11 views

Uploaded by Asim Rafiq Janjua

ieee

save

- 4. MADER Foucault s Metabody
- digital unit plan template 4
- 5.4 Evolution
- essay 34
- 23- Evolution of Populations Text
- Gene
- GENETICS1_95
- 6.1 Fib Handout
- Philosophy of Biology finals study guide (Terzis)
- causes-of-mutation l v11 if5 s1
- MBPT_MolecularGeneticPathology
- 5090_s05_er
- Effect of Irradiation on the Growth and Germination of Okra
- evolution reviewpacket
- 20170015.full.pdf
- qijun ISDA06
- stand pacing guide
- science framework alignment 6-8 2013
- fgene-05-00162
- Chapter 4
- 2. Extensions Exceptions Mendel_s Laws (2)
- k
- Mystery
- Daters thesis
- Results
- 6 SKEMA JAWAPAN KERTAS 2
- Irradiated Freaks
- Review Key
- Gene Interactions
- Ripening by Ethelene
- SIMD_Architecture.pdf
- Nfl
- ABC_Form
- japan.pdf
- Floor Plan
- Food tech
- SMEDA Poultry Breeder Farm
- Ch12 Parallel Proc3
- Small Industry Set Up and Costing_ Iodised Salt
- SIMD Architecture
- Historical Data
- MCQ's 2009-11
- IMECS2010_pp2236-2240
- The Movers
- my paper.pdf
- ICET2012 Camera 336
- Aztech
- Nishat Mills Limited 2014-Annual Report
- ICET2012 Camera 124
- Nishat Project FSA-Presentation
- chp 5
- my paper
- ICET2012 Camera 127
- ICET2012 Camera 141
- 1-Module 8051
- ICET2012 Camera 141
- GOOD ChipScope e
- ICET2012 Camera 294
- ICET2012 Camera 466

You are on page 1of 5

**Hypotrichosis with Juvenile Macular Dystrophy
**

Disease in Pakistani Population

Adeel Ahmed1, Khalid Saleem2

1 2

` Department of Computer Science

Quaid-i-Azam University

Islamabad, Pakistan

1

2

aahmedqau@gmail.com, ksaleem@qau.edu.pk

**Abstract—The splice-site mutation at the locus on human
**

chromosome 16q22.1 causes hypotrichosis with juvenile macular

dystrophy (HJMD) disease in Pakistani population [1]. Different

statistical methods have been used to estimate the age of

mutations. We have analyzed a CDH3 gene dataset which consists

of genotypes of the Pakistani family in order to compare two

methods for estimating an age of IVS10-1 G ĺ T mutation that

occurrs in some affected members of a family. The first method is

DMLE+ [2] that is a genealogy based method and estimate the

mutation age with population growth rate and genotype data. A

second method [3] that we used is based on allele frequency. We

have found that the mutation age vary with population size,

growth rate and mutant allele frequency. Estimates of IVS10-1

GĺT mutation based on DMLE+ [2] are 232, 238 and 226

generations with three simulated runs and 95% credible interval,

respectively. A method [3] gives an estimated time of 138

generations in units of 2N generations.

Keywords-Gene genealogy; Mutation; Population genetics;

Statistical computing; Linkage disequilibrium

I.

INTRODUCTION

**The age of mutation is the time of the origin of mutation
**

from its most recent common ancestor (MRCA). Estimating

an age of mutation that occurs in autosomes is slightly

different as it involves some stochastic processes as compared

to estimating an age using X-chromosome or Y-chromosome.

The age of mutation can be estimated based on genealogy and

from the allele frequency. Population genetics provides us a

way to study the distribution and change of allele frequency

under the certain evolutionary processes like natural selection,

genetic drift, mutation and gene flow.

Hypotrichosis with juvenile macular dystophy (HJMD;

OMIM 601553) is a rare autosomal recessive disorder in

CDH3 (OMIM 114021) gene in consanguineous Pakistani

family causes hair loss and eye blindness [1]. This disorder

occurs due to splice-site mutation. The affected individuals

revealed a homozygous recessive transversion mutation

(IVS10-1 G ĺ T). In CDH3 gene, a mutation occurs due to

genetic drift and resides in intron 10 near the splice acceptor

site of exon 11 on chromosome 16q22.1 [1].

