Biomedical Sciences I: Modes of Inheritance II (Lecture 6; Exam 1)

What is Mosaicism?

A condition where a single person or organism has two or more genetically distinct populations of cells, all originating from the same fertilized egg.

Somatic Mosaicism:

Mutation that occurs during embryogenesis and affects morphogenesis → segmental abnormality depending on the stage when the mutation occurred and the lineage of the cells affected.

Mutation in adult dividing cells leads to:

Carcinogenesis (normal cells transform into cancer cells)

*Form of somatic mosaicism

Germline mosicism:

A genetic condition where a mutation or gene variant is present in only some of a person’s egg or sperm cells, but not in their other body cells.

Unstable repeat expansions:

Expansion of a DNA segment consisting of repeating units of nucleotides.

Dynamic mutations are due to:

Unstable repeat expansions.

What are dynamic mutations?

A class of hereditary disease that is mostly neurological, caused by unstable repeat expansions.

(Have various patterns of inheritance)

What are Polyglutamine Disorders?

A group of nine inherited neurodegenerative disorders caused by expanded CAG trinucleotide repeats in specific genes that encode abnormally long glutamine tracts in proteins.

Huntington’s disease is an example of what kind of disorder?

Polyglutamine disorder.

Polyglutamine disorders characteristics:

• Anticipation = earlier onset with each generation

• Repeat Expansion = dictates the severity of symptoms

• Parental Transmission Bias = anticipation and repeat expansion more severe when inherited from father

Normal repeat expansions vs abnormal: HD

Normal: 5-35 repeats

Mild HD with late onset = 36-39 repeats

Severe HD = > 40 repeats

Fragile X Syndrome:

A genetic disorder that causes intellectual disability, learning challenges and developmental delays.

***Caused by the FMR1 gene on the X chromosome

What causes Fragile X Syndrome?

A change in the FMR1 gene on the X chromosome; caused by massive repeat expansion.

Fragile X Syndrome Characteristics:

• X-linked dominant inheritance with variable expressivity and low penetrance (50% in females)

• Caused by massive repeat expansion ( >200 CGG) in 5’ - UTR of FMR1 gene → increased methylation on CpGs and gene silencing

Patterns of mitochondrial inheritance result from the specific features of mitochondrial biology:

1. Maternal Inheritance

2. Replicative segregation

3. Homoplasmy / heteroplasmy

Homoplasmy:

All copies of mitochondrial DNA with a cell are completely identical.

(all either wild type or mutant DNA)

Heteroplasmy

The presence of more than one type of mutant DNA (mtDNA) within a single cell or organism.

Phenotypic expression depends on what proportions of wt and mutant mtDNA in the cells of a tissue?

Low penetrance and high expressivity of mitochondrial disorders.

Mitochondrial Bottleneck:

A biological process where only a small number of mtDNA molecules are passed from a mother to her offspring, or restricted during specific cell development.

Multifactorial disease:

A medical condition caused by a combination of multiple interacting genes and environment or lifestyle factors, rather than a single genetic mutation.

Classification of Multifactorial Diseases:

• Familial clustering but not in a mendelian pattern → complex inheritance

• Caused by additive effects of multiple genetic variants (polygenic) and environmental factors.

• Discrete qualitative traits (either present or not)

• Continuous quantitative traits (measurable physiological or biochemical parameters that vary among individuals)

Trait Distribution

Most quantitative traits follow a normal (gaussian) distribution.

Qualitative Traits and their distribution

Qualitative traits (disorders) have a liability distribution and the threshold of liability must be crossed for an individual to express the disease.

Why is empirical risk calculated?

Because it is difficult to determine recurrence risk; empirical risk is calculated based on studies of large numbers of affected families.

Criteria for multifactorial inheritance:

Recurrence risk is higher if:

• > 1 family member is affected

• The proband has a severe form of disease

• The proband is of the less commonly affected sex

T/F: Recurrence risk increasesrdapidly in distant relatives.

False. It decreases.

MZ twins vs DZ twins:

MZ Twins: (Identical) comes from one fertilized eff that splits into two.

DZ Twins: (Fraternal) come from two separate eggs fertilized by two different sperm.

What did twin studies show in differences between MZ and DZ twins?

Differences in MZ twins due ONLY to environmental factors.

(DZ twins have differences in both genetics and environment)

If both twins have the same disease, they are ____ for the trait.

Concordant.

If both twins do NOT have the same disease, they are _____ for the trait.

Discordant.

Concordance

If < 100% in MZ, there are non-genetic factors at play.

T/F: The greater the concordance in MZ vs DZ, the stronger the genetic component.

True.

Concordance rates and correlations are used to measure ____.

Heritability.

(proportion of phenotypic variation of a trait that is due to underlying genetic variation)

Heritability values:

Are specific for the population in which they were estimated.

Limitations to twin studies:

• Assumptions of equally similar environments for MZ and DZ (MZ twins raised separately would be perfect controls)

• Different somatic mutations after cleavage

• Methylation patterns (and X-inactivation patterns in females)

Adoption Studies:

Comparison of disease rates among adopted offspring of affected parents with the rates of adopted offspring of unaffected parents → establish genetic component.

