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MICROSATELLITES & HUMAN GENOME PROJECT.
Term Paper ID:28637
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Examines some of the properties of these short sequences of repetative DNA & mapping the human genome.... More...
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Paper Abstract:
Examines some of the properties of these short sequences of repetative DNA & mapping the human genome.
Paper Introduction:
Microsatellites
Introduction
The Human Genome Project, which aims to map out every gene human beings possess, will have effects throughout the biological sciences (Collins and Jegalian, 1999). The complete DNA sequencing of the entire human organism will answer a host of questions on how organisms evolved and how to treat a wide range of medical disorders, as well as determining whether it will ever be possible to completely synthesize human life.
Microsatellites are short sequences of repetitive DNA that are tandemly repeated and qualitatively similar, and are important in gene mapping (Hancock, 1996, p. 191). Other simple short sequences exist, but are not repeated tandemly. Microsatellites are widespread in the human genome. Many
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Thus the microsatellites representvaluable tools for analyzing families with evidence of hereditary obesityand for investigating the possible association between OB mutations andhuman obesity. They used a Markov ChainMonte Carlo analysis of five human Y chromosome microsatellitepolymorphisms based on samples from five diverse populations. Enrichment is assayed by comparing observed frequency to expectedfrequency from random association of nucleotides. Deciphering thecode of life. Markov Chain Monte Carlo analysis of human Y-chromosomemicrosatellites provides evidence of biased mutation. Strachan, & G. Microsatellites are widespread in the humangenome. Estimates of population coalescence times andpopulation size from their two largest samples, one African and oneEuropean, suggest the African population is older but smaller than theEuropean, and the European population had undergone significant expansion.The researchers conclude from their data that Markov Chain Monte Carloanalysis of microsatellite haplotypes can reveal information which is notapparent when microsatellites are considered individually. The DNA analysis of DNA from formalin-fixed biopsiesrevealed 31 markers suitable for heterozygosity studies. In a similar vein to the previous study, Lindqvist et al (1996) used aset of 391 microsatellite markers, 85 percent of which consist of tri- andtetranucleotide repeat markers, to design chromosome-specific panels thatallow a high degree of multiplexing with respect to fragment size andfluorophore. Lindqvist, A. To identify which parts of agene are used for coding, some kind of marker is needed to separate codingand non-coding areas. 191). The mouse obese gene (ob) apparently encodes a secreted proteinthat may function in the signaling pathway of adipose tissue (Green et al,1995). DQCAR alleles associated with non-DQ1-associated haplotypes had perfect CA repeat sequences, and the variationseen in allele size was attributable to the difference in the number of CArepeats. L., Weissenbach, J., & Friendman, J. The researchersdesigned these microsatellite marker panels for use in pathology andforensics. K., Balciuniene, J., Wadelius, C.,Lindholm, E., Alarcon-Riquelme, M. Few distinct clusters of closelyrelated populations associated with population-specific alleles emergedfrom a network of observed haplotypes which was characterized by a lack ofclustering of geographically proximal populations. Theseresearchers looked at the mutation pattern of the microsatellites DQCAR,located in the HLA class II region and tightly linked to HLA-DQB1. PNAS, 96, pp. 558-567. The result showed that most populations have the sameset of the most frequent alleles at these loci. E., & Gyllensten, U. Selection againstframeshift mutations limits microsatellite expansion in coding DNA. PCRMethods and Appls., 4, pp. But mapping alone is only of academic importance: thereal benefit of the mapping will be when the amino acid sequences can beassigned to specific genes, and the function of the various amino acidsequence along the gene can be determined. Theamplification efficiency was inversely related to repeat length andamplicon length. S., & Jegalian, K. To facilitate these studies, the authors assembles sevenmultiplex panels of candidate genes for obesity which are suitable forfluorescent genotyping. Shriver, Jin, Ferrell and Deka (1997) developed a method to analyzemicrosatellites that is useful in determining the demographic history ofpopulations. E., & Deka, R. This has serious implications forusing amplification products of microsatellites for further studies. G., & Gardner, R. Microsatellite markercontent mapping of 12 candidate genes for obesity: assembly of sevenobesity screening panels for automated genotyping. Twin studies, adoption studies, and studies of familial aggregationall indicate that obesity has a genetic component (Winick and