CN108804873A - The device of Non-invasive detection parent and embryo genetic exception - Google Patents
The device of Non-invasive detection parent and embryo genetic exception Download PDFInfo
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Abstract
The present invention provides the devices of Non-invasive detection parent and embryo genetic exception.The present invention realizes the Non-invasive detection of embryo genetic exception, can simultaneously Non-invasive detection embryo chromosome aneuploidy；Can Non-invasive detection parent simultaneously gene genetic it is abnormal.The present invention increases new detection function relative to the noninvasive antenatal embryo chromosome aneuploid detection being commonly used, but is increased without testing cost, a large amount of cost-effective.
Description
Technical field
The invention belongs to biological gene technical fields, and in particular to a kind of to realize noninvasive embryo using full exon sequencing technologies
The method of tire chromosome aneuploid and other embryo genetics exception.
Background technology
With the raising of technique of gene detection, data increase and statistical development, by free to pregnant woman blood plasma
The analysis of DNA (cfDNA) detection data can efficiently solve what current noninvasive antenatal embryo DNA detection methods can not detect
It is abnormal, to provide and accurately and effectively detecting there are the pregnant woman of risk.
It is known that in the presence of the various presentations caused by chromosome is abnormal, the cell chromosome of this kind of crowd all has
Certain numerical abnormality or textural anomaly.
With the discovery that there is free embryo DNA in maternal blood, can by the DNA molecular in pregnant woman blood plasma into
The sequencing of row full-length genome low depth high throughput is navigated to the DNA sequence dna measured accordingly by the method that biological information compares
Chromosome on.There are embryo's dissociative DNAs (coming from placental trophoblasts) in maternal peripheral blood plasma.5 weeks just after pregnancy
It can detect, after being pregnant 10 weeks, embryo's dissociative DNA accounts for peripheral blood dissociative DNA 3%~13%, and increases with the growth of pregnant week
Add, disappears within 2 hours after childbirth.It is dyed in the prior art using the noninvasive antenatal embryo that maternal blood dissociative DNA carries out
Body aneuploid detection technique (NIPT)：Judge that embryo 21- trisomys, 18- trisomys, 13- trisomys have been carried out.
But the prior art can not detect other genetic abnormalities of embryo by maternal blood dissociative DNA, in addition to embryo dyes
Body aneuploid.There are no detection technique combination full genome exon sequencing technologies and maternal blood dissociative DNA.Individually
It does noninvasive antenatal embryo chromosome aneuploid detection and maternal inheritance exception DNA testing costs is all higher.
Invention content
The technical problem to be solved by the present invention is to overcome the prior art to detect the incomplete defect of embryo's method, one is provided
The device and method that kind passes through maternal blood dissociative DNA Non-invasive detection parent and the genetic abnormality of embryo.
In order to solve the above technical problems, the present invention provide it is a kind of by maternal blood dissociative DNA Non-invasive detection parent and
The device of the genetic abnormality of embryo, described device include：
Detection module:The full exon high depth of plasma DNA of source parent is sequenced, sequencing depth is average
100X~1000X；Preferably 500X；
Computing module:From Maternal plasma dissociative DNA content calculation embryo's DNA content；
Specifically, all DNA variations in detection Maternal plasma DNA, calculate the variation abundance each to make a variation, if embryo
DNA content is u, and mother body D NA contents are 1-u, with f (x | θ)=a1N(0,σ1 2)+a2N(u/2,σ2 2)+a3N(u,σ3 2)+a4N(1-
u/2,σ4 2)+a5N((1-u)/2,σ5 2)+a6N((1+u)/2,σ6 2), ∑ ai=1,0<=ai<=1, fitting autosome variation is rich
The distribution of degree calculates the parameter of optimal fitting to get to embryo's DNA content；
u:Fetal DNA in maternal plasma DNA content；a1:The genetic mutation proportion of false positive；a2:Fetus is from father's
Ratio shared by genetic mutation；a3:Fetus and the different shared ratio of homozygous gene variation of parent；a4:Mother's homozygosis and fetus
Ratio shared by the genetic mutation of heterozygosis；a5:Mother does not entail the ratio shared by the heterozygous genes variation of fetus；a6:Mother loses
It is transmitted to the shared ratio of the heterozygous genes variation of fetus；1~σ 6:The standard deviation of each distributed model；N is normal state point in the formula
