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Motivations to study human genetic variation. The 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.

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motivations to study human genetic variation
Motivations to study human genetic variation

The 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).

haplotype map of the human genome
Haplotype Map of the Human Genome
  • Goals:
  • Define patterns of genetic variation across human genome
  • Guide selection of SNPs efficiently to “tag” common variants
  • Public release of all data (assays, genotypes)
        • Phase I: 1.3 M markers in 269 people
  • Phase II: +2.8 M markers in 270 people
hapmap project
HapMap Project
  • The 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 "tagSNPs" 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)
  • Linkage 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.
haplotypes example
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.

hapmap samples
HapMap Samples
  • 90 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)

Make Genetic Profiles

  • 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).

The SNP database today

March, 2010 105,098,087

The 1000 Genomes Project submitted 17.3M SNPs

The 2008 SNP Submissions for the James Watson Genome totaled 3,542,364

The 2008 SNP Submissions for the J. Craig Venter Genome totaled 4,018,050

The 2008 SNP Submissions for the Individual Chinese Genome totaled 5,077,954

The 2008 SNP Submissions for the Individual Korean Genome totaled 1,750,224

Derived from dbSNP release 130


SNP’s aren’t everything: Introducing Copy Number Variations

Redon et al. Nature 2006

copy number variation dataset
Copy Number Variation Dataset

Genome Structural Variation Consortium

Array-CGH using a whole genome tile path array

Median clone size ~170 kb

All 270 HapMap individuals

Measures amount of DNA, not RNA

Comparison between two samples

‘Test’ sample vs ‘Reference’ sample

typical analysis procedure
Typical Analysis Procedure

Values 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


More than 10% of the genome sequence

Structural Variation Project

Nature 447: 161-165, 2007


Copy Number Variations are ubiquitous in the human genome

The number of genome structural variants (>1 kb) that distinguish genomes of different individuals is at least on the order of 600–900 per individual.

J.O. Korbel et al., Science318(2007), pp. 420–426

hapmap 3
HapMap 3
  • Merged the results from Affymetrix and Illumina chips
  • Genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations
  • Sequenced ten 100-kilobase regions in 692 of these individuals

ASW African ancestry in Southwest USA

CEU Utah residents with Northern and Western European ancestry from the CEPH collection

CHB Han Chinese in Beijing, China

CHD Chinese in Metropolitan Denver, Colorado

GIH Gujarati Indians in Houston, Texas

JPT Japanese in Tokyo, Japan

LWK Luhya in Webuye, Kenya

MXL Mexican ancestry in Los Angeles, California

MKK Maasai in Kinyawa, Kenya

TSI Toscani in Italia

YRI Yoruba in Ibadan, Nigeria


SNP allele frequency estimation

Population differentiation

Linkage disequilibrium analysis

SNP Tagging

Imputation efficiency

Genomic locations of human CNVs

Genotypes for CNVs

Population genetic properties of CNVs (allele frequencies, population differentiation, etc.)

Mutation rate (frequency of de novo CNV) and potential mutational mechanisms

Linkage disequilibrium properties of CNVs

Tagging and imputation of CNVs

Signals of selection around CNVs

Association of SNPs and CNVs with expression phenotypes


Computational detection of structural genomic variation

Direct comparison of genomes through sequence alignments


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 level


Generate a lot of false positives due to sequence misassembly and gaps


Out of Africa

Scientific American, August 1999)

Modern humans arose in Africa and replaced other human species across the globe.


Out of Africa again and again

Itai Yanai, 2003

Templeton, A. Nature 416 (2002): 45 - 51

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 ? complete human genome sequences

•James Watson, 454. $70 million

  • •Craig Venter, Sanger, -$1 million
  • •African -HapMap –Illumina & Solid, $100,000
  • •Five African –Penn State University
  • •Chinese, Illumina
  • •Two Koreans
  • •Prof. Quake -Stanford --Nature genetics paper -$50,000, 1 week, Helicos
  • Stanford team -Clinical annotation of genome from “patient Zero”