Friedman,1998). A., Rubinsztein, C., & Amos, W. M. The panels are composed of 66 microsatellitemarkers linked tightly to 16 human gene products that are of potentialimportance in the control of body weight or linked to syndromes of obesity. Microsatellites are proving extremely useful in thisregard. M., Saha, N., Barrantes, R.,Chakraborty, R., & Ferrell, R. Deka, R., Jin, L., Shriver, M. 86-91. These researchers believethat the convergent nature of microsatellite mutation confounds populationrelationships, and optimal Y chromosome evolution will require the use ofadditional microsatellite loci and diallelic genetic markers with lowermutation rates. Functional units along thecourse of a gene must be identified and their function determined beforethe sequencing has any practical application. Genomicfingerprinting by microsatellite-primed PCR: a critical evaluation. This review will look at some properties of microsatellites and atsome of the information about the human genome that can be gained from thestudy of microsatellites, what they can tell us about the evolution ofmankind, and how they can be used to examine the genetic basis of disease. These findings suggest that differencesbetween coding and non-coding microsatellite frequencies are due to aspecific selection against frameshift mutations in coding regions, and thattri- and hexanucleotide repeats appear to be controlled primarily bymutation pressure. A view of modern human origins from Y chromosome microsatellitevariation. Dover(Eds.), Human Genome Evolution. Microsatellite enrichment is thought to result from the accumulatedeffects of replication slippage mutations (Metzger, Bytof and Wills, 2 ). M.(1995). These two studies show how microsatellites can be used in exploring themechanisms of disease. Tri- and hexanucleotide repeats are found consistentlyin significant excess over a wide range of lengths in both coding and non-coding regions, but other repeat types are much less frequent in codingthan in non-coding regions. 249-255. (1998). M. These results demonstrate that diversity in Africanpopulations appear to result from their greater antiquity. Microsatellites are also useful in elucidating the genetic basis ofdisease. They can be used to denote areas coding for various proteins bothin health and disease, and can be used to look at the evolution of modernman.Although they are not thought to represent a functional portion of thegenome, they are certainly not without a function for the scientists tryingto elucidate the complexities of human genetics. This indicates eitheran earlier expansion or a larger effective population size for Africanpopulations, and is most consistent with the hypothesized African origin ofmodern humans. Theiranalysis provided strong evidence for mutational bias favoring an increasein length at all loci. Winick, J. Genome Res., 9, pp. Cooper, G., Burroughs, N. Genome Res., 6,pp. 72-8 . In M. (1996).Chromosome-specific panels of tri- and tetranucleotide microsatellitemarkers for multiplex fluorescent detection and automated genotyping:evaluation of their utility in pathology and forensics. Genome Res., 7,pp. Hancock, J. This type of study was carried further by Seielstad, Bekele, Ibrahim,Toure and Traore (1998). Mutations in this gene are associated with the early development ofgross obesity. (1995). Shriver, M. D., Yu, L. Enrichment ofmicrosatellites in non-coding sequences occurs for all microsatellite typesin a similar exponential fashion within the length of the microsatellite.However, in the coding region, repeats appear to be under much morestringent control. Hypothetical ancestralhaplotypes reconstructed from this data are shared by multiple populationsacross racial and geographic boundaries. Seielstad, M., Bekele, E., Ibrahim, M., Toure, A., & Traore, M.(1999). Other simple short sequences exist, butare not repeated tandemly. These results indicated that several mutational mechanisms areinvolved in the generation of allelic diversity within the samemicrosatellite locus. (1999). J., Rand, D. C. 117 -1176. 1177-1184. D., Maffei, NM., Braden, V. Literature Review Microsatellites are often used as markers in studying the evolution ofdisease (Macauba, Jin, Hallmayer, Kimura and Mignot, 1997). E. Microsatellites containing strings of Abases also dominate the frequency distribution of longer motif satellites. Genetic evidence suggests that all modern humansshare a recent common ancestor of African origin The three lines ofevidence for this are that most genetic loci examined so far show greaterdiversity in African populations than in others; place the first branchbetween African and non-African populations in phylogenetic trees; andindicate recent dates for either the molecular coalescence or the time ofseparation between African and non-African populations. D., Jin, L., Ferrell, R. The lack of haplotypicstructure associated with the presumed ancestral haplotypes from allpopulations indicates a recent common ancestry and/or extensive malemigration during human evolutionary history. (1996). GenomeRes., 1 , pp. 191-211. Microsatellites Introduction The Human Genome Project, which aims to map out every gene humanbeings possess, will have effects throughout the biological sciences(Collins and Jegalian, 1999). References Collins, F. The markers were assessed for their ability in analysis ofDNA from blood, hair, and formalin-fixed archival tissue biopsies. (1999, December). Analysis of threedata sets from surveys of microsatellite loci in ethnographically definedpopulations showed distributions with nonzero peaks. 