978-1-4673-4450-0/12/$31.00 ©2012 IEEE

Sulman Basit3

3

Department of Biochemistry

Quaid-i-Azam University

Islamabad, Pakistan

3

basitphd@bs.qau.edu.pk

Our Contributions

We have estimated a time of splice site (IVS10-1 G ĺ T)

mutation occurs in a Pakistani family in CDH3 gene. We have

used two methods, first method is based on allele frequency

and is proposed by Kimura et al. [3] and second method is

DMLE+, proposed by Rannala et al. in 2001 [2] for age

prediction. We compared two approaches for predicting the

age of splice-site mutation with same parameters on the CDH3

gene dataset. We have found a mutation age predicted by one

method closely to the credible intervals as predicted by the

second method. We performed three independent simulation

runs of Markov chain Monte Carlo (MCMC) [2] and find the

consistent results about mutation age.

The organization of this paper is as follows: Section 2

describes the related work, Section 3 describes the proposed

statistical methods used for predicting a mutation age. In

Section 4, we describe about real dataset, Section 5 presents

experimental results, and Section 6 presents conclusions and

future work.

II.

RELATED WORK

**A mutation age can be predicted based on genealogy and
**

based on allele frequency. Here we discuss both methods as

these methods are within the scope of our work.

A. Estimate of Mutation Age based on Genealogy

A primarily work on intra-allelic variability was first

proposed by Serre et al. in 1990 [4] on ǻF508 mutation that

occurs in CFTR gene. In this approach, di-allelic loci are

considered from a sample taken from 240 French families. The

estimate of allele age can be obtained from a moment

estimator. To obtain a confidence interval of an age estimate

using a moment estimator, is uncertain [5]. The factors of

uncertainty are recombination rate and mutation rate.

