Molecular Basis of β‐Thalassemia in the Population of Tunisia

HEMOGLOBIN

Vol 28 No 3 pp 177ndash187 2004

ORIGINAL ARTICLE

Molecular Basis of b-Thalassemia in thePopulation of Tunisia

Slaheddine Fattoum Taeib Messaoud and Amina Bibi

Laboratoire de Biochimie et de Biologie Moleculaire

Hopital drsquoEnfants Tunis Tunisie

ABSTRACT

The present study attempts to delineate the spectrum of b-thalassemia (thal) mutations

in Tunisia by studying a large population from different parts of the country A total of

285 unrelated subjects 190 of whom had b-thal major 72 with Hb Sb-thal one with Hb

Cb-thal one with Hb O-Arabb-thal and 21 b-thal carriers were studied The

molecular defects were detected in 977 of the b-thalassemic chromosomes

(n = 475) Nineteen different b-thalassemic alleles were identified Two mutations

namely codon 39 (CT) and IVS-I-110 (GA) accounted for 700 of the studied

chromosomes followed by IVS-I-1 (GA) (45) Five other mutations frameshift

codon (FSC) 44 (ndashC) codon 30 (GC) IVS-I-2 (TG) IVS-II-745 (CG) and

FSC 6 (ndashA) are not uncommon in this population while the remaining 11 mutations

IVS-I-5 (GA) 30 (TA) codons 2526 (+T) IVS-I-6 (TC) FSC 5 (ndashCT) IVS-

II-848 (CA) FSC 8 (ndashAA) ndash87 (CG) IVS-I-5 (GC) IVS-II-1 (GA) and IVS-

II-849 (AC) are quite rare four of these have not been previously reported in the

Tunisian population Potential origin and spread of these mutations to Tunisia are

also discussed

Key Words b-thalassemia (thal) Mutations Regional distribution Tunisia

Correspondence Professor Slaheddine Fattoum Laboratoire de Biochimie et de Biologie

Moleculaire Hopital drsquoEnfants Place Bab-Saadoun 1007 Tunis Tunisie Fax +216-71-566-

463 E-mail slaheddinefattoumrnstn

177

DOI 101081HEM-120040307 0363-0269 (Print) 1532-432X (Online)

Copyright D 2004 by Marcel Dekker Inc wwwdekkercom

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INTRODUCTION

The b-thalassemias are a group of inherited monogenic red blood cell disorders

resulting from reduced (b+) or absent (b0) synthesis of the b-globin chain Their clinical

expression varies from a very severe transfusion-dependent form to mild disease not

requiring any blood transfusions or only occasionally Paralleling (but not necessarily

fully correlating) with such clinical heterogeneity there exists a wide mutational

spectrum with more than 200 mutations described so far worldwide (1) one-third of

which are reported to be of Mediterranean origin Nevertheless each regionpopulation

has been shown to have their own profile of common mutations Defining the precise

spectrum of mutations in a given population is of importance in implementing

strategies for genetic counseling and prenatal diagnosis

Figure 1 Geographical subdivision of Tunisia N = North NE = Northeast NW = Northwest

CE = Central East CW = Central West SE = Southeast SW = Southwest

178 Fattoum Messaoud and Bibi

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Previous surveys of the Tunisian population have indicated that thalassemias are

the most frequently encountered hemoglobinopathies in this country (2) Their

distribution concerned the regions of North Tunisia including all the northwestern

and northeastern areas (Bizerte and Zaghouan) the central western and central eastern

areas (Sousse) as well as southwestern Tunisia (Gafsa) (Fig 1)

Almost all b-thalassemic patients from Tunisia suffer from severe anemia and are

regularly transfused At the molecular level previous DNA analysis performed in 1988

on 68 b-thalassemia (thal) genes of patients from central Tunisia detected six different

mutations and failed to identify 38 of b-thal alleles (3) suggesting that the yet to be

deciphered molecular defects are present in this population at a significant frequency

Later on in 1991 a study conducted in the northern part of Tunisia on 44 b-thal

chromosomes (4) identified nine additional b-thal alleles

While the recorded b-thalassemic patients exceeds 520 cases originating from all

over the country the previous studies were limited to the central and northern regions of

Tunisia and hence cannot provide an accurate picture of b-thal mutations in Tunisia In

the present report we provide data of a study that is a logical extension of previous

studies It involves a cohort of 285 unrelated b-thal patients from various regions of

Tunisia With this study we have attempted to expand the mutational spectrum in Tunisia

in order to facilitate genetic counseling and antenatal diagnosis procedures

MATERIALS AND METHODS

Subjects

The patients and their relatives originate from different parts of Tunisia They were

identified either during targeted screening procedures or referred to us by other

hospitals for hemoglobin (Hb) study or prenatal diagnosis The participants grouped

according to the geographical origin of their families are shown in Table 1

Methods

Hematological data were obtained with an automated blood cell counter Informed

consent was obtained from all patients or parents Hemoglobin analyses were carried

