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Phenylalanine hydroxylase (PAH) Gene Paper

Phenylalanine hydroxylase (PAH) Gene

Background:

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Phenylalanine hydroxylase (PAH) encodes the liver-secreted enzyme of the same name, a catalyst for the hydroxylation of tyrosine from phenylalanine, a rate-limiting step in the catabolism of the latter. This reaction only occurs in the presence of the cofactor tetrahydrobiopterin (BH4) as well as molecular oxygen and iron (1).

Mutations in the PAH gene are generally caused by a change of an amino acid, for example, the change of arginine to tryptophan (2, 3). The numerous possible mutations in this gene result in a lack of enzyme activity. Thus, because of its main function, the deficiency in the activity of PAH causes a marked intolerance of the consumption of phenylalanine, an essential amino acid. This causes phenylketonuria (PKU), non-phenylketonuria hyperphenylalaninemia (non-PKU HPA), mild hyperphenylalaninemia (MHP), and other variant PKU (4, 5, 6).

Defects in the PAH gene leads to the deficiency or the disruption of the production of the PAH enzyme; this is most commonly related to the resulting disorder, phenylketonuria. PKU is an autosomal, inborn, recessive disorder of phenylalanine metabolism (7). There are three common types of PKU. First, there is classical PKU, caused by the mutation of both alleles of the PAH gene in chromosome 12 which results in a severe deficiency or complete absence of the PAH enzyme, leading to toxic levels of unhydroxylated phenylalanine, typically over 10 times higher than normal concentrations (i.e. over 1000 µmol compared to the normal 100 µmol). Next, there is MHP, the mildest form of the PAH enzyme deficiency, with phenylalanine levels below 600 µmol but above normal. Thirdly, there is non-PKU HPA, caused by mutations in the PAH locus that hinder BH4 synthesis and regeneration. This relatively milder form of the disorder often results in heterozygous cases through a combination of mild and severe mutations (4, 7, 8).

Severe classical PKU, if left untreated, is commonly known to result in the impedance of postnatal cognitive development causing mental retardation and in metabolic abnormalities causing increased phenylalanine in in the blood circulation and phenylpyruvic acid in the urine. PKU has also been known to cause skin abnormalities, organ damage, different kinds of posture peculiarities, pregnancy problems (maternal PKU), an odor describe as “mousy”, as well as other mental issues such as epilepsy, hyperactivity, and psychotic episodes (1,4,7,8). The most common negative effect associated with PKU, mental retardation, is caused by a neurotoxic effect of HPA. And while PKU is an inherited disorder, its negative effects could also be induced in the offspring of mothers with PKU, resulting not only in high fetus mortality rates but also in a high probability that the children are born with growth and mental retardations as well as malformations. This is known as PKU embryofetopathy or maternal PKU syndrome (8). Conversely, children born with non-PKU HPA and MHP have marked lower risks of being affect with the adverse effects of the disorder and can have normal development mentally and physically even with the absence of treatment (4,8).

Despite the severe potential effects of classical PKU, newborn screening for high levels of phenylalanine has helped early diagnosis of the disorder, which is then followed by rapid treatment. Dietary restrictions of phenylalanine has been used for early treatment of PKU which, while not necessarily lead to complete normalization of IQ, was shown to be predictive of overall IQ with the complete lack of treatment in classical PKU patients leading to severe and irreversible cognitive retardation.(1,8) Thus, primary screening of neonates and children as well as awareness of the disorder for the parents are essential (3, 6).

Results and Discussion:

PAH chromosomal map position and nearby genes:

The location of the PAH gene is at chromosome 12. Its long arm (q) is comprised of 13 exons with an approximate length of 90 kb.

Figure 1 Chromosome 12 (9)

Figure 1, above, is a representation of the entire chromosome 12 with both its short arm (p) and long arm (q) as it appears in the Ensembl website, albeit cropped to fit the page. This figure can be found by searching for the PAH gene and clicking on the “Location” link on the PAH listing. The website lists the location of the gene to be at “Chromosome 12: 103,232,104-103,311,381 reverse strand.”(2) Though the website does not explicitly state where in chromosome 12 PAH is located, one can infer additional details from the provided images. For example, confusion can ensue from the fact that the indicated location in the image in the Ensembl website is on the long arm on q23.2, while previous sources have stated that it is located on q22-24.2. However, from the code in the location and the additional images, one can infer that these are the transcribed portions of the gene, two of which are illustrated in the site. Furthermore, one can see that the PAH gene is flanked by the genes insulin-like growth factor 1 (IGF1), or somatomedin C, and achaete-scute complex homolog 1 (ASCL1). To obtain the information, though, one needs to explore the interactive image (see Figure 2 below) and go to the individual pages of the neighbor genes.

