US 2024/0404628 A1 · METHODS TO DETERMINE MATERNITY, PATERNITY, OR PARENTAGE AND COMPUTER SYSTEMS FOR IMPLEMENTATION THEREOF

Abstract

The subject invention pertains to the field of healthcare informalities and provides information and communication (ICT) technology useful for methods and tools for paternity and/or maternity testing. An analytical pipeline based on low-pass GS (e.g., 1-fold read depth), referred to herein as LpPat, is provided for paternity and/or maternity testing (e.g., with trio-based and duo-based analytical modes). By down-sampling the read-depth from 10 trios with confirmed paternity and maternity, an optimal read depth of 1-fold is demonstrated across other sequencing parameters with a turnaround time for the analysis of less than one hour. The robust performance has been validated by another 170 trios sequenced from different library construction methods and platforms. The algorithmic analysis provides a rapid, cost effective, and sequencing-platform-neutral paternity and/or maternity test, based on low-pass genetic sequencing.

A method to determine paternity, maternity, or parentage of a subject, the method comprising:

(i) aligning sequence reads from low-pass genome sequencing data equivalent to 1-fold or more read-depth of genomic DNA of biological samples to a human genome reference according to an aligned chromosome and one or more genomic coordinates yielding a respective aligned sequence read;
(ii) identifying a multiplicity of single-nucleotide variants (SNVs) in each respective aligned sequence read, wherein an SNV at each site has a mutant base type different from a base type at a corresponding site from a human genome reference;
(iii) identifying a number of homozygous SNVs and a number of diploid heterozygous SNVs from the multiplicity of SNVs identified in step (ii), wherein a homozygous SNV is identified as an SNV where a percentage of sequence reads supporting the mutant base type different from the base type at the corresponding site from the human genome reference is 100%, and a diploid heterozygous SNV is identified as an SNV where the percentage of sequence reads supporting the mutant base type different from the base type at the corresponding site from the human genome reference is at least about 25% and less than about 75%;
and
(iv) determining an inconsistent rate of base-type inheritance from a number of homozygous SNVs and a number of diploid heterozygous SNVs identified in step (iii) for two analytical models comprising a trio-based analysis model comprising a proband and two parents, a mother and a father;
and a duo-based analysis model comprising a proband and one parent, a mother or a father, wherein:
for the trio-based analysis, (a) a number of loci that both the mother and the father are in homozygous alignment but with different genotypes in the i-th chromosome is denoted as Ai;
(b) among the members denoted in (a), the number of SNVs that are homozygous in the proband but with different genotypes from the presumed father is denoted as pi for a paternity test and the number of SNVs that are homozygous in the proband but with different genotypes from the presumed mother is denoted as mi:
for a maternity test;
(c) the inconsistent rate of paternal inheritance αi in chromosome i is calculated based on formula (1), and the inconsistent rate of maternal inheritance βi in chromosome i is calculated based on formula (2);
α
⁢
i
=
pi
Ai
(
1
)
β
⁢
i
=
mi
Ai
(
2
)
(d) the paternity is determined by using an average rate λpat across all autosomal chromosomes based on formula (3), and the maternity is determined by using an average rate λmat across all autosomal chromosomes based on formula (4);
λ
_
⁢
pat
=
∑
i
=
1
n
=
22
⁢
α
⁢
i
22
(
3
)
λ
_
⁢
mat
=
∑
i
=
1
n
=
22
⁢
β
⁢
i
22
(
4
)
for duo-based analysis, (a) the number of homozygous SNVs in both proband and the presumed parent in chromosome i is denoted Adi;
(b) among the members denoted in (a), the number of homozygous SNVs that are with different genotypes between the proband and the presumed parent is denoted as qi;
(c) the inconsistent rate γi of parental inheritance in chromosome i is calculated based on formula (5);
γ
⁢
i
=
qi
Adi
(
5
)
(d) the respective paternity or maternity is determined using an average rate λparent across all autosomal chromosomes based on formula (6);
λ
_
⁢
parent
=
∑
i
=
1
n
=
22
⁢
γ
⁢
i
22
(
6
)
for determining the paternity, maternity, or parentage.

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Methods to determine maternity, paternity, or parentage and computer systems for implementation thereof

Life of this patent

Methods to determine maternity, paternity, or parentage and computer systems for implementation thereof

Life of this patent

Abstract

Claims20