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Researchers Submit Patent Application, "Method for Genetic Detection Using Interspersed Genetic Elements: a Multiplexed Dna Analysis System", for...

May 30, 2014



Researchers Submit Patent Application, "Method for Genetic Detection Using Interspersed Genetic Elements: a Multiplexed Dna Analysis System", for Approval

By a News Reporter-Staff News Editor at Health & Medicine Week -- From Washington, D.C., NewsRx journalists report that a patent application by the inventor Sinha, Sudhir (Matairie, LA), filed on October 15, 2013, was made available online on May 15, 2014 (see also Patents).

No assignee for this patent application has been made.

News editors obtained the following quote from the background information supplied by the inventors: "The present invention relates generally to human identification and bio-ancestry testing, and, more particularly, to improvements that enhance the sensitivity of detection during analysis of human DNA samples for human identity testing or for bio-ancestry studies.

"Short tandem repeat (STR) loci are the primary genetic markers used in human identity testing. These markers are highly polymorphic and afford a high degree of sensitivity of detection such that relatively low quantities (1 ng-250 pg) of template DNA can be analyzed (Andersen, J. F., et al., Further validation of a multiplex STR system for use in routine forensic identity testing, Forensic Science International, 78(1): 47-64 (1996); Brinkmann, B., et al., Mutation rate in human microsatellites: influence of the structure and length of the tandem repeat, The American Journal of Human Genetics, 62(6): 1408-1415 (1998); Collins, P. J., et al., Developmental validation of a single-tube Amplification of the 13 CODIS STR Loci, D2S1338, D19S433, and amelogenin: The AmpFSTR.RTM. Identifiler.RTM. PCR Amplification Kit, Journal of Forensic Sciences, 49(6): 1265-1277 (2004); LaFountain, M. J., et al., TWGDAM Validation of the AmpFeSTR Profiler Plus and AmpFeSTR COfiler STR Multiplex Systems Using Capillary Electrophoresis, Journal of Forensic Sciences, 46(5): 1191-1198 (2001); Micka, K. A., et al., Validation of multiplex polymorphic STR amplification sets developed for personal identification applications, Journal of Forensic Sciences, 41: 582-590 (1996); Moretti, T., et al., Validation of short tandem repeats (STRs) for forensic usage: performance testing of fluorescent multiplex STR systems and analysis of authentic and simulated forensic samples, Journal of Forensic Sciences, 46(3): 647 (2001)).

"Retrotransposable elements (REs), including long interspersed nuclear elements (LINEs), short interspersed nuclear elements (SINEs) and SVA elements, are another group of markers that can be useful for human identity testing. SINEs are a class of REs that are typically less than 500 nucleotides long; while LINEs are typically greater than 500 nucleotides long (A. F. A. Smit, The origin of interspersed repeats in the human genome, Current Opinion in Genetics Development, 6(6): 743-748 (1996); Batzer, M. A., et al., Alu repeats and human genomic diversity, Nature Reviews Genetics, 3(5): 370-379 (2002); Batzer, M. A., et al., African origin of human-specific polymorphic Alu insertions, Proceedings of the National Academy of Sciences, 91(25): 12288 (1994); Feng, Q., et al., Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition, Cell, 87(5): 905-916 (1996); Houck, C. M., et al., A ubiquitous family of repeated DNA sequences in the human genome, Journal of Molecular Biology, 132(3): 289-306 (1979); Kazazian, H. H., et al., The impact of L1 retrotransposons on the human genome, Nature Genetics, 19(1): 19-24 (1998); Ostertag, E. M., et al., Biology of mammalian L1 retrotransposons, Annual Review of Genetics, 35(1): 501-538 (2001)). LINE full-length elements are .about.6 kb in length, contain an internal promoter for polymerase and two open reading frames (ORFs) and end in a polyA-tail. SINEs include Alu elements, primate specific SINEs that have reached a copy number in excess of one million in the human genome. SINEs were originally defined by their interspersed nature and length (75-500 bp), but have been further characterized by their RNA polymerase III transcription. The third type of RE is the composite retrotransposon known as an SVA (SINE/VNTR/Alu) element (Wang, H., et al., SVA Elements: A Hominid-specific Retroposon Family, J. Mol. Biol. 354: 994-1007 (2005)). SVAs are composite elements named after their main components, SINE, a variable number of tandem repeats (VNTR), and Alu. As a consequence of the VNTR region, full-length SVA elements can vary greatly in size. These markers have potential application to identity testing, kinship analyses, and evolutionary studies (see Smit; Batzer, et al. (2002); Batzer, et al. (1994); Feng, et al.; Houck, et al.; Kazazian et al.; and Ostertag, et al., references, cited supra). Insertion and null allele (INNUL) markers may include SINEs, LINEs and SVAs.