Table 1 Geographical distribution of the studied population

N amp NE NW CW CE S Total

b-Thalassemia major 36 64 62 14 14 190

b-Thal carrier 7 6 4 3 1 21

Hb Sb-thal 14 50 6 2 ndash 72

Hb Cb-thal ndash 1 ndash ndash ndash 1

Hb O-Arabb-thal ndash 1 ndash ndash ndash 1

Total 57 122 72 19 15 285

Total () 200 428 252 67 53 1000

bb-Thalassemia Mutations in Tunisia 179

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-I-1

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T

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IVS

-II-

1

G

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out by cellulose acetate electrophoresis at pH 86 citrate agar electrophoresis at pH 61

(5) and by isoelectric focusing (IEF) (6) wherever appropriate Hbs A2 S C and

O-Arab levels were determined by the cellulose acetate elution procedure (7) Hb F

level was assessed by an alkali denaturation method (8) Much more recently we

started to use a high-performance liquid chromatography (HPLC)-based method for

the phenotype analysis

DNA was extracted from white blood cells according to the method described by

Poncz et al (9) b-Thal mutations were detected by polymerase chain reaction (PCR)-

based procedures (10) including the reverse dotndashblot technique as described elsewhere

(1112) Sequences (kindly provided by Dr Jacques Elion Hopital Robert Debre Paris

France) of oligonucleotide probes and PCR primers used in the reverse dotndashblots are

shown in Table 2 DNA sequencing was done by an automatic sequencing procedure

with a BigDye-Terminator cycle sequencing ready reaction kit (Applied BioSystems

Warrington Lancashire UK)

RESULTS

The reverse dot-blot procedure enabled us to identify 18 mutations namely the

codon 39 (CT) IVS-I-110 (GA) IVS-I-1 (GA) frameshift codon (FSC) 44 (ndashC)

IVS-I-2 (TG) codon 30 (GC) IVS-II-745 (CG) FSC 6 (ndashA) 87 (CG)

IVS-I-5 (GA) IVS-I-5 (GC) 30 (TA) IVS-I-6 (TC) IVS-II-1 (GA) FSC

Table 3 Frequency of b-thalassemia alleles in Tunisia

Mutation Type

Number of chromosomes

Homozygous

state

Heterozygote

state

Total

(n)

Frequency

()

Codon 39 CT b0 156 76 232 490

IVS-I-110 GA b+ 70 30 100 210

IVS-I- GA b0 14 7 21 45

FSC 44 ndashC b0 6 12 18 38

Codon 30 GC b+ 12 3 15 32

IVS-I-2 TG b0 12 2 14 30

IVS-II-745 CG b+ 6 6 12 26

FSC 6 ndashA b0 8 4 12 26

ndash87 CG b+ 4 4 8 17

IVS-I-5 GA b+ 2 5 7 15

IVS-I-5 GC b+ 4 1 5 10

ndash30 TA b+ 2 2 4 08

Codons 2526 +T b0 2 1 3 06

IVS-I-6 TC b+ 2 1 3 06

IVS-II-1 GA b0 2 1 3 06

FSC 5 ndashCT b0 2 ndash 2 04

IVS-II-848 CA b+ ndash 2 2 04

IVS-II-849 AC b0 2 ndash 2 04

Codon 8 ndashAA b0 ndash 1 1 02

Unidentified 4 7 11 23

Total 310 165 475 1000


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5 (ndashCT) IVS-II-848 (CA) IVS-II-849 (AC) FSC 8(ndashAA) DNA sequencing of

the targeted b-globin gene region permitted us to identify the codons 2526 (+T)

mutation previously reported in the Tunisian population (4)

For a total of 475 chromosomes 977 of the molecular defects were detected

Nineteen different mutations associated with either b0- or b+-thalassemias (Table 3)

Two of these with frequencies higher than 20 are prevalent in many regions and

account for 700 of the analyzed chromosomes The nonsense codon 39 (CT)

mutation is the most common defect followed by IVS-I-110 (GA) Four mutations

have frequencies ranging between 30 and 45 IVS-I-1 (GA) FSC 44 (ndashC) codon

30 (GC) and IVS-I-2 (TG) The two latter mutations were described for the first

time in Tunisian patients (3) Four other mutations were encountered less frequently

IVS-II-745 (CG) FSC 6 (ndashA) 87 (CG) and IVS-I-5 (GA) which are known

to be common in the Mediterranean region The remaining nine mutations are rare not

exceeding 1 in the Tunisian population About 23 of the b-thal alleles have not

been identified by the available diagnostic methods and need further investigation by

DNA sequencing of the entire b- globin gene

DISCUSSION

A large majority of b-thal alleles (672) are from northwestern and central

western regions defining these areas as high-risk areas for b-thal in Tunisia

Table 4 Distribution and frequency of the b-thalassemia alleles in different regions of Tunisia

