IP Library › Granted Patent US 12,444,482
Granted Patent B2
US 12,444,482 · App. 17/703,935 · Granted Oct 14, 2025

Multi-channel protein voxelization to predict variant pathogenicity using deep convolutional neural networks

Inventors: Tobias Hamp (Cambridge, GB); Kai-How Farh (Hillsborough, CA); Hong Gao (Palo Alto, CA)
Assignee: Illumina, Inc.
G16B40/20G06N3/044G06N3/045G16B15/20G16B20/20G16B30/00
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Quick Facts
Patent No.
US 12,444,482
App. No.
17/703,935
Granted
Oct 14, 2025
Kind
B2
Abstract

A system includes at least a voxelizer, an alternative allele encoder, an evolutionary conservation encoder, and a convolutional neural network. The voxelizer accesses a three-dimensional structure of a reference amino acid sequence of a protein and fits a three-dimensional grid of voxels on atoms in the three-dimensional structure on an amino acid-basis to generate amino acid-wise distance channels. The alternative allele encoder encodes an alternative allele sequence to each voxel in the three-dimensional grid of voxels. The evolutionary conservation encoder encodes an evolutionary conservation sequence to each voxel in the three-dimensional grid of voxels. The convolutional neural network applies three-dimensional convolutions to a tensor that includes the amino acid-wise distance channels encoded with the alternative allele sequence and respective evolutionary conservation sequences and determines a pathogenicity of a variant nucleotide based at least in part on the tensor.

Claims (60)

1. A system including memory and one or more processors operable to execute instructions, stored in the memory, to perform operations comprising:

utilizing a voxelizer to access a three-dimensional structure of a reference amino acid sequence of a protein, and fits a three-dimensional grid of voxels on atoms in the three-dimensional structure on an amino acid-basis to generate amino acid-wise distance channels,

wherein each of the amino acid-wise distance channels has a three-dimensional distance value for each voxel in the three-dimensional grid of voxels, and

wherein the three-dimensional distance value specifies a distance from a corresponding voxel in the three-dimensional grid of voxels to atoms of a corresponding reference amino acid in the reference amino acid sequence;

utilizing an alternative allele encoder to encode an alternative allele amino acid to each voxel in the three-dimensional grid of voxels,

wherein the alternative allele amino acid is a three-dimensional representation of a one-hot encoding of a variant amino acid expressed by a variant nucleotide;

utilizing an evolutionary conservation encoder to encode an evolutionary conservation sequence to each voxel in the three-dimensional grid of voxels,

wherein the evolutionary conservation sequence is a three-dimensional representation of amino acid-specific conservation frequencies across a plurality of species, and

wherein the amino acid-specific conservation frequencies are selected in dependence upon amino acid proximity to the corresponding voxel; and

utilizing a tensor generator to generate a tensor that includes the amino acid-wise distance channels encoded with the alternative allele amino acid and respective evolutionary conservation sequences.

2. A system including memory and one or more processors operable to execute instructions, stored in the memory, to perform operations comprising:

utilizing a voxelizer to access a three-dimensional structure of a reference amino acid sequence of a protein, and fits a three-dimensional grid of voxels on atoms in the three-dimensional structure on an amino acid-basis to generate atom category-wise distance channels,

wherein the atoms span a plurality of atom categories,

wherein atom categories in the plurality of atom categories specify atomic elements of the amino acids within the reference amino acid sequence,

wherein each of the atom category-wise distance channels has a three-dimensional distance value for each voxel in the three-dimensional grid of voxels, and

wherein the three-dimensional distance value specifies a distance from a corresponding voxel in the three-dimensional grid of voxels to atoms of corresponding atom categories in the plurality of atom categories;

utilizing an alternative allele encoder to encode an alternative allele amino acid to each voxel in the three-dimensional grid of voxels,

wherein the alternative allele amino acid is a three-dimensional representation of a one-hot encoding of a variant amino acid expressed by a variant nucleotide;

utilizing an evolutionary conservation encoder to encode an evolutionary conservation sequence to each voxel in the three-dimensional grid of voxels,

wherein the evolutionary conservation sequence is a three-dimensional representation of amino acid-specific conservation frequencies across a plurality of species, and

wherein the amino acid-specific conservation frequencies are selected in dependence upon amino acid proximity to the corresponding voxel; and

utilizing a tensor generator to generate a tensor that includes the atom category-wise distance channels encoded with the alternative allele amino acid and respective evolutionary conservation sequences.