Figure 2 Detailed view of region near PAH (9)

The NCBI website, however, while very extensive in details, and containing multiple transcripts pertaining to the PAH gene, can be somewhat confusing with regard to the Map Viewer. Going through the home page and directly searching for the desired gene results in a very large and confusing map, with the details of the gene and its neighboring gene beyond the page to right. For a beginner who is not quite sure what to look for, the NCBI Map Viewer can be very overwhelming. Focusing on the table and not the map, however, one can see that the PAH gene is located in Chromosome 12, in the long arm q22-q24.2; this information is under the heading “Cyto” (for cytogenic) and stated as “12q22-q24.2” (10). Again, this might not be immediately clear to a beginner. Furthermore, the different master map options (Morbid, Gene_cyto, etc.) individually show different arrangements of the symbols, not all of which seem to be genes. Thus, it is very hard to decipher which genes are actually near PAH, although zooming in on the “Genes on Sequence” and “Phenotype” maps do reveal the proximity of IGF1 and ASCL1. In all, for a beginner, the Ensembl website proved to be much easier to use to answer the first question.

The intron/exon structure of the PAH gene:

It was very difficult to find an illustration of the structure of the PAH gene in the NCBI website. However, the information page for the gene stated that the gene spans 90 kb with the entire sequence and its adjacent regions a total of 171 kb. Furthermore, it states that the gene contains 13 exons, which consequently means that it has 12 introns (number of introns is one less than the number of exons) (1). After some searching, however, beginning with clicking the available links for PAH in the Map Viewer table, the link “sv” led to a page with the title “Homo sapiens chromosome 12 genomic contig, GRCh37 reference primary assembly.” Searching for the gene gives the following (zoomed-in and cropped) structure:

 Figure 3 Structure of PAH gene (11)

Though not obvious from the first glance, later we will see that the bottom sequence actually represents the structure of the PAH, with the vertical green lines representing the 13 exons. After further searching, the following (rotated) PAH structure showing the 13 exons and 12 introns can be found in the Map Viewer under “ensRNA”:

 Figure 4 Another illustration of the structure of PAH gene (11)

Finding those, however, takes previous explicit knowledge and some work to track down the specific illustrations. In contrast, finding the number of exons and introns and an illustration of the structure of the PAH gene in the Ensembl website was very straightforward. The following illustration can be found in the same page as Figure 1:

Figure 5 Ensembl illustration of PAH gene structure

This strand, one of the transcripts available in the Ensembl page, clearly shows the 13 exons in a DNA sequence. Comparing this structure to Figures 3 and 4, the numbers and the arrangements of the exons and introns are exactly the same. However, relative to all the tedious searching needed to find the same answers in the NCBI website, the information needed for the question was instantly available from the Ensembl site, and the interface was very easy to understand.

Common PAH mutations:

Mutations in general can refer to abnormalities in function or structure of the concerned enzyme in the gene phenotype. As previously discussed, however, such as the causes of PKU and HPA, the human PAH gene has displayed allelic differences and pathogenic transformations throughout its structure. The common types of mutations and their occurrence according to a previous study are: missense mutations with 62% of the alleles, small or large deletions with 13%, splicing defects with 11%, silent polymorphisms with 6%, nonsense mutations with 5%, and insertions with 2% of the PAH alleles. (6)

Table1 PAH mutation statistics

Mutation Type:
# of Mutation(s)
Missense
336
Deletion
73
Splice
62
Silent
32
Nonsense
28
Insertion
10
Sil./Splice
3
Unknown
3

Total mutations: 547

Most reported Mutation

(Association): p.R408W (214)

