1. A method for synchronizing stream records between devices of a bearer control layer and a bearer layer, comprising:
returning, by a bearer layer device, a stream record corresponding to a stream synchronization request sent from a resource manager (RM), to the RM on the bearer control layer in response to the stream synchronization request sent from the RM; and
comparing, by the RM, a stream record stored in the RM with the stream record returned from the bearer layer device; and
performing, by the RM, a stream synchronization process on to-be-synchronized information in the bearer layer device in accordance with a comparison result;
wherein the process of performing the stream synchronization process by the RM comprises:
receiving, by the RM, the stream record corresponding to the stream synchronization request sent from the RM, returned from the bearer layer device,
searching stream records stored in the RM for the stream record returned from the bearer layer device, and
if the stream record returned from the bearer layer device is absent in the stream records stored in the RM, instructing the bearer layer device to delete the stream record absent in the stream records stored in the RM and returned from the bearer layer device;
if the stream record returned from the bearer layer device is present in the stream records stored in the RM, comparing the stream record stored in the RM with the stream record returned from the bearer layer device, and if the stream record stored in the RM and the stream record returned from the bearer layer device are inconsistent, sending the inconsistent stream record stored in the RM to the bearer layer device and instructing the bearer layer device to update the inconsistent stream record stored in the bearer layer device.
2. The method according to claim 1, wherein the process of returning by the bearer layer device the corresponding stream record to the RM comprises:
sending, by the RM, the stream synchronization request in a stream synchronization request message to the bearer layer device; and
returning, by the bearer layer device, the stream record corresponding to the stream synchronization request sent from the RM, to the RM in response to the stream synchronization request.
3. The method according to claim 1, wherein the process of returning by the bearer layer device the corresponding stream record to the RM comprises:
sending, by the RM, to the bearer layer device the stream synchronization request in a stream synchronization request message carrying flag information of a stream table entry to be synchronized; and
checking, by the bearer layer device, to determine whether a stream record carrying the flag information is present, and if there is no stream record carrying the flag information, returning an end message to the RM; if the stream record carrying the flag information is present, selecting and returning the stream record carrying the flag information to the RM.
4. The method according to claim 1, wherein the process of returning by the bearer layer device the stream record corresponding to the stream synchronization request sent from the RM, to the RM comprises:
sending, by the RM, to the bearer layer device a policy dispatch message carrying the to-be-synchronized information; and
returning, by the bearer layer device, the stream record corresponding to the to-be-synchronized information, to the RM in response to the to-be-synchronized information.
5. The method according to claim 1, wherein the process of returning by the bearer layer device the stream record corresponding to the stream synchronization request sent from the RM, to the RM comprises:
sending, by the RM, to the bearer layer device a policy dispatch message carrying the to-be-synchronized information, the to-be-synchronized information carrying flag information of a stream table entry to be synchronized; and
checking, by the bearer layer device, to determine whether a stream record carrying the flag information is present, and if there is no stream record carrying the flag information, returning an end message to the RM; if the stream record carrying the flag information is present, selecting and returning the stream record carrying the flag information to the RM.
6. The method according to claim 2, wherein the process of returning by the bearer layer device the stream record corresponding to the stream synchronization request sent from the RM, to the RM further comprises:
returning, by the bearer layer device, an end message to the RM after returning the stream record corresponding to the stream synchronization request sent from the RM, to the RM; and
determining, by the RM, an end of returning the stream record corresponding to the stream synchronization request sent from the RM, from the bearer layer device in accordance with the received end message.
7. The method according to claim 1, further comprising:
performing, by the bearer layer device, a deletion or update process in response to the received instruction, and returning processing result information to the RM.
8. The method according to claim 7, further comprising:
receiving, by the RM, the processing result information returned from the bearer layer device, if it is determined from the processing result information that the bearer layer device has synchronized the stream record absent in the stream record in the RM or the stream record inconsistent with the stream record in the RM successfully, ending the synchronization process; if it is determined from the processing result information that the bearer layer device has not synchronized stream record absent in the stream record in the RM or the stream record inconsistent with the stream record in the RM successfully, continuing with sending a new stream synchronization request to the bearer layer device.