Normal distribution can also be changed to bi-distribution or Poisson distribution by cloth, because it is two that normal distribution can be used as with Poisson distribution
The approximation of distribution, if it is Poisson distribution, N (U, σ in formulai 2) correspondence be changed to P (U)；
Contrast module one:DNA data comparison chromosomal aneuploidies are obtained using computing module, due in detection data
Contain embryo DNA and mother body D NA simultaneously, the DNA fragmentation quantity on every chromosome is counted, if embryo has chromosome non-whole
Times body exception then observes on corresponding chromosome that DNA fragmentation counts and is more than other chromosomes；
Judgment module one：From the exception identified in Maternal plasma dissociative DNA on embryo's single-gene DNA；Maternal plasma is free
The DNA and embryo DNA of parent oneself are mixed in DNA, we can not detach them from detection, but because of parent and embryo
The concentration of DNA has differences, and the DNA comparings of all detections to the mankind reference gene group hg19 or hg38, finds inspection
Survey position of the gained DNA fragmentation in reference gene group and with the unmatched base of reference gene group, detect all DNA variations,
The position each to make a variation, base variation and variation abundance are recorded, the parameter of gained is calculated according to computing module, note embryo's homozygosis becomes
Distribution X~N (u, the σ of different abundance3 2), distribution Y~N ((1-u)/2, σ of the heterozygous variance abundance of parent5 2), if a variation
Abundance be x, calculate p (X>X) with p (Y<X), if p (X>x)>p(Y<X) it then can determine that the source of variation in embryo；
u:Fetal DNA in maternal plasma DNA content；X:Fetus homozygosis variation abundance, σ 3:The distribution of fetus homozygosis variation abundance
Standard deviation, Y:The distribution of the heterozygous variance abundance of parent, σ 5:Parent does not entail the distribution of the heterozygous variance abundance of fetus
Standard deviation, N：Normal distribution, p:Probability；
Judgment module two：From the exception and judgment module one identified in Maternal plasma dissociative DNA on parent single-gene DNA
It is similar, if p (X>x)<p(Y<X), then it can determine that the source of variation in parent.
Preferably, because containing embryo DNA in Maternal plasma dissociative DNA, and the gene of the gene of embryo and parent is that have difference
Different, computing module.
Preferably, contrast module one specifically comprises the following steps:
A) DNA sequence dna for obtaining detection is found every sequence pair accurately and is answered compared with reference gene the group hg19 or hg38 of people
Position on genome；
B) compared with refSeq gene annotation databases, exon region and non-exon region are divided in the genome；
C) the quantity A=(a1, a2, a3 ...) for counting the DNA fragmentation detected on each exon region, counts people's base
Because organizing the upper quantity B=(b1, b2, b3 ...) by the DNA fragmentation that is detected on the non-exon region of each of exon segmentation；
D) the ratio X=that the DNA quantity that each exon region detects accounts for DNA fragmentation quantity on whole exons is calculated
A/(A*1T), similarly non-exon Y=A/ (A*1T)；Wherein, A：The vector of the quantity of the DNA fragmentation detected on exon；B：
The vector of the quantity of the DNA fragmentation detected on non-exon region；1T：The column vector formed by 1；
E) for nth bar chromosome, the detected value (X on the sample to be tested chromosome is chosenn, Yn) and multiple control references
Mean value (the X of samplenc,Ync) compare, pairs of hypothesis testing is done, if (Xn, Yn) and (Xnc,Ync) there were significant differences, significantly
Property threshold value be p<0.05, then the chromosome n of the sample to be tested may be abnormal.
Preferably, further include contrast module two after contrast module one:Use the plasma DNA Data Detection of sample
Chromosomal aneuploidy, it is every with adjustment by computing module from Maternal plasma dissociative DNA content calculation entirety embryo's DNA content
The content of embryo DNA on chromosome, then on more every chromosome embryo's DNA content and total embryo's DNA content ratio,
Find out the chromosome that embryo's DNA content is about whole 1.5 times of embryo's DNA content, if there is such chromosome, the then dyeing
Body exception and it can determine whether that extra chromosome comes from male parent.
Preferably, after being extracted to the plasma DNA of source parent in detection module, DNA library, and enrichment DNA are established
People's exon sequence in library.