Missense, as can be seen above, is the most common cause of mutation in the PAH gene, the molecular mechanism of this is the improper folding of the protein structure, causing aggregation or degradation. As mentioned earlier, the mutations of PAH are commonly caused by single changes in the amino acid. One of the missense mutations, for example, occurs in E1 nucleotide 1 with the change of ATG to GTG. However, there is also missense mutation in region E3 with sequence 187.000 in nucleotide 187; this is called ACC/CCC;CAC/AAC. The second most common type of mutation is deletion. An example of deletion mutation is in regions E2-12 with sequence 168.001 in nucleotide 168. This is called GAG/GAA;G/A and has been noted to have occurred in Palestinians Arabs. (2, 3, 12)  Other examples can be seen in Appendix (I).

As mentioned earlier, there are three common variations of PKU: classical PKU, MHP, and non-PKU HPA. These variations which are basically different degrees of severity of the disorder are caused by the different kinds of mutations that cause varying PAH activity as well as allelic variations. The latter effect at the locus of the gene determines the metabolic phenotype of the enzyme deficiency. In general, however, the mutations in the PAH gene are localized in a main part of the gene instead of being randomly distributed, as they occur either within or without the active site. What is interesting to note is that the PAH gene in intron 12 involves the single base change of guanine to adenine in the canonical 5-prime splice donor site where the first identified PKU mutation occurred. (3)

Two out of the 6 links given by the Gene Gateway page were no longer working, one was solely dedicated to SNP, one was a link to a database that had links to other databases, and the last two were already explored thoroughly in previous parts of this assignment. The data presented in this section were mostly from the entire site dedicated to PAH gene mutations, the Phenylalanine Hydoxylase Locus Knowledgebase (5). This site, also a database, was arrived at after searching through the Locus Specific Mutation Databases which in turn arrived at from Human Genome Variation Society: Variation Databases and Related Sites. While the OMIM site did give some details about previous studies related to PAH gene mutations, they were more of a history of the mutations and examples of the studies. Finding the needed information was difficult because one needed to go through link after link and website after website, sometimes even arriving at the same website numerous times through different pathways and still not obtaining any results. The PAHdb was by far, the only site that showed any data regarding the common mutations.

Single nucleotide polymorphisms (SNPs) of the PAH gene:

To date, 1220 SNPs for the PAH gene have been discovered, although GeneCards (2) states only 1097 from the NCBI website. In general, the SNPs involve the changing of a single base, as shown in Appendices I and II. Examples are the three found on exon 3, each of which has a single change of base, name cytocine, thiamine, and adeninine(13).

Examples of these PAH gene SNPs are the rs63749677, rs63749676, rs63581460 and rs63499960; some of these are tabulated in Appendix (II). These SNPs are not randomly distributed as out of the 13 exons, they are seen in exons 1-7 and 12. Searching the NCBI website, however, resulted in 55 entries of SNPs with the following format:

rs79931499 [Homo sapiens]

CAATCCTTTGGGTGTATGGGTCGTAG[C/G]GAACTGAGAAGGGCCGAGGTATTGT

12

The above entry, an example of the results from the query in the NCBI SNP website, shows essential information about the SNP as well as options one can view. Compared to the other related links, which did not yield any useful information other than linking back to this site, the NCBI site dedicated purely to SNPs was simple and the information was easy to retrieve. Due to the very large number of SNPs, however, it would be difficult to evaluate all of them.

Designing PCR primers:

The given instructions and the program given in the website were rather straightforward, so the designing of the primer was the easiest part of the activity. The mRNA sequence was easily downloadable and the program was user-friendly (14). Being able to design primers this way was very fast and easy. The resulting primers are in Appendix (III).

References:

1. [26/08/10]; Available from: <http://www.ncbi.nlm.nih.gov/omim/612349>

2. Hoeks M, den Heijer M, Janssen M. Adult issues in phenylketonuria. The Netherlands journal of medicine2009;67(1):2.

3. [21/09/09]; Available from: <http://www.ensembl.org/index.html>.

4. [26/08/10]; Available from: <http://www.genecards.org/cgi-bin/carddisp.pl?gene=PAH&search=pah#loc>

5. [26/08/10]; Available from: <http://www.pahdb.mcgill.ca>.

