Methods and systems for predicting effect of genomic variation on pre-mRNA splicing

A genome and gene transcription technology, applied in the fields of genomics, proteomics, instruments, etc., can solve problems such as hindering accurate prediction, time-consuming labor intensity, etc.

Pending Publication Date: 2020-01-14
TATA CONSULTANCY SERVICES LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Wet lab techniques are time-consuming and labor-intensive, while existing computational models involving support v

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  • Methods and systems for predicting effect of genomic variation on pre-mRNA splicing
  • Methods and systems for predicting effect of genomic variation on pre-mRNA splicing
  • Methods and systems for predicting effect of genomic variation on pre-mRNA splicing

Examples

Experimental program
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Effect test

Embodiment 1

[0044] Example 1 - OTC: In one embodiment, a mutation in intron 9 was detected in a Clinvar-based variant screen of the ornithine carbamoyltransferase encoding gene (OTC) as a site for disrupting the canonical splice acceptor Body C>G. An alternative splice acceptor site (MaxEnt: 8.30) was identified 25 bases downstream of the canonical splice acceptor junction (in the exonic region). A canonical branch point (score: 2.80), 29 bases upstream of the identified cryptic splice acceptor, was considered suitable. The inactivation of the canonical splice acceptor and the activation of the cryptic acceptor site have been verified experimentally with the help of PCR, and it has been demonstrated that the resulting deviation in splicing leads to an abnormal 50-amino C-terminal sequence in the protein, resulting in a hyperammonia Acid hormone crisis (hyperammoneamic crisis). The values ​​corresponding to OTC are shown in Table 1.

Embodiment 2

[0045] Example 2 - MAN2B1: In another embodiment, a T>C transition was found in intron 14 of the mannosidase alpha class 2B member 1 gene (MAN2B1), disrupting the canonical splice acceptor site. A cryptic branch site is activated upon loss of the canonical splice acceptor, and activation of the cryptic splice acceptor 31 nt downstream of the canonical 3' splice site also occurs (MaxEnt: 4.78), resulting in the first 31 nt of exon 15 The deletion of , resulting in a frameshift mutation due to the introduction of a stop codon, results in a premature termination of the protein (Table 1). With the aid of RT-PCR, disruption of the canonical 3' splice acceptor site and activation of cryptic splice sites leading to partial exon deletions have been demonstrated. In conclusion, the analytical method shows the potential to reveal one of the causes of α-mannosidase deficiency.

[0046]

[0047] Table 1

[0048] Experiments reveal some cases of discovery. In this paper, the reasons ...

Embodiment 3

[0049] Example 3 - Alanine-glyoxylate and serine-pyruvate transaminases (AGXT): In an exemplary embodiment, an A>G mutation was found in intron 5 by screening for AGXT gene variants. Because the variant is located at a canonical splice acceptor site, it was previously classified as a splice-site mutation, although the role of the variant and its specific impact on splicing bias has not been defined. As a result of the mutation (MaxEnt: 4.01 > -3.94), the canonical splice acceptor site for intron 5 was disrupted. Due to disruption of the natural splice acceptor site, a cryptic splice acceptor site (MaxEnt: 5.01) 28 nucleotides downstream of the canonical splice acceptor site was activated. In addition, when screening for suitable branch sites for cryptic splice acceptors, potential branch sites were found, namely 35 bases upstream of the cryptic splice acceptor site. In summary, on the basis of the proposed model, it can be observed that due to the mutation, the original splic...

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Abstract

The present disclosure relates generally to methods and systems for predicting the effect of genomic variation on pre-mRNA splicing. The method comprises the following steps of: receiving genome position information of at least one candidate variant of a gene transcript and coordinate information of the gene transcript; based on the coordinate information of the gene transcript and the genome position information of the at least one candidate variant, and classifying the at least one candidate variant into one of a clipped accepted position point region and a branched position point region; evaluating the effect of the at least one candidate variant on the pre-mRNA splicing based on the classification region from the classification of the at least one candidate variant; and predicting thepathogenicity of the at least one candidate variant based on the evaluated effect of the at least one candidate variant on the pre-mRNA splicing.

Description

[0001] Cross References and Priority to Related Applications [0002] This application claims priority to the complete Indian specification of Application No. 201821025433 entitled "System and method for predicting the effect of genomic variation on pre-mRNA splicing" filed in India on 7th July 2018. technical field [0003] The disclosure herein relates generally to mRNA splicing, and more specifically, to predicting the effect of genomic variation on pre-mRNA splicing. Background technique [0004] RNA splicing is the process of cleaving introns (introns) from a pre-mRNA and stitching them together with exons to form the final nucleotide sequence, which is the mRNA sequence that codes for a protein. In this regard, branch point (BP) selection and splice site (SS) selection are key steps in RNA splicing, but many popular splicing analysis tools do not model this mechanism. If there is a mutation near a major branch point of an intron, that branch point may become unusable....

Claims

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Application Information

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IPC IPC(8): G16B30/00
CPCG16B30/00G16B20/20G16B30/10
Inventor R·斯里尼瓦桑A·然P·乔杜里
Owner TATA CONSULTANCY SERVICES LTD
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