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” ???