9. A system for synchronizing stream records between devices of a bearer control layer and a bearer layer, comprising a bearer layer device and a resource manager (RM), wherein the RM comprises a request module and a determination module and the bearer layer device comprises a response module and a synchronization processing module; wherein
the request module is configured to send a stream synchronization request to the bearer layer device;
the response module is configured to return a stream record corresponding to the stream synchronization request sent from the request module, to the RM in response to the stream synchronization request sent from the request module;
the determination module is configured to compare the stream record returned from the response module with a stream record stored in the RM and to instruct the bearer layer device to perform a stream synchronization process on to-be-synchronized information in accordance with a comparison result; and
the synchronization processing module is configured to perform the stream synchronization process on the to-be-synchronized information in the bearer layer device in accordance with the instruction from the determination module;
wherein when the stream synchronization request sent from the request module comprises flag information of a to-be-synchronized stream record, the response module returns a stream record corresponding to the flag information to the RM in accordance with the received flag information of the stream record; and when the stream synchronization request sent from the request module comprises no flag information of the to-be-synchronized stream record, the response module returns all stream records stored in the response module to the RM;
wherein upon determining that the stream record returned from the response module is absent in the stream records stored in the RM, the determination module instructs the synchronization processing module to delete the stream record absent in the stream records stored in the RM; and upon determining that the stream record returned from the response module is present in the stream records stored in the RM, the determination module compares the stream record returned from the response module with the stream record stored in the RM, and if the stream record stored in the RM and the corresponding stream record returned from the bearer layer device are inconsistent, the determination module sends the inconsistent stream record to the synchronization processing module and instructs the synchronization processing module to update the stream record corresponding to the inconsistent stream record.
10. The system according to claim 9, wherein the response module returns an end message to the RM after returning the stream record corresponding to the stream synchronization request sent from the request module, to the RM, and the response module returns the end message to the RM upon determining that the flag information of the stream record sent from the request module is absent in the stream records stored in the bearer layer device.
11. The system according to claim 9, wherein the synchronization processing module returns processing result information to the RM at the end of the synchronization process, and the request module receives the processing result information returned from the bearer layer device and if it is determined from the processing result information that the bearer layer device has synchronized the stream record absent in the stream record in the RM or the stream record inconsistent with the stream record in the RM successfully, ends the synchronization process; if it is determined from the processing result information that the bearer layer device has not synchronized the stream record absent in the stream record in the RM or the stream record inconsistent with the stream record in the RM successfully, the request module continues with sending a new stream synchronization request.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method of karyotyping a human target cell to detect chromosomal imbalance therein, the method comprising:
(a) interrogating closely adjacent biallelic SNPs across the chromosome of the target cell
(b) comparing the result at (a) with the SNP haplotype of paternal and maternal chromosomes to assemble a notional haplotype of target cell chromosomes of paternal origin and of maternal origin
(c) assessing the notional SNP haplotype of target cell chromosomes of paternal origin and of maternal origin to detect aneuploidy of the chromosome in the target cell,
wherein the notional SNP haplotype of the target cell chromosomes of paternal origin and of maternal origin is assembled in step (b) using:
(i) informative SNP alleles that positively identify from which one of the four paternal and maternal chromosomes a chromosome in the target cell has originated, or positively identify from which paternal chromosome and which maternal chromosome a pair of chromosomes in the target cell has originated, and optionally
(ii) semi-informative SNP alleles that Positively identify from which of two possible combinations of the four possible pair-wise combinations of paternal and maternal chromosomes a pair of chromosomes in the target cell has originated.
2. (canceled)
3. A method as claimed in claim 1 wherein:
(i) at least 2, 3, 4, 5, 6, or 7 of the chromosomes selected from the group consisting of: X, Y, 22, 21, 18, 16 and 13 are interrogated, or
(ii) all 24 chromosomes are interrogated.
4.-6. (canceled)
7. A method as claimed in claim 1 wherein aneuploidy of the chromosome in the target cell is detected in step (c) by:
(c1) assessing the notional SNP haplotype of target cell chromosomes of paternal origin and of maternal origin and thereby assigning each chromosome as recombinant or non-recombinant and\\or present in 0, 1, or more copies,
(c2) deducing aneuploidy of the chromosome in the target cell wherein step (c1) indicates an imbalance of chromosomes of paternal origin and of maternal origin.