6. Carter K, Byck S, Waters P, Richards B, Nowacki P, Laframboise R, et al. Mutation at the phenylalanine hydroxylase gene (PAH) and its use to document population genetic variation: the Quebec experience. European Journal of Human Genetics1998;6(1):61-70.

7.  [26/08/10]; Available from: <http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gnd&part=phenylketonuria>

8. [26/08/10]; Available from: <http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=pku>

9. [26/08/10]; Available from: <http://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000171759;r=12:103232104-103311381;t=ENST00000307000>

10. [26/08/10]; Available from: <http://www.ncbi.nlm.nih.gov/projects/mapview/maps.cgi?taxid=9606&chr=12&MAPS=pheno,morbid,genec,decode,ensrna,ensgenes,rnaRn,rnaMm,rnaHs,rnaGga,rnaBt,gbdna,rna,ugHs,genes-r&cmd=focus&fill=80&query=uid(136508683,136446655,12845117,12579049,8990832,717234,698472,11088097,11049717,6481463,570698,568170,34586070,16320694,13572526,34590012,128619463,415205)&QSTR=pah>

11. [26/08/10]; Available from: <http://www.ncbi.nlm.nih.gov/projects/sviewer/?id=NT_029419.12&v=65375409..65454686>

12. *Robin A Williams, 2 Cyril DS Mamotte,2 *John R Burnett1,3. Phenylketonuria: An Inborn Error of Phenylalanine Metabolism

13.         [updated 21/09/09]; Available from: <http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=5053>

14.         [21/09/09]; Available from: <http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi>

Appendices:

Appendix (I) Examples

1.
Systematic Name:
c.1A>G
Region:
E1
Reference (1st):
Mutation Name:
p.M1V
Sequence:
0.000
JOHN SW, ROZEN R, LAFRAMBOISE R, LABERGE C, SCRIVER CR: Novel PKU mutation on haplotype 2 in French-Canadians. Am J Hum Genet 45:905-909, 1989
Other Name:
ATG/GTG
Length:
1
Nucleotide No.:
1
Rest. Site:
-Xba I
Mutation Type:
Missense
Syst. Name gDNA:

Date Entered:
1997-01-31
CpG/Fs/Pm:
No/No/No

2.
Systematic Name:
c.3G>A
Region:
E1
EIKEN HG, KNAPPSKOG PM, APOLD J, SKJELKVÅLE L, BOMAN H: A de novo phenylketonuria mutation: ATG (Met) to ATA (Ile) in the start codon of the phenylalanine hydroxylase gene. Hum Mut 1:388-391, 1992
Mutation Name:
p.M1I
Sequence:
3.000
Other Name:
ATG/ATA
Length:
1
Nucleotide No.:
3
Rest. Site:
-NspI
Mutation Type:
Missense
Syst. Name gDNA:

Date Entered:
1997-01-31
CpG/Fs/Pm:
No/No/No

3.
Systematic Name:
c.117C>G
Region:
E2
FORREST SM, DAHL HH, HOWELLS DW, DIANZANI I, COTTON RGH: Mutation detection in phenylketonuria by using chemical cleavage of mismatch: Importance of using probes from both normal and patient samples. Am J Hum Genet 49:175-183, 1991
Mutation Name:
p.F39L
Sequence:
117.000
Other Name:
TTC/TTG
Length:
1
Nucleotide No.:
117
Rest. Site:
-MboII, +MaeIII
Mutation Type:
Missense
Syst. Name gDNA:

Erlandsen H, Pey AL, Gámez A, Pérez B, Desviat LR, Aguado C, Koch R, Surendran S, Tyring S, Matalon R, Scriver CR, Ugarte M, Martínez A, Stevens RC.: Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations.
Date Entered:
1997-01-31
CpG/Fs/Pm:
No/No/No