Preferably, to the data of determined dna sequence 20G~30G bases after enrichment, the data of 30G bases are preferably measured,
DNA exon sequence length is single-ended or both-end 75bp~150bp length, preferably enrichment DNA exon sequence length both-end
150bp。
Preferably, the parent is pregnancy female subject, it is highly preferred that the parent is pregnant female.
There are one judge after contrast module one or contrast module two:If one result of contrast module is chromosome n abnormal,
Or 1.5 times that embryo's DNA content that the result of contrast module two is chromosome n is total embryo's DNA content, then extra chromosome
Come from male parent；If one result of contrast module is chromosome n abnormal, or the result of contrast module two is the embryo of chromosome n
DNA content is consistent with total embryo's DNA content, then extra chromosome comes from maternal
Preferably, pass through the device of maternal peripheral blood dissociative DNA Non-invasive detection parent and the genetic abnormality of embryo, the dress
Set including：
Detection module:The full exon high depth of plasma DNA of source parent is sequenced, sequencing depth is average
500X；
Computing module:It is all in detection Maternal plasma DNA from Maternal plasma dissociative DNA content calculation embryo's DNA content
DNA makes a variation, and calculates the variation abundance each to make a variation；
Contrast module one:DNA Data Detection chromosomal aneuploidies are obtained using detection module, in detection data simultaneously
Containing embryo DNA and mother body D NA, the DNA fragmentation quantity on every chromosome is counted, if embryo suffers from chromosome aneuploidy
Body is abnormal, then it is observed that DNA fragmentation is counted more than other chromosomes on corresponding chromosome；
Contrast module two:Using the plasma DNA Data Detection chromosomal aneuploidy of sample, by computing module
One:From Maternal plasma dissociative DNA content calculation entirety embryo's DNA content, similarly we can calculate embryo on every chromosome
The content of DNA, then on more every chromosome embryo's DNA content and total embryo's DNA content ratio, find out embryo DNA and contain
Amount is about the chromosome of whole 1.5 times of embryo's DNA content, if there is such chromosome, then the chromosome abnormality；
Judgment module one：From the exception identified in Maternal plasma dissociative DNA on embryo's single-gene DNA；Maternal plasma is free
The DNA and embryo DNA of parent oneself are mixed in DNA, we can not detach them from detection, but because of parent and embryo
The concentration of DNA has differences, and the DNA comparings of all detections to the mankind reference gene group hg19 or hg38, finds inspection
Survey position of the gained DNA fragmentation in reference gene group and with the unmatched base of reference gene group, detect all DNA variations,
The position each to make a variation, base variation and variation abundance are recorded, the parameter of gained is calculated according to computing module, note embryo's homozygosis becomes
Distribution X~N (u, the σ of different abundance3 2), distribution Y~N ((1-u)/2, σ of the heterozygous variance abundance of parent5 2), if a variation
Abundance be x, calculate p (X>X) with p (Y<X), if p (X>x)>p(Y<X) it then can determine that the source of variation in embryo；
Judgment module two：From the exception identified in Maternal plasma dissociative DNA on parent single-gene DNA, the same judgment module
One, if p (X>x)<p(Y<X), then it can determine that the source of variation in parent.
The present invention realizes the Non-invasive detection of embryo genetic exception, can simultaneously the non-multiple of Non-invasive detection embryo chromosome
Property；Can Non-invasive detection parent simultaneously chromosomal inheritance it is abnormal.The present invention is relative to the noninvasive antenatal embryo being commonly used
Chromosome aneuploid detection increases new detection function, but is increased without testing cost, a large amount of cost-effective.
Specific implementation mode
Said program is described further below in conjunction with specific embodiment.It should be understood that these embodiments are for illustrating
The present invention and be not limited to limit the scope of the invention.The implementation condition used in embodiment can be done according to the condition of specific producer
Further adjustment, the implementation condition being not specified is usually the condition in routine experiment.
It introduces and summarizes
The present invention by way of example rather than provides the mode of limitation to illustrate.It should be noted that in present disclosure
" one " or "an" embodiment is not necessarily referring to same specific implementation mode, and refers at least a kind of.Sample comes
Source Suzhou City Hospital of Traditional Chinese Medicine.
Embodiment one：
(1) the Cell-Free DNA BCT test tubes of STRECK companies is used to acquire pregnant 12 according to corresponding equipment operation instructions
The blood 5ml of all pregnant woman；
(2) use the QIAamp Circulating Nucleic Acid Kit kits of Kai Jie companies according to corresponding
Kit operation instructions extract the dissociative DNA in blood plasma,
(3) made according to corresponding kit using the KAPA Hyper Prep Kit kits of KAPA Biosys Corp.
