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Motivations to study human genetic variationThe evolution of our
species and its history.
Understand the genetics of diseases, esp. the more common
complex ones such as diabetes, cancer, cardiovascular, and
neurodegenerative.
To allow pharmaceutical treatments to be tailored to individuals
(adverse reactions based on genetics).
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Haplotype Map of the Human GenomeGoals:
Define patterns of genetic variation across human genomeGuide
selection of SNPs efficiently to tag common variantsPublic release
of all data (assays, genotypes)
Phase I: 1.3 M markers in 269 peoplePhase II: +2.8 M markers in
270 people
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HapMap ProjectThe HapMap Project tests linkage between SNPs in
various sub-populations.
For a group of linked SNPs recombination may be rare over tens
of thousands of bases
A few "tag SNPs" can be used to identify genotypes for groups of
linked SNPs
Makes it possible to survey the whole genome with fewer markers
(1/3-1/10th)
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HaplotypeLinkage is common in the human population, particularly
in genetically isolated sub-populations. A group of alleles for
neighboring genes on a segment of a chromosome are very often
inherited together.
Such a combination of linked alleles is known as a
haplotype.
When linked alleles are shared by members of a population, it is
called a linkage disequilibrium.
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Haplotypes (example)A chromosome region with only the SNPs
shown. Three haplotypes are shown. The two SNPs in color are
sufficient to identify (tag) each of the three haplotyes. For
example, if a chromosome has alleles A and T at these two tag SNPs,
then it has the first haplotype.
..A..C..A..T..G..T....A..C..C..G..C..T....G..T..C..G..G..A..
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HapMap Samples90 Yoruba individuals (30 parent-parent-offspring
trios) from Ibadan, Nigeria (YRI)
90 individuals (30 trios) of European descent from Utah
(CEU)
45 Han Chinese individuals from Beijing (CHB)
45 Japanese individuals from Tokyo (JPT)
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Scan these populations with a large number of SNP markers.
Find markers linked to drug response phenotypes.
It is interesting, but not necessary, to identify the exact
genes involved.Can work with associated populations, does not
require detailed information on disease in family
history(pedigree).Make Genetic Profiles
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March, 2010 105,098,087 The 1000 Genomes Project submitted 17.3M
SNPs
The 2008 SNP Submissions for the James Watson Genome totaled
3,542,364The 2008 SNP Submissions for the J. Craig Venter Genome
totaled 4,018,050 The 2008 SNP Submissions for the Individual
Chinese Genome totaled 5,077,954The 2008 SNP Submissions for the
Individual Korean Genome totaled 1,750,224The SNP database
todayDerived from dbSNP release
130http://www.ncbi.nlm.nih.gov/SNP/
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SNPs arent everything: Introducing Copy Number VariationsRedon
et al. Nature 2006
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Copy Number Variation DatasetGenome Structural Variation
Consortium
Array-CGH using a whole genome tile path array Median clone size
~170 kbAll 270 HapMap individualsMeasures amount of DNA, not
RNAComparison between two samplesTest sample vs Reference
sample
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Array-CGH technology
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Typical Analysis ProcedureValues are typically normalized so
that the mean log2 value for the entire array (or an individual
chromosome) is 0
Analysis consists of identifying segments where the test and
reference samples have unequal copy number
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1,447 CNVRs from 270 HapMap samples
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Structural Variation ProjectNature 447: 161-165, 2007
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The number of genome structural variants (>1 kb) that
distinguish genomes of different individuals is at least on the
order of 600900 per individual.J.O. Korbelet al., Science318(2007),
pp. 420426Copy Number Variations are ubiquitous in the human
genome
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HapMap 3Merged the results from Affymetrix and Illumina
chipsGenotyped 1.6 million common single nucleotide polymorphisms
(SNPs) in 1,184 reference individuals from 11 global
populationsSequenced ten 100-kilobase regions in 692 of these
individuals
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Centre dEtude du Polymorphisme Humain collected in Utah, USA,
with ancestry from northern and western Europe (CEU) Han Chinese in
Beijing, China (CHB) Japanese in Tokyo, Japan (JPT) Yoruba in
Ibadan, Nigeria (YRI) African ancestry in the southwestern USA
(ASW) Chinese in metropolitan Denver, Colorado, USA (CHD) Gujarati
Indians in Houston, Texas, USA (GIH) Luhya in Webuye, Kenya (LWK)
Maasai in Kinyawa, Kenya (MKK) Mexican ancestry in Los Angeles,
California, USA (MXL) Tuscans in Italy (Toscani in Italia, TSI)CEU,
ASW, MXL, MKK, and YRI
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Computational detection of structural genomic variationDirect
comparison of genomes through sequence alignments Advantages: All
types of genomic variation can be identified, including balanced
variants (inversions or translocations)No limit in the resolution
and breakpoints can be defined at nucleotide levelProblems:
Generate a lot of false positives due to sequence misassembly and
gaps
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Modern humans arose in Africa and replaced other human species
across the globe. Scientific American, August 1999)Out of
Africa
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*Out of Africa again and againTempleton, A. Nature 416 (2002):
45 - 51Itai Yanai, 2003
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The Human Genome Project cost ~USD 3,000,000,000
Illumina now offers a complete genome sequence from USD
50,000
Complete Genomics will offer a complete genome sequence from USD
5,000 soon There are now an estimated 50 complete human genome
sequences
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James Watson, 454. $70 millionCraig Venter, Sanger, -$1
millionAfrican -HapMap Illumina & Solid, $100,000Five African
Penn State UniversityChinese, IlluminaTwo Koreans Prof. Quake
-Stanford --Nature genetics paper -$50,000, 1 week, Helicos
Stanford team -Clinical annotation of genome from patient Zero
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The 10-gen data set
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********Log(2) = (test/reference)*