Appendix (II) SNPs of the PAH gene

Region
Contig
position
mRNA
pos
dbSNP rs#
cluster id
Hetero-
zygosity
Function
dbSNP
allele
Protein
residue
Codon
pos
Amino acid
pos
exon_12
26716405
1750
rs59326968
N.D.
synonymous
C
Asn [N]
3
426

contig reference
T
Asn [N]
3
426

exon_7
26728783
1314
rs5030851
N.D.
missense
T
Leu [L]
2
281

contig reference
C
Pro [P]
2
281

exon_6
26731200
1061
rs5030653
N.D.
missense
(22bp)
[CIKPMLAN]
1
197

frame shift
-/TGTATAAAACCCATGCTTGCTA

1
197

contig reference
(22bp)
[LYKTHACY]
1
197

26731262
1020
rs17852373
N.D.
missense
G
Gly [G]
2
183

contig reference
A
Glu [E]
2
183

exon_3
26770856
671
rs5030842
N.D.
missense
C
Pro [P]
1
67

contig reference
T
Ser [S]
1
67

contig reference
A
Ser [S]
3
36
exon_1
26793098
474

start codon

1

Appendix (III) Designed Primers

Exon1 ENSE00001141448
CAGCTGGGGGTAAGGGGGGCGGATTATTCATATAATTGTTATACCAGACGGTCGCAGGCT
TAGTCCAATTGCAGAGAACTCGCTTCCCAGGCTTCTGAGAGTCCCGGAAGTGCCTAAACC
TGTCTAATCGACGGGGCTTGGGTGGCCCGTCGCTCCCTGGCTTCTTCCCTTTACCCAGGG
CGGGCAGCGAAGTGGTGCCTCCTGCGTCCCCCACACCCTCCCTCAGCCCCTCCCCTCCGG
CCCGTCCTGGGCAGGTGACCTGGAGCATCCGGCAGGCTGCCCTGGCCTCCTGCGTCAGGA
CAACGCCCACGAGGGGCGTTACTGTGCGGAGATGCACCACGCAAGAGACACCCTTTGTAA
CTCTCTTCTCCTCCCTAGTGCGAGGTTAAAACCTTCAGCCCCACGTGCTGTTTGCAAACC
TGCCTGTACCTGAGGCCCTAAAAAGCCAGAGACCTCACTCCCGGGGAGCCAGCATGTCCA
CTGCGGTCCTGGAAAACCCAGGCTTGGGCAGGAAACTCTCTGACTTTGGACAG

PCR primer design:

No mispriming library specified
Using 1-based sequence positions
OLIGO                       start   len    tm       gc%   any    3′       seq
LEFT PRIMER          369   20   59.83   55.00  6.00  2.00   TCCTCCCTAGTGCGAGGTTA
RIGHT PRIMER       522   20   59.98   55.00  3.00  2.00   CAGAGAGTTTCCTGCCCAAG
SEQUENCE SIZE: 533
INCLUDED REGION SIZE: 533

PRODUCT SIZE: 154, PAIR ANY COMPL: 4.00, PAIR 3′ COMPL: 3.00

1 CAGCTGGGGGTAAGGGGGGCGGATTATTCATATAATTGTTATACCAGACGGTCGCAGGCT

61 TAGTCCAATTGCAGAGAACTCGCTTCCCAGGCTTCTGAGAGTCCCGGAAGTGCCTAAACC

121 TGTCTAATCGACGGGGCTTGGGTGGCCCGTCGCTCCCTGGCTTCTTCCCTTTACCCAGGG

181 CGGGCAGCGAAGTGGTGCCTCCTGCGTCCCCCACACCCTCCCTCAGCCCCTCCCCTCCGG

241 CCCGTCCTGGGCAGGTGACCTGGAGCATCCGGCAGGCTGCCCTGGCCTCCTGCGTCAGGA

301 CAACGCCCACGAGGGGCGTTACTGTGCGGAGATGCACCACGCAAGAGACACCCTTTGTAA

361 CTCTCTTCTCCTCCCTAGTGCGAGGTTAAAACCTTCAGCCCCACGTGCTGTTTGCAAACC
>>>>>>>>>>>>>>>>>>>>
421 TGCCTGTACCTGAGGCCCTAAAAAGCCAGAGACCTCACTCCCGGGGAGCCAGCATGTCCA

481 CTGCGGTCCTGGAAAACCCAGGCTTGGGCAGGAAACTCTCTGACTTTGGACAG
<<<<<<<<<<<<<<<<<<<<
KEYS (in order of precedence):
>>>>>> left primer
<<<<<< right primer