11916-11921. (1997).Microsatellite data support an early population expansion in Africa.Genome Res., 7, pp. G. Am., pp. However, some of the plant species primers producedfingerprints with the E, coli template DNA as well, and further studiesshowed that these bands were generated by mismatch priming in a way similarto random amplified polymorphic DNAs. Genome Res., 8, p. Microsatellites have been used to trace the evolution of modern man.Five microsatellite loci from the non-recombining portion of the human Ychromosome were analyzed in 15 diverse human populations to evaluate theirusefulness in reconstructing human evolution and early male migrations(Deka et al, 1996). Most primers generated distinct amplification products, which gavebanding patterns on gel electrophoresis which acted as fingerprints foridentifying them. Different mutation rates at the same locus musttherefore be taken into account when using microsatellites as markers indisease evolution studies. 586-591. Mapping the human OB gene on a yeastartificial chromosome, eight microsatellite-type genetic markers werefound, including seven (CA)n repeat-type Genethon markers in closeproximity to the human OB gene. Whileprevious studies have shown a very low level of size variation in DQCARalleles within a subfamily of HLA-DQ subtypes (DQ1), DQCAR alleles in non-(DQ1) subtypes showed a high degree of polymorphism. Weising, K., Atkinson, R. Sci. 635-641. Using sequenceanalysis, these researchers showed that DQ1-associated DQCAR alleles have asingle C to A nucleotide substitution interrupting a CA repeat array. Metzger, D., Bytof, J., & Wills, C. Dispersion of human Ychromosome haplotypes based on five microsatellites in global populations.Genome Res., 6, pp. 985. V., Proenca, R., DeSilva, U.,Zhang, Y., Chua, S. The genetic factors responsible for obesity have not yet beenelucidated. (2 ). Similar information in the human homolog, the OB gene,would be useful in examining the role of the gene in human obesity, andthese researchers, using Northern blot analysis, showed that OB RNA ispresent in high levels in adipose tissue, at lower levels in placenta andheart, and undetectable in a wide range of other tissues. Macaubas, C., Jin, L., Hallmayer, J., Kimura, A., & Mignot, E.(1997). These researchersanalyzed variations at 1 Y chromosome microsatellite loci that were typedin 5 6 males representing 49 populations and every inhabited continent.This exhaustive study revealed significantly greater Y chromosome diversityin Africa than anywhere else; that the first branch of the phylogenetictrees of the continental populations fell between Africa and all non-African populations, and the branching was dated with the (sigma mu)2distance measure to 58 -17,4 or 12,8 -36,8 years BP, depending on themutation used. They believeincorporation of population size into the analysis will allow for estimatesof the timing and magnitude of major population trends through the courseof history. D., & Friedman, J. This study agrees with the findings of Seieltad, Bekele,Ibrahim, Toure and Traore, Yet another study, by Cooper et al (1999), also suggests and Africanorigin for modern human using microsatellites. Jackson, T. pp. C., Leibel, R. Theyalso noted frequent CA to GA mutations in DQ1-associated microsatelliteswith identical allele sizes. 5-12. B. Discussion Mapping of the entire human genome is a complex and extremely time-consuming project. The complete DNA sequencing of the entirehuman organism will answer a host of questions on how organisms evolved andhow to treat a wide range of medical disorders, as well as determiningwhether it will ever be possible to completely synthesize human life. Genome Res., 5, pp. Single PCR primers complementary to microsatellite repeats were usedto amplify genomic DNA samples from plants, humans, yeasts, and Escherichiacoli. (1996) Microsatellites and other simple sequences inthe evolution of the human genome. Many microsatellites occur as mono- and dinucleotides, where(A/T)n is the most common motif. Using computer simulations of microsatellite loci, they showthat the distribution of PK (the number of repeat unit differences betweenalleles when each allele in a sample is compared with every other allele inthe sample) changes in a distinctive manner as a function of either timesince population expansion or effective population size. The complex mutation pattern of a microsatellite. Comparativemapping of mouse and human DNA indicated the human OB gene should bepresent on the 7q chromosome. K., Magnusson, P. Green, E. Microsatellites are short sequences of repetitive DNA that aretandemly repeated and qualitatively similar, and are important in genemapping (Hancock, 1996, p.
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