Apparatus, Method, and System for Creating Phylogenetic Tree

Patent metadata

Field	Value
Publication number	US-2016357902-A1
Application number	US-201615072671-A
Country	US
Kind code	A1
Filing date	Mar 17, 2016
Priority date	Jun 3, 2015
Publication date	Dec 8, 2016
Grant date	—

Abstract

According to the present invention, a phylogenetic tree can be created on the basis of frequency data regarding a large number of mutations detected from the samples of a cancer. Each sample to be analyzed contains a mixture of plural clones having different genomes. Mutations having about the same frequencies are grouped to make plural groups, and an analysis is executed based on data listing the mutation frequencies of individual groups (called mutation group frequency data). It is assumed that pairs of clones corresponding respectively to mutation groups such that frequencies of one group is equal to or greater than that of another in all the samples have parent-child relations, and a graph structure having the clones as vertices and the parent-child relations as edges is created. In this graph, parent-child relations contradictory to the mutation group frequency data are removed, and a clone to become a parent is selected in consideration of correlation coefficients among the mutation group frequencies in the samples.

First claim

What is claimed is:

1 . A phylogenetic tree creation apparatus comprising: a graph creation section; a parent-child relation determination section; and an input section for inputting mutation group frequency data,
wherein, in the case where there is a plurality of samples each of which contains a mixture of a plurality of clones having different genomes, mutations having about the same frequencies are grouped into one group to make a plurality of groups, and data listing the frequencies of individual groups is referred to as the mutation Group frequency data, wherein the graph creation section creates a parent-child graph, which is a graph where vertices are set to the clones and edges are set to candidates for parent-child relations on the basis of the mutation group frequency data; and wherein the parent-child relation determination section selects clones to become parents of the clones in consideration of correlation coefficients showing correlations among the mutation group frequencies in the plurality of samples, and creates a phylogenetic tree for the plurality of clones.

2 . The phylogenetic tree creation apparatus according to claim 1 ,
wherein the parent-child relation determination section selects pairs of clones corresponding respectively to mutation groups such that the frequency of one group is always equal to or greater than the corresponding frequency of another group in all the plurality of samples as candidates for a parent-child relation of two clones.

3 . The phylogenetic tree creation apparatus according to claim 1 , further comprising a shortcut elimination section,
wherein the shortcut elimination section removes candidates for parent-child relations that are contradictory to the mutation group frequency data in the parent-child graph, after the graph creation section creates the parent-child relations and before the processing of the parent-child relation determination section is performed.

4 . The phylogenetic tree creation apparatus according to claim 3 ,
wherein, in the case where a plurality of candidates for parent clones in the parent-child relations (u) still remain after the elimination of parent-child relations executed by the shortcut elimination section, the parent-child relation determination section selects a candidate that is most likely a parent among the plurality of the candidates, and creates the phylogenetic tree using the selected candidate.

5 . The phylogenetic tree creation apparatus according to claim 1 ,
wherein, the apparatus takes as input the mutation co-occurrence data which contain a judgment whether a pair of mutations in the samples occurs in the same cell or not as well as an evidence and a reliability for the judgment; and wherein the parent-child relation determination section selects the pair of clones as a candidate for the parent-child relation on the basis of the mutation co-occurrence data.

6 . The phylogenetic tree creation apparatus according to claim 1 ,
wherein, in order to select a pair of two clones (clones u and v) that is a candidate for the parent-child relation, a parent candidate score s(u, v) that is defined by Expression (1) is calculated in the parent-child relation determination section,
s ( u, v )= e ( u, v )+ c ( u, v )+ r ( u, v )   (1)

wherein e(u, v) is a nonzero value if the parent-child relation of the clones u and v are backed up by fluorescence hybridization, c(u, v) is a nonzero value if the parent-child relation of the clones u and v is backed up by mutations that co-occur on the same sequence, and this can be confirmed, r(u, v) is a correlation coefficient among the mutation group frequencies in the plurality of samples, and wherein, a clone u that gives the maximum value to the parent candidate score is selected as a parent of the clone v.

7 . The phylogenetic tree creation apparatus according to claim 6 ,
wherein the phylogenetic tree creation apparatus creates a phylogenetic tree for clones on the basis of samples of a cancer; inputs mutation co-occurrence data, which is obtained using fluorescence hybridization, from a plurality of samples of tissues including cells of the cancer in order to check the presence or absence of the co-occurrence regarding e(u, v) of Expression (1); and inputs mutation co-occurrence data which is obtained from sequence data obtained using the NGS analysis regarding c(u, v).

8 . The phylogenetic tree creation apparatus according to claim 7 , further comprising a memory section for storing the mutation group frequency data, the mutation co-occurrence data and the phylogenetic tree regarding samples of cancer cells such that each of the samples contains a mixture of a plurality of clones having different genomes,
wherein the mutation co-occurrence data contains data for confirming the presence or absence of the co-occurrence of the pair of mutations, in which a judgment whether a pair of mutations occurs in the same cell or not as well as the evidence and the reliability for the judgment is recorded.

9 . The phylogenetic tree creation apparatus according to claim 8 ,
wherein the nonzero value of e(u, v) in Expression (1) is a value obtained by multiplying a parameter E that is given in advance and recorded in the memory section by the reliability, and in the case where there is information about a plurality of mutations regarding the clones u and v, a general reliability obtained in consideration of all the reliabilities of pieces of information about the plurality of mutation pairs is used as the reliability.

10 . The phylogenetic tree creation apparatus according to claim 8 ,
wherein the memory section holds information of NGS sequences obtained from the samples of the cancer cells, and c(u, v) in Expression (1) is set to the nonzero value in the case where there are mutations that belong to u and v on the same NGS sequence, and it can be presumed that the mutation belonging to the clone u is surely included in a cell having the mutation belonging to the clone v by referring to the sequence, and otherwise is set to zero.

11 . A method for creating a phylogenetic tree for clones, comprising the steps of:
reading mutation group frequency data as input data, wherein, in the case where there is a plurality of samples each of which contains a mixture of a plurality of clones having different genomes, mutations having about the same frequencies are grouped into one group to make a plurality of groups, and data listing the frequencies of individual groups is referred to as the mutation group frequency data; creating a parent-child graph in the case where a graph structure in which vertices are set to the clones are and edges are set to candidates for parent-child relations on the basis of the mutation group frequency data is referred to as the parent-child graph; selecting clones to become parents of the individual clones in consideration of correlation coefficients showing correlations among the mutation group frequencies in the plurality of samples; and creating a phylogenetic tree for the plurality of clones.

12 . A system for creating a phylogenetic tree for clones, comprising: a graph creation section; a shortcut elimination section; a parent-child relation determination section; and a memory section,
wherein, in the case where there is a plurality of samples each of which contains a mixture of a plurality of clones having different genomes, mutations having about the same frequencies are grouped into one group to make a plurality of groups, data listing the frequencies of individual groups is referred to as mutation group frequency data; the graph creation section creates the parent-child graph; an

Assignees

• Hitachi Ltd

Inventors

• Yasuda Tomohiro

Classifications

• G16B99/00

  Subject matter not provided for in other groups of this subclass · CPC title

• G16B10/00 Primary

  ICT specially adapted for evolutionary bioinformatics, e.g. phylogenetic tree construction or analysis · CPC title

• G06F19/14 Primary

  Physics · mapped topic