Methods and processes for non-invasive assessment of genetic variations

Abstract

Provided herein are methods, processes and apparatuses for non-invasive assessment of genetic variations.

What is claimed is: 
     
         1 . A system comprising one or more processors and a memory, which memory comprises:
 (1) counts of nucleic acid sequence reads mapped to genomic sections of a reference genome, which sequence reads are reads of circulating cell-free nucleic acid for a test sample from a pregnant female,   (2) a median X chromosome representation for a set of pregnant females bearing a female fetus, and   (3) a slope and intercept from a linear regression of X chromosome representations and Y chromosome representations determined for a set of pregnant females bearing a male fetus,   and which memory comprises instructions executable by the one or more processors configured to:   (a) from the counts in (1), generate an experimental Y chromosome representation, and   (b) determine a fraction of fetal nucleic acid in the test sample according to the experimental Y chromosome representation generated in (a), the median X chromosome representation for the set of pregnant females bearing a female fetus in (2), and the slope and the intercept in (3).   
     
     
         2 . The system of  claim 1 , wherein the median X chromosome representation for the set of pregnant females bearing a female fetus in (2) is the median of X chromosome representations. 
     
     
         3 . The system of  claim 2 , wherein at least one of the X chromosome representations is a ratio of (i) counts of sequence reads mapped to the genomic sections of the reference genome in the X chromosome, and (ii) counts of sequence reads mapped to genomic sections of the reference genome in a portion of the chromosomes or all of the chromosomes. 
     
     
         4 . The system of  claim 1 , wherein at least one of the X chromosome representations for the set of pregnant females bearing a male fetus in (3) is a ratio of (i) counts of sequence reads mapped to the genomic sections of the reference genome in the X chromosome, and (ii) counts of sequence reads mapped to genomic sections of the reference genome in a portion of the chromosomes or all of the chromosomes. 
     
     
         5 . The system of  claim 4 , wherein at least one of the Y chromosome representations for the set of pregnant females bearing a male fetus in (3) is a ratio of (i) counts of sequence reads mapped to the genomic sections of the reference genome in the Y chromosome, and (ii) counts of sequence reads mapped to genomic sections of the reference genome in a portion of the chromosomes or all of the chromosomes. 
     
     
         6 . The system of  claim 1 , wherein the experimental Y chromosome representation in (a) is a ratio of (i) counts of sequence reads mapped to the genomic sections of the reference genome in the Y chromosome, and (ii) counts of sequence reads mapped to genomic sections of the reference genome in a portion of the chromosomes or all of the chromosomes for the test sample. 
     
     
         7 . The system of  claim 1 , wherein the fraction of the fetal nucleic acid is determined according to equation (62): 
       
         
           
             
               
                 
                   
                     f 
                     = 
                     
                       2 
                       ⁢ 
                       
                         
                           
                             
                               I 
                               + 
                               
                                 S 
                                 ( 
                                 x 
                               
                             
                             〉 
                           
                           - 
                           y 
                         
                         
                           
                             S 
                             ( 
                             x 
                           
                           〉 
                         
                       
                     
                   
                 
                 
                   
                     ( 
                     62 
                     ) 
                   
                 
               
             
           
         
         wherein I is the intercept, S is the slope, (x) is the median X chromosome representation for the set of pregnant females bearing a female fetus and y is the experimental Y chromosome representation generated in (a). 
       
     
     
         8 . The system of  claim 1 , wherein the linear regression in (3) is constrained by a point representing a median chromosome X representation and a median chromosome Y representation for pregnant females bearing a female fetus. 
     
     
         9 . The system of  claim 1 , wherein the counts of sequence reads mapped to genomic sections of the reference genome in a portion of the chromosomes are the counts of sequence reads mapped to genomic sections of the reference genome in autosomes. 
     
     
         10 . The system of  claim 1 , wherein the slope is determined according to X chromosome representations for a set of pregnant females bearing a male fetus, Y chromosome representations for the set of pregnant females bearing a male fetus, the median X chromosome representation for the set of pregnant females bearing a female fetus, and a median Y chromosome representation for a set of pregnant females bearing a female fetus, wherein:
 the median Y chromosome representation is the median of Y chromosome representations, and   at least one of the Y chromosome representations is a ratio of (i) counts of sequence reads mapped to the genomic sections of the reference genome in the Y chromosome, and (ii) counts of sequence reads mapped to genomic sections of the reference genome in a portion of the chromosomes or all of the chromosomes.   
     
     
         11 . The system of  claim 1 , wherein the intercept is determined according to the slope, the median X chromosome representation for the set of pregnant females bearing a female fetus, and a median Y chromosome representation for a set of pregnant females bearing a female fetus, wherein:
 the median Y chromosome representation is the median of Y chromosome representations, and   at least one of the Y chromosome representations is a ratio of (i) counts of sequence reads mapped to the genomic sections of the reference genome in the Y chromosome, and (ii) counts of sequence reads mapped to genomic sections of the reference genome in a portion of the chromosomes or all of the chromosomes.   
     
     
         12 . The system of  claim 1 , wherein each set of pregnant females in (2) and (3) is a set of about 500 or more females. 
     
     
         13 . The system of  claim 1 , wherein the counts in (1) are normalized counts. 
     
     
         14 . The system of  claim 13 , wherein the counts in (1) are guanine and cytosine (GC) normalized counts. 
     
     
         15 . The system of  claim 1 , wherein the fetal fraction is provided with an accuracy of equal to or greater than 90% and/or a precision equal to or greater than 90%. 
     
     
         16 . The system of  claim 1 , wherein the test sample is from a pregnant female bearing a male fetus. 
     
     
         17 . The system of  claim 1 , wherein the test sample is blood serum or blood plasma. 
     
     
         18 . The system of  claim 1 , wherein the instructions executable by the one or more processors are further configured to determine fetal sex. 
     
     
         19 . The system of  claim 1 , further comprising a sequencing apparatus configured to generate the sequence reads from the circulating cell-free nucleic acid by a massively parallel sequencing process. 
     
     
         20 . The system of  claim 19 , wherein the sequencing apparatus is configured to generate the sequence reads from the circulating cell-free nucleic acid by a genome-wide massively parallel sequencing process.