Limitations to adoption studies:

• Non-random adoption process

• Selective placement

Congenital Malformations:

Approx. 2% of births, mostly of multifactorial etiology

• Congenital heart defects

• Cleft-lip and palate

What is the most common congenital malformation?

Congenital heart defects. 8/1000 births

(Generally aggregated in families but might appear as different defects)

Cleft-lip and palate malformations:

2.5 / 1000 births.

• Non-genetic ; caused by ibuprofen, barbiturates, maternal smoking, folic acid and vit A deficiency, exposure to chemicals

• Genetic ;

  • Syndromic: Single-gene (generally accompanied by other anomalies.)

  • Non-syndromic: isolated feature

Cardiovascular disorders:

• Coronary artery disease

• Stroke

• Hypertension

T/F: Women are at higher rish for coronary artery disease.

False. Male are higher risk.

Coronary artery disease:

• Environmental factors: Smoking, obesity, sedentarism, consumption of saturated fats

• Family studies:

  • Genetic component to CAD (LDL receptor, apolipoprotein genes, lipoprotein lipase, etc.)

  • Risk twice as high in families with CAD

Who has increased risk for CAD?

• > 1 affected relative

• Affected relative of female sex

• Onset age of relative < 55 years

Stroke

2-3 fold risk increase if the parent had a stroke.

• CMZ = 10%

• CDZ = 5%

• Genetic: Genes coding for coagulation factors (eg. clotting factor V)

• Environmental: Obesity, diabetes, smoking

Hypertension

Approx. 0.5 heritability for both systolic and diastolic hypertension.

• > 20 genes responsible for rare hypertension syndromes.

• Environmental: Decreased physical activity, stress, obesity

• Genetic: Genes regulating the angiotensin system

Breast Cancer:

2x increased risk in women with first-degree affected relatives, increases with additional affected relatives and if those developed cancer at < 50 years.

Genes that cause breast cancer;

• BRCA1 & 2

• Other DNA repair genes

Environmental factors for breast cancer:

• Nulliparity

• First child at > 30 years

• High-fat diet

• Alcohol abuse

• Estrogen replacement therapy

Colorectal cancer

2-3x increased risk with affected relatives.

• Genetic: Mutation in APC gene or other DNA mismatch repair genes

• Environmental: Sedentarism, high-fat, low-fiber diet

Prostate Cancer

2-3x increased risk with an affected relative.

• Heritability = approx 0.4

• Difficult genetic analysis given the late age onset (past 70 years)

  • Several SNPs located in an area surrounding an enhancer for the MYC oncogene.

  • Non-genetic factors: high-fat diet

Diabetes: Type 1

• Risk from mother 1-3%

• Risk from father 4-7%

• CMZ = 50%, CDZ = 10%

  • Genes: HLA class II (high incidence in homozygotes for DR3 and DR4), insulin gene

  • Environmental: Viral infections

Diabetes: Type 2

Recurrence risk: 15-30%

• CMZ >90%, CDZ = 25%

  • Genes: TCF7L2, PPAR-y, KCNJ11

Obesity: Adoption Studies

Adoption studies show that the weight of adopted children correlated with the weight of natural parents, not with that of adoptive parents → strong genetic component

Obesity: Heritability

0.6-0.8

Genetic: Mutations in leptin and leptin receptors, neuropeptide Y, melanocortin-4 receptor, FTO (homozygotes have 70% increased risk)

Alzheimer’s disease:

2x increased risk with affected first-degree relatives.

Approx. 10% have autosomal dominant inheritance (early onset before 60 years)

Genetic component Alzheimer’s disease:

• Early-onset: Presenilin 1 and 2 (responsible for B-amyloid formation), APP (amyloid-B precursor)

• Late-onset: apolipoprotein E - E4 (APOE)

Environmental factors: Alzheimer’s disease

• Head trauma

• DDT (banned pesticide)

Alcoholism:

Familial cluster - 5x higher risk in offspring of affected parents.

• CMZ : >60%

• CDZ: <30%

Adoption studies show that offspring of alcoholics raised by non-alcoholics have 4x increased risk.

Alcoholism: Type I or Type II

• Type I: Later age onset (>25 years), equal males and females, less severe, easier to treat

• Type II: Males <25 years, more severe and difficult to treat

Genes involved in Alcoholism:

• Alcohol dehydrogenase (ADH)

• Acetaldehyde dehydrogenase (ALDH)

Neuropsychiatric disorders:

• Schizophrenia

• Autism Spectrum disorder

Schizophrenia:

Recurrence risk for offspring of affected parents = 8-10% (>10x than general population).

Increased risk in second/third-degree relatives

• CMZ = 50%

• CDZ = 15%

>100 candidate genes in glutamatergic and dopaminergic pathways.

Autism Spectrum Disorder:

3-4x more common in males.

• Heritability: > 0.7

• High number of mutations mostly inherited paternally → high risk in offspring of older fathers