"The structure of REs is described in FIG. 1. The Alu family of interspersed repeats is the most successful of the mobile genetic elements within primate genomes, having amplified to a copy number of greater than 500,000 per haploid genome. Alu elements mobilize via an RNA polymerase III-derived intermediate in a process defined as retroposition. Alu repeats are approximately 300 bp in length and are ancestrally derived from the 7SL RNA gene. Each Alu element is dimeric in structure and is flanked by short intact direct repeats. These direct repeat sequences are formed when an Alu element inserts within staggered nicks in the genome. In addition, each Alu element has an oligo dA-rich region in the middle and at the 3' end (FIG. 1). The amplification of Alu repeats to such large copy numbers has occurred over a period of 65 million years and the process is still active in the present day genome (A. F. A. Smit, The origin of interspersed repeats in the human genome, Current Opinion in Genetics Development, 6(6): 743-748 (1996); Zangenberg, et al., cited supra; Budowle, B., SNP typing strategies, Forensic Science International, 146: S139 (2004)).

"Alu sequences within the human genome can be divided into subfamilies of related members based upon the presence of diagnostic mutations shared in common by subfamily members. These subfamilies are of different evolutionary ages with the younger ones (Ya5, Ya8 and Yb8) being primarily restricted to the human genome (Houck, C. M., et al., A ubiquitous family of repeated DNA sequences in the human genome, Journal of Molecular Biology, 132(3): 289-306 (1979); Kazazian, H. H., et al., The impact of L1 retrotransposons on the human genome, Nature Genetics, 19(1): 19-24 (1998)). These subfamilies arose in a hierarchical manner over evolutionary time with the younger subfamily members retaining the diagnostic mutations of the older subfamily that preceded it.

"The Ya5/8 and the Yb8 subfamilies are independent derivatives of the Y subfamily of Alu repeats. The young subfamilies are present in relatively small copy numbers within the genome compared to the bulk of the Alu repeats, which primarily belong to the PS and AS subfamilies. For instance, the Y subfamily is comprised of approximately 100,000 members; Ya5 subfamily, 1000 members; Ya8 subfamily, 50 members and the Yb8 subfamily, approximately 1000 members (Moretti, T., et al., Validation of short tandem repeats (STRs) for forensic usage: performance testing of fluorescent multiplex STR systems and analysis of authentic and simulated forensic samples, Journal of Forensic Sciences, 46(3): 647 (2001)).

"The youngest subfamilies of Alu elements, Ya5, Ya8 and Yb8 first arose in the primate genomes approximately 5 million years ago (Batzer, M. A., et al., African origin of human-specific polymorphic Alu insertions, Proceedings of the National Academy of Sciences, 91(25): 12288 (1994); Feng, Q., et al., Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition, Cell, 87(5): 905-916 (1996)). Amplification of Alu elements within humans is still an ongoing process. As human population groups migrated and colonized different parts of the world, all new Alu insertions in individuals belonging to the newer populations were absent in the original population, and vice versa. In other words, several elements that belong to the young subfamilies are dimorphic for their presence/absence within different human population groups (Syvanen, A. C., et al., Identification of individuals by analysis of biallelic DNA markers, using PCR and solid-phase minisequencing, American Journal of Human Genetics, 52(1): 46-59 (1993); LaRue, B. L., et al., A validation study of the Qiagen Investigator DIPplex.RTM. kit; an INDEL-based assay for human identification, International Journal of Legal Medicine, 2012, 1-8).

