KR20140108177A - Method and apparatus for diagnosing fetal chromosomal aneuploidy using genomic sequencing - Google Patents
Method and apparatus for diagnosing fetal chromosomal aneuploidy using genomic sequencing Download PDFInfo
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Abstract
Description
The present invention relates to a non-invasive method for fetal prenatal diagnosis. More particularly, the present invention relates to a method for diagnosing malformation by analyzing sequencing information on a genomic DNA extracted from blood of a mother and determining the chromosomal aneuploidy of the fetus, and an apparatus therefor will be.
'Prenatal diagnosis' refers to the process of diagnosing and diagnosing the fetal disease before the birth of the fetus. According to recent national statistics, congenital malformations account for about 3% of all neonates and about 20% of congenital malformations have been reported to be caused by chromosomal abnormalities. Especially known as Down syndrome, 26% of congenital malformations. Due to the increased birth rate and the development of various prenatal diagnostic devices, interest in prenatal diagnosis is increasing day by day. In particular, if there is a structural abnormality of a chromosome in an elderly pregnant woman over 35 years of age, a pregnant woman having a delivery history of a child with a chromosomal abnormality, or a parent, a family history of hereditary disease, , Maternal serum screening and ultrasound examination should be performed for antenatal diagnosis.
Prenatal diagnosis can be divided into invasive and noninvasive diagnostic methods. Examples of invasive diagnostic methods include chorionic villi sampling (CVS) performed between 10 and 12 weeks of gestation, immunoassay between 15 and 20 weeks of gestation to determine fetal chromosomes by measuring the concentration of AFP in amniotic fluid Amniocentesis is an analytical method, and cordocentesis is a method of extracting fetal blood directly from umbilical cord under ultrasound induction between 18 and 20 weeks of gestation. However, invasive diagnostic methods such as these can cause abortion, disease or anomaly by impacting the fetus during the examination, and non-invasive diagnostic methods have been developed to overcome these problems. For example, the pre-embryonic genetic diagnosis method is a technique for selecting an embryo free of pre-intrauterine implantation defects using molecular genetics or cytogenetic techniques used in in vitro fertilization. In addition, quantitative-fluorescent PCR (QF-PCR) fluorescence assays for rapid diagnosis of aneuploidy fluorescence are used to fluoresce short tandem repeats (STR) of DNA that are specific for each chromosome. It is a rapid screening test method that amplifies by multiplex PCR method and measures the amount of amplified DNA with fluorescence by DNA auto-sequencer. In addition, a chromosomal microarray (CMA) method is known for collecting and inspecting mapped DNA sequences mapped onto a glass slide in order to find a copy number change.
Meanwhile, with the development of sequencing technology, it becomes possible to decode large-scale genome information, and thus genome analysis methods based on the next-generation sequencing (NGS) technology are used in the field of prenatal diagnosis. In particular, it is known that the fetal genome contains about 10% of the whole genome in the blood of the mother, and prenatal diagnosis methods for analyzing the chromosomes of the fetal cells by separating the fetal cells from the maternal blood are known . Korean Patent Application No. 2010-7003969 discloses a method for diagnosing fetal chromosomal aberration using massively parallel genomic sequencing. Also, U.S. Patent No. 8195415 discloses a method for quantitatively analyzing the result of sequencing DNA obtained from maternal blood by mapping each chromosome to a specific length. Although the present invention has similar aspects to the present invention in that the abnormality of fetal chromosome number is judged by using the result of large-scale parallel genome sequence analysis, all the methods of setting parameter values are different from the present invention.
It is an object of the present invention to provide a method and apparatus for easily diagnosing chromosomal abnormality of a fetus using a fetal genome contained in the blood of a mother.
In order to achieve the above object, the present invention provides a method for analyzing genomic DNA extracted from blood of pregnant mothers of normal fetuses and chromosome-bearing fetuses, And the Z-score CutOff value of the fetus is checked. Based on the Z-score CutOff value of the Z-score value obtained by using the extracted parameters for the subjects to be diagnosed, And provides a method for diagnosing the water quality.
Specifically,
Collecting a blood sample containing a fetal genome from a pregnant female subject;
Extracting genomic DNA from the blood sample and performing massively parallel sequencing;
Mapping the sequenced read sequences to a human reference dielectric;
Identifying a depth distribution of the readings by a predetermined interval to remove a portion of the sequence information having low reliability from the analysis target;
Checking the GC content of the remaining portion of the sequence and setting a portion with high reliability as an analysis target;
Calculating a Z-score according to the following equation using the depth value of the sections set as the analysis target for the entire autosome,
Obtaining an average value for each chromosome with respect to the Z-scores calculated for each section; And
And a step of judging whether or not a 'chromosomal abnormality' is caused by applying the Z-score CutOff standard based on the statistical model to the Z-score average value calculated for each chromosome.