In 1999, Griffiths et al. [6] proposed infinitely sites

mutation model that is represented by a unique gene tree. Here

the age of mutations and an age of most recent common

ancestor are estimated and the conditional distribution of ages

Bayesian linkage disequilibrium gene mapping is an intra-allelic coalescent model that uses a multiple genetic markers to find a linkage among marker alleles. Therefore. In this model. A coalescent model that models the evolution of DNA sequences. III. a deleterious mutation occurs due to natural selection or random genetic drift. This method is implemented in program DMLE+ [2]. [15] has estimated an age variant based on replicates observed in a population. A study of likelihood is taken on the basis of discrete branching process model. To obtain confident results of an allele age. In 2003. age estimation for growing population is set to the genetic clock according to Luria-Delbruck correction as follows: gc = gc + g0 (3) where ‘g’ is a number of generations estimated from (2) and g0= . MCMC method is used to generate joint posterior density of parameter based on Metropolis-Hastings algorithm. . An age estimated by (2) is an under estimate for growing population and the genetic clock tics is more slowly than expected. This method allows a mutation to occur more than once in a genealogy tree but it is ncessary that mutation-carrying haplotypes to be known. In coalescent process mutations are imposed on the tree as a poisson processes of rate ș/2. Thompson et al. gives the ancestral relationship among the number of DNA sequences.y) is a Green function of the diffusion. [9] implemented a multiple marker likelihood method for estimating a mutation age. He has estimated a time when allele is reached at present frequency by using diffusion methods. Therefore. Griffiths [13] has estimated an expected age of allele ‘A’ having frequency ‘x’ as a sample path average in diffusion process that is E(Age) = 01 G (x. A neutrality tests are performed to test a hypothesis that whether a population is evolved according to Wright Fisher model with constant effective population size or not. a gene program tree is used for mutation age calculation. Linkage disequilibrium can be helpful in finding an age of mutation and a location of mutation. Maruyama et al. where fd = ed / ed – 1 in a growing population with growth rate ‘d’. A coalescent model is proposed by Griffiths et al.are found for a Melanesian population using a ȕ-globin locus by considering a diploid dataset [7]. Colombo [16] has estimated an age of N370S mutation using (2). point out the haplotype on which the mutation arises. Here. Stochastic evolution process is required for age defined as a random variable. Probability distribution of trees can be calculated by fundamental recursion for probability Monte Carlo simulation approach. In 2002. A Markov chain Monte Carlo method is used to estimate a mutation age and location jointly called joint based estimation. g = log ı / log (1 – ș) (2) where ı is a LD measure and ș is a recombination fraction. Here. B. proposed a diffusion model [11] to find an approximate age of neutral mutant allele when a allele frequency is fixed and it also gives an age before the fixation of allele. Yu et al. Monte Carlo experiments are performed. in 1998 [14]. In this work. an extension of Bayesian linkage disequilibrium mapping is described. Estimate a Mutation Age based on Allele Frequency In 1975. y) u0 (y) / u0 (x) dy (1) where G (x. MCMC methods are used to estimate the likelihood function. position of disease locus and ancestral haplotypes. a different mutation rates can be set for different types of markers but a growth rate is not taken ino account. he concluded that a mean age is larger than variance of age. in which it is assumed that €n. so here a selection coefficient is considered as constant against heterozygotes. The author has applied a result when mutation rate is low and population size is constant. In 2000. Here it is assumed that each variant has a unique origin and each mutant gene reproduces independently. In 1996. Goldgar et al. and is defined as a 4NM.(1/d) ln (ș fd). When a mutation occurred then there will be ‘k’ ancestors of the sample. expected value of mutant allele is calculated along a sample path starts from initial frequency ‘p’of allele at time 0 and reaches ‘x’ at some time later. A population parameter used here is ș. where ș is a parameter of a function of population size ‘N’ and a mutation rate ‘M’ per sequence per generation. Likelihood analysis provides a confidence interval range in which a variant is originated. PROPOSED STATISTICAL METHODS USED FOR MUTATION AGE ESTIMATION We have estimated an age of splice-site (IVS10-1 G ĺ T) mutation using DMLE+ [2] and a method [3].b denoted the age of mutant gene that is there exist ‘b’ copies of mutant gene in a sample of ‘n’ chromosomes. Conditional distribution of €n. u0 (x) is the probability of absorption at initial frequency of ‘x’. A genotype data is considered in a population of Africa. A modified Goldgar method [10] is presented where the author has modified the likelihood to allow the haplotype uncertainty that is a mutation occurs more than once in a genealogy tree if the haplotypes carrying the mutation is unsured. Since. In 1976. Li [12] has introduced a new method to find an age of deleterious mutation that causes a severe disease. [8] proposed the Parsimony principle to deduce a number of mutations. In 1975. and estimates the time of the origin of mutation.k is distributed as UTk + Sk+1.

[3] proposed an expected age of mutant allele that has frequency ‘x’ in a constant population size. genetic drift. mutation and geneflow. Mutation Analysis and Input Paremeters for DMLE+ Mutation analysis is performed by using genotype of family members of both affected and control indiviudals of the Pakistani family with microsatellite markers closely linked to the CDH3 gene. The disease-associated haplotypes are shown beneath each symbol.3) progarm. according to [17].Figure 1. unaffected subjects. a splice-site mutation is discovered by Jelani et al.x log x (4) . Second method [3] that we have used for estimating an age of splice site mutation is based on allele frequency. • Proportion of disease chromosomes in a sample is 0. These parameters are • Genotype data as shown in Fig. So we considered a growth rate of the population of Pakistan according to 2008. Therefore. The remaining parameters are set as default parameters of DMLE+. • We have set a variable ‘Mendilian Inheritance’ as recessive. Pedigree of the family with hypotrichosis and juvenile macular dystrophy. Change in the frequency of allele in population occurs due to some evolutionary processes like natural selection. 1. Kimura et al. 1. affected subjects. [1] A. • Since. a growth rate of Pakistani population was 0.02. Filled symbols. We have given different parameters as collected over the CDH3 gene dataset to inputs to the DMLE+ (release 2. that is . In 1973. • Genetic distances that we have used between markers are shown in Fig.001. open symbols.2 x / 1 . in 2008 [1].