"Realizing the potential of these dimorphic Alu elements as genetic markers, investigators have identified the dimorphic Alu repeats from a larger background of fixed Alu elements. Using the Alu insertion PCR assay described in FIG. 2, each Alu element was tested against a panel of several human genomic DNA samples as templates for the levels of polymorphism. Each and every dimorphic Alu repeat has been thoroughly characterized for its respective allele frequency in as many as 50 different worldwide population groups (Syvanen, A. C., et al., Identification of individuals by analysis of biallelic DNA markers, using PCR and solid-phase minisequencing, American Journal of Human Genetics, 52(1): 46-59 (1993); LaRue, B. L., et al., referenced supra; Shriver, M. D., et al., Ethnic-affiliation estimation by use of population-specific DNA markers, American Journal of Human Genetics, 60(4): 957 (1997)).

"Ustyugova, S. V., et al. (Cell line fingerprinting using retroelement insertion polymorphism. BioTechniques, 38(4): 561-565 (2005)), demonstrated that REs could be used for cell line identification. Novick, et al. (Polymorphic human specific Alu insertions as markers for human identification. Electrophoresis, 16(1): 1596-1601 (1995)), and Mamedov, et al. (A new set of markers for human identification based on 32 polymorphic Alu insertions, European Journal of Human Genetics, 18(7): 808-814 (2010)), recently described a set of Alu's (a type of SINE) for paternity testing. Both of these studies intimated that the systems could be applied to forensic analyses. The REs have low mutation rates which makes them appealing for kinship analyses compared with the less stable STRs. In addition, they do not yield stutter artifacts, due to slippage during the PCR, which can reduce some interpretation issues associated with STRs in forensic mixture profiles (Andersen, J. F., et al., Further validation of a multiplex STR system for use in routine forensic identity testing, Forensic Science International, 78(1): 47-64 (1996); Brinkmann, B., et al., Mutation rate in human microsatellites: influence of the structure and length of the tandem repeat, The American Journal of Human Genetics, 62(6): 1408-1415 (1998); Moretti, T., et al., Validation of short tandem repeats (STRs) for forensic usage: performance testing of fluorescent multiplex STR systems and analysis of authentic and simulated forensic samples, Journal of Forensic Sciences, 46(3): 647 (2001)).

"Forensic samples often are compromised in quality and quantity. Degraded samples may contain fragments of DNA that are less than 250 bp in length, and the quantities may be limited to subnanogram levels of recoverable DNA (Burger, J., et al., DNA preservation: A microsatellite DNA study on ancient skeletal remains, Electrophoresis, 20(8): 1722-1728 (1999); Fondevila, M., et al., Challenging DNA: assessment of a range of genotyping approaches for highly degraded forensic samples, Forensic Science International: Genetics Supplement Series, 1(1): 26-28 (2008); Golenberg, E. M., et al., Effect of Highly Fragmented DNA on PCR, Nucleic Acids Research, 24(24): 5026-5033 (1996); R. Hughes-Stamm, S., et al., Assessment of DNA degradation and the genotyping success of highly degraded samples, International Journal of Legal Medicine, 125(3): 341-348 (2011)). REs can range in size from hundreds (SINEs) to several thousand (LINEs) by in length (see Smit; Batzer, et al. (2002); Batzer, et al. (1994); Feng, et al.; Houck, et al.; Kazazian et al.; and Ostertag, et al., references, cited supra). Previous attempts to use Alu sequences for identity testing capitalized on the size difference between insertion and null alleles by amplifying the entire region with the same forward and reverse primers (Novick, G. E., et al., Polymorphic human specific Alu insertions as markers for human identification, Electrophoresis, 16(1): 1596-1601 (1995)). The insertion allele would be 200-400 bp larger than the null allele, and could be detected electrophoretically based on size differences. While useful for paternity testing and some population studies where DNA quality is not compromised, the large size difference between amplicons of the null and insertion alleles will impact amplification efficiency during the PCR and is a limitation for forensic samples. The limitation is differential amplification favoring the smaller amplicon (i.e., the null allele) and possibly dropping out of the insertion element, which is exacerbated if the sample is highly degraded.

"The use of SINEs such as Alu repeats in determining human identity has been studied and reported (see Mamedov, et al., and Novick, et al., cited supra). Until now, however, due to the inherent size difference associated with INNULs, the use of REs has not been useful in a practical sense. Although REs make up over 40% of the human genome (Lander, E. S., et al., Initial sequencing and analysis of the human genome, Nature, 409(6822): 860-921 (2001)) and present myriad potential targets for human identity testing, these INNULS (i.e., insertion and null alleles, instead of INDELs because one of the allele forms is not the result of a deletion) have received limited attention for use in forensic human identity testing (Zangenberg, et al., Multiplex PCR: Optimization Guidelines, in PCR Applications: Protocols for Functional Genomics, Academic Press, San Diego, Calif., 1999, p. 73-94).