3. The system of claim 1 , wherein the voxelizer centers the three-dimensional grid of voxels on an alpha-carbon atom of respective residues of reference amino acids in the reference amino acid sequence.

4. The system of claim 3 , wherein the voxelizer centers the three-dimensional grid of voxels on an alpha-carbon atom of a residue of a particular reference amino acid positioned at the variant amino acid.

5. The system of claim 4 , further configured to encode, in the tensor, a directionality of the reference amino acids in the reference amino acid sequence and a position of the particular reference amino acid by multiplying, with a directionality parameter, three-dimensional distance values for those reference amino acids that precede the particular reference amino acid.

6. The system of claim 5 , wherein the three-dimensional distance values correspond to nearest-atom distances from corresponding voxel centers in the three-dimensional grid of voxels to nearest atoms of corresponding reference amino acids in the reference amino acid sequence.

7. The system of claim 6 , wherein the reference amino acids have alpha-carbon atoms, wherein the three-dimensional distance values correspond to nearest-alpha-carbon atom distances from the corresponding voxel centers to nearest alpha-carbon atoms of corresponding reference amino acids in the reference amino acid sequence.

8. The system of claim 6 , wherein the reference amino acids have beta-carbon atoms, wherein the three-dimensional distance values correspond to nearest-beta-carbon atom distances from the corresponding voxel centers to nearest beta-carbon atoms of corresponding reference amino acids in the reference amino acid sequence.

9. The system of claim 6 , wherein the reference amino acids have backbone atoms, wherein the three-dimensional distance values correspond to nearest-backbone atom distances from the corresponding voxel centers to nearest backbone atoms of corresponding reference amino acids in the reference amino acid sequence.

10. The system of claim 6 , wherein the reference amino acids have sidechain atoms, wherein the three-dimensional distance values correspond to nearest-sidechain atom distances from the corresponding voxel centers to nearest sidechain atoms of corresponding reference amino acids in the reference amino acid sequence.

11. The system of claim 4 , further configured to encode, in the tensor, a nearest atom channel that specifies a distance from each voxel to a nearest atom, wherein the nearest atom is selected irrespective of the reference amino acids and atomic elements of the reference amino acids.

12. The system of claim 1 , further comprising a reference allele encoder that voxel-wise encodes a reference allele amino acid to each voxel in the three-dimensional grid of voxels.

13. The system of claim 12 , wherein the reference allele amino acid is a three-dimensional representation of a one-hot encoding of a reference amino acid that experiences the variant amino acid.

14. The system of claim 1 , wherein the amino acid-specific conservation frequencies specify conservation levels of respective amino acids across the plurality of species.

15. The system of claim 1 , further comprising an annotations encoder that voxel-wise encodes one or more annotation channels to each voxel in the three-dimensional grid of voxels, and

wherein the one or more annotation channels are three-dimensional representations of a one-hot encoding of residue annotations.

16. The system of claim 1 , further comprising a structure confidence encoder that voxel-wise encodes one or more structure confidence channels to each voxel in the three-dimensional grid of voxels, and

wherein the one or more structure confidence channels are three-dimensional representations of confidence scores that specify quality of respective residue structures.

17. The system of claim 1 , wherein the operations further comprise utilizing a convolutional neural network to apply three-dimensional convolutions to the tensor to determine a pathogenicity of the variant nucleotide.

18. The system of claim 2 , wherein the operations further comprise utilizing a convolutional neural network to apply three-dimensional convolutions to the tensor to determine a pathogenicity of the variant nucleotide.