Mutation

N amp NE NW CW CE S

n n n n n

Codon 39 CT 39 419 103 560 61 455 19 576 8 276

IVS-I-110 GA 9 97 27 147 47 351 5 151 12 414

IVS-I-1 GA 10 108 6 33 5 37 ndash ndash ndash ndash

FSC 44 ndashC 10 108 7 38 ndash ndash 1 30 ndash ndash

IVS-I-2 TG ndash ndash ndash ndash 4 3 3 91 7 242

Codon 30 GC 2 21 8 44 5 27 ndash ndash ndash ndash

IVS-II-745 CG 3 32 9 49 ndash ndash ndash ndash ndash ndash

FSC 6 ndashA 6 65 2 11 2 15 2 61 ndash ndash

87 CG 5 54 1 05 2 15 ndash ndash ndash ndash


IVS-I-5 GC ndash ndash 5 27 ndash ndash ndash ndash ndash ndash

30 TA ndash ndash 4 22 ndash ndash ndash ndash ndash ndash

Codons 2526 +T ndash ndash 3 16 ndash ndash ndash ndash ndash ndash

IVS-I-6 TC ndash ndash 1 05 2 15 ndash ndash ndash ndash

IVS-II-1 GA 1 11 2 11 ndash ndash ndash ndash ndash ndash

FSC 5 ndashCT 2 21 ndash ndash ndash ndash ndash ndash ndash ndash

IVS-II-848 CA ndash ndash ndash ndash ndash ndash 1 30 1 34

IVS-II-849 AC 2 21 ndash ndash ndash ndash ndash ndash ndash ndash

FSC 8 ndashAA ndash ndash ndash ndash ndash ndash ndash ndash 1 34

Unidentified 3 32 1 05 5 37 2 61 ndash ndash

Total 93 1000 184 1000 134 1000 33 1000 29 1000


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Nevertheless they were also found in almost every part of Tunisia albeit at different

frequencies (Table 4) and the most common mutations namely codon 39 (CT) and

IVS-I-110 (GA) are found at significant frequencies in almost all parts of the

country Interestingly the IVS-I-1 (GA) allele was found in the north and northwest

areas with a peak of prevalence around Bizerte where the largest number of patients

carrying this mutation was found Similarly the IVS-II-745 (CG) allele was found

with a high frequency around Beja although an isolated case from Central Tunisia had

been reported previously (3) In addition the codons 2526 (+T) mutation (4) clusters

around Beja in the northwest and the IVS-I-2 (TG) allele was found in Gafsa and

Tozeur in the southwest as well as in Mahdia and Sfax in the central eastern region

The latter two mutations have been found in the homozygous state in these areas They

may represent autochthonous alleles of Tunisia The codon 30 (GC) mutation also

found in the homozygous state around Jendouba and extending towards the central

western area has also been reported from many parts of the world It would be of

interest to investigate if this mutation is related to those found in American Blacks

(13) India (14) and United Arab Emirates (1516) by determining the linked sequence

polymorphisms We also note the presence of other mutations in our population that

have already been described such as the IVS-I-5 (GA) in Algeria (17) IVS-II-848

(CA) in Egypt (18) 30 (TA) in Turkey (19) and FSC 44 (ndashC) in the Kurdish

population (20)

Over 190 thalassemia major patients in our series (805) were found to carry the

same mutation on both chromosomes demonstrating the high proportion of true

homozygotes among Tunisian thalassemic patients Homozygosity observed for the most

frequent b-thal mutations as well (strikingly) as for the rare ones suggest that the high

consanguinity rate observed in the Tunisian population with a mean of around 33 but

reaching 60 in some regions (21) is very likely responsible for this situation

Of the 32 different b-thal alleles reported in the Maghreb countries (Table 5) the

eight most common mutations were observed in all three countries but at variable

frequencies They account for 815 882 and 778 respectively of the total b-thal

mutations found in Tunisia Algeria (22) and Morocco (23) The codon 39 (CT) and

IVS-I-1 (GA) mutations are common in these three countries with a clear

predominance of codon 39 which was presumably introduced into North Africa

through the Roman and Phoenician civilizations between the 12th and 11th centuries

BC The IVS-I-110 (GA) mutation was observed in Tunisia and Algeria but not in

Morroco This mutation might have been introduced during the Ottoman domination

between the 16th and 19th centuries in these two countries and Morocco was spared

this influence On the other hand the common Mediterranean IVS-I-6 (TC) mutation

which seems to be rare in Algeria and Tunisia is much more frequent in Morocco

(148) and may be related to the input via Portugal and Spain The FSC 8 (ndashAA)

anomaly is the most frequent allele (along with the codon 39 mutation) in Morocco

while it is very rare in Tunisia and seems to be absent in Algeria The FSC 6 (ndashA)

appears to be more prevalent in Algeria (171) than in the other two countries In

fact the distribution of b-thal mutations is different from one region to another in the

population of Algeria (2224) The FSC 44 (ndashC) was observed only in the Tunisian

population where it seems to be relatively common as it is the fourth most common

b-thal allele in this study This mutation was also reported in the Mediterranean Basin

and other eastern parts with a high frequency in the Kurdish population (25)


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Haplotyping of this mutation would be useful to provide further information about its

origin in the Tunisian population

In conclusion a total of 19 different b-thal mutations have been identified in the

population of Tunisia The eight most common mutations account for 863 of the

total b-thal mutations including the two predominant alleles namely the codon 39

(CT) and IVS-I-110 (GA) We also found that two mutations typical of Tunisia

Table 5 Frequency of b-thalassemia mutations in the Maghreb countries

References

Tunisia () Algeria () Morocco ()

