Medical Genetics – Summary
1. Subject and goals of Medical genetics. Medical and social significance, classification and incidence of
hereditary and congenital abnormalities.
Medical Genetics – a branch of medicine that deals with the inheritance, diagnosis and treatment of
diseases, caused by single gene mutations, chromosome abnormalities and multifactorial predispositions.
Types of Genetic Disease
1. Single gene – also known as mendelian, monogenic: conditions rgar aee produced by the effects of
one gene. Over 14,000 entities. Transmission is autosomal dominant, autosomal recessive and X-
linked.
2. Chromosome disorders – entire chromosomes or large segments of them are missing, duplicated or
altered. Loss of a tiny amount of chromosome material – molecular cytogenetics – FISH, array CGH
3. Multifactorial – due to a combination of multiple genetic and environmental causes
a. e.g. single birth defects – cleft lip, cleft palate
b. common adult disorders – heart disease, diabetes, psychoses, cancer
4. Mitochondrial – a small number of diseases caused by alterations in the small cytoplasmic
mitochondrial genes
5. Disorders due to somatic cell mutations – acquired somatic genetic diseases, not all genetic errors
are present from conception, and if the error occurs during the lifetime = somatic mutation.
Type of genetic disease Lifetime prevalence
> Single gene 14-17 ‰
Autosomal dominant ≈ 9.5 ‰
Autosomal recessive ≈ 2.5 ‰
X-linked ≈2‰
➢ Chromosomal abnormalities 7–9 ‰
➢ Common disorders with a 7-18 ‰ significant genetic component
➢ Congenital malformations 20-30 ‰
Total approximate 37.5-72.0 ‰
2. Organization and size of human genome. Structure of genes.
Genome – the totality of an organisms DNA, the human genome has 23 chromosome pairs with 3x109 base
pairs (3 billion nucleotide pairs) and 22,000 genes.
Chromosome structure
• Packing of DNA into chromatin and chromosomes
• Levels of packing and organization of chromatin:
o Chromatin
o Histones
o Nucleosome
o Looped domains
Special features of chromosomes
• Euchromatin – forms the main body of the chromosome and has a relatively high density of coding
regions or genes.
• Heterochromatin – chromatin that is either devoid or genes or hs inactive genes
o Constitutive
o Facultative (barr body)
• Centromere – facilitates seperation
• Telomeres – facilitate DNA replication
,Single Copy DNA
• Makes up 45% of genome
• Less than 2% of our DNA actually encodes protein
• The protein coding genes can code for:
o Enzymes
o Hormones
o Receptors
o Structural proteins
o Regulatory proteins
• Psuedogenes – homologous to normal genes but are not functionally expressed. Minor changes
prevent the transcription or translation of these genes
Repetitive DNA
• Makes up 55% of the genome
o Satellite DNA (10%) –
▪ A-satellite – tandem repeats of 171 to X million bp
▪ Minisatellite – tandem repeats of 14-500 bp
▪ Microsatellite – tandem repeats of 1-13 bp
o Dispersed DNA (45%) –
▪ SINES – short, interspersed repeated sequences of 90-500bp
▪ LINES – long repeated sequences 7000 bp
Control of Gene Expression
• 20% of the genes – house keeping genes are transcribed in all cells of the body. They encode
products that are required for the cells maintenance and metabolism
• 80% of the genes – tissue specific genes are transcribed only in specific tissues at specific times in
most cells only a small proportion of genes are actively transcribed. Explaining large variety of
different cell types making different protein products even though they all have the exact same DNA.
Types of Control:
• Transcriptional control – chromosomal packaging, chemical modification of DNA (methylation)
placement of cis-acting reglatory regions
• Posttranscriptional control – involves mRNA processing and transportation
• Translational control – involves mRNA -ribosome binding and mRNA degradation
• Postranslational control – protein processing, transportation and degradation
Transcriptional Control
• Binding of general transcription (basal) factors to specific DNA promoter elements (TATA box) allow
RNA polymerase to bind to the promoter region.
• Enhancers (DNA sequences) increase the level of transcription and are located at a distance from
structural genes.
o Their activity is mediated by specific transcription factors: activators and coactivators
(hormones, growth factors) which help to initiate the transcription of genes in specific cell
types at specific points of time
• Silencers (DNA sequences) help to repress the transcription genes through a similar series of
interactions
• Mutations in enhancers, silencers, or promoter sequences genes encoding transcription factors can
lead to genetic disease.
