Non Mendelian Inheritance

Dr S M H Ghaderian, MD, PhD

Associate Professor of Medical Genetics

8 floor, Medical Genetics Department

School of Medicine

Shahid Beheshti University of Medical Sciences

Maternal inheritance and Mitochondrial genes

• The basis of the law of segregation is that both

parents contribute genes equally to offspring.

• This is not the case for genes in mitochondria,

the organelles that house the biochemicall

reactions that provide energy.

• It carries just 37 genes.

Mitochondrial Genomes

• Mitochondria organelles found in the cytoplasm of all aerobic eukaryotic cells, are involved in cellular respiration.

• It is the process of oxidizing food molecules, such as glucose, to carbon dioxide and water.

• The energy released is in the form of ATP.

• Many mitochondrial genomes are circular, double-stranded, supercoiled DNA molecules.

• Linear mitochondrial genomes are found in some protozoa and some fungi.

• In many cases, the GC content of mtDNA differs greatly from that of the nuclear DNA.

Genome structure

• No histones or smilar proteins are associated with mtDNA.

• Multiple copies of the genomes are found within mitochondria that are located in multiple nucleoid regions.

• In animals, the circular mitochondrial genome is less than 20 kb; for example, human mtDNA is 16,569 bp, in contrast, the mtDNA of yeast is about 80 kb, and that of plants ranges from 100,000 to 2 million bp.

Mitochondrial differences

• The main difference between animal, plant, and fungal mitochondria is that essentially the entire mitochondrial genomes of animals encode products, whereas the mitochondrial genomes of fungi and plants have extra DNA that does not code for products.

The circular mitochondrial DNA genome. Locations of protein-encoding genes (for reduced

nicotinamide adenine dinucleotide [NADH] dehydrogenase, cytochrome c oxidase, cytochrome c

oxidoreductase, and adenosine triphosphate [ATP] synthase) are shown, as are the locations of the

two ribosomal RNA genes and 22 transfer RNA genes (designated by single letters). The replication

origins of the heavy (OH) and light (OL) chains and the noncoding D loop (also known as the control

region) are shown. Modified from MITOMAP. A Human Mitochondrial Genome Database.

http://www.mitomap.org, 2008.

Each human cell contains several hundred or more

mitochondria in its cytoplasm.

Through the complex process of oxidative

phosphorylation, mitochondria produce adenosine

triphosphate (ATP), the energy source essential for

cellular metabolism.

Mitochondria are thus critically important for cell survival.

The mutation rate of mtDNA is about 10 times higher than

that of nuclear DNA.

This is caused by a relative lack of DNA repair

mechanisms in the mtDNA and also by damage from free

oxygen radicals released during the oxidative

phosphorylation process.

Because each cell contains a population of mtDNA

molecules, a single cell can harbor some molecules that

have an mtDNA mutation and other molecules that do not.

This heterogeneity in DNA composition, termed

heteroplasmy, is an important cause of variable

expression in mitochondrial diseases.

The larger the percentage of mutant mtDNA molecules,

the more severe the expression of the disease.

Each tissue type requires a certain amount of ATP for

normal function.

Although some variation in ATP levels may be tolerated,

there is typically a threshold level below which cells

begin to degenerate and die.

Organ systems with large ATP requirements and high

thresholds tend to be the ones most seriously affected

by mitochondrial diseases.

For example, the central nervous system consumes

about 20% of the body’s ATP production and therefore

is often affected by mtDNA mutations.

Like the globin disorders, mitochondrial disorders can

be classified according to the type of mutation that

causes them.

Missense mutations in protein-coding mtDNA genes cause

one of the best known mtDNA diseases, Leber hereditary

optic neuropathy (LHON).

This disease, which affects about 1 in 10,000 persons, is

characterized by rapid loss of vision in the central visual

field as a result of optic nerve death.

Vision loss typically begins in the third decade of life and is

usually irreversible.

Heteroplasmy is minimal in LHON, so expression tends to

be relatively uniform and pedigrees for this disorder

usually display a clear pattern of mitochondrial inheritance.

Single-base mutations in a tRNA gene can result in

myoclonic epilepsy with ragged-red fiber syndrome

(MERRF), a disorder characterized by epilepsy, dementia,

ataxia (uncoordinated muscle movement), and myopathy

(muscle disease).

MERRF is characterized by heteroplasmic mtDNA and is

thus highly variable in its expression.

Another example of a mitochondrial disease caused by a

single-base tRNA mutation is mitochondrial

encephalomyopathy and stroke-like episodes (MELAS).

Like MERRF, MELAS is heteroplasmic and highly variable

in expression.

The final class of mtDNA mutations consists of

duplications and deletions.

These can produce Kearns–Sayre disease (muscle

weakness, cerebellar damage, and heart failure);

Pearson syndrome (infantile pancreatic insufficiency,

pancytopenia, and lactic acidosis); and chronic

progressive external ophthalmoplegia (CPEO).

Hundreds of disease-causing mtDNA mutations,

including single-base mutations, deletions, and

duplications, have been reported.

It has been estimated that approximately 1 in 4000

individuals is affected by a mitochondrial disease, and

the majority of these are due to mitochondrial mutations

(the remainder a caused by nuclear mutations in

protein products expressed in the mitochondria).

