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Recent Advances in the Understanding of Human Genetic Variation

Recent Advances in the Understanding of Human Genetic Variation

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Unprecedented advances have occurred in our understanding of human genetic variation. The catalysts have been the completion of the Human Genome Project, the HapMap project and the encyclopaedia of DNA elements (ENCODE). The information now available as a result is proportional to several advances in genotyping technology that allow previously unheard levels of sequencing within very short time periods.
Unprecedented advances have occurred in our understanding of human genetic variation. The catalysts have been the completion of the Human Genome Project, the HapMap project and the encyclopaedia of DNA elements (ENCODE). The information now available as a result is proportional to several advances in genotyping technology that allow previously unheard levels of sequencing within very short time periods.

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Published by: Undergraduate Awards on Sep 01, 2012
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10/27/2013

 
Recent Advancesin theUnderstanding of Human GeneticVariation
Enda Shevlin
Unprecedented advances have occurredin our understanding of human geneticvariation. The catalysts of this have beenthe completion of the Human GenomeProject, the HapMap project and theencyclopaedia of DNA elements(ENCODE). The plethora of informationnow available as a result of these projects is proportional to severaladvances in genotyping technology thatallow for huge levels of sequencingwithin very short time periods. Copynumber variation and single nucleotide polymorphisms have emerged as the keygenerators of genetic variation inhumans and are linked to many complexdiseases such as age-related macular degeneration and Crohn’s disease.Genome-wide association studies haveallowed the study of hundreds of thousands of SNPs at a time and in turnrelate them to a variety of observable phenotypes such as eye pigmentation.
Introduction
The previous decade has seen anexplosion in research focusing on humangenetics with the results propelling boththe scientific and lay communities into anew era of understanding regarding theimportance of our genes in determiningour past, present and future. The firstmajor step was the initiation of theHuman Genome Project, (HGP) in 1990.The project’sgoalswere:* to determine the complete sequence of the 3 billion DNA subunits (bases)* identify all human genes,* make these genes accessible for further biological study.The ultimate goal was a completeunderstanding of human genetics as“knowledge of thehuman genomeis asnecessary to the continuing progress of medicine and other health sciences asknowledge of human anatomy has beenfor the present state of medicine”[1].Its completion in 2003 gave rise to manyinteresting discoveries such that there isonly a 0.1% difference betweenindividual genomes and, perhaps morerelevant to future research, the1
 
identification of approximately 1.4million locations where single-nucleotide polymorphisms (SNPs) occur within the human genome. Thisinformation promises to revolutionizethe processes for finding chromosomallocations for disease-associatedsequences and tracing human history.(Note: the study of copy number variations (CNVs) has revised theestimate of the difference betweenindividual genomes: two randomlyselected genomes in fact differ by atleast 1% and most of this difference isdue to copy number variations [26].)The success of the HGP has spanned anumber of other ambitious projectsincluding ENCODE and theinternational HapMap project.ENCODE, (ENCyclopedia Of DnaElements) is an extension of the HGPwhich aims to identify all functionalelements of the human genome [2]. TheHapmap project aims to develop ahaplotype map of the human genome bycomparing the genetic sequences of different individuals in order to identifychromosomal regions where geneticvariants are shared [3]. All three of theabove have produced huge amounts of information on what are now consideredvery important genotypic indicators of disease: copy number variation andSNPs. The various technologies thathave helped bring about these advancessuch as micro-array, parallel sequencing,Multiplex Ligation-dependent ProbeAmplification
(
MLPA), and rt-PCR must also be noted in any discussion of this topic. Of great importance as wellare the ethical, legal and social issues(ELSI) that have received as muchattention in the media as the scientificadvances themselves.
Advances in technology allows foradvances in understanding
Regarding the past decade and theaforementioned projects, it’s fair to saythat advances in discovery andunderstanding have occurred in tandemwith advances in the technology. TheHGP essentially provided a market for the development of these newtechnologies and throughout its lifemany papers have been published [5,6],2
 
incrementally advancing the technologyavailable to researchers and as a directresult, increasing the number of basessequenced while simultaneouslydecreasing the time taken to sequencethem (Figure 1). Originally, the targetwas to sequence 500 Mb/year at approx.$0.25 per finished base. By November 2002 however,
Figure 1. Graph showing the decrease in basesequencing costs ($US) and the simultaneousincrease in the total no. of bases sequenced(billion.), throughout the lifetime of the HGP.(Source: ORNL HGP info.)
Source:
 
ORNL [4]
>1,400Mb/year was being sequenced atapprox. $0.09 per base. [7]The technology stalwarts such asdideoxy or chain termination,
 
PCR,DNA microarrays and shotgunsequencing will no doubt retain essential places in any researcher’s toolbox butthe high demand for low cost sequencinghas recently given rise to a number of high-throughput sequencingtechnologies. One of these, developed byMarguiles et al.[8], known commerciallyas 454 sequencing, has been widelydeployed in genomic research. The process first shears the genome to beanalysed into fragments no greater than500 nucleotides in length (the max. readlength is expected to increase within oneyear.) Adapters, or linkers, are thenligated to the fragments and these in turnare attached to primer coated beads inaqueous bubbles within an oil-emulsion phase. PCR amplification in each dropletresults in each bead being coated withmillions of clonal copies of the uniqueDNA template. The actual sequencingrequires that the beads be immobilised ina single layer to allow reaction reagentsto flow over them. This process is called pyrosequencing [9]. It works on the“sequencing by synthesis” principle bydetecting the activity of DNA 3

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