Non Mendelian Inheritance
Transcript of Non Mendelian Inheritance
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