"Advantageously, a convenient way to design synthetic primers for PCR amplification of relatively short, repeating sequences, known as the mini-primer design, has been previously described in U.S. Pat. No. 7,794,983 B2, to Sinha, et al., which is hereby incorporated by reference. Using the mini-primer design, interspersed genetic elements containing characteristic direct repeat sequences (direct repeats) may be amplified and quantitated.

"The above information disclosed in this Background section is only for enhancement of understanding of the background of the invention, and, therefore, it may contain information that does not form the prior art that is already known to a person of ordinary skill in the art."

As a supplement to the background information on this patent application, NewsRx correspondents also obtained the inventor's summary information for this patent application: "Accordingly, one object of the present invention is to provide, using the mini-primer design, synthetic primers for Interspersed Element Insertion polymorphisms that would facilitate the production of small PCR products having as few as 50 to 150 base pairs (bp) when human genomic DNA is amplified.

"This short sequence PCR amplification process takes advantage of the fact that all retrotransposon insertions have a characteristic sequence at the beginning and the end of insertion referred as Target Site Duplication (TSD). Another object of the present invention is to design synthetic primers to include part or full TSD sequences to provide specific insertion or no-insertion alleles in multiplex systems.

"Another object of the present invention is to design, optimize and validate a multiplex amplification system (single amplification for multiple targets) containing LINEs, SINEs and SVAs for forensic applications.

"Another object of the present invention is to design, optimize and validate a multiplex amplification system (single amplification for multiple targets) containing LINEs, SINEs and SVAs for bio-ancestry applications.

"Another object of the present invention is to use the power of discrimination and analytical performance of the short sequence PCR amplification process to select markers as being suitable for either forensic or bio-ancestry applications.

"Another object of the present invention is to develop a practical method for using LINEs and SVAs as potential markers in a DNA amplification system for human identification.

"Another object of the present invention is to develop a multiplex amplification system that makes use of RE markers and is useful in forensic cases in which the DNA samples have been substantially degraded.

"These and other objects may be attained by utilizing the mini-primer strategy with INNUL markers, which include SINEs, LINEs, and SVAs and can be effectively used as markers for human identification and bio-ancestry studies regardless of the size of the inserted element. The size of the amplicons for INNULs and the difference between allelic states can be reduced substantially such that these markers have utility for analyzing high and low quality human DNA samples. In addition, the present invention demonstrates a sensitivity of detection that can be sufficient to enable human identity and bio-ancestry studies on forensic and anthropological samples. Depending on the markers selected and the distribution of the alleles in global populations, INNULs can be selected for human identity testing or for bio-ancestry studies.

"The optimization of INNUL markers into a single-tube, multi-locus reaction furthers these goals. The inclusion of these markers in a multiplexed reaction produces an INNUL-based human identity test set that is a powerful tool for use in forensic settings without the need for further investment in new instrumentation. The multiplexed system is able to amplify multiple target sequences at the same time with no non-specific amplification products and also exhibits the sensitivity to amplify DNA concentration as low as 100 pg or less. With a size range of 46-124 base pairs, this novel multiplexed system contains the smallest size amplicons that are both amenable for use with extensively degraded DNA samples and available to the forensic community. Thus, the INNUL multiplex system of the present invention provides a statistically discriminating tool that is useful for forensic applications where the sample is limited in quantity as well as quality.

"One embodiment of the present invention includes a method for genetic detection comprising providing a sample to be analyzed, selecting a plurality of Retrotransposable element (RE) markers, each selected RE marker being an INNUL marker that is associated with both a filled allele representing a filled genomic site and an empty allele representing an empty genomic site, each INNUL marker comprising a nucleic acid sequence, the nucleic acid sequence being found at a location within the genome of a target species, providing a primer set corresponding to each selected INNUL marker, each primer set consisting of a forward primer and two reverse primers, the two reverse primers consisting of a primer corresponding to a filled site of the INNUL marker and a primer corresponding to an empty site of the INNUL marker, combining the primer sets with the sample to form a reaction mixture, amplifying the markers using the primer sets to form a mixture of amplification products, separating the amplification products from the remainder of the reaction mixture, and detecting and quantitating each labeled amplification product.