J. 2000.098. So by using r = 0. including 6 affected and 7 unaffected members using automated DNA sequencer. Ohta. 34. et al. 18. U. 1. B. R. M. We have performed three independent simulation runs using MCMC [2] method with same parameters in order to obtain the consistent results for the age of IVS10-1 G ĺ T mutation. M. According to molecular population theory [8]. the age of mutation in years. E. A mutation age estimated by method [3] is found nearly to the credible intervals estimated using DMLE+ but method [3] is a good choice. S. 894-895. 1973. Slatkin et al. a growth rate ‘r’ of Pakistani population was 0. is w * 20 = k years. R. We have applied two approaches. pp. vol.0138 x 10000 = 138 generations.S. A. 68-73. Kimura and T. Ahmad. if a mutation occurs in certain gene due to some evolutionary process and when parameteric information is not readily available. if we assume a constant population size of N=10000. Estimated mutation age (generations) According to (4).B.1 and are affected with HJMD disease as shown in Fig. IR. vol. 6 affected members carry splice site (IVS10-1 G ĺ T) mutation on chromosome 16q22. pp: 225-249. 75. CONCLUSIONS In this paper. This formula gives an age in scaled time units say ‘z’. 91. Simon-Bouy. P.2 * P / 1 – P ) * ln ( P ) iii) AGEINYEARS ĸ L * E ( t1 ) iv) return AGEINYEARS In 2000. “ Genetics. This dataset is provided by the Department of Biochemistry. ” Proc. we will be applying these methods on more datasets.” Journal of Clinical and Experimental Dermatology. “A novel splice-site mutation in the CDH3 gene in hypotrichosis with juvenile macular dystrophy. Table I shows the estimated mutation ages using DMLE+. We have observed that the mutation age vary with population growth rate and the allele frequency. “Studies of RFLP closely linked to the cystic fibrosis locus throughout Europe lead to new considerations in population genetics. ” The Annals of Applied Probability.02. 2002. which are found very close to each other and within the range of credible intervals. 374] VI. J. Quaid-i-Azam University. We have found that the expected time E(t1) = 0. Serre.0138 in scaled time units. are applied over the CDH3 gene dataset of a consanguineous Pakistani family. Chishti and W. In future. S. Harding. C. The estimated time of mutation predicted by using DMLE+ method is more reliable as it is the best representation of gene genealogies and their variability as compared to method [3]. 1990. B. IR. the expected time of mutation is 0. 2) Output: Mutation age in years i) P ĸ IR ii) E ( t1 ) ĸ ( . 84. . M.” Annual Review of Genomics and Hum. pp. “The age of a neutral mutant persisting in a finite population. Genet. ” Hum. Boyce and J. Among them.02 we have set a 95% credible interval in units of generations. 1999. Islamabad. M. Jaume-Roig. B.where ‘x’ is the frequency of a mutant allele. Clegg. “Molecular and population genetic analysis of allelic sequence diversity at the human ȕ-globin locus. Balassopoulou. According to molecular population theory [8]. 2008. pp:449-454. method [2] and method [3] over CDH3 gene dataset and successfully estimating a mutation age with 95% credibility. L. Method: Mutation Age Calculation 1) Input: N. The mutation analysis was carried out over the genotype data by examining the 13 members of a family. vol.L. A. in 2008. Therefore. Reeve. We have analyzed a CDH3 gene dataset for a family of Pakistani population whose some members have splice-site (IVS10-1 G ĺ T) mutation that causes HJMD disease. Total numbers of chromosomes are 13 including case and controls and are used as inputs for DMLE+ program. Acad. pp. Rannala and J. The MLE is (5) DATASET The statistical methods discussed in Section 3 for age estimation. vol. To find an age in years we have assumed a length of human generation that is 20 years [8]. [5] has used this fomula for age estimation and formulated a maximum likelihood estimation (MLE) for the expected time of mutation. B. Nat. “The Ages of Mutations in Gene Trees.” Bioinformatics. Tavare. 385] [156. 3) ProcedureMutationAge (N. Griffiths and S. pp: 567-590.0138 of the mutation is different from the MLE. 01.. L a) N: Total number of individuals in a population b) IR: Incidence Rate c) P: Mutant Allele Frequency TABLE I. Jelani. vol. Fullerton. Simulation Run (MCMC) Equation (5) gives us a maximum likelihood estimation for mutation age that is 0. 9. vol. if we assume a population size N=10000 which is a minimum estimate of population size of modern humans during the period before recent growth and assume that this poluation size is constant then the mutation age is 0. 199–212.. 95% credible interval (DMLE) 1 2 3 232 238 226 [144. Rannala. Slatkin and B. we have considered the problem of mutation age estimation. AGEINYEARS) IV. pp: 18051809.. Genet. [4] V. d) L: Generation Length – ln (1 – p) – 2 / n ESTIMATES OF MUTATION AGE FOR IVS10-1 G ĺ T [5] [6] [7] M. REFERENCES [1] [2] [3] EXPERIMENTAL RESULTS According to [17].A. then z * 10000 = w generations. 1994. M.P. vol. 364] [152. Sc. Pakistan. “DMLE+: Bayesian linkage disequilibrium gene mapping. “Estimating Allele Age. Mornet.

