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Applied research in human genetics. Weibin Shi Michele Sale. The central focus of human genetics research:. Identification of genes that cause disease. Which polymorphisms in Which genes in Which individuals Exposed to which environmental factors Increase risk of developing disease?.

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the central focus of human genetics research
The central focus of human genetics research:

Identification of genes that cause disease

Which polymorphisms in

Which genes in

Which individuals

Exposed to which environmental factors

Increase risk of developing disease?


Defining what to study

  • As in any biomedical study, need to precisely define the disease under study
  • Define primary phenotype and secondary phenotypes
  • Understanding risk factors
    • Genetic or Environmental?
      • Ethnic differences
      • Age/gender influence
refining whether the disease under study is genetic
Refining whether the disease under study is genetic
  • Family studies: Familial aggregation
  • Twin studies: Concordance rate of disorder for monozygotic twins (MZ) vs. the rate for dyzogotic (DZ) twins
  • Adoption studies: diseasefrequency of adoptees’ biological vs. their adopted parents or siblings
  • Ethnic differences

Best Proof of All?

Connect genetic variation to the disease!


Linkage analysis and Association analysis are effective in identifying Mendelian disorder genes but are less effective in identifying complex disease genes


Difficulties of genetic studies of complex disease in humans

  • Heterogeneity of human populations
  • Several to many genes involved
  • modest effects for any single gene
  • Environmental influences
mouse model of human genetic disease
Mouse model of human genetic disease
  • Advantages over other mammals:
  • Small size (<40g), short generation time (8-9 wks), large litter size (5~10 puppies)
  • Numerous inbred strains and gene-targeted
  • Easy control of environmental factors

Mouse genome shares great similarity with the human genome

Mouse-Human Comparison 2.5 vs. 3.2 billion bp long

> 99% of genes have homologs

> 95% of genome “syntenic” (relative gene-order conservation)


Variation among mouse strains in susceptibility

to diet-induced atherosclerosis

  • Discrete/qualitative trait - traits that are present or absent.
  • Continuous/quantitative trait - traits that have measurable characteristics across a range of values. This class includes the vast majority of diseases afflicting humans.
quantitative trait locus qtl analysis

Gene 1

Gene 2

Gene 3

Gene 4

Gene 5

Gene 6

Quantitative trait locus (QTL) analysis







QTL analysis starts with selection of two phenotypically different strains


Statistical analysis

Map Manager QTXb20 ( and R/qtl (http://www.biostat. are available for testing the association of a phenotype with each marker.

Log of the-odds-ratio (LOD) score is used to define the significance of the association of a genetic marker with a trait.


Interval mapping provides best estimation on the location of genes affecting atherosclerotic lesions


Dissect major QTL by

construction and analysis of congenic strains

Congenic strain: identical to an inbred strain except for a differential chromosomal segment


Sequence Comparison

  • If crosses include those of sequenced strains, search database for polymorphisms of positional candidate genes in the QTL regions.

15 common inbred strains (B6, AJ, 129, DBA, C3H …)now available at MGI, NCBI, and Ensembl

  • Re-sequence coding and promoter regions of strong candidate genes.

Gene expression database

  • Where is your gene expressed?

  • Is there microarry data for your gene?


Test the significance of QTL genes found in mouse by association analysis using human populations

applied research in human genetics1

Applied research in human genetics

Michèle Sale, Ph.D.

Center for Public Health Genomics

Tel: 982-0368

national dna day
National DNA Day!
  • April 25
  • Commemorates the discovery of the structure of DNA in 1953 and the sequencing of the human genome 50 years later
genetic information non discrimination act of 2007 gina
Genetic Information Non-Discrimination Act of 2007 (GINA)

A version first introduced in 1995

GINA would:

Prohibit access to individuals' personal genetic information by insurance companies making health coverage plan enrollment decisions, and by employers making hiring decisions;

Prohibit insurance companies from requesting that applicants for group or individual health coverage plans be subjected to genetic testing or screening, and prohibit them from discriminating against health plan applicants based on individual genetic information; and

Prohibit employers from using genetic information to refuse employment, and prohibit them from collecting employees' personal genetic information without their explicit consent.

Nearly 40 states have had individual forms of the legislation in place

Passed by House:

April 25, 2007 (420-3), and again

March 7, 2008 (as part of the Paul Wellstone Mental Health and Addiction Equity Act, 268-148)

Senator Tom Coburn (R, Oklahoma) had placed hold on bill in the senate

April 24, 2008: GINA passes in Senate (95-0)

the first type 2 diabetes gwas papers
The first type 2 diabetes GWAS papers…
  • Sladek et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007 Feb 22; 445:881-5.
  • Frayling et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007 May 11; 316:889-94.
  • Steinthorsdottir et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet. 2007 Jun; 39:770-5.
  • Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007 Jun 7; 447:661-78.
  • Saxena et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007 Jun 1;316(5829):1331-6
  • Zeggini et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007 Jun 1; 316:1336-41.
  • Scott et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007 Jun 1; 316:1341-5.

Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research, Science 2007 Jun 1;316(5829):1331-6

association results from wtcc replication study
Association results from WTCC replication study

Zeggini, E. et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316, 1336–1341 (2007).

Frayling TM. Nat Rev Genet 2007 Sep; 8:657-62

transcription factor 7 like 2 tcf7l2
Transcription-factor 7-like 2 (TCF7L2)

Major new diabetes gene

Identified as a diabetes gene by

Grant et al.Nat Genet 2006 March; 38: 320-323

Not previously suspected to be involved in diabetes

Known to influence levels of at least 60 other genes!

Shown to have a role in insulin secretion (Lyssenko et al. J Clin Invest. 2007 Aug; 117:2155-63)

effect sizes of 11 confirmed diabetes variants
Effect sizes of 11 confirmed diabetes variants

Frayling TM. Nat Rev Genet 2007 Sep; 8:657-62

but this variant is rarer in east asian and native american populations
But this variant is rarer inEast Asian and Native American populations
  • However, other variants in the same gene are associated with diabetes
investigation of european diabetes alleles in african americans
Investigation of “European” diabetes alleles in African Americans

*Dominant model (<10 counts for minor alllele homozygote)

Lewis et al. Diabetes 2008 (in press)

allele frequencies differ
Allele frequencies differ

Lewis et al. Diabetes 2008 (in press)

neonatal diabetes
Neonatal diabetes

Mutations of the ATP-sensitive inwardly-rectifying potassium channel subunit Kir6.2 (KCNJ11) gene cause 30-58% of cases of diabetes diagnosed in patients under six months of age

The majority of cases (80-90%) are de novo mutations, so won’t be identified on the basis of family history

neonatal diabetes kcnj11 mutations
Neonatal diabetes –KCNJ11 mutations

In the beta-cell, glucose metabolism increases intracellular ATP production from ADP

This leads to the closure of ATP-sensitive potassium channels and membrane depolarization

Subsequent activation of voltage-dependent calcium channels and influx of calcium results in insulin granule exocytosis

Patients with KCNJ11 mutations have KATP channels with decreased sensitivity to ATP

Channels remain open in the presence of glucose

Reducing insulin secretion

Pearson ER et al. N Engl J Med 2006, 355 (5), 467-477

neonatal diabetes1
Neonatal diabetes

Since patients present with hyperglycemia, undetectable C-peptide, and frequently have ketoacidosis (30%), they are often initially treated with insulin

A study of 49 patients showed that 90% could successfully be treated with sulfonylureas

Pearson ER et al. N Engl J Med 2006, 355 (5), 467-477

cytochrome p450 table
Cytochrome P450 table

Stamer and Stuber. Genetic factors in pain and its treatment. Curr Opin Anaesthesiol. 2007 Oct;20(5):478-84.


Lanfear and McLeod. Pharmacogenetics: using DNA to optimize drug therapy. Am Fam Physician. 2007 Oct 15;76(8):1179-82.

clinical trials
Clinical trials

Genetic testing may allow selective recruitment of participants in whom drug is expected to be most efficacious

Lower costs to bring drug to market

Will it be approved for a select genetic group?

ethical issues
Ethical issues







you can t change your genes why does genetics matter
You can’t change your genes – Why does genetics matter?

Identify new pathways involved in disease predisposition

New “druggable” targets

More specific diagnosis


Identify genetic factors that influence an individual’s response to a particular therapy

Selection of therapies

Clinical trial design


Recovery rates

Long-term sequelae

Era of “personalized medicine”

you can t change your genes why does genetics matter1
You can’t change your genes – Why does genetics matter?

Better prediction of who is at greatest risk and targeted early intervention


results from venter s genome
Results from Venter’s Genome

After QC filtering, 4.1 Million variants, 1.288M are novel to dbSNP (30%)

SNPs, indels, inversions, segmental duplication, and more complex variation

78% of 4.1M are SNPs; the other 22% cover 9Mb of variant bases

62 Copy Number Variants = 10Mb

Total of variation = 0.5% of genome

Heterozygous Indels range from 1 - 321 bp

Levy et al, PLoS Biology, 2007

j craig venter
J. Craig Venter


A gene variant linked to moist ear wax production

Genes linked to both heart disease (SORL1)  and longevity

Genes linked to

Alzheimer’s (APOE)

Macular degeneration

High cholesterol

Carries up to seven gene types linked to tobacco addiction

project jim
‘Project Jim’

1.3 percent of Watson’s genome did not match the existing reference genome.

> 600,000 novel SNPs

< 68,000 insertions and deletions compared to the reference sequence, 3bp - 7kbases

Bio-IT World June 2007