This paper 2224 23

Most common mutations Codon 39 TC 486 276 155 IVS-I-110 GA 212 247 200 FSC 6 ndashA 26 171 100 FSC 8 ndashAA 02 ndash 155 IVS-I-6 TC 06 33 148 IVS-I-1 GA 45 117 130 29 AG ndash 38 70 FSC 44 ndashC 38 ndash ndash

Less common mutations IVS-I-2 TC ndash 33 30 Codon 30 GC 32 09 ndash IVS-I-2 TG 30 ndash ndash IVS-II-745 CG 26 09 10 Codon 37 GA ndash ndash 20 Poly A TC ndash ndash 20 87 CG 17 ndash ndash IVS-I-5 GA 15 09 ndash IVS-I-2 TA ndash 13 ndash

Rare mutations IVS-I-5 GC 10 04 ndash +20 CT ndash ndash 10 101 CT ndash ndash 10 28 AG ndash ndash 10 IVS-I-130 GA ndash ndash 10 25 bp deletion 3rsquoIVS-I ndash ndash 10 IVS-II-1 GA 06 ndash 10 30 TA 08 04 ndash Codons 2526 +T 06 ndash ndash FSC 5 ndashCT 04 ndash ndash IVS-II-843 TG ndash 04 ndash IVS-II-848 CA 04 04 ndash IVS-II-849 AC 04 ndash ndash Codon 27 (Hb Knossos) ndash 04 ndash Hb Lepore-Boston-Washington ndash 04 ndash

Unidentified 23 21 3

Total number of studied chromosomes 475 239 90


IVS-I-2 (TG) and codons 2526 (+ T) could represent autochthonous alleles to this

country Knowledge of the b-thal spectrum and their geographical distribution are of

interest and a prerequisite for effective genetic counseling and prevention of this

hereditary disorder in our population

ACKNOWLEDGMENTS

We would like to acknowledge the help of Dr Jacques Elion INSERM U458

Hopital Robert Debre Paris France in many steps of our study particularly for

initiating the reverse dotndashblot procedure and for very fruitful discussions We wish to

thank all our colleagues who have kindly referred their patients to us This work has

been supported by the Tunisian Secretariat drsquoEtat a la Recherche Scientifique et a la

Technologie (LR2000 Lab Sante -01)

REFERENCES

1 Huisman THJ Carver MFH The b- and d-thalassemia repository (ninth edition

part I) Hemoglobin 1998 22(2)169ndash1952 Fattoum S Abbes S Some data on the epidemiology of hemoglobinopathies in

Tunisia Hemoglobin 1985 9(4)423ndash4293 Chibani J Vidaud M Duquesnoy P Berge-Lefranc JL Pirastu M Ellouze F Rosa

J Goossens M The peculiar spectrum of b-thalassemia genes in Tunisia Hum

Genet 1988 78190ndash1924 Fattoum S Guemira F Oner C Oner R Li H-W Kutlar F Huisman THJ

b-Thalassemia Hb S b-thalassemia and sickle cell anemia among Tunisians

Hemoglobin 1991 15(1amp2)11ndash215 Huisman THJ Jonxis JHP The Hemoglobinopathies Techniques of Identification

In Clinical and Biochemical Analysis Vol 6 New York Marcel Dekker Inc1977

6 Righetti PG Gianazza E Bianchi-Bosisio A Cossu G Conventional isoelectric

focusing and immobilized pH gradients for hemoglobin separation and identifi-

cation In Huisman THJ ed The Hemoglobinopathies Edinburgh Churchill

Livingstone Vol 15 198647ndash707 Marengo-Rowe AJ Rapid electrophoresis and quantification of hemoglobins on

cellulose acetate J Clin Pathol 1965 18790ndash7928 Pembrey ME McWade P Weatherall DJ Reliable routine estimation of small

amounts of foetal hemoglobin by alkali denaturation J Clin Pathol 197225(8)738ndash740

9 Poncz M Solwiejczyk D Harpel B Mory Y Schwartz E Surrey S Construction of

human genes libraries from small amounts of peripheral blood analysis of b-like

globin genes Hemoglobin 1982 6(1)27ndash3610 Saiki RK Walsh PS Levenson CH Erlich HA Genetic analysis of amplified DNA

with immobilized sequence-specific oligonucleotide probes Proc Natl Acad Sci

U S A 1989 866230ndash623411 Maggio A Giambona A Cai SP Wall J Kan YW Chehab FF Rapid and


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oglo

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onal

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onl

y

simultaneous typing of Hemoglobin S Hemoglobin C and seven Mediterranean

mutations by covalent reverse dot-blot analysis application to prenatal diagnosis in

Sicily Blood 1993 81(1)239ndash24212 Cai SP Wall J Kan YW Chehab FF Reverse dot blot probes for the screening of

b-thalassemia mutations in Asians and American Blacks Hum Mutat 19943(1)59ndash63

13 Redondo-Gonzalez JM Stoming TA Kutlar F Kutlar A Hu H Wilson JB

Huisman THJ Hb Monroe or a2b230(B12)ArgThr a variant associated b-thal-

assemia due to a GC substitution adjacent to the donor splice site of the first

intron Hemoglobin 1989 13(1)67ndash7414 Agarwal S Pradhan M Gupta UR Sarwai S Agarwal SS Geographic and ethnic

distribution of b-thalassemia mutations in Uttar Pradesh India Hemoglobin 200024(2)89ndash97

