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Genetic Assays for Detecting Viral Recombination Rate

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Genetic Assays for Detecting Viral Recombination Rate (19) *EP003024948B1* (11) EP 3 024 948 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12Q 1/6827 (2018.01) C12Q 1/70 (2006.01) 15.01.2020 Bulletin 2020/03 (86) International application number: (21) Application number: 14829649.4 PCT/US2014/048301 (22) Date of filing: 25.07.2014 (87) International publication number: WO 2015/013681 (29.01.2015 Gazette 2015/04) (54) GENETIC ASSAYS FOR DETECTING VIRAL RECOMBINATION RATE GENETISCHE TESTS ZUR BESTIMMUNG EINER VIRALEN REKOMBINATIONSFREQUENZ DOSAGES GÉNÉTIQUES POUR DÉTERMINER UNE FREQUENCE DE LA RECOMBINATION VIRALE (84) Designated Contracting States: • A. D. TADMOR ET AL: "Probing Individual AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Environmental Bacteria for Viruses by Using GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Microfluidic Digital PCR", SCIENCE, vol. 333, no. PL PT RO RS SE SI SK SM TR 6038, 1 July 2011 (2011-07-01), pages 58-62, XP055344735, ISSN: 0036-8075, DOI: (30) Priority: 25.07.2013 US 201361858311 P 10.1126/science.1200758 -& A. D. TADMOR ET 01.11.2013 US 201361899027 P AL: "Probing Individual Environmental Bacteria for Viruses by Using Microfluidic Digital PCR - (43) Date of publication of application: Supporting Online Material", SCIENCE, vol. 333, 01.06.2016 Bulletin 2016/22 no. 6038, 30 June 2011 (2011-06-30), pages 1-48, XP055344921, ISSN: 0036-8075, DOI: (73) Proprietor: Bio-rad Laboratories, Inc. 10.1126/science.1200758 Hercules, CA 94547 (US) • K. MOTOMURA ET AL: "Genetic Recombination between Human Immunodeficiency Virus Type 1 (72) Inventors: (HIV-1) and HIV-2, Two Distinct Human • KARLIN-NEUMANN, George Lentiviruses", JOURNAL OF VIROLOGY., vol. 82, Palo Alto, CA 94304 (US) no. 4, 15 February 2008 (2008-02-15), pages • TZONEV, Svilen 1923-1933, XP055344736, US ISSN: 0022-538X, Pleasanton, CA 94566 (US) DOI: 10.1128/JVI.01937-07 • WANG JIANBIN ET AL: "Genome-wide (74) Representative: dompatent von Kreisler Selting Single-Cell Analysis of Recombination Activity Werner - and De Novo Mutation Rates in Human Sperm", Partnerschaft von Patent- und Rechtsanwälten CELL, vol. 150, no. 2, 20 July 2012 (2012-07-20) , mbB pages 402-412, XP028930183, ISSN: 0092-8674, Deichmannhaus am Dom DOI: 10.1016/J.CELL.2012.06.030 Bahnhofsvorplatz 1 • Jun Takehisa ET AL: "Human Immunodeficiency 50667 Köln (DE) Virus Type 1 Intergroup (M/O) Recombination in Cameroon", Journal of Virology, 1 August 1999 (56) References cited: (1999-08-01), pages 6810-6820, XP055345814, WO-A1-2007/008605 WO-A1-2013/093530 UNITED STATES Retrieved from the Internet: WO-A2-01/04360 WO-A2-2005/054506 URL:http://jvi.asm.org/content/73/8/6810.f WO-A2-2007/044091 WO-A2-2015/048571 ull.pdf#page=1&view=FitH US-A1- 2002 151 040 US-A1- 2004 005 710 US-A1- 2004 091 905 US-A1- 2006 286 580 US-A1- 2009 047 669 US-A1- 2010 092 973 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 3 024 948 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 3 024 948 B1 • MALOU ET AL.: ’Immuno-PCR: a promising ultrasensitive diagnostic method to detect antigens and antibodies’ TRENDS IN MICROBIOLOGY vol. 19, no. 6, 01 June 2011, pages 296 - 301, XP028374584 2 EP 3 024 948 B1 Description BACKGROUND OF THE INVENTION 5 [0001] Recombination, particularly viral recombination, can dramatically impact both evolution and epidemiology. In viruses, the recombination rate depends on the frequency at which co-infections occur and the frequency of genetic exchange between different viral genomes within an infected host cell. The ability to measure the recombination rate is important for understanding viral growth, virulence, and for creating attenuated strains for development of new vaccines. [0002] Current methods for measuring the recombination rate, for example approaches involving gel electrophoresis 10 and sequencing are either imprecise and/or time-consuming and often result in overestimation of the level of recombi- nation. The methods, compositions, systems, and kits for recombination assays disclosed herein overcome many of these challenges. The methods, compositions, systems, and kits provided herein can also be used for other types of recombination analyses, such as bacterial recombination, recombination of V(D)J or VJ domains in immune cells, as well as other types of analyses such as haplotype analysis. 15 [0003] A. D. Tadmor ET AL: "Probing Individual Environmental Bacteria for Viruses by Using Microfluidic Digital PCR", Science, vol. 333(6038), 2011, pages 58-62 discloses determination of integration of phages into bacterial genomes. [0004] K. MOTOMURA ET AL: "Genetic Recombination between Human Immunodeficiency Virus Type 1 (HIV-1) and HIV-2, Two Distinct Human Lentiviruses", JOURNAL OF VIROLOGY, vol. 82(4), 2008, pages 1923-1933 determines integration by GFP signals and sequences the recombined viral genomes. 