Genet. G. “The first arrival time and mean age of a deleterious mutant gene in a finite population. S. M. Veenstra.” BMC Genetics. Tomlinson. C. J. G. B. O. pp: 692–997. R. L. "Age Estimate of the N370S Mutation Causing Gaucher Disease in Ashkenazi Jews and European Populations: A Reappraisal of Haplotype Data. Foulkes. Li. Kelsell. Offit. J. vol. “Haplotype and Phenotype Analysis of Six Recurrent BRCA1 mutation in 61 families. M. Hum. Niell. B. "The frequency spectrum of a mutation and its age. E. Acad. Neuhausen. Thompson. Nat.A. King. “How old is this mutation?. Lenoir. pp: 241-251.html.. W. 11:39. Li. 72. Narod. P. Griffiths.a study of three Ashkenazi Jewish founder mutations. "The age of mutation in a general coalescent tree. H. T. R. Greenwood. D. vol. THE WORLD FACTBOOK. vol. UK. Weber. Ponder.1998. Stratton. Friedman. L. Struewing. T. J. 1975. 1975. Gruber and W.” Am. . Genet.. pp: 271280. Kimura. pp: 273295. Solomon. C. Statist.. N. Goldgar. D. EA. J. K. Tavare. 14.Stochastic Models. S.[8] [9] [10] [11] [12] [13] [14] [15] [16] [17] N. 276-287. 58. 1602-1604. L. Serova. Colombo. ”Mol. D. Hum. 2000. Y."Commun. 2010. S. Genet. Sci. Vol. Cannon-Albright." Am. 2002. pp: 2131-2141. ” Results of an International study. Yu. D. “Estimation of age and rate of increase of rare variants.cia. Mazoyer. E. 28:442–52. Tonin. Fu and W. Evol.“Moments for sum of an Arbitrary Function of Gene Frequency along a Stochastic Path of Gene Frequency Change.gov/library/ publications/the-world-factbook/fields/2002. S. pp. Source: https://www. Kolnick. R. MT. Biol. Durocher. 1996. “DNA Polymorphism in a World Wide Sample of Human X Chromosomes. Maruyama and M. 27. in a general diffusion model. Bishop. Couch. Sun. S. B. H. 66.” Theoretical Population Biology. Hum. C. 19. M. vol." Proc.” Am. Am J Hum. Hamel. vol.S. Caligo. F.C. vol. pp. 64. U. F. StoppaLyonnet. Griffiths and S. Genet. Easton. 1976. 2003. A. D. J.