15 Baysal E Hemoglobinopathies in the United Arab Emirates Hemoglobin 200125(2)247ndash253

16 Adekile AD Historical and anthropological correlates of bS haplotypes and a- and

b-thalassemia alleles in the Arabian Peninsula Hemoglobin 1997 21(3)281ndash29617 Lapoumeroulie C Pagnier J Bank A Labie D Krishnamoorthy R b-Thalassemia

due to a novel mutation in IVS-1 sequence donor site consensus creating a

restriction site Biochem Biophys Res Commun 1986 139709ndash71318 Waye JS Borys S Eng B Patterson M Chui DHK Badr El-Din OMK Khairy Aref M

M Afify Z Spectrum of b-thalassemia mutations in Egypt Hemoglobin 199923(3)255ndash262

19 Fei YJ Stoming TA Efremov GD Efremov DG Battacharia R Gonzalez-Redondo JM

JM Altay C Gurgey A Huisman THJ b-Thalassemia due to a TA mutation

within the ATA box Biochem Biophys Res Commun 1988 153741ndash74720 Kinniburgh AJ Maquat LE Schedl T Rachmilewitz E Ross J mRNA-deficient b-

thalassemia results from a single nucleotide deletion Nucleic Acids Res 198210(18)5421ndash5427

21 Riou S El Younsi C Chaabouni H Consanguinity in the population of Northern

Tunisia La Tunisie Medicale 1989 67(3)167ndash17222 Bennani C Bouhass R Perrin-Pecontral P Tamouza R Malou M Elion J

Trabuchet G Beldjord C Benabadji M Labie D Anthropological approach to the

heterogeneity of b-thalassemia mutations in Northern Africa Hum Biol 199466(3)369ndash382

23 Lemsaddek W Picanco I Seuanes F Mahmal L Benchekroun S Khattab M

Nogueira P Osorio-Almeida L Spectrum of b thalassemia mutations and Hb F

levels in the heterozygous Moroccan population Am J Hematol 2003 73161ndash16824 Bouhass R Perrin P Trabuchet G The spectrum of b-thalassemia mutations in the

Oran region of Algeria Hemoglobin 1994 18(3)211ndash21925 Weatherall DJ Clegg JB The Thalassaemia Syndromes 4th ed Oxford Blackwell

Scientific Publications 2001

Received December 16 2003Accepted February 16 2004


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INTRODUCTION

The b-thalassemias are a group of inherited monogenic red blood cell disorders

resulting from reduced (b+) or absent (b0) synthesis of the b-globin chain Their clinical

expression varies from a very severe transfusion-dependent form to mild disease not

requiring any blood transfusions or only occasionally Paralleling (but not necessarily

fully correlating) with such clinical heterogeneity there exists a wide mutational

spectrum with more than 200 mutations described so far worldwide (1) one-third of

which are reported to be of Mediterranean origin Nevertheless each regionpopulation

has been shown to have their own profile of common mutations Defining the precise

spectrum of mutations in a given population is of importance in implementing

strategies for genetic counseling and prenatal diagnosis

Figure 1 Geographical subdivision of Tunisia N = North NE = Northeast NW = Northwest