Linkage

• Most of the traits that Mendel studied in pea

plants were conferred by genes on different

chromosomes (two were actually at opposite

ends of the same chromosome).

• When genes are located close to each other

on the same chromosome, they usually do not

separate during meiosis.

• Linkage refers to the transmission of genes

on the same chromosome.

• Linked genes do not assort independently and

do not produce Mendelian ratios for crosses

tracking two or more genes.

Rules of Non-Mendelian Inheritance 1

• Ratios typical of Mendelian segregation are not found because meiosis-based Mendelian segregation is not involved.

• In multicellular eukaryotes, the results of reciprocal crosses involving extranuclear genes are not the same as reciprocal crosses involving nuclear genes because meiosis-based Mendelian segregation is not involved.

Rules of Non-Mendelian Inheritance 2

• Extranuclear genes cannot be mapped to the

chromosomes in the nucleus.

• Non-Mendelian inheritance is not affected by

substituting a nucleus with a different

genotype.

When Gene expression appears to

alter Mendelian ratios• For some characteristics, though, offspring

classes do not occur in the proportions that Punnet squares or probabilites predict.

• In these instances, Mendel’s laws operate, and the underlying genotypic ratios persist, but either the nature of the phenotype or influences from other genes or the environment alter phenotypic ratios, that is, what is actually seen.

Lethal allele combinations

• A genotype (allele combination) that causes

death is, by definition, lethal. In humans, early-

acting lethal alleles cause spontaneous

abortion (technically called miscarriages if they

occur after the embryonic period).

• Sometimes a double dose of a dominant allele

is lethal, as is the case for Mexican hairless

dogs.

Multiple alleles

• A person has two alleles for any autosomal gene-one allele on each homolog.

• However, agene can exist in more than two allelic forms in a population because it can mutate in many ways.

• Different allele combinations can produce variations in phenotype.

• PKU an inborn error of metabolism in which an enzyme is deficient or absent, causing the amino acid phenylalanine to build up in brain cells.

• More than 300 mutant alleles combine to form four basic phenotypes: classic PKU with profound mental retardation, Moderate PKU, Mild PKU, asymptomatic PKU, with excretion of excess phenylalanine in urine.

Different dominance relationships• In complete dominance, one allele is

expressed, while the other isn’t.

• In incomplete dominance, the heterozygous

phenotype is intermediate between that of

either homozygote.

• Tay-Sachs disease displays complete

dominance because the heterozygote (carrier)

is as healthy as homozygous dominant

individual.

• However if phenotype is based on enzyme

level, then the heterozygous is intermediate

between the homozygous dominant (full

enzyme level) and homozygous recessive (no

enzyme).

Codominant

• Different alleles that are both expressed in a

heterozygote are codominant.

• The ABO blood group is based on the

expression of codominant allels.

• I (isoagglutinin), the three alleles are I A, I B,

and i.

Epistasis-One Gene affects another’s

expression

• Mendel’s laws can appear to not operate when one gene makes or otherwise affects the phenotype associated with another.

• This phenomenon is called epistasis.(do not confuse this with dominance relationships between alleles of the same gene).

• Bombay phenotype, for example, is a result of two interacting genes: the I and H genes. The normal H allele encodes an enzyme that inserts a sugar molecule, called antigen H, onto a particular glycoprotein on the surface of an immature red blood cell.

• The A and B antigenes attach to the H antigen.

Penetrance and Expressivity

• The same allele combination can produce different degree of a phenotype in different individuals because a gene does not act alone.

• Nutrition, exposure to toxins, other illnesses, and actions of other genes may influence the expression of most genes.

• For example CF in one patient with develop asthma may be much sicker than individual without other inherited disease.

• The terms penetrance and expressivity describe degrees of expression of a single gene.

• Penetrance refers to the all-or none expression of a genotype; Expressivity refers to severity or extent.

• Complete and incomplete penetrant

Pleiotropy-One Gene, Many Effects

• A Mendelian disorder with many symptoms, or

agene that controls several functions or has

more than one effect, is termed pleiotropic.

• For example prophyria variegata, an

autosomal dominant, pleiotropic, inborn error

of metabolism.

• The disease affected several members of the

royal families of Europe.

Phenocopies-when it’s not in the gene

• An environmentally caused trait that appears

to be inherited is a phenocopy.

• Such a trait can either produce symptoms that

resemble those of a Mendelian disorder or

mimic inheritance patterns by occurring in

certain relatives.

• For example, the limb birth defect caused by

the drug thalidomid is a phenocopy of the

inherited illness phocomelia.

Genetic Heterogencity-more than one way to

inherit trait

• Different genes can produce the same phenotype, a phenomenon called genetic heterogenecity.

• This redundancy of function can make it appear that Mendel’s laws are not operating. For example 132 forms of hearing loss are transmitted as autosomal recessive traits.

• If a man who is homozygous for a hearing loss gene on one chromosome has a child with a woman who is homozygous for another hearing loss gene on a different chromosome, then the child would not be deaf, because he or she would be heterozygous for both hearing-related genes.

The human genome sequence adds

perspective

• Sequencing of the human genome has

modified and in some cases clarified the

extension to Mendel’s laws.

References

1. Emerys Elements Of Medical Genetics 15th Edition 2017

by Peter D Turnpenny

2. Medical Genetics E-Book 6th Edition 2019

by Lynn B. Jorde, John C. Carey, Michael J. Bamshad