CN113270138B - Analysis method for enriching fetal free DNA (deoxyribonucleic acid) for copy number variation based on bioinformatics - Google Patents
Analysis method for enriching fetal free DNA (deoxyribonucleic acid) for copy number variation based on bioinformatics Download PDFInfo
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Abstract
The invention discloses an analysis method for enriching fetal free DNA for copy number variation based on bioinformatics. According to the invention, the fetal DNA content is calculated by calculating the ratio of the number of sex chromosome reads to the total number of autosomal reads after homogenization of different fragment lengths, and the length range of free DNA fragments with the highest fetal DNA content is selected for subsequent aneuploidy and CNV analysis. The invention can improve the concentration proportion of the fetal DNA and greatly improve the accuracy of the application of analyzing the fetal chromosome aneuploidy, chromosome fragment copy number abnormality and the like.
Description
Technical Field
The invention belongs to the field of bioinformatic data analysis applied to noninvasive prenatal screening based on NGS sequencing, and particularly relates to an analysis method for enriching fetal free DNA for copy number variation based on bioinformatics.
Background
In 1997, denise Lo, university of hong Kong, found that free DNA fragments from fetuses were present in blood, with an average content of approximately 13% of the total free DNA content in maternal blood. The method can accurately detect chromosome and fragment copy number abnormality, sex determination, single gene disease screening and the like of a fetus by separating and extracting free DNA fragments in the peripheral blood of pregnant women for more than 12 weeks and adopting a large-scale parallel sequencing method.
At present, the enrichment of the free DNA of the fetus is mainly carried out by an electrophoresis separation method or an experimental method of magnetic bead enrichment. However, since the content of free DNA fragments of the fetus is extremely low, it is difficult to separate free DNA fragments of different lengths and sample loss is also caused. The two enrichment methods also increase the complexity of the experiment and the extension of the time period of library establishment, the redundancy of reads on the comparison can be increased by the data generated by the two methods, and meanwhile, the uniformity of the distribution of the reads on the reference genome is poor, so that the false positive rate can be increased.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, and considers that with the reduction of the sequencing cost of the next generation, the sequencing quantity is increased within a certain range, DNA molecules from a fetus are extracted as much as possible, and the fetal DNA ratio is improved by a biological information screening method, so that the method has higher accuracy in analyzing the fetal chromosome aneuploidy and chromosome fragment CNV, and can reduce the proportion of heavy loading or heavy blood sampling caused by the insufficient fetal DNA content, and the qualification rate of the detected sample is higher, thereby further reducing the cost.
Because fetal plasma free DNA is shorter than maternal free DNA fragments, we calculated fragment length distribution based on two reads aligned to positions on the reference genome by double-ended sequencing at the sequencing data level without changing the experimental DNA extraction and banking methods. Based on the fragment length distribution, taking 10bp as step, respectively selecting 50-200, 50-210, 50-220, 50-230, 50-240 and 50-250;60-200, 60-210, 60-220, 60-230, 60-240, 60-250; …,120-200,120-210,120-220,120-230,120-240,120-250 … free DNA fragments length reads within these regions, the number of reads per chromosome and within each sliding window was calculated for each sample, GC, and the number of reads per sample was normalized with the total alignment to the number of reads for autosomes.
Calculating the content of fetal DNA by calculating the ratio of the number of sex chromosome reads to the total number of autosomal reads after homogenization of different fragment lengths, and selecting the length range of free DNA fragment with the highest fetal DNA content for subsequent aneuploidy and CNV analysis
For autosomes and female fetal X chromosomes, the calculated copy number of CNV is subtracted by the normal copy number of 2, and the chimeric proportion (MosRatio) of the CNV is obtained by multiplying 100%; for X chromosome and Y chromosome of male fetus, the calculated copy number of CNV is subtracted by normal copy number 1, and the chimeric proportion of CNV is obtained by multiplying 100%. If the chimeric ratio is less than 50%, it is generally reflected in the magnitude of the fetal DNA content, which is positively correlated with the fetal DNA content. If the current sample has more CNVs (possibly including benign and pathogenic CNVs), the median of the chimeric proportion of all CNVs is approximately equivalent to the fetal DNA content.
The specific alternative scheme of the invention is as follows:
the invention discloses an analysis method for enriching fetal free DNA based on bioinformatics, which comprises the following steps:
1) Comparing the double-end reads to a reference genome in a fault-tolerant manner, and recording the GC of the chromosomes, the coordinate positions and the reads on the reference genome;
2) Reserving reads with double ends aligned to a reference genome and insert size within 1 kb; the insert size refers to the distance of a pair of aligned ends to reads on a reference genome;
3) Making a frequency distribution diagram of insert size within a range of 50-500 bp to obtain a fragment distribution rule;
4) Taking the set bp number as step, respectively selecting reads with insert size in a set region; calculating the numbers of reads and GC (gas chromatography) on each chromosome and in each sliding window for each sample, and carrying out homogenization treatment on the numbers of reads of each sample by using the total comparison to the numbers of reads of autosomes;
5) And calculating the fetal DNA content of the ratio of reads after homogenization treatment to reads of autosomes after total homogenization on the X chromosomes of different insert size fragment distribution ranges of each sample, and selecting the insert size fragment distribution range with the highest fetal DNA content as data of subsequent analysis.
