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Notes by Harriet Wood
Genetic Terms
Inheritance
Passage of hereditary traits from one generation to the next.
Diploid
Number (2n)
The nuclei of all human cells (except gametes) contains 23 pairs of
chromosomes – one from the mother and one from the father.
Homologue
One of the two chromosomes that make up a pair.
Alleles
Alternate forms of varieties of a gene. Each allele produces variations
in inherited characteristics.
‘A permanent heritable change in an allele that produces a different
variation of the same trait’ - Mutations can be inherited or acquired.
Mutations
Types:
1. Point mutation
A simple change in one base of the gene sequence.
Original:
THE FAT CAT ATE THE WEE RAT
Point mutation: THE FAT HAT ATE THE WEE RAT
2. Frame- shift mutation
One or more bases are inserted of deleted.
Adding or removing bases changes the subsequent sequence.
May result in a shortened protein.
Original: THE FAT CAT ATE THE WEE RAT
Frame shift: THE FAT CAA TET HEW EER AT
3. Deletion
Mutations resulting in missing DNA.
Can cause frame shift mutations.
Original: THE FAT CAT ATE THE WEE RAT
Deletion: THE FAT ATE THE WEE RAT
4. Inversion
An entire section of DNA is reversed.
Original: THE FAT CAT ATE THE WEE RAT
Inversion: THE FAT TAR EEW WHT ETA TAC
5. Insertion
Mutations that result in the addition of extra DNA.
Can cause frame shift mutations.
Original: THE FAT CAT ATE THE WEE RAT
Insertion: THE RAT XLW ATE THE WEE RAT
6. DNA expression mutation
There are many types of mutations that change not the protein
itself but where and how much of a protein is made.
These types of changes in DNA can result in proteins being made
at the wrong time or in the wrong cell type.
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Notes by Harriet Wood
Genotype
The genetic makeup of an organism.
Phenotype
The expression of the genes present in an individual.
Dominant
Allele
Recessive
Trait
An allele that dominates of masks the presence of another allele and is
fully expressed – The trait expressed is called a Dominant Trait.
The allele whose presence is completely masked - The trait it controls
is called a Recessive Trait.
Homozygous
A person with the same allele on homologous chromosomes is said to
be homozygous for the trait e.g. PP or pp.
Heterozygous
An individual with different alleles on the homologous chromosome
is said to be heterozygous for the trait e.g. Pp.
Carriers
Heterozygous individuals who carry a recessive gene but do not
express it but can pass it onto their offspring.
Incomplete
Dominance
Neither member of an allelic pair is dominant over the other. The
heterozygote has a phenotype intermediate between the monozygous
dominant and homozygous recessive phenotypes.
E.g. Inheritance of Sickle-cell disease (SCD)
Some genes may have more than 2 alternate forms.
e.g. Inheritance of the ABO blood group.
Six possible genotypes:
Multiple
Allele
Inheritance
GENOTYPE
IAIA or IAi
IBIB or IBi
IAIB
ii
Blood Type (PHENOTYPE)
A
B
AB
O
IA = Produces A antigen
IB = Produces B antigen
i = Produces neither A or B antigen.
Because an individual with type AB blood has characteristics of both
type A and type B RBC’s expressed in the phenotype, alleles IA and IB
are said to be ‘codominant’.
Codominant
Refers to two alleles that each contribute to the phenotype of a
heterozygote.
Polygenic
Inheritance
Most inherited traits are not controlled by one gene but instead by the
combined effect of 2 or more genes.
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Notes by Harriet Wood
Complex
Inheritance
The combined effects of many gene and environmental factors.
One genotype can have many possible phenotypes depending on the
environment OR one phenotype can include many possible genotypes.
E.G. Skin colour, hair colour, eye colour, height, metabolism rate,
body build.
P generation
Parental generation.
F1 generation
First filial generation.
F2 generation
Second filial generation.