ADDITIONAL OLIGOS
start   len    tm       gc%   any      3′            seq

1 LEFT PRIMER         339   20   59.77   50.00   3.00   1.00     ACGCAAGAGACACCCTTTGT
RIGHT PRIMER       522   20   59.98   55.00   3.00   2.00      CAGAGAGTTTCCTGCCCAAG
PRODUCT SIZE: 184, PAIR ANY COMPL: 6.00, PAIR 3′ COMPL: 2.00

2 LEFT PRIMER        318   20   59.32   55.00  4.00  2.00 GTTACTGTGCGGAGATGCAC
RIGHT PRIMER       522   20   59.98   55.00  3.00  2.00 CAGAGAGTTTCCTGCCCAAG
PRODUCT SIZE: 205, PAIR ANY COMPL: 4.00, PAIR 3′ COMPL: 2.00

3 LEFT PRIMER        157   20   60.07   55.00  2.00  0.00 CTGGCTTCTTCCCTTTACCC
RIGHT PRIMER       337   20   59.32   55.00  4.00  3.00 GTGCATCTCCGCACAGTAAC
PRODUCT SIZE: 181, PAIR ANY COMPL: 4.00, PAIR 3′ COMPL: 1.00

4 LEFT PRIMER        156   20   60.07   55.00  3.00  0.00 CCTGGCTTCTTCCCTTTACC
RIGHT PRIMER       337   20   59.32   55.00  4.00  3.00 GTGCATCTCCGCACAGTAAC
PRODUCT SIZE: 182, PAIR ANY COMPL: 4.00, PAIR 3′ COMPL: 2.00

Statistics
con   too    in    in          no    tm    tm  high  high        high
sid  many   tar  excl   bad    GC   too   too   any    3′  poly   end
ered    Ns   get   reg   GC% clamp   low  high compl compl     X  stab    ok
Left    3637     0     0     0   162     0   419  2558     0     2    22    73   401
Right   3701     0     0     0   130     0   321  2817     0     2     0    78   353
Pair Stats:
considered 140, unacceptable product size 129, high end compl 3, ok 8
primer3 release 1.1.4

KEYS (in order of precedence):
>>>>>> left primer
<<<<<< right primer

ADDITIONAL OLIGOS
start   len    tm       gc%   any    3′         seq

1 LEFT PRIMER         19   20   60.21   50.00  5.00  2.00     GCAGTGCCCTCCAGAAAATA
RIGHT PRIMER       265   20   58.12   40.00  3.00  0.00   TCAAAGATGACCCCAAAAGA
PRODUCT SIZE: 247, PAIR ANY COMPL: 2.00, PAIR 3′ COMPL: 0.00

2 LEFT PRIMER         19   20   60.21   50.00  5.00  2.00    GCAGTGCCCTCCAGAAAATA
RIGHT PRIMER       260   22   60.05   40.91  4.00  0.00   GATGACCCCAAAAGATTTACCA
PRODUCT SIZE: 242, PAIR ANY COMPL: 4.00, PAIR 3′ COMPL: 1.00

3 LEFT PRIMER         45   20   60.39   50.00  6.00  1.00    AGCCATGGACAGAATGTGGT
RIGHT PRIMER       265   20   58.12   40.00  3.00  0.00   TCAAAGATGACCCCAAAAGA
PRODUCT SIZE: 221, PAIR ANY COMPL: 4.00, PAIR 3′ COMPL: 1.00

4 LEFT PRIMER         19   20   60.21   50.00  5.00  2.00     GCAGTGCCCTCCAGAAAATA
RIGHT PRIMER       258   20   57.92   40.00  4.00  0.00   TGACCCCAAAAGATTTACCA
PRODUCT SIZE: 240, PAIR ANY COMPL: 4.00, PAIR 3′ COMPL: 1.00

Statistics
con   too    in    in          no    tm    tm  high  high        high
sid  many   tar  excl   bad    GC   too   too   any    3′  poly   end
ered    Ns   get   reg   GC% clamp   low  high compl compl     X  stab    ok
Left    7708     0     0     0   791     0  4562   600     0    14     0    52  1689
Right   7734     0     0     0  1269     0  4609   311     0     6     0    44  1495
Pair Stats:
considered 2222, unacceptable product size 2195, high end compl 6, ok 21
primer3 release 1.1.4

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