"In certain embodiments of the present invention, each forward primer used in the above method may have a structure comprising an observable label. In certain embodiments, each reverse primer used in the above method may have a structure comprising an observable label.

"In certain embodiments of the present invention, each forward primer used in the above method may have a structure comprising a fluorescent organic dye. In certain embodiments, each reverse primer used in the above method may have a structure comprising a fluorescent organic dye.

"In certain embodiments of the present invention, the observable labels may be selected from 6FAM.TM., JOE.TM., TAMRA.TM. and ROX.TM.

"In certain embodiments of the present invention, amplification of the markers may be done using a real-time polymerase chain reaction (PCR) system.

"In certain embodiments of the present invention, each amplification product may be labeled with a distinct observable label.

"In certain embodiments of the present invention, each primer set may correspond to a PCR amplicon corresponding to a filled allele and a PCR amplicon corresponding to an empty allele, and each PCR amplicon may have a size of from about 46 base pairs to about 200 base pairs.

"In certain embodiments of the present invention, the selected INNUL markers may be selected from SINEs, LINEs and SVAs.

"In certain embodiments of the present invention, the selected INNUL markers may be selected from Alus and LINEs.

"In some embodiments of the present invention, the set of INNUL markers used may be selected for human identity testing purposes on the basis of the distribution of the alleles in global populations.

"In some embodiments of the present invention, the set of INNUL markers used may be selected for bio-ancestry studies on the basis of the distribution of the alleles in global populations.

"In certain embodiments of the present invention, useful forensic or bio-ancestry-related determinations may be obtained for samples comprising as little as 100 pg of DNA.

"In certain embodiments of the present invention, each selected INNUL marker comprises a Target Site Duplication (TSD) sequence, also referred to as a direct repeat sequence, and each reverse primer comprises a nucleic acid sequence that includes all or part of the TSD sequence.

"In certain embodiments of the present invention, the genetic detection method may include INNUL markers selected from CHR20-79712, Ya5-MLS48, Yb8NBC13, Ya5ACA1736, Yb8NBC106, Y5ac2305, HS4.69, AC4027, CH1-6217, Yb8AC1796, Yac52265, MLS9, TARBP1, SVA306, Amelogenin, SVA323, Ya5NBC51, Yb8AC1141, Yb7AD155 and Ya5-MLS18. In one embodiment, a multiplex system for genetic detection may comprise the amplification of filled and empty amplicons corresponding to each of these fifteen INNUL markers plus Amelogenin.

"In certain embodiments of the present invention, the reaction products may be separated from the remainder of the PCR reaction mixture and from each other using electrophoresis.

"In certain embodiments of the present invention, each INNUL marker may comprise a filled allele and an empty allele, and the size difference between each filled allele and the corresponding empty allele may be in the range of from about 2 to about 8 base pairs.

"Embodiments of the present invention may include a multiplexed DNA analysis system comprising a sample of DNA, a set of thirty or fewer INNUL markers, each INNUL marker comprising a filled allele and an empty allele, a set of three primers corresponding to each INNUL marker, each set of primers including a forward primer and two reverse primers, the forward primer including a detectable label, one reverse primer corresponding to the filled allele and the other reverse primer corresponding to the empty allele, a polymerase chain reaction (PCR) amplification system that produces PCR amplification products, means for separating PCR amplification products from reactants and from each other, means for detecting and quantitating PCR amplification products using the detectable label, and means for deriving a useful forensic-related or bioancestry-related conclusion from the quantitative PCR results.

"In certain embodiments of the present invention, the separating means of the multiplexed DNA analysis system may be electrophoresis.

"In certain embodiments of the present invention, the multiplexed DNA analysis system may be based on amplification of a set of 15 INNUL allele markers plus Amelogenin.

"In certain embodiments of the present invention, the multiplexed DNA analysis system may include forward primers that are labeled with fluorescent organic dyes. In some embodiments, the fluorescent organic dyes may be selected from the group of four dyes consisting of 6-FAM.TM., JOE.TM., TAMRA.TM. and ROX.TM.