CE = Central East CW = Central West SE = Southeast SW = Southwest


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Subjects





Methods










Total 57 122 72 19 15 285

Total () 200 428 252 67 53 1000


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AC

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Ag

AC

CT

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M

AG

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AN

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AA

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M

CT

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AG

AT

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GT

AT

FS

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C

AA

AC

AG

AC

AC

CA

TG

GT

GC

AC

CT

GA

CT

CC

T

M

TC

AA

AC

AG

AC

AC

CA

TG

GT

GC

AC

CT

GA

GT

CG

FS

C4

4

ndashC

N

TC

TT

TG

AG

TC

CT

TT

GG

GG

A

M

CA

GA

TC

CC

CA

AA

GA

CT

CA

A

Co

do

n3

0

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CN

A

TA

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AA

CC

TG

CC

CA

G

M

CT

GG

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AC

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GT

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G

AN

C

CT

TG

AT

AC

CA

AC

CT

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M

GC

AG

GT

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AT

AT

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AG

G

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G

CN

C

CT

TG

AT

AC

CA

AC

CT

GC

M

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AG

GT

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AG

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CT

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AT

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AC

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GC

M

CA

GG

TT

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TC

AA

GG

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IVS

-I-2

T

GN

A

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AA

CC

TG

CC

CA

G

M

AT

AC

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CC

CT

GC

CC

AG


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413

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IVS

-II-

1

G

AN

A

AC

TT

CA

GG

GT

GA

GT

CT

AT

M

CT

TC

AG

GA

TG

AG

TC

TA

TG

G

FS

C6

ndash

AN

T

GA

CT

CC

TG

AG

GA

GA

AG

T

M

GC

AG

AC

TT

CT

CC

CA

GG

FS

C8

ndash

AA

N

AG

GA

GA

AG

TC

TG

CC

GT

T

M

AC

GG

CA

GA

CC

TC

CT

CA

ndash8

7

C

GN

G

GA

GC

CA

CA

CC

CT

AG

M

AC

CC

TA

GC

GT

GT

GG

C

ndash3

0

T

AN

G

CA

GG

GA

GG

GC

AG

GA

GC

CA

GG

GC

TG

GG

CA

A

M

AT

AA

AA

GT

CA

GG

GC

AG

AG

CC

AT

CT

AT

TG

CT

IVS

-II-

84

8

C

AN

G

GA

GC

TG

TG

GG

AG

GA

Ch

ina

III

gT

gT

AC

AC

AT

AT

Tg

AC

CA

AA

M

CT

CC

CA

CC

GC

TC

CT

GG

F

CA

CT

gA

CC

TC

CC

AC

AT

TC

CC

IVS

-II-

74

5

C

GN

C

AA

TC

CA

GC

TA

CC

AT

TC

M

GA

AT

GG

TA

CC

TG

GA

TT

G

IVS

-II-

84

9

A

CN

G

GA

GC

TG

TG

GG

AG

GA

M

AT

CT

TC

CT

CC

CA

CG

GC

TC

aB

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late

dp

rim

ers


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info

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com

by

Lak

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rsity

on

031

413

For

pers

onal

use

onl

y















RESULTS






Mutation Type


Homozygous

state

Heterozygote

state

Total

(n)

Frequency

()

Codon 39 CT b0 156 76 232 490

IVS-I-110 GA b+ 70 30 100 210

IVS-I- GA b0 14 7 21 45

FSC 44 ndashC b0 6 12 18 38

Codon 30 GC b+ 12 3 15 32

IVS-I-2 TG b0 12 2 14 30

IVS-II-745 CG b+ 6 6 12 26


ndash87 CG b+ 4 4 8 17

IVS-I-5 GA b+ 2 5 7 15

IVS-I-5 GC b+ 4 1 5 10

ndash30 TA b+ 2 2 4 08

Codons 2526 +T b0 2 1 3 06

IVS-I-6 TC b+ 2 1 3 06

IVS-II-1 GA b0 2 1 3 06






Total 310 165 475 1000


For

pers

onal

use

onl

y

















DISCUSSION




Mutation

N amp NE NW CW CE S

n n n n n

Codon 39 CT 39 419 103 560 61 455 19 576 8 276

IVS-I-110 GA 9 97 27 147 47 351 5 151 12 414



















Total 93 1000 184 1000 134 1000 33 1000 29 1000


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population (20)





























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For

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onal

use

onl

y








References


This paper 2224 23











ACKNOWLEDGMENTS







REFERENCES





















Hem

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413

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onal

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Hem

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031

413

For

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onal

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Subjects





Methods










Total 57 122 72 19 15 285

Total () 200 428 252 67 53 1000


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ble

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lig

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G

M

CT

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AC

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AC

CT

GA

CT

CC

T

M

TC

AA

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AG

AC

AC

CA

TG

GT

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AC

CT

GA

GT

CG

FS

C4

4

ndashC

N

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GG

GG

A

M

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GA

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CC

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AA

GA

CT

CA

A

Co

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A

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G

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M

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IVS

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1

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AN

A

AC

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GT

GA

GT

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AT

M

CT

TC

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GA

TG

AG

TC

TA

TG

G

FS

C6

ndash

AN

T

GA

CT

CC

TG

AG

GA

GA

AG

T

M

GC

AG

AC

TT

CT

CC

CA

GG

FS

C8

ndash

AA

N

AG

GA

GA

AG

TC

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CC

GT

T

M

AC

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GA

CC

TC

CT

CA

ndash8

7

C

GN

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GA

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CC

CT

AG

M

AC

CC

TA

GC

GT

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C

ndash3

0

T

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GG

GA

GG

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AG

GA

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GG

GC

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A

M

AT

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8

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AG

GA

Ch

ina

III

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gT

AC

AC

AT

AT

Tg

AC

CA

AA

M

CT

CC

CA

CC

GC

TC

CT

GG

F

CA

CT

gA

CC

TC

CC

AC

AT

TC

CC

IVS

-II-

74

5

C

GN

C

AA

TC

CA

GC

TA

CC

AT

TC

M

GA

AT

GG

TA

CC

TG

GA

TT

G

IVS

-II-

84

9

A

CN

G

GA

GC

TG

TG

GG

AG

GA

M

AT

CT

TC

CT

CC

CA

CG

GC

TC

aB

ioti

ny

late

dp

rim

ers


Hem

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bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y















RESULTS






Mutation Type


Homozygous

state

Heterozygote

state

Total

(n)

Frequency

()