Autosomes
22 pairs of chromosomes that look alike and have the same
appearance in both males and females.
Sex
The two members of the 23rd pair; they look different in males and
Chromosomes females.
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Notes by Harriet Wood
Mendelian Inheritance → Described by Mendel in 1865.
Autosomal Dominant Inheritance
Commonest mode of Mendelian Inheritance.
Affected individual carries the abnormal gene in the heterozygous state on one pair of
autosomes (chromosomes 1-22).
Offspring have a 1/2 (50%) chance of inheriting abnormal gene from affected parent.
Variation in expression: Within a family some affected individuals manifest disorder
mildly and some more severely.
Non-penetrance: Lack of S&S in an individual who must have inherited abnormal gene.
No FH of disorder may be due to:
- A new mutation.
- Gonadal mosaicism – v.occasionally a healthy parent has the mutation only in a
number of gametes in the gonad.
- Non-paternity – apparent father is not the biological father.
Homozygosity: If both parents affected (rare) there is a 1/4 risk that a child will be
homozygous for the mutant gene.
Examples of ADI
-
Achodroplasia
Familial hypercholesterolaemia
Marfan’s syndrome
Neurofibromatosis
Otoclerosis (variation in expression)
Tuberous sclerosis
-
Echlers-Danlos syndrome
Huntington’s disease
Myotonic dystrophy
Osteogenesis impergecta
Polyposis coli
Diagram of Mendelian Inheritance- see Google images
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Notes by Harriet Wood
Autosomal Recessive Inheritance
Affected individual is homozygous for the abnormal gene – Inherited an abnormal allele
from each parent - Both patents are unaffected heterozygous carriers.
For two carrier parents the risk to each child of being affected is 1/4.
All offspring of affected individuals will be carriers.
Consanguinity:
- It is thought we all carry at least one abnormal recessive gene.
- Marrying a relative ↑ chance of a couple carrying the same abnormal recessive
gene so ↑ risk of having a child with a recessive disorder.
Population-based carrier testing and antenatal diagnosis:
- Rate of recessive gene vary between racial groups, when they occur frequently
testing can occur.
- E.g. CF in north Europeans, sickle cell disease in black Africans and Americans,
thalassaemias in Mediterranean or Asians, Tay-Sachs disease in Ashkenazi Jews.
Examples of ARI
-
Congenital adrenal hyperplasia
Friedreich’s ataxia
Glycogen storage disease
Oculocutaneous albinism
Tay-Sachs disease
Werdnig-Hoffmann disease
-
Cystic fibrosis
Galactosaemia
Hurler’s syndrome (MPSI)
Sickle cell disease
Thalassaemia
Diagram of Autosomal Recessive Inheritance See Google Images
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Notes by Harriet Wood
X-Linked Recessive Inheritance
An abnormal recessive gene is carried on the X chromosome.
In X linked inheritance:
- Males are affected.
- Females can be carriers – usually health – occasionally show mild signs.
- Sons of a female carrier has a 1/2 risk of being affected – regardless of father.
- Daughters of a female carrier has a 1/2 risk of being a carrier.
- Daughters of affected males will all be carriers.
- Sons of affected males will not be affected (father passes Y chromosome to son).
FH may be –ve:
- New mutations and gonadal mosacisim are fairly common.
To identify a carrier female:
- Interpretation of the pedigree.
- Looking for mild clinical manifestations.
- Specific biochemical/ molecular test.
Examples of X-LRI
- Colour blindness (red-green).
- Duchenne’s and Becker’s muscular dystrophies.
- Fragile X syndrome.
- Glucose-6-phosphate Dehydrogenase (G6PD) deficiency.
- Haemophilia A and B.
- Hunter’s syndrome.