The invention further discloses an analysis method of copy number variation, which comprises the following steps:
a. obtaining the distribution range of the insert size fragments with the highest fetal DNA content as analysis data based on the analysis method for enriching fetal free DNA based on bioinformatics;
b. the selected reads are set according to the bin size, step is set, and the number of reads and GC in each sliding window (bin) are calculated respectively;
c. making a dot diagram of all read counts and GC in a single sample, wherein the horizontal axis is GC, the vertical axis is RC (read count), fitting a curve by using a LOESS regression model, taking the GC in each bin into the fitted curve to obtain a fitting predicted value P, taking RC of all sliding windows as a median M, and obtaining corrected RC (RCcorrected) by multiplying RC of each bin by a correction factor F corresponding to each bin, wherein the correction factor F is the ratio of P to M;
d. taking the natural logarithm of the ratio of RCcorlected in each bin of the sample to be tested to RCcorlected in each bin of more than 10 samples of the same sex by the same-batch same-library construction method, the same-sequencing platform, and the same-sequencing platform to obtain the log2ratio of each bin;
e. each bin on each chromosome is fragmented, resulting in each fragment (seg) and its corresponding log2ratio data.
f. Obtaining the copy number CN of each fragment of the chromosome;
g. obtaining the chimeric ratio MosRatio by using the absolute value of the difference value between CN and 2 of each segment;
h. fragments with MosRatio less than 0.05 were filtered out, leaving fragments with MosRatio greater than 0.05 and fragment length greater than 1M as the fetal CNV end result.
The invention solves the problem that the fetal chromosome aneuploidy or the copy number abnormality of the fetal chromosome fragment cannot be accurately detected due to low fetal DNA concentration in the field of noninvasive prenatal screening. The invention relates to data analysis level optimization. The comparison of non-fragment screening enrichment and fragment screening enrichment is tested by applying the method of the invention. Based on the enrichment of the fetal DNA short fragments in the biological information layer, the fetal DNA content is improved by about 1.5 percent on average, the fetal DNA content is obviously reduced by less than 4 percent threshold, the detection success rate is greatly increased, and the fetal aneuploidy and CNV false negative are obviously reduced; and the fetal CNV and maternal CNV are obviously distinguished, so that false positives (background noise signals) caused by nonspecific comparison or other interference conditions are obviously reduced, and the detection specificity is obviously improved.
Compared with the free DNA fragment length screening without a biological signal layer in the prior art, the fetal free DNA content of the fragment screening is improved by about 1.5%. The false positive of CNV is obviously reduced, and the specificity of the fetal CNV is improved.
Drawings
FIG. 1 is a schematic flow chart of the method of the present invention.
FIG. 2 is a graph showing the density distribution of the free DNA fragment length distribution data of all pairs of reads in the examples; each line represents the free DNA fragment length distribution for each sample;
FIG. 3 is a graph showing the results of the present invention on the increase in fetal free DNA content compared to prior art protocols;
FIG. 4 is a schematic diagram showing the improvement in specificity of fetal CNV; the left side shows the distribution of the chimeric ratio of fetal CNV without enrichment, and the right side shows the distribution of the chimeric ratio of fetal CNV after enrichment of short-fragment fetal DNA with raw meal.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and fully with reference to the accompanying drawings, in which it is evident that the embodiments described are only some, but not all embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
As shown in fig. 1, which is a schematic flow chart of the method of the present invention, the method of the present invention is summarized as follows:
1) Comparing the double-end reads to a reference genome in a fault-tolerant manner through double-end sequencing at a sequencing data layer, and recording and comparing the chromosome, the coordinate position and the GC of the reads on the reference genome;
2) Reserving reads with double ends aligned to a reference genome and insert size within 1 kb; the insert size refers to the distance of a pair of aligned ends to reads on a reference genome;
3) Making a frequency distribution diagram of insert size within a range of 50-500 bp to obtain a fragment distribution rule;
4) Taking the set bp number as step, respectively selecting reads with insert size in a set region; calculating the numbers of reads and GC (gas chromatography) on each chromosome and in each sliding window for each sample, and carrying out homogenization treatment on the numbers of reads of each sample by using the total comparison to the numbers of reads of autosomes;
5) And calculating the fetal DNA content of the ratio of reads after homogenization treatment to reads of autosomes after total homogenization on the X chromosomes of different insert size fragment distribution ranges of each sample, and selecting the insert size fragment distribution range with the highest fetal DNA content as data of subsequent analysis.