Library is built to the plasma DNA extracted with specification,
(4) the SeqCap EZ Human Exome Probes v3.0DNA capture agent boxes of Nimblegen companies are used
According to people's exon sequence in corresponding kit operation instructions enrichment DNA library,
(5) the Nextseq500 model high-flux sequence instruments of Illumina companies is used to survey the DNA sequence dna after enrichment
Determine the data of 32G bases, DNA sequence dna length is 150 length of both-end,
(6) 70647 variations are detected from sequencing data, the variation abundance of each variation is between 0~1.It uses
These data and mixture normal distribution model formula calculate u=0.074, i.e. foetal DNA institute in maternal blood dissociative DNA
Accounting example is 7.4%.
(7) obtained DNA sequence dna will be detected compared with mankind's reference sequences hg19 with bwa softwares,
(8) to each exon, introne, the intergenic region DNA sequence dna number on every chromosome of the people of the detection data
Gauge number, according to the method for the invention (3), by the data obtained compared with the reference data for other the multiple samples got ready,
It was found that all DNA fragmentation quantity proportions are 1.2373% on No. 21 chromosomes of this detection sample, and other multiple dyes
No. 21 chromosome proportions of the reference baseline of colour solid normal sample composition are 1.1931%, and on No. 21 chromosomes of the sample
Exon, introne, the opposite DNA quantity on intergenic region are significantly higher than the reference baseline of other multiple samples compositions, show
Work property p-value=0.0032, is judged as No. 21 chromosome trisomy defect of the embryo
(9) foetal DNA content is calculated using variation on every chromosome according to the method for the invention (4), calculates gained
No. 21 chromosome embryo's DNA contents are u=0.11, and overall embryo's DNA content is u=0.74, other chromosomes embryo's DNA content
Embryo's DNA content is noticeably greater than overall embryo's DNA content, and about 1.5 times all on 0.73 or so, No. 21 chromosome.
(10) according to the method for the invention (5), No. 21 chromosome abnormalities of the sample, and No. 21 chromosome embryo DNA contain
Amount is 1.5 times of total embryo's DNA content, is judged as that embryo carries No. 21 chromosome trisomy defects, and extra chromosome comes from father
This.
(11) according to the judging result of the method for the invention (1) (3) (4) (5), 3 parts of testing results are exported：A. institute is used
The genetic mutation for having mother generates the examining report of mother；B. the genetic mutation using all embryos, generates the detection report of embryo
It accuses；C. the report that embryo whether there is chromosome abnormality is generated.
Embodiment two：
(1) for the DNA sequence data of embodiment one, embryo's DNA content, meter are calculated using the method for the invention (4)
It is 3% to calculate gained embryo's DNA content, and mother body D NA contents 97%, embryo's DNA content is in crowd's average value zone of reasonableness.
(2) variation is calculated to DNA sequence data obtained by this detection, it is found that there are more than 90 defects to make a variation in DNA, these
Most of abundance of variation is distributed near 1.5% and 50%, and the method (3), (6), (7) calculate through the invention, wherein
For more than 30 defect source of variations in embryo, more than 60 derive from parent.
Specific embodiment described above is only the preferred embodiment of the present invention, it is noted that for the art
For those of ordinary skill, without departing from the principle of the present invention, several improvement or replacement can also be made, these improvement
Or it replaces and should also be as being considered as protection scope of the present invention.