- 4. MADER Foucault s MetabodyUploaded byJayjit Sarkar
- digital unit plan template 4Uploaded byapi-269032180
- 5.4 EvolutionUploaded byWendy Hsiao
- essay 34Uploaded byapi-213708874
- 23- Evolution of Populations TextUploaded byJustin Chang
- GeneUploaded byvmshanes
- GENETICS1_95Uploaded byOrson Simon
- 6.1 Fib HandoutUploaded bymelindamd8
- Philosophy of Biology finals study guide (Terzis)Uploaded byBatool A
- causes-of-mutation l v11 if5 s1Uploaded byapi-264809813
- MBPT_MolecularGeneticPathologyUploaded bynemoakrn
- 5090_s05_erUploaded byAhmed Kaleem Khan Niazi
- Effect of Irradiation on the Growth and Germination of OkraUploaded byLennon Davalos
- evolution reviewpacketUploaded byapi-235160519
- 20170015.full.pdfUploaded byPerched Above
- qijun ISDA06Uploaded byGracia Martinez
- stand pacing guideUploaded byapi-252463198
- science framework alignment 6-8 2013Uploaded byapi-231469705
- fgene-05-00162Uploaded byNishant Uzir
- Chapter 4Uploaded byGlen Mangali
- 2. Extensions Exceptions Mendel_s Laws (2)Uploaded byFarhana Anuar
- kUploaded byHannah Lau
- MysteryUploaded bycjhayden114
- Daters thesisUploaded byProfessor Stephen D. Waner
- ResultsUploaded byNamikaze Azizur Rahim
- 6 SKEMA JAWAPAN KERTAS 2Uploaded byنور الفاتحة
- Irradiated FreaksUploaded byothertim
- Review KeyUploaded bybelovedaffection
- Gene InteractionsUploaded byDuane Hall
- Ripening by EtheleneUploaded bykasun1237459

- SIMD_Architecture.pdfUploaded byAsim Rafiq Janjua
- NflUploaded byAsim Rafiq Janjua
- ABC_FormUploaded byAsim Rafiq Janjua
- japan.pdfUploaded byAsim Rafiq Janjua
- Floor PlanUploaded byAsim Rafiq Janjua
- Food techUploaded byAsim Rafiq Janjua
- SMEDA Poultry Breeder FarmUploaded byAsim Rafiq Janjua
- Ch12 Parallel Proc3Uploaded byAsim Rafiq Janjua
- Small Industry Set Up and Costing_ Iodised SaltUploaded byAsim Rafiq Janjua
- SIMD ArchitectureUploaded byAsim Rafiq Janjua
- Historical DataUploaded byAsim Rafiq Janjua
- MCQ's 2009-11Uploaded byAsim Rafiq Janjua
- IMECS2010_pp2236-2240Uploaded byAsim Rafiq Janjua
- The MoversUploaded byAsim Rafiq Janjua
- my paper.pdfUploaded byAsim Rafiq Janjua
- ICET2012 Camera 336Uploaded byAsim Rafiq Janjua
- AztechUploaded byAsim Rafiq Janjua
- Nishat Mills Limited 2014-Annual ReportUploaded byAsim Rafiq Janjua
- ICET2012 Camera 124Uploaded byAsim Rafiq Janjua
- Nishat Project FSA-PresentationUploaded byAsim Rafiq Janjua
- chp 5Uploaded byAsim Rafiq Janjua
- my paperUploaded byAsim Rafiq Janjua
- ICET2012 Camera 127Uploaded byAsim Rafiq Janjua
- ICET2012 Camera 141Uploaded byAsim Rafiq Janjua
- 1-Module 8051Uploaded byAsim Rafiq Janjua
- ICET2012 Camera 141Uploaded byAsim Rafiq Janjua
- GOOD ChipScope eUploaded byAsim Rafiq Janjua
- ICET2012 Camera 294Uploaded byAsim Rafiq Janjua
- ICET2012 Camera 466Uploaded byAsim Rafiq Janjua