In one embodiment of the present invention, the 'interval' may be set in units of 300 kb on genomic DNA.
In one embodiment of the present invention, the step of removing a portion with low confidence in the sequence information from the analysis object may include a method of removing a mismatch portion, a method of removing a read sequence portion attached to various portions, , And methods of removing redundant leads in PCR.
In one embodiment of the present invention, the method for determining the portion with high reliability by examining the GC content is performed by analyzing the GC content only for the sequence portion satisfying the condition of 0.35 <GC content <0.45 And the like.
In one embodiment of the present invention, the diagnostic method may be a method for diagnosing whether or not a chromosome selected from the group consisting of chromosomes 13, 18, and 21 of the fetus is abnormal.
The diagnostic method according to the present invention is advantageous in that it can be analyzed by using a blood sample of a mother, so that it does not harm the mother or the fetus and is simple. In addition, it was confirmed that even a small amount of fetal chromosome can be diagnosed accurately. Therefore, the method of the present invention can be usefully used as a prenatal diagnostic method for early detection of abnormality due to abnormality of chromosomes in fetus.
1 is a flow chart illustrating a diagnostic method of the present invention.
2 is a detailed flowchart of step 3) of the diagnostic method according to an embodiment of the present invention.
3 is a detailed flowchart of step 1) of the diagnostic method according to the embodiment of the present invention.
FIG. 4 is a plot showing the distribution of the base quality of the base sequence and the types of the base sequences with respect to raw data generated through sequencing.
FIG. 5 shows a result of confirming a read depth distribution for a genomic DNA set to 300kb intervals according to an embodiment of the present invention.
Fig. 6 shows the result of analyzing the GC content. The left figure shows the distribution of the whole DNA image, and the right figure is the enlarged part where the frequency is high (dark part). The area that appears dark is the area with high frequency.
FIG. 7 is a diagram illustrating a method for determining the completeness of chromosomes 13, 18, and 21 of the fetus with the method of the present invention for a genomic DNA set to a 300 kb region according to an embodiment of the present invention .
Figure 8 is a table showing the accuracy of the diagnostic method of the present invention. The results were compared with those of the fetuses diagnosed by karyotype analysis (4 chromosomes 18, 7 chromosomes 7), and the numbers determined to be 'abnormal' according to the method of the present invention were chromosome 18 (100%), chromosome 21 (7%), and normal (74%) were diagnosed as normal.
9 is a configuration diagram of the diagnostic apparatus of the present invention.
The present invention relates to a method for diagnosing fetal chromosomal integrity by analyzing genomic DNA extracted from the blood of mothers who are pregnant with normal fetuses,
1) extracting genomic DNA from a blood sample collected from a pregnant female subject and performing massively parallel sequencing;
2) mapping the sequenced read sequences to a human reference genome;
3) determining a depth distribution and a GC content of the read sequences by a predetermined interval and setting the depth distribution and the GC content for analysis;
4) calculating a Z-score according to the following equation using the depth value of the sections set as the analysis target for the entire autosome
5) calculating an average value for each chromosome with respect to the calculated Z-scores;
6) The step of judging whether or not a 'chromosomal abnormality' is determined by applying the Z-score mean value calculated for each chromosome to the Z-score CutOff standard based on the statistical model (FIG. 1).
In one embodiment of the present invention, a known DNA extraction method can be widely used as a method for extracting genomic DNA from the blood sample in the step 1). Massively parallel sequencing is performed by qualitative and quantitative analysis of samples and libraries are prepared for samples that pass the quality control standard. The method of producing the library is to fragment the samples that pass the quality control standard. The end-repair DNA was purified by using the Agencourt AMPure XP bead and the A adapter and Ion P1 adapter with Ion Xpress ™ barcode. ligation, and fill the voids of adapter and gDNA with Nick Repair Polymerase and purify. amplify the adapter-ligated lirary, purify the amplified sample, and inspect it using a Bioanalyzer. The library that has passed the quality inspection prepares ISP using One-Touch2 device for template prep. Once the ISP has been created for sequencing, install Sequencing 200kit V2 on the Proton and load the ISP created on the PI chip. Place the chip on the device and perform a chip check to confirm that there is no problem with the chip and the reagent, and proceed to decode the base sequence. Check that the Loading, Live ISPs, and Library ISPs are correct on the Monitor Tab in the Torrent Browser.
