The Land Beyond Mendelian Monogenic
inheritance: Some Newer areas of
Human Genetics:

Modifier Genes
 Oligogenic, Digenic,Tri or biallelic Inheritance
 Multifactorial Inheritance of Common Disorders
and Normal Variation
 Epigenetics (methylation, Histone modification)
New Pathways, Methods, Aims
“Mendelian” Monogenic (Single Gene)
Disorders
Defects (Deleterious Mutations) in a single gene
(monogenic), passed on from parent(s) lead to full blown
disease in all individuals inheriting the mutation(s)
Variability in the Phenotypic Manifestations
of Mutant Genes for Monogenic Disorders
Penetrance: the probability that a mutant gene will have
any phenotypic expression
Expressivity: the severity of expression of disease
Pleiotropy: multiple effects of a single gene defect
Reduced Penetrance and Incomplete penetrance
Variable expressivity
The Land Beyond Mendelian Monogenic
inheritance:
Some Newer areas of Human Genetics
Modifier Genes
Oligogenic, Digenic,Tri or Biallelic Inheritance
Multifactorial Inheritance of Common Disorders and
Normal Variation
Epigenetics (methylation, Histone modification)
New Pathways, Methods, Aims
Evidence Consistent with Modifier
Genes Acting in Monogenic Disorders*
Same mutation results in different phenotype
Sibs with different phenotype
Animal Models: differences in disease expression in
different strains of animals with inherited disease
Variable Expressivity (even in the same kindred)
Penetrance: % of individuals who do not develop disease
(also “age related penetrance”)
* environment has to be considered
Examples of Genes that modify the
phenotype of “Single Gene Disorders”
in Humans
Amelioration of homozygous Beta Thalassemia by
heterozygosity for alpha Thalassemia
Amelioration of Sickle cell, beta Thalassemia by HPHF
(High Hb F)
DFNB26: modifier gene localized : Dominant modifier
DFNM1 suppresses recessive deafness of DFNB26
The Land Beyond Mendelian
Monogenic inheritance: Some
Newer Areas of Human Genetics
Modifier Genes
Oligogenic, Digenic,Tri or Biallelic Inheritance
Multifactorial Inheritance of Common Disorders and
Normal Variation
Epigenetics (methylation, Histone modification)
New Pathways, Methods, Aims
“Oligogenic Disorders” , Digenic
Disease, Biallelic, Triallelic
Definition: “Mutations in each of two (or more) unlinked
genes are present in a single individual. The combination of
the two genetic hits causes a disease phenotype that is not
apparent when an individual carries only one of these gene
alterations” *
Proposed Disorders where this form of inheritance has
been identified:*
Retinits Pigmentosa
Bardet- Biedel
Deafness
Hirschprung
Severe Insulin resistance
* Ming JE & Muenke M AJHG 2002
Bardet=Biedel syndrome:
genetically heterogeneous disorder with linkage
to 8 loci.
Clinical features: include mental retardation, pigmentary
retinopathy, polydactyly, obesity and hypogenitalism.
“Triallelic Inheritance” Some forms of Bardet-Biedel
syndrome requires recessive mutations in 1 of six loci plus
an additional mutaion in a second locus
Tri-allelic Inheritance in Bardet Biedel Syndrome
Science293; 2213 Burghes et al, 2256 Katsanis et al 2001
The Land Beyond Mendelian
Monogenic inheritance: Some
Newer areas of Human Genetics
Modifier Genes
Oligogenic, Digenic,Tri or biallelic Inheritance
Multifactorial Inheritance of Common Disorders and Normal
Variation
Epigenetics (methylation, Histone modification)
Change in focus of investigations for
understanding human genetics
SINGLE GENE DISORDERS  COMPLEX TRAITS (MULTIFACTORIAL
Defects (Deleterious Mutations) in a single gene
(monogenic), passed on from parent(s) lead to full blown
disease in all individuals inheriting the mutation(s)
COMPLEX TRAITS (MULTIFACTORIAL)
Variants at multiple different genes combine to result in the trait
(e.g. perfect pitch)
Normal variation as well as disease or disease susceptibility,
variation in handling of environmental substances (e.g. drugs,
toxins, infectious agents)
Many common diseases have genetic components
Bipolar disorder, heart attack,
breast cancer, diabetes, prostate
cancer, arthritis
…as do many quantitative traits…
Height, blood pressure, insulin
secretion, weight, waist-hip
ratio, timing of puberty, bone
density
…but the genetic architecture is usually complex
Gene 1
Genes
Gene 2
...
