USRE37984E1 - Process for analyzing length polymorphisms in DNA regions - Google Patents

Process for analyzing length polymorphisms in DNA regions Download PDF

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USRE37984E1
USRE37984E1 US09/591,383 US59138300A USRE37984E US RE37984 E1 USRE37984 E1 US RE37984E1 US 59138300 A US59138300 A US 59138300A US RE37984 E USRE37984 E US RE37984E
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dna
cryptically
sequence
primer
primers
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Herbert Jäckle
Diethard Tautz
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Max Planck Gesellschaft zur Foerderung der Wissenschaften
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions
    • C12Q1/6858—Allele-specific amplification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6888—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the invention relates to a process for determining identity and kinship of organisms on the basis of length polymorphisms in the regions of simple or cryptically simple DNA sequences.
  • Higuchi et al. ( 5 a) describe a further process for analyzing a length polymorphic locus, comprising a primer-controlled polymerization reaction of certain mitochondrial DNA sequences. This process cannot be used for paternity determination due to the mitochondrial markers used thereby.
  • this problem is solved by providing a process for determining identity and kinship of organisms on the basis of length polymorphisms in DNA regions, which process comprises the following steps:
  • the individual primer molecules of the primer pairs are annealed to the DNA region to be analyzed at a distance of 50 to 500 nucleotides apart so that they encompass it at the given distance. Thereby the DNA region to be analyzed is surrounded by the hybridization molecules of the primer pair.
  • the primer-directed chain reaction is known as such from EP-A2 0 200 362 ( 1 ), from EP-A1 0 237 362 ( 1 a) and from ( 2 ). It refers to a process for amplification of specific DNA fragments in which a PCR (polymerase chain reaction) is carried out. In this process the specific amplification is achieved by using oligonucleotide primers flanking the target-molecule in an anti-parallel manner. Thereby in a template-dependent extension of the primers by a polymerase DNA fragments are synthesized which themselves are again available as templates for a new cycle of primer extension.
  • the DNA synthesis is performed by heat denaturation of the starting molecules, followed by hybridization of the corresponding primers and by chain extension with a polymerase. By means of a further heat denaturation a following cycle is then performed. Thereby the specifically amplified region grows in an exponential way and finally a fragment detectable by normal gel electrophoresis is formed. The length of this fragment is determined by the length of the primers and the intermediate region and is similar or equal to the sum of the lengths of the primers and the intermediate region.
  • thermostable synthesis components allows control of the process by simple and easily automated heating and cooling cycles.
  • Simple and cryptically simple DNA sequences are repetitive components of all eukaryotic genomes which to some extent can be found also in prokaryotic genomes ( 6 - 9 ).
  • simple DNA sequences comprise short DNA motifs containing at least one nucleotide and not more than approximately 6 to 10 nucleotides arranged as a dozen to approximately one hundred tandem repeats.
  • These simple DNA sequences have been found by hybridization with synthetic DNA sequences and by direct sequencing in all hitherto analyzed eukaryotic genomes and also in the human genome ( 8 , 10 ). All possible permutations of short motifs can presumably be found therein in different frequency ( 9 ).
  • Cryptically simple DNA sequences are characterized by a more than accidentally frequent, but irregularly direct repeat of short DNA motifs ( 9 ).
  • Cryptically simple DNA sequences are normally only found indirectly in already sequenced DNA regions by means of a corresponding computer programme. They are, however, at least just as frequent or even more frequent than simple DNA sequences.
  • the simple and cryptically simple DNA sequences are likely to have formed by genomic mechanisms having the tendency to duplicate once more already existing short duplications of any DNA sequence motifs or to partly delete in any DNA sequence motifs longer regions of already existing simple or cryptically simple DNA sequences ( 8 - 10 ). Therefore one can start from the assumption that these regions are usually length polymorphic. The process according to the invention is based on this length polymorphism.
  • Simple or cryptically simple DNA sequences that are suitable for the process according to the invention can be found with or without a computer programme in DNA sequences that are already known ( 9 ).
  • a simple or cryptically simple DNA sequence is suitable for use in the method of the present invention if it has a length of approximately 20 to 300 nucleotides and if it is flanked by random sequences, i.e. DNA sequences without internal repeats. From the region of DNA sequences without internal sequence repeats fragments that flank the simple or cryptically simple DNA sequence are selected. Suitable complementary synthetic oligonucleotides are then prepared which can hybridize to the flanking DNA sequences.
  • An oligonucleotide is suitable for this purpose if its nucleotide composition and its nucleotide sequence can be found most probably only once in the genome to be examined, thus being specific to the DNA region to be individually analyzed.
  • the simple or cryptically simple DNA sequence is substantially composed of the trinucleotide motif 5′ CAG 3′ / 5′ CTG 3′ .
  • two primer pairs are preferably employed. In a particularly preferred embodiment 2 to 50 primer pairs are employed.
  • the primers used in the process according to the invention have a length of 15 to 25 nucleotides.