The step 3) comprises the steps of: 3-1) checking whether the analysis target is set for each section set for the sequence information, and removing a sequence section identified as a non-compliant sequence section from the analysis target; And 3-2) examining the GC content with respect to the remaining sequence part, and setting a part corresponding to the reference range as an analysis target (FIG. 2).
In step 3-1), the depth distribution of the readings is checked for each predetermined interval to remove the low reliability part of the sequence information from the analysis object, but the present invention is not limited thereto. In one embodiment, the interval may be set in increments of 300 kb. The reason for setting the interval to 300 kb is to filter by using the nucleotide sequence GC ratio. When set to 300 kb, the depth of chromosomes and the GC This is because it is easy to make statistical analysis because it can form a group of ratios.
In step 3-1), the sequence of the target to be deleted may include a sequence having a plurality of sequences, PCR duplicated reads, and the reason for eliminating sequences having multiple sequences is that the sequence sequence The reason for eliminating PCR duplication reads is that it is necessary to amplify the sequence for sequencing and to remove the part that is more error amplified. In addition, since the high repeat region has a high depth, it is necessary to remove 80% (80% of the order of each value in the ascending order of each value) Higher values were removed and values lower than the point at which the 20 percentile (the order in ascending order of each value is 20 percent of the number of each value) was removed to remove the portion where noise could occur , And the region without thickness is excluded from the analysis because it is the most N region. In order to analyze statistically, it is necessary to select a group with a certain degree of deviation. However, in the above case, the part that is too high or the parts that are low can affect the average or the total value, so we have removed the unmapped part and the too high part to select the proper group.
In one embodiment of the present invention, in step 3-2), the GC content of the portion of the sequence remaining after the removal is removed to determine only the sequence region satisfying the condition of 0.35 <GC content <0.45 Lt; / RTI > Since the GC content of a human genome is known to be about 40%, it is intended to increase the accuracy by analyzing only sequence information close to the human GC content.
The step 4) is to set a Z-score according to the following equation using the depth value of the sections set as the analysis target for the entire autosome.
The Z-score value according to the present invention is a value based on the mean and standard deviation of the depth of lead for each section calculated for the entire autosomes. That is, we have created a Z-score group with a standard deviation of 1 and an average of 0 for the whole area. Therefore, we have standardized all values.
The diagnostic method according to the present invention can diagnose the chromosomal abnormality of at least one chromosome selected from the group consisting of chromosomes 13, 18 and 21 of the fetus. Chromosomal abnormalities on chromosome 13 are associated with Patau syndrome. Patau syndrome occurs in one out of 20,000 to 25,000 fetuses and is known to die within 1 year due to severe congenital anomalies of important organs such as the central nervous system and heart. Chromosome 18 is associated with Edwards syndrome. Edwards' syndrome occurs in about one in every eight thousand fetuses and is three to four times more common in girls. It is known to die within 10 weeks due to severe malformations and mental retardation of various organs. Chromosome 21 is associated with Down syndrome. It occurs in 1 out of 800 people, and it shows symptoms such as mental retardation, somatic anomaly, growth disorder. The life span is about 20 to 30 years old.
In one embodiment of the present invention, the step (6) is a step of determining whether a chromosome abnormality is a Z-score average calculated for each chromosome, and the two groups (normal group, chromosomal abnormal group) (Mann-Whitney test), which is a nonparametric method that does not depend on the characteristics of the parameters, because the difference in size can not be compared with the mean. The Z-score reference value (cutoff) set as the difference between the lowest Z-score values was applied, and when it exceeded the reference value, it was judged as a chromosome abnormality.
Hereinafter, the present invention will be described in detail with reference to examples. However, these examples are intended to further illustrate the present invention, and the scope of the present invention is not limited to these examples.
< Example 1> extracted from maternal blood gDNA Base sequence decode
Five milliliters of blood was collected from 85 pregnant women over 12 weeks of gestation, and 1-1) was centrifuged to separate plasma. 1-2) After dissociating the separated plasma, gDNA was extracted using a QIAGEN DNA mini kit. 1-3) A library was prepared according to the library production guidelines of Life tech, and IPS was generated. 1-4) After that, Sequencing 200kit V2 was installed in the Proton instrument, and IPS prepared in the PI chip was loaded and sequenced (FIG. 3). FIG. 4 is a plot showing the distribution of the base quality of base sequences and the types of base sequences with respect to data (raw data) generated through sequencing in the embodiment of the present invention.