8. A method as claimed in claim 1 wherein a chromosome in the target cell is identified as non-recombinant wherein the results of its notional SNP haplotype are consistent with:
(i) its SNP alleles being identical to the SNP alleles of one of the two paternal chromosomes or one of the two maternal chromosomes along the length of the chromosome, and
(ii) an absence of the SNP alleles of the alternative of the two paternal or maternal chromosomes, and wherein a chromosome in the target cell is identified as recombinant wherein the results of its notional SNP haplotype correspond to SNP alleles of both of the two paternal chromosomes or two maternal chromosomes in one or more alternating segments consistent with normal recombination between the two chromosomes.
9. (canceled)
10. A method as claimed in claim 1 wherein the notional SNP haplotype of target cell chromosomes indicates the presence of both of the two paternal chromosomes or two maternal chromosomes in a pattern and\\or frequency inconsistent with normal recombination between the two chromosomes, the cell is deduced to be trisomic for all or part of the relevant chromosome or chromosome segment.
11. A method as claimed in claim 10 wherein consistency with normal recombination is assessed based on the statistical likelihood of normal recombination between particular adjacent, informative SNP alleles of the two paternal chromosomes or two maternal chromosomes during the first meiotic division, and wherein the statistical likelihood is assessed based on one or more of the following criteria:
(i) the average number of recombination events for the specific paternal or maternal chromosome,
(ii) distance between apparent recombination events on each chromosome arm, and their position relative to each other, the centromere and the telomere.
12.-13. (canceled)
14. A method as claimed in claim 1 wherein the notional SNP haplotype of target cell chromosomes indicates
(i) the presence of one chromosome of paternal origin and one chromosome of maternal origin and the cell is deduced to be normal diploid in respect of the relevant chromosome, or indicates
(ii) an absence of any chromosome or chromosome segment of paternal origin and maternal origin, the cell is deduced to be nullsomic for the relevant chromosome or chromosome segment, or indicates
(iii) an absence of a chromosome or chromosome segment of either paternal origin or maternal origin but not both, the cell is deduced to be monosomic for the relevant chromosome or chromosome segment.
15.-16. (canceled)
17. A method as claimed in claim 1 wherein the average distance between the interrogated SNPs is less than 0.1, 0.2, 0.3, 0.4 or 0.5 kb or less than 0.1, 0.2, 0.3, 0.4 or 0.5 cM.
18. (canceled)
19. A method as claimed in claim 1 further comprising the step of quantitation of interrogated SNP alleles.
20. A method as claimed in claim 1 further comprising:
(i) diagnosing the presence of an inherited genetic disease in the target cell by comparing the notional SNP haplotype of the target cell with the SNP alleles of the paternal chromosomes and the maternal chromosomes and one or more affected siblings to diagnose the disease in the target cell by linkage and\\or
(ii) diagnosing susceptibility to a common disease or cancer in the target cell by comparing the notional SNP haplotype with a haplotype known to be associated with said disease.
21. (canceled)
22. A method as claimed in claim 1 wherein the SNP haplotype of paternal and maternal chromosomes is derived from analysis of the SNP haplotype of cells removed from sibling fertilized embryos following in vitro fertilisation (IVF) following whole genome amplification or from analysis of multiple single parental haploid gametes following whole genome amplification.
23. (canceled)
24. A method as claimed in claim 1 wherein the target cell has been provided from a mammalian embryo which has optionally resulted from IVF and is optionally a Pre-implantation embryo.
25.-26. (canceled)
27. A method as claimed in claim 1 wherein a number equal to 1, 2, 3, 4, or 5 target cells are provided and tested.
28. A method as claimed in claim 1 wherein SNP interrogation is preceded by whole genome amplification.
29. (canceled)
30. A method as claimed in claim 1 wherein the SNP interrogation is performed by means of an oligonucleotide chip.
31. A computer-usable medium having computer-readable program code stored thereon for causing a computer to execute a method to determine aneuploidy or chromosomal recombination in a target cell, which method is the method of claim 1.