  • the individual primer pairs are selected in such a way that the corresponding specific polymerase chain reaction products of the individual primer pairs are separable into individual bands on a suitable gel.
  • the detection of the specific polymerase chain reaction products is carried out by radioactive labelling or by non-radioactive labelling, e.g. with fluorescent dye-stuff.
  • the labelling of the oligonucleotide pairs can be carried out radioactively or with a fluorescent dyestuff, as described in (12).
  • kits with which the process according to the invention can be carried out are a subject matter of the present invention.
  • the primers contained therein are optionally labelled radioactively, e.g. with 35 S or 14 C, or fluorescently.
  • the synthesis products obtained in the process according to the invention can be separated using high-resolution gel systems, such as usual sequencing gels. At the same time also the length of the synthesis products can be determined. Polymorphisms which are formed by insertions or deletions of individual or several motifs of the simple or cryptically simple DNA sequence are recognizable by an altered position of the synthesis products in the gel. With an appropriate selection of the primer pairs and with an appropriate resolution capacity of the gel system approximately 20 to 50 independent polymorphic regions can be simultaneously examined. Thus, the identity of an individual can be reliably ascertained due to the individual combination of length distributions of the synthesis products obtained.
  • a genomic DNA to be examined is subjected to a partial restriction cleavage. Restriction enzymes are used that do normally not cleave in simple or cryptically simple DNA sequences.
  • the DNA fragments obtained are cloned in a suitable vector, e.g. in lambda phage derivatives or in M13-phages and are then screened by usual methods for simple or cryptically simple DNA sequences; cf. (11).
  • the probe molecules used are synthetic DNA molecules containing various permutations of simple or cryptically simple DNA sequences. Thus, hybridizing plaques can be identified. Then the recombinant DNA contained therein can be isolated and characterized by sequencing. The DNA sequence thus obtained can then be screened for DNA sequences which are suitable for the testing procedure according to the invention.
  • the process according to the invention was carried out with Drosophila-DNA as a model system.
  • Drosophila-DNA as a model system.
  • simple and cryptically simple DNA sequences are present in all eukaryotic genomes and to some extent also in prokaryotic genomes, one can assume that the results achieved with the Drosophila model system can also be achieved in the analysis of other genomes, particularly in the examination of the human genome.
  • the process according to the invention is suitable for the determination of identity and kinship of organisms, for example of human beings.
  • the process is also suitable to determine the course of hereditary propagation of genetic diseases for which the locus is known and sequenced. For this purpose one or several simple or cryptically simple sequences are selected which are located in or next to the locus to be analyzed. The specific length pattern of these regions is correlated with the mutated locus, as is common practice with known RFLP-markers; cf. (14). With the families concerned on the basis of this information genetic advice can be given or prenatal diagnosis can be made in a manner analogous to that known for RFLP-markers.
  • the process according to the invention is further suitable for determining polymorphisms in simple or cryptically simple DNA sequences of animals and plants. Therefore, in animal breeding, e.g. of horses, dogs or cattle, and kinship to high-grade breeding individuals can be reliably proved.
  • the advantage of the process according to the invention vis-a-vis the hitherto known processes lies in its broad applicability, rapid practicability and in its high sensitivity.
  • the amplification step taken for the length polymorphic simple or cryptically simple DNA sequences in the process according to the invention makes it superfluous to take an independent ascertaining step, such as a subsequent hybridization reaction. Therefore the process according to the invention is particularly well suited for automation and for routine testing and serial examination.
  • FIG. 1 Hybridization of a Gene Library with a simple DNA sequence as probe molecule.
  • FIG. 2 Sequence (SEQ. ID NO. 5) of the region tested for polymorphism in Example 2.
  • the regions to which complementary oligonucleotides were synthesized are underlined with a wavy line.
  • the region of the simple DNA sequence is underlined with a double line.
  • the direct repeat of 8 nucleotides is marked with two arrows.
  • the HaeIII-cleavage site is marked in italics.
  • FIG. 3 Analysis of the length variations of 11 wild type strains in Drosophila
  • the DNA sequences amplified by means of PCR and cleaved with HaeIII are shown in lanes 1 to 11 .
  • a sequencing reaction is shown serving as length marker.
  • the position of the fragments to be expected is marked with arrows on the left side.
  • the positions of the fragment classes additionally observed is marked with lines.
  • FIG. 4 Test for Reproducibility
  • FIG. 5 Sequence (SEQ IN NO. 6) of the DNA region used in Example 4.
  • FIG. 6 Paternity analysis in human beings.
  • the DNA fragments amplified by means of PCR and separated on the gel are shown.
  • the DNA of the mother in the following lanes the DNA of the father to be tested as well as of the three tested children have been applied.
  • the sixth lane (marked with “C”) a control-DNA has been applied which is to indicate only the size categories.
  • the main bands and their size categories are marked on the right side.
  • Drosophila-DNA is completely cleaved with the restriction endonuclease EcoRI and the resulting fragments are cloned into the lambda vector 641.
