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Method and device for carrying out GC correction on chromosome sequencing results

A chromosome and sequence information technology, applied in the field of fetal genetic abnormality detection, can solve the problems of interference detection accuracy, difficulty, data distortion, etc.

Active Publication Date: 2014-10-29
BGI GENOMICS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this method has difficulties with sex chromosome disorders, especially Y-chromosome-related disorders, because the method may introduce slight distortions in the data, which can interfere with the accuracy of the test

Method used

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  • Method and device for carrying out GC correction on chromosome sequencing results
  • Method and device for carrying out GC correction on chromosome sequencing results
  • Method and device for carrying out GC correction on chromosome sequencing results

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0119] Example 1 Analysis of Factors Affecting Detection Sensitivity: GC Bias and Gender

[0120] A schematic framework of steps for calculating coverage depth and GC content is shown in figure 1 . The inventors used software to generate reference unique reads by cutting the hg18 reference sequence into l-mers (here l-mers are the reads that were artificially dissected from the human sequence reference with the same length "l" as the sample sequencing reads) , collect these "unique" l-mers as reference unique reads for inventors. Second, the inventors mapped their sequencing sample reads to reference unique reads for each chromosome. Third, the inventors removed outliers by applying a quintile outlier cutoff to obtain a clean dataset. Finally, the inventors calculated the coverage depth for each chromosome for each sample, and calculated for each sample the GC content of the sequenced unique reads that mapped to each chromosome.

[0121] To investigate how GC content af...

Embodiment 2

[0124] Embodiment 2 statistical model

[0125] Using this phenomenon discussed above, the inventors attempted to fit the relationship between coverage depth and corresponding GC content using local polynomials. Coverage depth is composed of the following function of GC and normally distributed residuals:

[0126] cr i,j =f(GC i,j )+ε i,j ,j=1,2,...,22,X,Y (4)

[0127] where f(GC i,j ) represents the relationship between the coverage depth of sample i, chromosome j and the corresponding GC content, ε i,j Represents the residual of sample i and chromosome j. There is not a strong linear relationship between the depth of coverage and the corresponding GC content, so the inventors applied the loess algorithm to fit the depth of coverage to the corresponding GC content, from which the inventors calculated the Say the important value, namely the fit coverage depth:

[0128] cr i , j ...

Embodiment 3

[0132] Example 3 Fetal Fraction Estimation

[0133] Since fetal fraction is so important to the inventor's assay, the inventor estimated the fetal fraction prior to the testing procedure. As noted above, the inventors sequenced 19 adult males, and when comparing their coverage depths with those of female fetuses, the inventors found that the chromosome X coverage depth in males was nearly 1 / 2 that of females, and that chromosome X in males The depth of Y coverage is approximately 0.5 times greater than that of females. Therefore, the inventors can rely on the coverage depth of chromosomes X and Y and consider GC correlations to estimate the fetal fraction as Equation 8, Equation 9 and Equation 10:

[0134] fy i = ( cr i , Y - c ^ ...

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Abstract

The invention relates to a non-diagnostic method for noninvasively detecting fetal hereditary disorder by sequencing nucleotides from a maternal biological sample on a large scale, and further provides a method for eliminating sequencing result GC bias caused by chromosome GC content difference. The method disclosed by the invention not only enables detection to be more accurate, but also provides a non-diagnostic comprehensive method for detecting fatal aneuploidy including sex chromosomal disease cases, for example, XO, XXX, XXY, XYY, and the like.

Description

[0001] related application [0002] This application is a divisional application of the Chinese patent application 201180067286.X with the filing date on June 29, 2011 and titled "Noninvasive Detection of Fetal Genetic Abnormalities". technical field [0003] The present invention relates to a non-invasive method of detecting fetal genetic abnormalities by DNA sequencing of samples from pregnant women. More specifically, the invention relates to data analysis to remove GC bias introduced by amplifying and sequencing DNA samples. The invention also relates to statistical analysis for the purpose of detecting fetal genetic abnormalities, such as chromosomal abnormalities including aneuploidy. Background technique [0004] Routine prenatal diagnostic methods involving invasive steps such as chorionic villus sampling and amniocentesis have potential risks to both the fetus and the mother. Noninvasive screening for fetal aneuploidy using maternal serum markers and ultrasound i...

Claims

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Application Information

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IPC IPC(8): C12Q1/68C12M1/00
CPCC12Q1/6883C12Q2600/156G16B20/00G16B30/00
Inventor 蒋馥蔓陈会飞柴相花袁玉英张秀清陈芳
Owner BGI GENOMICS CO LTD
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