Codon 39 CT b0 156 76 232 490

IVS-I-110 GA b+ 70 30 100 210

IVS-I- GA b0 14 7 21 45

FSC 44 ndashC b0 6 12 18 38

Codon 30 GC b+ 12 3 15 32

IVS-I-2 TG b0 12 2 14 30

IVS-II-745 CG b+ 6 6 12 26


ndash87 CG b+ 4 4 8 17

IVS-I-5 GA b+ 2 5 7 15

IVS-I-5 GC b+ 4 1 5 10

ndash30 TA b+ 2 2 4 08

Codons 2526 +T b0 2 1 3 06

IVS-I-6 TC b+ 2 1 3 06

IVS-II-1 GA b0 2 1 3 06






Total 310 165 475 1000


For

pers

onal

use

onl

y

















DISCUSSION




Mutation

N amp NE NW CW CE S

n n n n n

Codon 39 CT 39 419 103 560 61 455 19 576 8 276

IVS-I-110 GA 9 97 27 147 47 351 5 151 12 414



















Total 93 1000 184 1000 134 1000 33 1000 29 1000


Hem

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bin

Dow

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ded

from

info

rmah

ealth

care

com

by

Lak

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nive

rsity

on

031

413




















population (20)





























Hem

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bin

Dow

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ded

from

info

rmah

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care

com

by

Lak

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d U

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rsity

on

031

413

For

pers

onal

use

onl

y








References


This paper 2224 23











ACKNOWLEDGMENTS







REFERENCES





















Hem

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from

info

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care

com

by

Lak

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on

031

413

For

pers

onal

use

onl

y































Hem

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413

For

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Ta

ble

2

DN

Ase

qu

ence

so

fth

eo

lig

on

ucl

eoti

de

pro

bes

and

PC

Rp

rim

ers

use

dfo

rth

ere

ver

sed

otndash

blo

th

yb

rid

izat

ion

assa

y

Mu

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nu

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tid

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rob

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s

(NH

2)

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do

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C

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AG

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Ch

ina

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TA

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TC

AC

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Ag

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CT

CA

M

AG

AA

CC

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TA

GG

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AG

GP

co6

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Tg

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10

G

AN

G

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AA

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M

CT

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G

AN

A

TA

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G

M

CT

GG

GC

AG

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C5

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AA

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AG

AC

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CT

GA

CT

CC

T

M

TC

AA

AC

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AC

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CA

TG

GT

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AC

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GA

GT

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FS

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4

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TC

CT

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GG

GG

A

M

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TC

CC

CA

AA

GA

CT

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Co

do

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G

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AA

CC

TG

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G

M

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GT

AT

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G

AN

C

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CA

AC

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M

GC

AG

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IVS

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G

CN

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CA

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M

GC

AG

GT

TG

CT

AT

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AG

IVS

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T

CN

C

CT

TG

AT

AC

CA

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GC

M

CA

GG

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GG

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TC

AA

GG

T

IVS

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M

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Hem

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ealth

care

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Lak

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on

031

413

For

pers

onal

use

onl

y

IVS

-II-

1

G

AN

A

AC

TT

CA

GG

GT

GA

GT

CT

AT

M

CT

TC

AG

GA

TG

AG

TC

TA

TG

G

FS

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ndash

AN

T

GA

CT

CC

TG

AG

GA

GA

AG

T

M

GC

AG

AC

TT

CT

CC

CA

GG

FS

C8

ndash

AA

N

AG

GA

GA

AG

TC

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CC

GT

T

M

AC

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CC

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ndash8

7

C

GN

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M

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ndash3

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ina

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AC

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AA

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CT

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TC

CT

GG

F

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gA

CC

TC

CC

AC

AT

TC

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IVS

-II-

74

5

C

GN

C

AA

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TA

CC

AT

TC

M

GA

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GA

TT

G

IVS

-II-

84

9

A

CN

G

GA

GC

TG

TG

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GA

M

AT

CT

TC

CT

CC

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CG

GC

TC

aB

ioti

ny

late

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rim

ers


Hem

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bin

Dow

nloa

ded

from

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rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y















RESULTS






Mutation Type


Homozygous

state

Heterozygote

state

Total

(n)

Frequency

()

Codon 39 CT b0 156 76 232 490

IVS-I-110 GA b+ 70 30 100 210

IVS-I- GA b0 14 7 21 45

FSC 44 ndashC b0 6 12 18 38

Codon 30 GC b+ 12 3 15 32

IVS-I-2 TG b0 12 2 14 30

IVS-II-745 CG b+ 6 6 12 26


ndash87 CG b+ 4 4 8 17

IVS-I-5 GA b+ 2 5 7 15

IVS-I-5 GC b+ 4 1 5 10

ndash30 TA b+ 2 2 4 08

Codons 2526 +T b0 2 1 3 06

IVS-I-6 TC b+ 2 1 3 06

IVS-II-1 GA b0 2 1 3 06






Total 310 165 475 1000


For

pers

onal

use

onl

y

















DISCUSSION




Mutation

N amp NE NW CW CE S

n n n n n

Codon 39 CT 39 419 103 560 61 455 19 576 8 276

IVS-I-110 GA 9 97 27 147 47 351 5 151 12 414



















Total 93 1000 184 1000 134 1000 33 1000 29 1000


Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413




















population (20)





























Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y








References


This paper 2224 23











ACKNOWLEDGMENTS







REFERENCES





















Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y































Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y

IVS

-II-

1

G

AN

A

AC

TT

CA

GG

GT

GA

GT

CT

AT

M

CT

TC

AG

GA

TG

AG

TC

TA

TG

G

FS

C6

ndash

AN

T

GA

CT

CC

TG

AG

GA

GA

AG

T

M

GC

AG

AC

TT

CT

CC

CA

GG

FS

C8

ndash

AA

N

AG

GA

GA

AG

TC

TG

CC

GT

T

M

AC

GG

CA

GA

CC

TC

CT

CA

ndash8

7

C

GN

G

GA

GC

CA

CA

CC

CT

AG

M

AC

CC

TA

GC

GT

GT

GG

C

ndash3

0

T

AN

G

CA

GG

GA

GG

GC

AG

GA

GC

CA

GG

GC

TG

GG

CA

A

M

AT

AA

AA

GT

CA

GG

GC

AG

AG

CC

AT

CT

AT

TG

CT

IVS

-II-

84

8

C

AN

G

GA

GC

TG

TG

GG

AG

GA

Ch

ina

III

gT

gT

AC

AC

AT

AT

Tg

AC

CA

AA

M

CT

CC

CA

CC

GC

TC

CT

GG

F

CA

CT

gA

CC

TC

CC

AC

AT

TC

CC

IVS

-II-

74

5

C

GN

C

AA

TC

CA

GC

TA

CC

AT

TC

M

GA

AT

GG

TA

CC

TG

GA

TT

G

IVS

-II-

84

9

A

CN

G

GA

GC

TG

TG

GG

AG

GA

M

AT

CT

TC

CT

CC

CA

CG

GC

TC

aB

ioti

ny

late

dp

rim

ers


Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y















RESULTS






Mutation Type


Homozygous

state

Heterozygote

state

Total

(n)

Frequency

()

Codon 39 CT b0 156 76 232 490

IVS-I-110 GA b+ 70 30 100 210

IVS-I- GA b0 14 7 21 45

FSC 44 ndashC b0 6 12 18 38

Codon 30 GC b+ 12 3 15 32

IVS-I-2 TG b0 12 2 14 30

IVS-II-745 CG b+ 6 6 12 26


ndash87 CG b+ 4 4 8 17

IVS-I-5 GA b+ 2 5 7 15

IVS-I-5 GC b+ 4 1 5 10

ndash30 TA b+ 2 2 4 08

Codons 2526 +T b0 2 1 3 06

IVS-I-6 TC b+ 2 1 3 06

IVS-II-1 GA b0 2 1 3 06






Total 310 165 475 1000


For

pers

onal

use

onl

y

















DISCUSSION




Mutation

N amp NE NW CW CE S

n n n n n

Codon 39 CT 39 419 103 560 61 455 19 576 8 276

IVS-I-110 GA 9 97 27 147 47 351 5 151 12 414



















Total 93 1000 184 1000 134 1000 33 1000 29 1000


Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413




















population (20)





























Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y








References


This paper 2224 23











ACKNOWLEDGMENTS







REFERENCES





















Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y































Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y















RESULTS






Mutation Type


Homozygous

state

Heterozygote

state

Total

(n)

Frequency

()

Codon 39 CT b0 156 76 232 490

IVS-I-110 GA b+ 70 30 100 210

IVS-I- GA b0 14 7 21 45

FSC 44 ndashC b0 6 12 18 38

Codon 30 GC b+ 12 3 15 32

IVS-I-2 TG b0 12 2 14 30

IVS-II-745 CG b+ 6 6 12 26


ndash87 CG b+ 4 4 8 17

IVS-I-5 GA b+ 2 5 7 15

IVS-I-5 GC b+ 4 1 5 10

ndash30 TA b+ 2 2 4 08

Codons 2526 +T b0 2 1 3 06

IVS-I-6 TC b+ 2 1 3 06

IVS-II-1 GA b0 2 1 3 06






Total 310 165 475 1000


For

pers

onal

use

onl

y

















DISCUSSION




Mutation

N amp NE NW CW CE S

n n n n n

Codon 39 CT 39 419 103 560 61 455 19 576 8 276

IVS-I-110 GA 9 97 27 147 47 351 5 151 12 414



















Total 93 1000 184 1000 134 1000 33 1000 29 1000


Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413




















population (20)





























Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y








References


This paper 2224 23











ACKNOWLEDGMENTS







REFERENCES





















Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y































Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y

















DISCUSSION




Mutation

N amp NE NW CW CE S

n n n n n

Codon 39 CT 39 419 103 560 61 455 19 576 8 276

IVS-I-110 GA 9 97 27 147 47 351 5 151 12 414



















Total 93 1000 184 1000 134 1000 33 1000 29 1000


Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413




















population (20)





























Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y








References


This paper 2224 23











ACKNOWLEDGMENTS







REFERENCES





















Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y































Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y




















population (20)





























Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y








References


This paper 2224 23











ACKNOWLEDGMENTS







REFERENCES





















Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y































Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y








References


This paper 2224 23











ACKNOWLEDGMENTS







REFERENCES





















Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y































Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y





ACKNOWLEDGMENTS







REFERENCES





















Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y































Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y































Hem

oglo

bin

Dow

nloa

ded

from

info

rmah

ealth

care

com

by

Lak

ehea

d U

nive

rsity

on

031

413

For

pers

onal

use

onl

y

Molecular Basis of β‐Thalassemia in the Population of Tunisia

Documents

Transcript of Molecular Basis of β‐Thalassemia in the Population of Tunisia