  • EcoRI restriction endonuclease EcoRI
  • the corresponding independent plaques are transferred to a nitrocellulose filter and hybridized with a probe molecule containing the simple DNA sequence motif CAG/CTG.
  • the filters are hybridized and washed at 65° C.
  • the hybridizing solution contains 5 ⁇ SSPE, 5 ⁇ Denhardt's solution, 0.1% sodium dodecyl sulfate (SDS) and approximately 1 ⁇ 10 6 cpm/ml of radioactively labelled ( 32 P) DNA as probe molecule.
  • the wash solution contains 2 ⁇ SSPE and 0.1% SDS (the reaction product of Denhardt's solution and SSPE is described in ( 11 )).
  • plaques formed show a positive signal; cf. FIG. 1 .
  • Some of these plaques are purified, DNA is isolated and sequenced. In the obtained DNA sequences regions can be identified containing the simple DNA sequence CAG/CTG; cf. (7).
  • Oligonucleotide 1 (SEQ. ID No. 1): 5′-TAAGCTTGGGAATCA-3′
  • Oligonucleotide 2 (SEQ. ID No. 2): 5′-ATTGAACTTTGTATC-3′
  • DNA sequences are located immediately at the beginning or at the end of the sequence shown in FIG. 2 .
  • the synthesized oligonucleotides are labelled with 32 P at their 5′ end. Then a PCR reaction with the labelled primers is carried out. On the whole 20 cycles are carried out by denaturating at 95° C. for 90 seconds, hybridizing at 45° C. for 90 seconds and then synthesizing at 72° C. for 120 seconds.
  • DNAs to be examined the genomic DNAs of 11 wild type strains of Drosophila melanogaster from various regions all over the world are employed. These Drosophila wild type strains originally are descendants of individual fertilized females and have been collected during the last 10 years.
  • the amplified fragments are cleaved with the restriction endonuclease HaeIII. This should normally yield two fragments having a length of 202 and 177 nucleotides, respectively. This step is normally not necessary for routine experiments. Here it only serves to refine the analysis.
  • the resulting fragments are separated on a 5% sequencing gel, the gel is subsequently dried and an X-ray film is exposed to the dried gel. Both DNA fragments expected show a marked polymorphism in the various Drosophila wild type strains.
  • the 202 nucleotide fragment which contains the simple DNA sequence shows four different size categories; see FIG. 3 . These size categories are shifted by three nucleotides each.
  • Example 2 The variations in length observed could also be caused by polymerase errors during the experiment.
  • the experiment carried out in Example 2 is repeated with two different DNA preparations of the Drosophila strains No. 3 in 10 independent reaction mixtures. It can be taken from FIG. 4 that all reaction mixtures lead to the same bands. Similar experiments were also carried out for different loci. In no case, however, a change of the band length could be observed. This shows that the process is reliably reproducible.
  • a primer pair is used which flanks a sequential region from the autosomal human heart muscle actin gene. This sequence contains a simple sequence with a GT/CA dinucleotide repeat structure (FIG. 5 ). As primers the following oligonucleotides are used:
  • Primer 1 (SEQ ID No. 3): 5′-CTCCCCCACACAAAGAAG-3′
  • Primer 2 (SEQ ID No. 4): 5′-TTCCATACCTGGGAACGA-3′
  • Primer 2 is labelled at its 5′ end with 32 P and both oligonucleotides are then used for a PCR reaction. On the whole 25 cycles with a denaturation phase of 1 min. at 94° C., an hybridizing phase of 2 min. at 45° C. and a synthesis phase of 1 min at 72° C. (last synthesis phase for 5 min) are carried out. The reaction products are then separated on a 6% denaturating acrylamide gel, the gel is dried and exposed. The result can be seen in FIG. 6 . Each of the tested individuals shows two main bands (for explanation of the further bands, see below), i.e. it is heterozygous for different length variants of this locus.
  • Mother and father have the length variant “109 nt” in common, they do, however, differ in the other variant, with the mother having a “127 nt” and the father a “121 nt” variant.
  • the children must have inherited one of each of these variants from father and mother. For two of the children this is actually the case, whereas the third child (labelled with “?”) shows a new “113 nt” variant, which can neither be derived from the mother nor from the tested father. Therefore, one has to assume that this child had another father.
  • a cloned control-DNA having only one length variant has also been treated. Like the other samples it shows a main band and several secondary bands.
  • the secondary bands are caused by PCR artifacts formed during the amplification.
  • the first type results from the fact that the Taq-polymerase has the tendency to attach an additional nucleotide to the completely synthesized DNA strand. Thereby the band is formed which runs a nucleotide above the main band. This effect varies from reaction to reaction, but does not disturb the analysis of the band pattern.
  • a second type of artifact is formed by “slippage” during the amplification process. This leads to the bands which can be seen at the dinucleotide distance below the main bands. These artifact bands could have a disturbing effect on the analysis, if they overlap actual length variants.

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DE3834636A DE3834636A1 (de) 1988-10-11 1988-10-11 Verfahren zur analyse von laengenpolymorphismen in dna-bereichen
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