Claims (8)
1. the device of a kind of Non-invasive detection parent and embryo genetic exception, described device include：
Detection module:The full exon high depth of plasma DNA of source parent is sequenced, sequencing depth be average 100X~
1000X；
Computing module:All DNA from Maternal plasma dissociative DNA content calculation embryo's DNA content, detection Maternal plasma DNA
Variation calculates the variation abundance each to make a variation；
Specifically, all DNA variations in detection Maternal plasma DNA, calculate the variation abundance each to make a variation, if the DNA of embryo
Content is u, and mother body D NA contents are 1-u, with f (x | θ)=a1N(0,σ1 2)+a2N(u/2,σ2 2)+a3N(u,σ3 2)+a4N(1-u/2,
σ4 2)+a5N((1-u)/2,σ5 2)+a6N((1+u)/2,σ6 2), ∑ ai=1,0<=ai<=1, fitting autosome variation abundance
Distribution calculates the parameter of optimal fitting to get to embryo's DNA content；The meaning of wherein parameter is:
u:Fetal DNA in maternal plasma DNA content, a1:The genetic mutation proportion of false positive, a2:Gene of the fetus from father
The shared ratio of variation, a3:Fetus and the different shared ratio of homozygous gene variation of parent, a4:Mother's homozygosis and fetus heterozygosis
Genetic mutation shared by ratio, a5:Mother does not entail the ratio shared by the heterozygous genes variation of fetus, a6:Mother entails
Ratio shared by the heterozygous genes variation of fetus, 1~σ 6:The standard deviation of each distributed model, N is normal distribution；
Contrast module one:DNA Data Detection chromosomal aneuploidies are obtained using computing module, are contained simultaneously in detection data
Embryo DNA and mother body D NA counts the DNA fragmentation quantity on every chromosome；
Judgment module one：From the exception identified in Maternal plasma dissociative DNA on embryo's single-gene DNA；The DNA numbers of all detections
Arrive the mankind reference gene group hg19 or hg38 according to comparing, find detection position of the gained DNA fragmentation in reference gene group and
With the unmatched base of reference gene group, all DNA variations are detected, it is rich to record the position each to make a variation, base variation and variation
Degree calculates the parameter of gained, distribution X~N (u, the σ of note embryo's homozygosis variation abundance according to computing module3 2), the heterozygosis of parent becomes
Distribution Y~N ((1-u)/2, σ of different abundance5 2), if the abundance of a variation is x, calculate p (X>X) with p (Y<X), if p (X
>x)>p(Y<X) it then can determine that the source of variation in embryo；
Judgment module two：It is similar from the exception and judgment module one identified in Maternal plasma dissociative DNA on parent single-gene DNA,
If p (X>x)<p(Y<X), then it can determine that the source of variation in parent.
2. the apparatus according to claim 1, which is characterized in that in the formula of the computing module, or by N normal distributions
It is changed to bi-distribution or Poisson distribution.
3. the apparatus according to claim 1, which is characterized in that the contrast module one specifically comprises the following steps:
A) DNA sequence dna for obtaining detection finds every sequence pair accurately and answers gene compared with reference gene the group hg19 or hg38 of people
Position in group；
B) compared with refSeq gene annotation databases, exon region and non-exon region are divided in the genome；
C) count the DNA fragmentation detected on each exon region quantity A=(a1, a2, a3 ... n), count each non-outer
The DNA fragmentation detected on aobvious subregion quantity B=(b1, b2, b3 ... n)；
D) the ratio X=A/ that the DNA quantity that each exon region detects accounts for DNA fragmentation quantity on whole exons is calculated
(A*1T), similarly non-exon Y=A/ (A*1T)；Wherein, A：The vector of the quantity of the DNA fragmentation detected on exon；B：It is non-
The vector of the quantity of the DNA fragmentation detected on exon region；1T：The column vector formed by 1；
E) for nth bar chromosome, the detected value (X on the sample to be tested chromosome is chosenn, Yn) and multiple control reference samples
Mean value (Xnc,Ync) compare, pairs of hypothesis testing is done, if (Xn, Yn) and (Xnc,Ync) there were significant differences, conspicuousness
Threshold value is P<0.05, then the chromosome n of the sample to be tested may be abnormal.
4. device according to claim 1 or 3, which is characterized in that further include contrast module after the contrast module one
Two:Using the plasma DNA Data Detection chromosomal aneuploidy of sample, by computing module:From Maternal plasma dissociative DNA
Content calculation entirety embryo's DNA content, with the content for adjusting embryo DNA on every chromosome, then on more every chromosome
The ratio of embryo's DNA content and total embryo's DNA content whether there is 1.5 times.
5. the apparatus according to claim 1, it is characterised in that, the plasma DNA of source parent is carried in detection module
After taking, DNA library, and people's exon sequence in enrichment DNA library are established.
6. the apparatus according to claim 1, which is characterized in that determined dna sequence 20G~30G bases after enrichment
Data.
7. device according to claim 6, which is characterized in that DNA sequence dna length is single-ended or both-end 75bp~150bp long
Degree.
8. the apparatus according to claim 1, which is characterized in that the parent is pregnancy female subject.
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