73200k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 62700k-63000k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 73650k-73950k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 62850k-63150k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 193200k-193500k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 63000k-63300k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 181350k-181650k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 63150k-63450k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 84150k-84450k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 63300k-63600k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 157500k-157800k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 63450k-63750k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 21750k-22050k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 63600k-63900k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 80850k-81150k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 63750k-64050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 110250k-110550k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 63900k-64200k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 110250k-110550k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 64050k-64350k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 87150k-87450k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 64200k-64500k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 12300k-12600k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 64350k-64650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 111600k-111900k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 64500k-64800k, the window that the base position that its corresponding Equations of The Second Kind karyomit(e) window is Chromosome 9 is 9900k-10200k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 64650k-64950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 85050k-85350k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 64800k-65100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 72600k-72900k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 64950k-65250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 92100k-92400k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 65100k-65400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 117450k-117750k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 65250k-65550k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 113400k-113700k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 65400k-65700k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 181500k-181800k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 65700k-66000k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 137100k-137400k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 65850k-66150k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 3 chromosomal base position is 174600k-174900k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 66450k-66750k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 145800k-146100k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 66600k-66900k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 21 chromosomal base position is 27300k-27600k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 66750k-67050k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 123300k-123600k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 66900k-67200k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 181950k-182250k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 67050k-67350k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 8 chromosomal base position is 13800k-14100k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 67200k-67500k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 81000k-81300k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 67350k-67650k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 162150k-162450k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 67500k-67800k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 85050k-85350k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 67650k-67950k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 2 chromosomal base position is 52050k-52350k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 67800k-68100k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 30900k-31200k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 67950k-68250k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 12 chromosomal base position is 39450k-39750k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 68100k-68400k, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 68400k-68700k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 68550k-68850, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 5 chromosomal base position is 88350k-88650k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 68700k-69000, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 4 chromosomal base position is 87300k-87600k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 68850k-69150, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 6 chromosomal base position is 70350k-70650k;
In the time that the chromosomal window of the first kind is No. 18 chromosomal base position window that is 69000k-69300, its corresponding Equations of The Second Kind karyomit(e) window is the window that No. 7 chromosomal base position is 85950k-86250k.
The method of 12. claims 7, the sample of wherein said individuality to be detected is the biological specimen from pregnant woman's the DNA that contains fetus.
The method of 13. claims 12, the biological specimen of the wherein said DNA that contains fetus from pregnant woman is selected from blood plasma, serum, urine and saliva.
The method of 14. claims 12, the biological specimen of the wherein said DNA that contains fetus from pregnant woman is selected from detachment of cervix cell and uterine cervix washing fluid.
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Cited By (3)

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Publication number Priority date Publication date Assignee Title
CN104789466A (en) * 2015-05-06 2015-07-22 安诺优达基因科技(北京)有限公司 Kit and device for detecting aneuploidy of chromosomes
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
CN108920899A (en) * 2018-06-10 2018-11-30 杭州迈迪科生物科技有限公司 A kind of single exon copy number variation prediction technique based on target area sequencing

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CN1930303A (en) * 2003-10-08 2007-03-14 波士顿大学信托人 Methods for prenatal diagnosis of chromosomal abnormalities
CN101137760A (en) * 2005-03-18 2008-03-05 香港中文大学 Method for the detection of chromosomal aneuploidies

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Publication number Priority date Publication date Assignee Title
CN1930303A (en) * 2003-10-08 2007-03-14 波士顿大学信托人 Methods for prenatal diagnosis of chromosomal abnormalities
CN101137760A (en) * 2005-03-18 2008-03-05 香港中文大学 Method for the detection of chromosomal aneuploidies

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104789466A (en) * 2015-05-06 2015-07-22 安诺优达基因科技(北京)有限公司 Kit and device for detecting aneuploidy of chromosomes
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
CN108920899A (en) * 2018-06-10 2018-11-30 杭州迈迪科生物科技有限公司 A kind of single exon copy number variation prediction technique based on target area sequencing

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