,Mitochondrial Genes
• Mitochondria – only organelles outside of the nucleus that contain their own DNA – 2-10 copies per
organelle
• Mitochondrial DNA (mt-DNA) differs from nuclear DNA
o It is double stranded but is circular and not linear
o It consists mostly of unique DNA sequences – NO introns
o The mutation rate of the mitochondrial DNA is about 10 times higher – due to lack of DNA
repair mechanisms
o Transmitted to the next generation by MOTHERS
• Mitochondrial DNA codes for:
o 13 proteins – components of the OXPHOS
o 2 rRNAs
o 22 tRNAs
3. Etiology of single gene disorders. Main types of nuclear DNA mutations responsible for hereditary
diseases.
Mutation - a change in genetic material, either of a single gene (DNA sequence) or in the number and
structure of the chromosomes
• Somatic mutation -in cells other than reproductive
• Germline mutations -in cells that produce gametes
• Alleles - the differing DNA sequences among individuals as a result of mutations
• Polymorphic locus - 2 alleles, each having a frequency that exceed 1% of the population. 1/3 of
loci coding for proteins are polymorphic
• normal variations disease-causing alleles
Mutation Rates
• the probability with which a particular mutational event takes place per generation
• at nucleotide level – about 10 to the power of minus 9 bases per cell division are mutations that have
escaped the process of DNA repair.
• At gene level – from 10-4 to 10-7 per locus per cell division depending on:
o Gene size – more likely with large genes
o Mutation hotspots – methylated CG to TG
o Advanced paternal age – marfan achondroplasia
o A parent of specific sex –
repeat expansion
Mutations in genes can occur because of:
• Deletions
• Insertions
• Duplications
• Substitutions
• Gene fusion
• Amplifications
, Deletions:
• Uncommon, indicated by the absence / altered size of a DNA fragment
• Thalassemia
o Cluster of simiar DNA sequences in close proximity
• Cystic Fibrosis
o Deletion of F508 phenylalanine from CFTR protein
• DMD/DMB
o Deletions of several exons within the gene
o With or without frame shift
• Growth Hormone Deficiency
o Deletion of a cluster of DNA sequences in close proximity
• Familial Hypercholesterolemia
o LDL receptor gene – highly repetitive alu sequences
Duplications:
• Common
• Charcot marie tooth disease
type 1A
• Mispairing between
homologous DNA sequences in
close proximity
Insertions
• Rare
• Hemophilia – insertion of a
LINE in the factor VIII gene
• Neurofibromatosis – insertion
of an Alu (SINE) sequence
• As common as transposition of
DNA
Substitutions
• The most common cause of mutagenesis
• Missense mutations – a single nucleotide substitution
• Sickle cell anemia
• Phenylkentonuria
• Thalassemia
Gene fusion
• Hemoglopin lepore
• Red/green colour blindness
• Unequal crossing over
• The generation of hemoglobin leopre and its anti-lepore counterpart by unequal crossing over.
Amplifications – Expanded repeats
• A recently disovered mutation mechanism
• Fragile X syndrome
• Huntingtons disease
• Muscular dystrophy
• Friedreich ataxia
• Increase in size of repeat DNA sequences normally present within or near certain genes.
1. Subject and goals of Medical genetics. Medical and social significance, classification and incidence of
hereditary and congenital abnormalities.
Medical Genetics – a branch of medicine that deals with the inheritance, diagnosis and treatment of
diseases, caused by single gene mutations, chromosome abnormalities and multifactorial predispositions.
Types of Genetic Disease
1. Single gene – also known as mendelian, monogenic: conditions rgar aee produced by the effects of
one gene. Over 14,000 entities. Transmission is autosomal dominant, autosomal recessive and X-
linked.
2. Chromosome disorders – entire chromosomes or large segments of them are missing, duplicated or
altered. Loss of a tiny amount of chromosome material – molecular cytogenetics – FISH, array CGH
3. Multifactorial – due to a combination of multiple genetic and environmental causes
a. e.g. single birth defects – cleft lip, cleft palate
b. common adult disorders – heart disease, diabetes, psychoses, cancer
4. Mitochondrial – a small number of diseases caused by alterations in the small cytoplasmic
mitochondrial genes
5. Disorders due to somatic cell mutations – acquired somatic genetic diseases, not all genetic errors
are present from conception, and if the error occurs during the lifetime = somatic mutation.
