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Patterns of single gene
inheritance
Mahmoud A. Alfaqih BDS PhD
Jordan University of Science and Technology
School of Medicine
Department of Biochemistry and Physiology
Reading material
Genetics in Medicine by Thompson
and Thompson, 7th Edition
Chapter 7
Overview and concepts
Need to understand the following terms:
 Locus
 Allele: Wild type Vs. Variant (mutant)
 Mutation
 Haplotype
 Polymorphic locus
Genotype Vs. phenotype
Genotype: set of alleles that make up his or her
genetic constitution, either collectively at all loci
or, more typically, at a single locus
Phenotype: the observable expression of a
genotype as a morphological, clinical, cellular, or
biochemical trait.
Pleiotropic
 When single abnormal gene produces diverse
phenotypic effects
The connection between the gene defect and
the various manifestations is neither obvious
nor well understood
Single gene disorders
• A disorder that is determined primarily by the
alleles at a single locus
• Homozygous Vs. heterozygous
• Compound heterozygote: a genotype in which
two different mutant alleles of the same gene
are present, rather than one normal and one
mutant.
Hemizygous
• In the special case in which a male has an
abnormal allele for a gene located on the X
chromosome and there is no other copy of the
gene
Pedigrees
• Single-gene disorders are characterized by their
patterns of transmission in families
• To establish the pattern of transmission, a usual
first step is:
 Obtain information about the family history.
 Summarize the details in the form of a pedigree
 Pedigree is a graphical presentation of family tree
Important definitions in pedigrees
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Kindred
Proband
Sibs
Sibship: family of sibs
First degree relatives: sibs, offspring, parents
Second degree relatives: Grandparents,
grandchildren, uncles and aunts, nephews and nieces
• Third degree relatives: first cousins
Important definitions in pedigrees
• Consanguineous: Couples that have one or
more shared ancestors
• Sporadic case: if the disorder is determined to
be due to new mutation in the proband
MENDELIAN INHERITANCE
Autosomal and X linked inheritance
• Autosomal disorders, in general, affect males and females
equally.
• Males have only a single X and are therefore hemizygous with
respect to X-linked genes
• Females can be heterozygous or homozygous at X-linked loci.
• Alleles for most X-linked genes are expressed from only one of
the two X chromosomes in any given cell of a female
Recessive Inheritance
• Phenotype expressed only in homozygotes (or male
hemizygotes) and not in heterozygotes is recessive.
• Recessive disorders are due to mutations that reduce or
eliminate the function of the gene product
• Also called loss-of-function mutations.
Dominant inheritance
• A phenotype expressed in both homozygotes and
heterozygotes for a mutant allele is inherited as a dominant
• In a pure dominant disease, homozygotes and heterozygotes
for the mutant allele are both affected equally (very rare)
• Dominant disorders more severe in homozygotes than in
heterozygotes (incomplete dominance), more common
Factors affecting pedigree patterns
1. Penetrance and Expressivity
2. New mutations
3. Age of onset
Penetrance
New mutation
Other factors that complicate
pedigree analysis
1. Allelic heterogeneity
2. Locus heterogeneity: Retinitis pigmentosa
3. Phenotypic heterogeneity
Autosomal Recessive Inheritance
Typical pedigree of autosomal
recessive inheritance
Factors that increase carrier mating
1. Consanguinity
2. Inbreeding
3. Genetic isolates
Consanguinity
Autosomal dominant inheritance
Sex limited inheritance
• When autosomal dominant phenotypes have
a sex ratio that differs significantly from 1:1
• The defect is autosomally transmitted but
expressed in only one sex
• Example: male-limited precocious puberty
X-linked recessive inheritance
X linked dominant inheritance
Notice the lack of male-to-male transmission
Mitochondrial inheritance:
Mitochondrial genome
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One circular chromosome
16.5 kb in size
Located inside the mitochondrial organelle
Most cells contain at least 1000 mtDNA
molecules
• Mature oocyte has more than 100,000 copies
of mtDNA
Mitochondrial genome
 Codes for 37 genes:
 13 polypeptides that are subunits of enzymes of oxidative
phosphorylation
 two types of ribosomal RNA
 22 transfer RNAs required for translating the transcripts of the
mitochondria-encoded polypeptides
 More than 100 different rearrangements and 100 different
point mutations have been identified in mtDNA that cause
disease
 Disease often involves the central nervous and
musculoskeletal systems
Replicative segregation of mtDNA
 Absence of the tightly controlled segregation seen during
mitosis and meiosis of nuclear chromosomes
 At cell division, copies of mtDNA in each of the mitochondria
in a cell replicate and sort randomly among new mitochondria
 The mitochondria, in turn, are distributed randomly between
the two daughter cells
Homoplasmy and heteroplasmy
 When a mutation arises in the mtDNA, it is at first present in only
one of the mtDNA molecules in a mitochondrion
 With replicative segregation, a mitochondrion containing a mutant
mtDNA will acquire multiple copies of mutant DNA
 With cell division, a cell containing a mixture of normal and mutant
mtDNAs can distribute very different proportions of mutant and
wild-type mitochondrial DNA to its daughter cells
• One daughter cell may receive mitochondria that contain only a
pure population of normal mtDNA or a pure population of mutant
mtDNA or a mixture of both
Maternal inheritance of mtDNA
 Sperm mitochondria are generally eliminated from the
embryo
 mtDNA is inherited from the mother
 All the children of a female who is homoplasmic for a mtDNA
mutation will inherit the mutation
 None of the offspring of a male carrying the same mutation
will inherit the defective DNA