32. A computer-usable medium having computer-readable program code stored thereon for causing a computer to execute a method to determine aneuploidy or chromosomal recombination in a target cell, which method comprises:
(a) accessing a database comprising genotype data obtained from a plurality of closely adjacent biallelic SNP loci present in a chromosome of the target cell,
(b) accessing a database comprising SNP haplotype data of the corresponding paternal and maternal chromosomes,
(c) comparing target cell SNP data from the database of step (a) with SNP haplotype data from the database of step (b) to assemble a notional haplotype of regions of the target cell chromosomes of paternal origin and of maternal origin,
(d) assessing the notional SNP haplotype of target cell chromosomes of paternal origin and of maternal origin to determine aneuploidy or chromosomal recombination of the chromosome in the target cell.
33. A computer-usable medium as claimed in claim 32 wherein each SNP locus of the \u2018x\u2019 SNPs of the database in step (b) is assigned a value \u2018n\u2019 in accordance with which of the 16 combinations of four parental SNP alleles is present at that locus, and wherein step (c) comprises assembling a notional haplotype at that locus by comparing:
(i) the genotype data for the biallelic SNP at that locus from the database of step (a) and,
(ii) the value \u2018n\u2019 at that locus from the database of step (b) with,
(iii) a chromosomal origin table,
and thereby assigning the locus of the target cell chromosomes as originating from a paternal or maternal chromosome.
34. A computer-usable medium as claimed in claim 32 wherein the notional SNP haplotype of regions of the target cell chromosomes of paternal origin and of maternal origin is assembled using a subset of the \u2018x\u2019 SNP loci from the database in step (b), which subset consists of:
(i) informative SNP alleles that positively identify which one of the four paternal and maternal chromosomes, a chromosome in the target cell has originated from, or positively identify which paternal chromosome and which maternal chromosome a pair of chromosomes in the target cell have originated from, and optionally
(ii) semi-informative SNP alleles that positively identify which of two possible combinations of the four possible pair-wise combinations of paternal and maternal chromosomes, a pair of chromosomes in the target cell has originated from, wherein a threshold number of positive and negative informative and optionally semi-informative SNPs is set, and a karyotype is determined only when this number is exceeded.
35.-37. (canceled)
38. A computer-usable medium as claimed in claim 32 wherein the chromosome in the target cell is identified as non-recombinant wherein the results of its notional SNP haplotype are consistent with:
(i) its SNP alleles being identical to the SNP alleles of one of the two paternal chromosomes or one of the two maternal chromosomes along the length of the chromosome, and
(ii) an absence of the SNP alleles of the alternative of the two paternal or maternal chromosomes, and wherein the chromosome in the target cell is identified as recombinant wherein the results of its notional SNP haplotype correspond to SNP alleles of both of the two paternal chromosomes or two maternal chromosomes in one or more alternating segments consistent with normal recombination between the two chromosomes.
39. (canceled)
40. A computer-usable medium as claimed in claim 32 wherein:
(i) the chromosome in the target cell is identified as trisomic for the chromosome where the notional SNP haplotype of the target cell chromosome indicates the presence of both of the two paternal chromosomes or two maternal chromosomes in a pattern and\\or frequency inconsistent with normal recombination between the two chromosomes;
(ii) the chromosome in the target cell is identified as nullsomic for the chromosome where the notional SNP haplotype of target cell chromosome indicates an absence of the chromosome or a segment thereof of both paternal origin and maternal origin; or
(iii) the chromosome in the target cell is identified as monosomic for the chromosome where the notional SNP haplotype of the target cell chromosome indicates an absence of the chromosome or a segment thereof of paternal origin and maternal origin but not both.
41.-45. (canceled)
46. A system for karyotyping a target cell to detect chromosomal imbalance therein, the system comprising:
(i) means for interrogating closely adjacent biallelic SNPs across the chromosome of the target cell, which is an oligonucleotide chip, and
(ii) a computer programmed to execute a method as claimed in claim 1.
47.-49. (canceled)
50. A system for karyotyping a target cell to detect chromosomal imbalance therein, the system comprising:
(i) means for interrogating closely adjacent biallelic SNPs across the chromosome of the target cell, which is an oligonucleotide chip, and
(ii) a computer programmed with the computer-usable medium as claimed in claim 31.