< Example 2> decrypted gDNA Reference mapping of sequences ( reference mapping )
In order to eliminate the error due to PCR Duplication, the sequence mapped to the same position was assumed to be PCR Duplication and the sequence was removed. Table 1 shows that the decoded base sequences of each sample decoded as a result of decoding the nucleotide sequence were 7,478,574 read on average, the average number of total produced nucleotide sequences was 961,605,947 bp, the average number of sequences mapped was 7,417,179 Read, the ratio is 99.18%. Also, the amount produced in proportion to the number of nucleotide sequences of the reference sequence produced an average of 0.32X base sequence for each sample, assuming that the number of nucleotide sequences of the reference sequence was 1X.
< Example 3> Lead Thickness by Region ( depth ) Extraction and GC Content calculation
Actually, in order to confirm whether the leads are evenly attached on the genome, the depth of the lead was extracted by a slide window 500bp per 300kb section, and the depth distribution of the genome was confirmed by a line plot (Fig. 5 ).
In order to confirm the GC bias, the GC content was calculated using a human reference sequence and expressed as a Scatter plot (FIG. 6). In FIG. 6, the higher the color, the higher the frequency corresponding to the portion. Since the GC content is known to be 40% in the case of an ordinary person, the analysis of the present invention was performed by selecting regions having a GC content of 35 to 45%.
In addition, since the high repeat region has a high depth, it has a point of 80 percentile (the order in ascending order of each value is 80 percent of the number of each value) To remove the higher values and to remove the portion where noise may occur for the analysis, it is lower than the point where 20 percentile (the order in ascending order of each value is 20% of the number of each value) Values were removed.
< Example 4> The Z- score Diagnosis result by calculation
≪ 4-1 > The Z- score Calculation of
The mean and standard deviation of the total autosome were determined using the depth of the lead set for each section set at 300kb. A Z-score group with an average of 0 and a standard deviation of 1 was created, and each chromosome The mean value of the Z-score was obtained and used for diagnosis (Fig. 7). In FIG. 7, since the two groups (normal group, chromosomal abnormal group) which can not be assumed to follow the normal distribution can not compare the size difference by means of the average, The Mann-Whitney test was used to extract the Z-score cutoff. When the value was higher than the extracted Z-score cutoff, it was judged to be 'chromosomal abnormality'. This setting is selected through the Mann-Whitney test, which is a ranking sum statistic model. Therefore, more accurate diagnosis will be possible as the number of patients identified as normal and chromosomal abnormalities increases. However, in the embodiment of the present invention, since the total number of samples is 85, only the corresponding values are available.
<4-2> Diagnosis result
As a result of testing the diagnostic method of the present invention for 27 subjects by the above method, it was impossible to discriminate the chromosomal abnormality (T13) at the 13th chromosomal aberration (T18) Four out of four patients were diagnosed as confirmed. Finally, the chromosomal abnormality 21 (T21) was diagnosed as 7 out of 7 cases (Fig. 8).
The above results show that the diagnostic method of the present invention is a method of determining a chromosome abnormality relatively accurately even when the depth of the lead is low as a result of chromosome analysis. Thus, it was confirmed through the method of the present invention that prenatal diagnosis related to fetal chromosome number is possible.
FIG. 9 shows a
The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.
10: Sequencing unit
20:
30: Analysis target setting section
40: Z-score calculating unit
50:
60:
100: Diagnostic device
Claims (10)
2) mapping the sequenced read sequences to a human reference genome;
3) determining a depth distribution and a GC content of the read sequences by a predetermined interval and setting the depth distribution and the GC content for analysis;
4) obtaining a Z-score value according to the following equation using the depth value of the sections set as the analysis target for the entire autosome
5) calculating a Z-score average value for each chromosome with respect to the Z-score value;
6) determining the chromosomal abnormality by confirming the average value of the Z-score calculated for each chromosome, and providing the information for diagnosis of fetal chromosomal integrity.
The step (1)
(a) separating the blood plasma by centrifuging the collected blood;
(b) dissolving the separated plasma and extracting gDNA;
(c) preparing a library for the extracted gDNA and generating an IPS;
(d) loading the generated IPS to decode the base sequence.
Wherein said step of step 3) is set in units of 300 kb on genomic DNA.
The step (3)
(a) inspecting the target of analysis for each of the sequence information, and removing a sequence section identified as an inappropriate sequence section from the analysis target; And
(b) examining the GC content with respect to the remaining sequence part and setting a part corresponding to the reference range as an analysis target.
