6. modes of inheritance II

atypical inheritance

Mosaicism

Dynamic mutations: unstable repeats

Mitochondrial disorders

Mosaicism

Individual with at least 2 cell lines that differ genetically, but are derived from a single zygote

Mutations that occur after conception in a single cell during either pre/postnatal life are producing clonal descendants that are genetically different from the original zygote

Whether mosaicism involves germline cells, somatic cells, or both
depends on:

the time the mutation has occurred during embryogenesis

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 → carcinogenesis

Germline mosaicism

Unaffected individuals with no evidence of disease-causing mutation (not detected in the DNA from buccal swabs or peripheral blood cells)

may be at risk of having offspring with highly penetrant autosomal dominant or X-linked disease

Dynamic mutations: unstable repeats

In all other types of inheritance, a mutation is stable through generations

A class of hereditary disease (mostly neurological) are due to unstable repeat expansions = expansion of a DNA segment consisting of repeating units of nucleotides

Various patterns of inheritance

Polyglutamine disorders

Huntington’s disease

string of consecutive Glu (CAG) of variable length in the mutant protein

characteristics of poilyglutamine disorders

Follows inheritance pattern similar to autosomal dominant (50% risk) with
a few specific characteristics

• Anticipation = earlier onset with each generation

• Repeat expansion (nr. of repeats) dictates the severity of symptoms

• parental transmission bias

parental transmission bias

Anticipation and repeat expansion more severe when inherited from father

normal vs a lot of repeats → age of onset + severity for HD

Normal number of repeats = 5-35; mild HD with late onset

36-39; severe HD >40 repeats

Fragile X syndrome

most heritable form of mild intellectual disability

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

Disease caused by massive repeat expansion (>200 CGG) in 5’-UTR of FMR1 gene → increased methylation on CpGs (constriction of the region under the microscope) and gene silencing

Mitochondrial disorders

Do NOT follow mendelian inheritance, strict maternal inheritance

Each cell contains several hundred mitochondria, and each mitochondria
has several copies of mtDNA (mtDNA has no introns)

>100 rearrangements and point mutations (increased oxidative stress
and lack of repair mechanisms) in the mtDNA → increased pleiotropy

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

1. Maternal inheritance

2. Replicative segregation

3. Homoplasmy/heteroplasmy

Patterns of mitochondrial inheritance result from the
specific features of mitochondrial biology: 1. Maternal inheritance

Sperm mitochondria is not present in the zygote

Patterns of mitochondrial inheritance result from the
specific features of mitochondrial biology: 2. Replicative segregation

During cell division mtDNA replicates and copies are distributed randomly among newly synthesized mitochondria → significant variability in disease manifestation among tissues and individuals

Patterns of mitochondrial inheritance result from the
specific features of mitochondrial biology: 3. Homoplasmy/heteroplasmy

De novo mutations appear in only one of the mtDNA in one mitochondrion, but mtDNA replication produces multiple mutant mtDNA

Replicative segregation accounts for the random distribution of mutant and wt mitochondria to daughter cells

homoplasmy

Pure population of either wt or mutant mtDNA

heteroplasmy

Mixed population

Phenotypic expression depends on: 

the relative proportions of wt and mutant mtDNA in the cells of a tissue → low penetrance and high expressivity of mitochondrial disorders

mitochondrial genetic bottleneck

the number of mitochondria in developing oocytes is reduced before
expansion to the number seen in mature oocyte 

leads to variability in proportion of mutant mtDNA in offspring

multifactorial inheritance 

everything below

Multifactorial diseases

complex inheritance

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

Classification:
– Discrete qualitative traits (either present or not)
– Continuous quantitative traits

complex inheritance

Familial clustering, but NOT in a mendelian pattern

quantitative traits

measurable physiological or biochemical parameters that vary among individuals

Trait distribution of quantitative traits

Most quantitative traits follow a normal (gaussian)
distribution
– eg. >200 loci associated with height

Qualitative traits distribution

have a liability distribution

the threshold of liability must be crossed for an individual to express the disease

Criteria for multifactorial inheritance

Difficult to determine recurrence risk, therefore empirical risk is calculated based on studies of large number of affected families

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

Recurrence risk decreases rapidly in distant relatives

the empirical risk varies drastically between populations due to

variability in allele frequency and environmental factors

Relative contributions of genes and environment: 1. Twin studies

Differences in monozygotic twins (MZ) due ONLY to environmental factors (dizygotic twins (DZ) serve as comparison)

concordant for the trait

If both twins have same disease

if not, discordant

Concordance

Concordance < 100% in monozygotic twins → non-genetic factors at play

The greater the concordance in MZ vs. DZ, the stronger the genetic component

Concordance rates and correlations are used to measure heritability

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

Assumption 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)

Relative contributions of genes and environment: 2. 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

Congenital malformation examples 

Congenital heart defects + Cleft-lip and palate 

cardiovascular disorder examples

coronary artery disease, stroke, hypertension

cancer examples

breast, colorectal, + prostate

diabetes examples

T1DM + T2DM

other multifactorial disease examples

obesity, alzheimers, alcoholism

Neuropsychiatric disorder examples

autism, schizophrenia