the land beyond mendelian monogenic inheritance: some newer areas of human genetics: modifier genes...
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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)
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
Variability in the Phenotypic Manifestationsof Mutant Genes for Monogenic Disorders
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 HumansAmelioration 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 PigmentosaBardet- BiedelDeafnessHirschprungSevere Insulin resistance
* Ming JE & Muenke M AJHG 2002
Bardet=Biedel syndrome: genetically heterogeneous disorder with linkageto 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 Disordersand Normal Variation Epigenetics (methylation, Histone modification)
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)
Change in focus of investigations for understanding human genetics
Many common diseases have genetic components
Bipolar disorder, heart attack, breast cancer, diabetes, prostate cancer, arthritis
Height, blood pressure, insulin secretion, weight, waist-hip ratio, timing of puberty, bone density
…as do many quantitative traits…
…but the genetic architecture is usually complex
. .
.
Genes
Environment
Gene 1
Gene 2
Gene 3
Gene N
Nutrition
Etc.
Environment in utero
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% concordantDZ 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 Candidate gene gene
association association studiesstudies
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
ApoE4
Healthyindividuals
Alzheimerspatients
from J.N. Hirschhorn, M.D., Ph.D.
SUSCEPTIBILITY AND RESISTANCETO 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 Low folate Reductase (val vs ala....) High homocysteine
Early pregnancy loss " " " "
Recurrent pregnancy loss Blood group P 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 p4. 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.
Modifiers of Single Gene Defects
Contributors to Risk for Multifactorial Disease NOD2 for Inflammatory Bowel Disease
Susceptibility Genes (Gene variants interacting with environmentalfactors ie pathogens, drugs )
Types of Gene-Gene, Gene-Environment Interactions
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 Disordersand 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
DNA methylation CpGHistone modifications: acetylation, methylation of lysine residues 4 or 9 in H3RNA noncoding; antisense (alpha globin)
Labile regulation vs epigenetic regulation (can pass to daughter cells)
Functional genomics:
- assignment of function to the identified genes
- determining the organization and control of genetic path- ways that interact to yield physiology of the organism
- new computational, biochemical, physical and mathe- matical methodology ( and return to old)
What about all the other unidentified monogenic diseases???
What is still “missing” ???