BIOL 311 Human Genetics
Fall 2006
Lecture: Complex Diseases
Reading: Chapter 15
Lecture outline:
1. Twin studies
2. Segregation analysis
3. Non-parametric linkage analysis
4. Linkage disequilibrium
5. Breast Cancer
6. Alzheimer's
Lecture:
Genes contribute to many human diseases and early deaths. Identifying "susceptibility
genes" for complex diseases such as cancers, diabetes, Alzheimers and schizophrenia is
very difficult.
Nature vs. nurture: How much of these diseases is contributed by genes, how much by
environment?
Familial clustering: Close relatives may have higher incidence of a disease than expected
based on chance--suggests possible genetic component.
1. Twin studies
 monozygotic twins ("identical twins")
 genetically identical
 have different rearrangements in the immune genes
dizygotic twins ("raternal twins")
 are genetic siblings
 share half their genes on average
For traits that show higher concordance in MZ vs. DS twins, generally assume some
genetic contribution.
Table 15.2 Twin Studies in Schizophrenia
Study
1
2
3
4
5
Concordant MZ pairs
25-38%
24-48%
15-31%
38-50%
33%
1
Concordant DZ pairs
4-10%
10-19%
7%
5-13%
4%
MZ twins separated at birth--possible way of distinguishing between genetic and
environmental influences.
2. Segregation analysis
 statistical tool
 corrects the observed results for segregation of trait for bias in not counting lucky
unaffected families
LOD analysis usually can't be applied for linkage of complex characters; only applicable
for Mendelian traits.
Diagnostic criteria for complex traits difficult to establish.
Try to track subset of individuals with trait where it appears to be transmitted with
Mendelian inheritance pattern.
Has lead to false leads such as a "schizophrenia gene".
Has been successful for identifying genes for hereditary forms of breast cancer and
Alzheimers, although sporadic forms are still a mystery.
3. Non-parametric linkage analysis
Not based on transmission of a Mendelian trait
Look for alleles on chromosome segments shared by affected individuals
IBD: segments identical by descent, copies of same ancestral allele.
IBS: segments identical by state
Track haplotypes and disease state
Track disease in families by examining affected siblings "ASP"=affected sib pairs likely
to share same chromosome segment that carries disease gene.
Best to track multiple markers "multipoint analysis".
Nonparametric LOD scores (NPL) can be calculated.
Probability cutoffs for statistical significance
Analysis
IBD testing sib pairs
IBS testing sib pairs
NPL score
3.6-5.3, >5.4 highly significant
4.0
Many possible reasons why an allele and phenotype are associated, many NOT
GENETIC.
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4. Linkage disequilibrium
 Associations between marker and disease in unrelated individuals.
 In unrelated individuals only region right around disease gene are the same, other
linked markers not the same.
May have peak of linkage disequilibrium close to disease gene, i.e. CF.
May have peak a little distance from gene, i.e. HD Fig. 15.5
Examples of complex traits
1) Breast cancer: cloning of BRCA1 gene
2) Alzheimers and association with APOE
5. Hereditary Breast Cancer
 Most cancer is sporadic.
 Cancer families are those with several members with a rare cancer.
 Often show Mendelian transmission.
 Hereditary breast cancer 4-5% of cases
Features of hereditary breast cancer
 Early age of onset
 Sometimes risk for both breast and ovarian cancer passed on
 Cancer in both breasts (bilateral tumors)
 Some males affected
Led to identification of two genes, BRCA1, BRCA2
Cloning of BRCA1 Fig. 15-7
 Linkage analysis of 1500 families
 Statistical analysis of segregation
 Identified those with essentially Mendelian inheritance of autosomal dominant
trait
 Since susceptibility gene showed Mendelian inheritance, could do LOD analysis
 Identified locus at 17q21
 Z = 3.28 to 5.98 with closely linked marker
 Remember Z greater than or equal to +3 shows significance, therefore marker and
disease most likely linked
 Positional cloning was carried out to isolate the BRCA1 gene
BRCA1 gene
 Tumor suppressor gene
 24 exons
 encodes 1863 amino acid protein
 protein involved in transcriptional control, DNA repair
BRCA1 and BRCA2 do NOT seem to play an important role in most sporadic breast
cancer cases.
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BRCA1 mutation 85-90% chance of developing breast cancer, 40% risk of ovarian
cancer
BRCA2 mutation 85%-90% chance of breast cancer, no increased risk for ovarian cancer.
6. Alzheimers
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5% of adults over 65
20% of adults over 80
progressive loss of memory
disturbances in emotional behavior
loss of neurons with amyloid containing plaques
early onset families--dominant Mendelian traits
 identified 3 genes--10% of early onset cases
 APP (amyloid protein)
 Presenilin 1 & 2
Late onset families--linkage to chromosome 19
 Mapped to APOE (Apolipoprotein E)
 E4 allele: associated with Alzheimers
 E2 allele: resistant to Alzheimers
Homozygotes of E4 have 14x risk of Alzheimers
Heterozygotes E4/E3 3x risk
APOE accounts for 50% of late onset susceptibility regions
Many other candidate susceptibility regions do not pan out statistically
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