Diagram of X-Linked Inheritanc- see Google images
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Notes by Harriet Wood
Polygenic or Multifactorial Inheritance
‘Described the pattern of inheritance observed for several relatively common
conditions which appear to result from the interaction of a genetic predisposition with
adverse environmental factors’
It is the spectrum of causes of disease from environmental factors (e.g. trauma) to purely
genetic causes (e.g. Mendelian disorders).
Normal traits such as height and intelligence are also inherited in this way.
The liability of an individual to develop a disease of multifactorial/polygenic aetiology
has a normal distribution – The condition occurs when a certain threshold level of
liability is exceeded.
Relatives of an affected person show an ↑ liability so a greater proportion will lie beyond
the threshold and manifest the disorder.
Factors ↑ risk to relatives:
- Having a more severe form of the disorder.
- Close relationship to affected person.
- Multiple affected family members.
- Sex difference in prevalence.
Conditions with multifactorial inheritance
Congenital malformations:
- Neural tube defects e.g. spina bifida.
- Congenital heart disease.
- Cleft lip and palate.
- Pyloric stenosis.
- Congenital dislocation of the hip.
- Talipes.
- Hypospadias.
Adult life:
- Atherosclerosis and coronary heart disease.
- Diabetes mellitus.
- Asthma.
- Epilepsy.
- Hypertension.
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Notes by Harriet Wood
Genetic Syndromes
Edwards’ Syndrome – Trisomy 18
Incidence
- 1/8000 live births - Most die in infancy.
S&S
-
Small chin.
Low-set ears.
Overlapping fingers (thumb across palm,
overlapping middle and ring finger).
Rocker-bottom feet.
Cardiac and renal malformation.
Prenatal Diagnosis
- USS in 2nd trimester.
- Confirmed by amniocentesis and chromosome analysis.
Patau’s Syndrome – Trisomy 13
Incidence
- 1/14000 live births - Most die in infancy.
S&S
-
Structural defect of brain.
Scalp lesions.
Microcephaly – circumference of head small for age/sex.
Small eye (microphthalmia) and other eye defects.
Polydactyly – More than 5 fingers and/or toes.
Cleft palate.
Cardiac and renal malformations.
Prenatal diagnosis
- Same as Edward’s Syndrome.
Turner’s Syndrome – 45, X
Incidence
- 1/2500 live-born females.
- >95% result in early miscarriage.
- Does not ↑ with maternal age. Low risk of reoccurrence.
Prenatal diagnosis
- Detected by USS when a cystic hygroma and other evidence of foetal oedema is
present.
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Notes by Harriet Wood
S&S
-
Lymphoedema of hands and feet in neonate.
Short stature.
Neck webbing.
Wide carrying angle (cubitus valgus).
Widely spaced nipples.
Congenital heart defects (particularly coarctation of the aorta).
Ovarian dysgenesis = Infertility.
Normal intellectual development.
Genetics
- (50%) There are 45 chromosomes, with only one X chromosome.
- Remaining:
o Deletion of the short arm of one X chromosome.
o Isochromosome that has two long arms but no short arm.
o Variety of other structural defects of one of the X chromosomes.
Treatment
- Growth hormone treatment.
- Oestrogen replacement for development of 2nd sexual characteristics at puberty
(infertility persists).
Klinefelter’s Syndrome – 48, XXY
Incidence
- 1-2/1000 live born-males.
S&S
-
Infertility – Most common presentation.
Hypogonadism with small testes.
Pubertal development apparently normal.
Gynaecomastia in adolescence.
Tall stature.
Intelligence – Usually in normal range, but may have educational and
psychological problems.
Important Note
These notes were written by Harriet Wood, as a medical student in 2009. They are presented in
good faith and every effort has been taken to ensure their accuracy. Nevertheless, medical practice
changes over time and it is always important to check the information with your clinical teachers
and with other reliable sources. Disclaimer: no responsibility can be taken by either the author or
publisher for any loss, damage or injury occasioned to any person acting or refraining from action
as a result of this information. Please give feedback on this document and report any inaccuracies
to: [email protected]
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