System and method for cleaning noisy genetic data from target individuals using genetic data from genetically related individuals

• US 10,597,724 B2
• Filed: 05/14/2019
• Issued: 03/24/2020
• Est. Priority Date: 11/26/2005
• Status: Active Grant

• Current Assignee: Natera Incorporated (Natera)
• Original Assignee: Natera Incorporated (Natera)
• Inventors: Rabinowitz, Matthew, Banjevic, Milena, Demko, Zachary, Johnson, David
• Primary Examiner(s): Lin, Jerry
• Application Number:
  US16/411,507
• Publication Number:
  US 20190264288A1
• Time in Patent Office: 315 Days
• Field of Search: 702 19
• CPC Class Codes: C12Q 1/6827 for detection of mutation or polymorphism
• CPC Class Codes: C12Q 1/6876 Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2537/16 Assays for determining copy number or wherein the copy number is of special importance
• CPC Class Codes: C12Q 2537/165 Mathematical modelling, e.g. logarithm, ratio
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/20 Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
• CPC Class Codes: G16B 20/40 Population genetics; Linkage disequilibrium
• CPC Class Codes: G16B 25/00 ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
• CPC Class Codes: G16B 30/00 ICT specially adapted for sequence analysis involving nucleotides or amino acids
• CPC Class Codes: G16B 40/00 ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding

Abstract

A system and method for determining the genetic data for one or a small set of cells, or from fragmentary DNA, where a limited quantity of genetic data is available, are disclosed. Genetic data for the target individual is acquired and amplified using known methods, and poorly measured base pairs, missing alleles and missing regions are reconstructed using expected similarities between the target genome and the genome of genetically related subjects. In accordance with one embodiment of the invention, incomplete genetic data is acquired from embryonic cells, fetal cells, or cell-free fetal DNA isolated from the mother'"'"'s blood, and the incomplete genetic data is reconstructed using the more complete genetic data from a larger sample diploid cells from one or both parents, with or without genetic data from haploid cells from one or both parents, and/or genetic data taken from other related individuals.

Claims

1. A method for determining genetic data for DNA from a first individual in a biological sample of a second individual, the method comprising:

amplifying a plurality of polymorphic loci on cell-free DNA extracted from the biological sample to generate amplified products;

measuring an amount of the amplified products by sequencing-by-synthesis to obtain genetic data at the plurality of polymorphic loci;

determining the most likely genetic data for DNA from the first individual based on allele frequencies in the genetic data at the plurality of polymorphic loci.

2. The method of claim 1, wherein the polymorphic loci are SNP loci.

3. The method of claim 1, wherein the polymorphic loci are on a plurality of chromosomes.

4. The method of claim 1, wherein the amplifying comprises targeted PCR.

5. The method of claim 1, wherein the amplifying comprises targeted PCR and universal PCR.

6. The method of claim 1, wherein the sequencing-by-synthesis comprises clonal amplification of the amplified products and measurement of sequences of the clonally amplified DNA.

7. The method of claim 1, wherein the biological sample is a blood sample.