19. A computer-implemented method comprising:

utilizing a voxelizer to access a three-dimensional structure of a reference amino acid sequence of a protein, and fits a three-dimensional grid of voxels on atoms in the three-dimensional structure on an amino acid-basis to generate amino acid-wise distance channels,

wherein each of the amino acid-wise distance channels has a three-dimensional distance value for each voxel in the three-dimensional grid of voxels, and

wherein the three-dimensional distance value specifies a distance from a corresponding voxel in the three-dimensional grid of voxels to atoms of a corresponding reference amino acid in the reference amino acid sequence;

utilizing an alternative allele encoder to encode an alternative allele amino acid to each voxel in the three-dimensional grid of voxels,

wherein the alternative allele amino acid is a three-dimensional representation of a one-hot encoding of a variant amino acid expressed by a variant nucleotide;

utilizing an evolutionary conservation encoder to encode an evolutionary conservation sequence to each voxel in the three-dimensional grid of voxels,

wherein the evolutionary conservation sequence is a three-dimensional representation of amino acid-specific conservation frequencies across a plurality of species, and

wherein the amino acid-specific conservation frequencies are selected in dependence upon amino acid proximity to the corresponding voxel; and

utilizing a tensor generator to generate a tensor that includes the amino acid-wise distance channels encoded with the alternative allele amino acid and respective evolutionary conservation sequences.

20. A non-transitory computer readable storage medium storing instructions executable by a processor to perform operations comprising:

utilizing a voxelizer to access a three-dimensional structure of a reference amino acid sequence of a protein, and fits a three-dimensional grid of voxels on atoms in the three-dimensional structure on an amino acid-basis to generate amino acid-wise distance channels,

wherein each of the amino acid-wise distance channels has a three-dimensional distance value for each voxel in the three-dimensional grid of voxels, and

wherein the three-dimensional distance value specifies a distance from a corresponding voxel in the three-dimensional grid of voxels to atoms of a corresponding reference amino acid in the reference amino acid sequence;

utilizing an alternative allele encoder to encode an alternative allele amino acid to each voxel in the three-dimensional grid of voxels,

wherein the alternative allele amino acid is a three-dimensional representation of a one-hot encoding of a variant amino acid expressed by a variant nucleotide;

utilizing an evolutionary conservation encoder to encode an evolutionary conservation sequence to each voxel in the three-dimensional grid of voxels,

wherein the evolutionary conservation sequence is a three-dimensional representation of amino acid-specific conservation frequencies across a plurality of species, and

wherein the amino acid-specific conservation frequencies are selected in dependence upon amino acid proximity to the corresponding voxel; and

utilizing a tensor generator to generate a tensor that includes the amino acid-wise distance channels encoded with the alternative allele amino acid and respective evolutionary conservation sequences.

Assignments (7)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 22, 2023
From: ILLUMINA CAMBRIDGE LIMITED
To: ILLUMINA, INC.
Reel/Frame 066124/0385 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 18, 2023
From: GAO, HONG
To: ILLUMINA, INC.
Reel/Frame 062406/0538 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 18, 2023
From: FARH, KAI-HOW
To: ILLUMINA, INC.
Reel/Frame 062406/0664 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 18, 2023
From: HAMP, TOBIAS
To: ILLUMINA CAMBRIDGE LIMITED
Reel/Frame 062406/0783 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 18, 2023
From: FARH, KAI-HOW
To: ILLUMINA, INC.
Reel/Frame 062407/0364 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 18, 2023
From: GAO, HONG
To: ILLUMINA, INC.
Reel/Frame 062407/0438 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 18, 2023
From: HAMP, TOBIAS
To: ILLUMINA CAMBRIDGE LIMITED
Reel/Frame 062407/0561 →
Continuity (3)
Provisional Application 63175767 · Apr 16, 2021
Provisional Application 63175495 · Apr 15, 2021
Related Publication 20220336056A1 · Oct 20, 2022
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