The step (a)
A method of removing a mismatch portion, a method of removing a read sequence portion attached to various portions, and a method of removing redundant leads in a PCR are carried out by any one or more methods selected from the group consisting of ≪ / RTI >
The step (a)
For high repeat regions, values higher than the 80 percentile are removed from the analysis, and for regions where mapping is less, values lower than 20 percentile are removed from the analysis. Lt; / RTI >
The step (b)
0.35 < GC content < 0.45.
The step (6)
Wherein a cutoff value set through a Mann-Whitney test, which is a ranking sum test statistical model, is applied.
Wherein said method is for diagnosing whether or not any one or more chromosomes selected from the group consisting of chromosomes 13, 18 and 21 of the fetus are to be tested.
A mapping unit for mapping the sequenced read sequences to a human reference dielectric;
An analysis target setting unit for determining a depth distribution and a GC content of the read sequences by a predetermined interval and setting the same as an analysis target;
A Z-score calculating unit for calculating a Z-score using the depth value of the sections set as the analysis target,
An average value calculation unit for calculating an average value for each chromosome with respect to the calculated Z-score; And
And a judging unit for judging a chromosomal abnormality by confirming the average value of the Z-score calculated for each chromosome.
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Cited By (6)
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| KR101678959B1 (en) | 2015-12-08 | 2016-11-23 | 왕선주 | Non-invasive prenatal testing(nipt) system for testing fetal genetic abnormality |
| KR101678962B1 (en) * | 2015-08-21 | 2016-12-06 | 이승재 | Apparatus and Method for Non-invasive Prenatal Testing(NIPT) using Massively Parallel Shot-gun Sequencing(MPSS) |
| WO2017023148A1 (en) * | 2015-08-06 | 2017-02-09 | 이원 다이애그노믹스 게놈센타(주) | Novel method capable of differentiating fetal sex and fetal sex chromosome abnormality on various platforms |
| WO2017051996A1 (en) * | 2015-09-24 | 2017-03-30 | 에스케이텔레콤 주식회사 | Non-invasive type fetal chromosomal aneuploidy determination method |
| WO2017131359A1 (en) * | 2016-01-25 | 2017-08-03 | 지놈케어 주식회사 | Method for detecting fetal chromosomal aneuploidy |
| KR20170140107A (en) * | 2016-06-10 | 2017-12-20 | 이원다이애그노믹스(주) | Non-invasive prenatal testing methods and devices based on multiple z-scores |
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| KR20160113145A (en) * | 2007-07-23 | 2016-09-28 | 더 차이니즈 유니버시티 오브 홍콩 | Determining a nucleic acid sequence imbalance |
| CA2737643C (en) * | 2008-09-20 | 2020-10-06 | Hei-Mun Fan | Noninvasive diagnosis of fetal aneuploidy by sequencing |
| US20110312503A1 (en) | 2010-01-23 | 2011-12-22 | Artemis Health, Inc. | Methods of fetal abnormality detection |
| PL2561103T3 (en) * | 2011-06-29 | 2015-02-27 | Bgi Diagnosis Co Ltd | Noninvasive detection of fetal genetic abnormality |
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| WO2017023148A1 (en) * | 2015-08-06 | 2017-02-09 | 이원 다이애그노믹스 게놈센타(주) | Novel method capable of differentiating fetal sex and fetal sex chromosome abnormality on various platforms |
| US11339426B2 (en) | 2015-08-06 | 2022-05-24 | Eone Diagnomics Genome Center Co., Ltd. | Method capable of differentiating fetal sex and fetal sex chromosome abnormality on various platforms |
| KR101678962B1 (en) * | 2015-08-21 | 2016-12-06 | 이승재 | Apparatus and Method for Non-invasive Prenatal Testing(NIPT) using Massively Parallel Shot-gun Sequencing(MPSS) |
| WO2017051996A1 (en) * | 2015-09-24 | 2017-03-30 | 에스케이텔레콤 주식회사 | Non-invasive type fetal chromosomal aneuploidy determination method |
| KR101678959B1 (en) | 2015-12-08 | 2016-11-23 | 왕선주 | Non-invasive prenatal testing(nipt) system for testing fetal genetic abnormality |
| WO2017131359A1 (en) * | 2016-01-25 | 2017-08-03 | 지놈케어 주식회사 | Method for detecting fetal chromosomal aneuploidy |
| US11710565B2 (en) | 2016-01-25 | 2023-07-25 | Theragen Genomecare Co., Ltd. | Method of detecting fetal chromosomal aneuploidy |
| KR20170140107A (en) * | 2016-06-10 | 2017-12-20 | 이원다이애그노믹스(주) | Non-invasive prenatal testing methods and devices based on multiple z-scores |
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| WO2014133369A1 (en) | 2014-09-04 |
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