The reads selected in step 5 of the present invention analyze the aneuploidy of the fetal 13, 18, 21 chromosome, and the calculation method is also referred to in the document (https:// pubmed. Ncbi. Lm. Nih. Gov/23299662 /).
The reads selected in step 5 of the invention can also be used for analysis of fetal aneuploidy and copy number variation, and the reference steps are as follows:
b. the selected reads are set according to the bin size, step is set, and the number of reads and GC in each sliding window (bin) are calculated respectively;
c. making a dot diagram of all read counts and GC in a single sample, wherein the horizontal axis is GC, the vertical axis is RC (read count), fitting a curve by using a LOESS regression model, taking the GC in each bin into the fitted curve to obtain a fitting predicted value P, taking RC of all sliding windows as a median M, and obtaining corrected RC (RCcorrected) by multiplying RC of each bin by a correction factor F corresponding to each bin, wherein the correction factor F is the ratio of P to M;
d. taking the natural logarithm of the ratio of RCcorlected in each bin of the sample to be tested to RCcorlected in each bin of more than 10 samples of the same sex by the same-batch same-library construction method, the same-sequencing platform, and the same-sequencing platform to obtain the log2ratio of each bin;
e. each bin on each chromosome is fragmented, resulting in each fragment (seg) and its corresponding log2ratio data.
f. Obtaining the copy number CN of each fragment of the chromosome;
g. obtaining the chimeric ratio MosRatio by using the absolute value of the difference value between CN and 2 of each segment;
h. fragments with MosRatio less than 0.05 were filtered out, leaving fragments with MosRatio greater than 0.05 and fragment length greater than 1M as the fetal CNV end result.
The invention is further illustrated below with reference to specific examples.
In this example 284 NIPT data of a double-end sequencing mode from a model Illumina NextSeq CN500 sequencer are compared to a reference genome (hg 19 version) in a fault-free manner, reads with both ends being compared to the reference genome are selected, the length distribution of free DNA fragments is calculated according to the distance between the coordinates of both ends of paired reads on the comparison on the reference genome, and the length distribution data of the free DNA fragments of all paired reads are used as a density distribution graph. As shown in fig. 2.
Based on the distribution rule of the graph, we use 10bp as step to select 50-200, 50-210, 50-220, 50-230, 50-240 and 50-250 respectively; 60-200, 60-210, 60-220, 60-230, 60-240, 60-250; …,120-200,120-210,120-220,120-230,120-240,120-250 reads with free DNA fragment lengths in these regions, the number of reads per chromosome and within each sliding window, GC, were calculated for each sample, and the number of reads per sample was normalized with the total alignment to the number of reads for autosomes.
The ratio of reads after homogenization treatment on X chromosomes of different insert size fragment distributions of each sample to reads of autosomes after total homogenization is calculated as fetal DNA content, and the calculation of fetal DNA content can be referred to in the literature (https:// pubmed. Ncbi. Lm. Nih. Gov/23299662 /), and the insert size fragment distribution with the highest fetal DNA content is selected as data for subsequent analysis. Aneuploidy of each chromosome was calculated separately for each sample using the other samples of the same lot as controls, and fetal chromosome 13, 18, 21 aneuploidy was analyzed.
For CNV analysis, the invention calculates the number of reads and GC in each sliding window (bin) according to 100kb bin size,20kb step
Making a dot diagram of all read counts and GC (accurate to a decimal point) in a single sample, fitting a curve by using a LOESS regression model, taking the GC in each bin into the fitted curve to obtain a fitted predicted value (P), taking the RC of all sliding windows as a median (M), and obtaining a corrected RC (RCcorrected) by multiplying the RC of each bin by the correction factor F corresponding to each bin, wherein the correction factor F is the ratio of P to M
The RCcorrected in each bin of the sample to be tested is compared with the natural logarithm of the ratio of the RCcorrected in each bin of more than 10 samples with the same sex by the same-batch same-library construction method, the same-sequencing platform, and the same-sequencing platform to obtain the log2ratio of each bin
Each bin on each chromosome was fragmented using the Circular Binary Segmentation (CBS) algorithm, resulting in each fragment (seg) and its corresponding log2ratio data.
For female test samples, the log2ratio of each fragment is raised to a power of 2 and then multiplied by 2, i.e., 2X 2 (log 2 ratio), to obtain the Copy Number (CN) of each fragment of chromosome 1-22 and chromosome X. The copy number calculation method for fragments on chromosome 1-22 of the male test sample is consistent with that of females, and the copy numbers of X and Y chromosomes are calculated as 2 (log 2 ratio).