Gene 3
Gene N
Environment
Nutrition
Environment
in utero
Etc.
From JN Hirschhorn MD PhD
How do we know genetics plays a role?
Family studies
• Risk to siblings and other
relatives is greater than in
the general population
• Example: type 2 diabetes
– Risk to siblings: 30%
– Population risk: 5-10%
How do we know genetics plays a role?
Twin studies
Identical (monozygotic) twins are more similar than
fraternal twins (dizygotic)
Example: type 2 diabetes
MZ twins: >80% concordant
DZ twins: 30-50% concordant
Associating inherited (DNA) variation
with biological variation
• Each person’s genome is
slightly different
• Some differences alter
biological function
• Which differences matter?
Approaches to finding the relevant genes
Single gene disorders
Linkage studies
Animal or other models
Expression profiling
Candidate
gene
association
studies
Other approaches
Confirmation
Approaches to Identifying Genes
Involved in Multifactorial Disease
Genome Wide Scan:
linkage (trios or sib pairs)
not dependent on specific hypothesis
Association Studies
(case control but family studies as well)
aimed at testing of specific genes
over 500 studies published in past 2 years
most studies not replicated
(still may be correct)
Paradigm for such investigations not
certain
Finding DNA variants that increase
disease risk
• Identify the relevant gene
• Characterize variation in the gene
• Association studies of gene variants
– Find variants that are more common in affected individuals
Association studies to find disease alleles
ApoE4
Healthy
individuals
ApoE4
Alzheimers
patients
from J.N. Hirschhorn, M.D., Ph.D.
SUSCEPTIBILITY AND RESISTANCE
TO INFECTIOUS DISEASES
______________________________________________
DISEASE
GENE
MECHANISM
______________________________________________
AIDS
CCR5, CCR2, SDF-1(CXCR4L) Lymphocyte receptors
Parvovirus B19
P blood group
RBC viral receptor
Malaria (P.vivax)
Duffy blood group
RBC receptor
SUSCEPTIBILITY TO COMMON DISEASE AND TREATMENT
______________________________________________
DISEASE
GENE
MECHANISM
______________________________________________
Neural Tube Defect
Methyltetrahydrofolate
Reductase (val vs ala....)
Early pregnancy loss
"
Recurrent pregnancy loss
Blood group P
"
Low folate
High homocysteine
"
"
Maternal immunity
Association studies are powerful but problematic
• Most reported associations have not been consistently
reproduced
• Most true associated variants increase risk modestly
• 10-50% increased risk of disease
Example - Association of the ADAM33 gene with asthma
and bronchial hyperresponsiveness (Nature 2002)
1. Thorough characterization of patients
(clinical, lab & function)
2. Genome wide scan with affected sib-pairs (UK & US)
3. Determined greater “identity by descent” of marker than expected
observed 31%vs predicted (25%) on 20 p
4. Constructed map and gene content of region (despite claim
that genome has been sequenced)
5. Repeat case control after SNP, Haplotype discovery
(20 genes studied in detail)
6. Repeated family based study by TDT
(transmission distortion test)
7. Gene implicated (ADAM33) is a rational target.
Types of Gene-Gene, Gene-Environment
Interactions
Modifiers of Single Gene Defects
Contributors to Risk for Multifactorial Disease
NOD2 for Inflammatory Bowel Disease
Susceptibility Genes
(Gene variants interacting with environmental
factors ie pathogens, drugs )
Mitochondrial
mutation/SNP
The Land Beyond Mendelian
Monogenic inheritance: Some
Newer areas of Human Genetics
Modifier Genes
Oligogenic, Digenic,Tri or biallelic Inheritance
Multifactorial Inheritance of Common Disorders and Normal
Variation
Epigenetics (methylation, Histone modification)
Epigenetics: stable and heritable (or potentially heritable)
changes in gene expression that do not entail a change in
DNA Sequence
Jiang, Bressler & Beaudet 2004 Annu Rev Genomics Hum Genet
All meiotically and mitotically heritable changes in gene
expression that are not coded in the DNA sequence itself
Egger et al Nature 2004
Labile regulation vs epigenetic regulation (can pass to daughter cells)
DNA methylation CpG
Histone modifications: acetylation, methylation of lysine
residues 4 or 9 in H3
RNA noncoding; antisense (alpha globin)
What is still “missing” ???
Functional genomics:
- assignment of function to the identified genes
- determining the organization and control of genetic pathways that interact to yield physiology of the organism
- new computational, biochemical, physical and mathematical methodology ( and return to old)
What about all the other unidentified monogenic diseases???