20 SUMMARY OF THE INVENTION [0005] This disclosure provides methods for analyzing recombination, particularly viral recombination. The methods are particularly useful for minimizing artifactual biases arising from recombination between viral or other genomes (e.g., 25 any microbial genome) during the assay process. [0006] In a first aspect, provided herein is a method of determining a viral recombination rate or frequency, as defined in claim 1. [0007] In some cases, the sample comprises RNA. The sample may comprise DNA. [0008] In some cases, the first and second genomes are viral genomes. In some cases, the first and second viral 30 genomes are from different families. In some cases, the different families are selected from the group consisting of: Adenoviridae, Herpesviridae, Papillomaviridae, Polyomaviridae, Poxviridae, Hepadnaviridae, Parvoviridae, Astroviridae, Caliciviridae, Picornaviridae, Coronaviridae, Flaviviridae, Togaviridae, Hepeviridae, Retroviridae, Orthomyxoviridae, Are- naviridae, Bunyaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, and Reoviridae. [0009] In some cases, the first or second viral genome is selected from the group consisting of: Adenovirus, Coxsack- 35 ievirus, Epstein-Barr virus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Herpes simplex virus, type 2, Cytome- galovirus, Human herpesvirus, type 8, HIV, Influenza virus, Measles virus, Mumps virus, Human papillomavirus, Parain- fluenza virus, Poliovirus, Rabies virus, Respiratory syncytial virus, Varicella-zoster virus, and a variant strain thereof. [0010] In some cases, the first and second viral genomes are from a different viral strain. In some cases, the first and second viral genomes are from a different viral species. In some cases, the first and second viral genomes are from an 40 influenza strain. In some cases, the first and second viral genomes are HIV viral genomes. In some cases, the influenza strain is H1N1, H5N1, H3N2, H7N9, or H1N2, or a recombinant strain thereof. In some cases, the first and second viral genomes are from viruses that are capable of infecting different host cell types, wherein the different host cell types are selected from the group consisting of: an avian, a dog, a swine, a human, and a horse host cell. In some cases, the first and second viral genomes are from viruses that are capable of infecting different host cell types, wherein the different 45 host cell types are selected from the group consisting of: cows, goats, rodents, rabbits, mice, dogs, guinea pigs, and rats. [0011] In some cases, at least one of the first and second viral sequences comprises a genetic variation. In some cases, the genetic variation is selected from the group consisting of: single nucleotide polymorphisms (SNPs), insertions, inversions, rearrangements, transversions, deletions, indels, microsatellite repeats, minisatellite repeats, short tandem repeats, transposable elements, large scale structural variants, and combinations thereof. In some cases, the genetic 50 variation is a polymorphism between two or more parental strains. [0012] In some cases, the first and the second viral sequences are combined with a label prior to the reaction of step (c). In some cases, the first and second viral sequences are each labeled with a different color. In some cases, the sample further comprises a third viral sequence that is an allele of the first viral sequence. In some cases, the first and second viral sequences are labeled with a different color and the third viral sequence is labeled with a label that is the 55 same color as the label of the first viral sequence but that has a different intensity than the label of the first viral sequence. [0013] In some cases, the method has an accuracy of greater than 75%. In some cases, the method has an accuracy of at least 80%, 90%, 95%, 97%, or 99%. In some cases, the method has a sensitivity of greater than 75%. %. In some cases, the method has a sensitivity of at least 80%, 90%, 95%, 97%, or 99%. In some cases, the method is capable of 3 EP 3 024 948 B1 detecting the recombined nucleic acids in the sample wherein less than 5% of the total genomic nucleic acids in the sample are the recombined nucleic acids. In some cases, the method is capable of detecting the recombined nucleic acids in the sample wherein less than 4%, 3%, 2%, 1%, or 0.1% of the total genomic nucleic acids in the sample are the recombined nucleic acids. In some cases, the method is capable of detecting the recombined nucleic acids in the 5 sample wherein less than 5% of the genomic nucleic acids comprising the first sequence derived from the first genome are the recombined nucleic acids.
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