The absolute value of the difference between CN and 2 for each segment is used to obtain the chimeric ratio (MosRatio).
Fragments with MosRatio less than 0.05 were filtered out, leaving fragments with MosRatio greater than 0.05 and fragment length greater than 1M as the fetal CNV end result.
The fetal free DNA content of the fragment-screened was improved by about 1.5% in a tie compared to the free DNA fragment length screening without the birth signal layer (fig. 3). The false positives of CNV are significantly reduced and the specificity of fetal CNV is improved (fig. 4, left side shows the distribution of fetal CNV chimerism ratio without enrichment, right side shows the distribution of fetal CNV chimerism ratio after enrichment of short fragment fetal DNA).
Claims (3)
1. An analytical method for enriching fetal free DNA for copy number variation based on bioinformatics, comprising the steps of:
a. obtaining the distribution range of the insert size fragments with the highest fetal DNA content by adopting an analysis method for enriching fetal free DNA based on bioinformatics as analysis data;
the analysis method for enriching the fetal free DNA based on the bioinformatics comprises the following steps:
1) Comparing the double-end reads to a reference genome in a fault-tolerant manner, and recording the GC of the chromosomes, the coordinate positions and the reads on the reference genome;
2) Reserving reads with double ends aligned to a reference genome and insert size within 1 kb; the insert size refers to the distance of a pair of aligned ends to reads on a reference genome;
3) Making a frequency distribution diagram of insert size within a range of 50-500 bp to obtain a fragment distribution rule;
4) Taking the set bp number as step, respectively selecting reads with insert size in a set region; calculating the numbers of reads and GC (gas chromatography) on each chromosome and in each sliding window bin for each sample, and carrying out homogenization treatment on the numbers of reads of each sample by using total comparison to the numbers of reads of autosomes;
5) Calculating the fetal DNA content of the ratio of reads after the homogenization treatment to reads of autosomes after the total homogenization on the comparison of X chromosomes of different insert size fragment distribution ranges of each sample, and selecting the insert size fragment distribution range with the highest fetal DNA content as data of subsequent analysis;
b. the selected reads are subjected to size setting and step setting, and the number of reads and GC in each sliding window bin are calculated respectively;
c. making a point diagram of all read counts and GC in a single sample, wherein the horizontal axis is GC, the vertical axis is RC, RC is the read count, a curve is fitted by using a LOESS regression model, the GC in each bin is brought into the fitted curve to obtain a fitted predicted value P, the RC of each sliding window bin is taken as a median M, a correction factor F is the ratio of P to M, and the RC of each bin is multiplied by a correction factor F corresponding to each bin to obtain corrected RC, namely RCcorrected;
d. taking the natural logarithm of the ratio of RCcorlected in each bin of the sample to be tested to RCcorlected in each bin of more than 10 samples of the same sex by the same-batch same-library construction method, the same-sequencing platform, and the same-sequencing platform to obtain the log2ratio of each bin;
e. fragmenting each bin on each chromosome to obtain each fragment and log2ratio data corresponding to each fragment;
f. obtaining the copy number CN of each fragment of the chromosome;
for a female sample to be tested, taking the log2ratio of each segment to the power of 2 and then multiplying by 2, namely 2X 2 (log 2 ratio), to obtain the copy number CN of each segment of chromosome 1-22 and chromosome X;
for a male sample to be tested, taking the log2ratio of each segment to the power of 2 and then multiplying by 2, namely 2X 2 (log 2 ratio), the copy numbers of the X and Y chromosomes are calculated to be 2 (log 2 ratio), and the copy number CN of each segment of chromosome 1-22, X and Y is obtained;
g. obtaining the chimeric ratio MosRatio by using the absolute value of the difference value between CN and 2 of each segment;
h. fragments with MosRatio less than 0.05 were filtered out, and fragments with MosRatio greater than 0.05 and fragment length greater than 1M were retained as the end result of fetal copy number variation CNV.
2. The method for analyzing copy number variation according to claim 1, wherein the step 4) is specifically:
taking 10bp as step, respectively selecting 50-200, 50-210, 50-220, 50-230, 50-240 and 50-250;60-200, 60-210, 60-220, 60-230, 60-240, 60-250, …,120-200,120-210,120-220,120-230,120-240,120-250 free DNA fragment lengths lie in the reads ds in these regions, the number of reads on each chromosome and within each sliding window bin, GC are calculated for each sample, and the number of reads for each sample is subjected to a homogenization treatment with the number of reads for total alignment to autosomes.
3. The method according to claim 1, wherein in the step b, the numbers of reads and GCs in each sliding window bin are calculated according to 100kb bin size,20kb step.
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