"In certain embodiments of the present invention, the amplification products of the above methods and systems may be characterized by Next Generation Sequence analysis (NGS) methods.

"In certain embodiments of the present invention, the amplification products of the above methods and systems may be characterized by rapid DNA analysis platforms.

BRIEF DESCRIPTION OF THE FIGURES

"The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

"A more complete appreciation of the invention, and many of the attendant advantages thereof, will be readily apparent as the same becomes better understood by reference to the following detailed description when considered in conjunction with the accompanying figures, wherein:

"FIG. 1 illustrates Alu, L1 and WA. Full-length retrotransposons are not drawn to scale. As represented, all three REs have at the beginning and end a target site duplication (TSD) consisting of identical DNA sequences. The mini primer design strategy exploits these TS Ds for amplification and detection of insertion or null alleles.

"FIG. 2 illustrates the schematic of the Alu element insert on PCR assay.

"The Alu sequence is represented by the shaded line. The chromosomal locus harboring the Alu element is represented by the thick dark line, and the flanking unique sequence derived PCR primers are denoted by the arrows.

"The PCR assay results in the production of approximately a 100 bp or a 400 bp DNA fragment or both as outlined in the figure. Individuals that are homozygous for the Alu insertion will amplify only 400 bp fragment (#1), while those that are homozygous for the absence of Alu insertion at this locus will amplify only a 100 bp fragment (#3). Individuals heterozygous for the Alu insertion will amplify both the 400 bp and 100 bp fragments (#2).

"FIG. 3 illustrates a primer design for the filled and empty sites of RE marker Ya5ac2305. The primer sequences for mini-primer design are underlined. The traditional 'core primer' design sequences, as reported earlier, are in bold and italics. The forward primer is identical in both sites. The uniqueness for each site lies within the reverse primer sequences. In the Filled Site reaction (A), the reverse primer contains the direct repeat sequence (red box), flanking genomic sequence and some of the 5' Alu insert sequence. Empty Site reaction (B) reverse primer contains the whole direct repeat plus flanking genomic sequence.

"FIG. 4 illustrates a multiplex design showing markers, dyes, and amplicon sizes for each locus.

"FIG. 5 illustrates an electropherogram representing 15 RE markers and Amelogenin multiplexed using five fluorophores: 6-FAM.TM. (blue), JOE.TM. (green), TMR (TAMRA.TM., black but represents yellow), ROX.TM. (red), and CC5 (orange) as the size standard using 3130 Genetic Analyzer.

"FIG. 6 illustrates average heterozygous peak heights for 150 database samples. RFU vs. Marker.

"FIG. 7 illustrates a heterozygosity of database samples.

"FIG. 8 illustrates the PowerPlex16HS (PP16HS) vs. InnoTyper.TM. (IT). Results confirmed that InnoTyper.TM. was two times more sensitive in number of alleles detected.

"FIG. 9 illustrates the Identifiler.RTM. Plus (IDP) vs. InnoTyper.TM. (IT). Results confirmed that InnoTyper.TM. was four times more sensitive in number of alleles detected.

"FIG. 10 illustrates the Minifiler Plus.TM. (Mini) vs. InnoTyper.TM. (IT) multiplex. Results confirmed that InnoTyper.TM. was ten percent more sensitive in number of alleles detected.

"FIG. 11 illustrates a comparison of degraded DNA profiles using STR kits PowerPlex 16 HS, Identifiler Plus.TM., Minifiler.TM. and InnoTyper.TM. multiplex.

"FIG. 12 illustrates a sensitivity study of markers showing the average peak height of empty and filled primers at varying concentrations of DNA (0.5-0.05 ng/.mu.L). Empty results showed slightly higher peak intensities than Filled results.

"FIG. 13 illustrates the InnoTyper.TM. species results."

For additional information on this patent application, see: Sinha, Sudhir. Method for Genetic Detection Using Interspersed Genetic Elements: a Multiplexed Dna Analysis System. Filed October 15, 2013 and posted May 15, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=2528&p=51&f=G&l=50&d=PG01&S1=20140508.PD.&OS=PD/20140508&RS=PD/20140508

Keywords for this news article include: Patents, Genetics, Amelogenin, Polymerase, DNA Research, Enzymes and Coenzymes, Dental Enamel Proteins.

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