Type of genetic disease Lifetime prevalence
> Single gene 14-17 ‰
Autosomal dominant ≈ 9.5 ‰
Autosomal recessive ≈ 2.5 ‰
X-linked ≈2‰
➢ Chromosomal abnormalities 7–9 ‰
➢ Common disorders with a 7-18 ‰ significant genetic component
➢ Congenital malformations 20-30 ‰
Total approximate 37.5-72.0 ‰
2. Organization and size of human genome. Structure of genes.
Genome – the totality of an organisms DNA, the human genome has 23 chromosome pairs with 3x109 base
pairs (3 billion nucleotide pairs) and 22,000 genes.
Chromosome structure
• Packing of DNA into chromatin and chromosomes
• Levels of packing and organization of chromatin:
o Chromatin
o Histones
o Nucleosome
o Looped domains
Special features of chromosomes
• Euchromatin – forms the main body of the chromosome and has a relatively high density of coding
regions or genes.
• Heterochromatin – chromatin that is either devoid or genes or hs inactive genes
o Constitutive
o Facultative (barr body)
• Centromere – facilitates seperation
• Telomeres – facilitate DNA replication
,Single Copy DNA
• Makes up 45% of genome
• Less than 2% of our DNA actually encodes protein
• The protein coding genes can code for:
o Enzymes
o Hormones
o Receptors
o Structural proteins
o Regulatory proteins
• Psuedogenes – homologous to normal genes but are not functionally expressed. Minor changes
prevent the transcription or translation of these genes
Repetitive DNA
• Makes up 55% of the genome
o Satellite DNA (10%) –
▪ A-satellite – tandem repeats of 171 to X million bp
▪ Minisatellite – tandem repeats of 14-500 bp
▪ Microsatellite – tandem repeats of 1-13 bp
o Dispersed DNA (45%) –
▪ SINES – short, interspersed repeated sequences of 90-500bp
▪ LINES – long repeated sequences 7000 bp
Control of Gene Expression
• 20% of the genes – house keeping genes are transcribed in all cells of the body. They encode
products that are required for the cells maintenance and metabolism
• 80% of the genes – tissue specific genes are transcribed only in specific tissues at specific times in
most cells only a small proportion of genes are actively transcribed. Explaining large variety of
different cell types making different protein products even though they all have the exact same DNA.
Types of Control:
• Transcriptional control – chromosomal packaging, chemical modification of DNA (methylation)
placement of cis-acting reglatory regions
• Posttranscriptional control – involves mRNA processing and transportation
• Translational control – involves mRNA -ribosome binding and mRNA degradation
• Postranslational control – protein processing, transportation and degradation
Transcriptional Control
• Binding of general transcription (basal) factors to specific DNA promoter elements (TATA box) allow
RNA polymerase to bind to the promoter region.
• Enhancers (DNA sequences) increase the level of transcription and are located at a distance from
structural genes.
o Their activity is mediated by specific transcription factors: activators and coactivators
(hormones, growth factors) which help to initiate the transcription of genes in specific cell
types at specific points of time
• Silencers (DNA sequences) help to repress the transcription genes through a similar series of
interactions
• Mutations in enhancers, silencers, or promoter sequences genes encoding transcription factors can
lead to genetic disease.
,Mitochondrial Genes
• Mitochondria – only organelles outside of the nucleus that contain their own DNA – 2-10 copies per
organelle
• Mitochondrial DNA (mt-DNA) differs from nuclear DNA
o It is double stranded but is circular and not linear
o It consists mostly of unique DNA sequences – NO introns
o The mutation rate of the mitochondrial DNA is about 10 times higher – due to lack of DNA
repair mechanisms
o Transmitted to the next generation by MOTHERS
• Mitochondrial DNA codes for:
o 13 proteins – components of the OXPHOS
o 2 rRNAs
o 22 tRNAs
3. Etiology of single gene disorders. Main types of nuclear DNA mutations responsible for hereditary
diseases.
Mutation - a change in genetic material, either of a single gene (DNA sequence) or in the number and
structure of the chromosomes
• Somatic mutation -in cells other than reproductive
• Germline mutations -in cells that produce gametes
• Alleles - the differing DNA sequences among individuals as a result of mutations
• Polymorphic locus - 2 alleles, each having a frequency that exceed 1% of the population. 1/3 of
loci coding for proteins are polymorphic
• normal variations disease-causing alleles
Mutation Rates
• the probability with which a particular mutational event takes place per generation
• at nucleotide level – about 10 to the power of minus 9 bases per cell division are mutations that have
escaped the process of DNA repair.
• At gene level – from 10-4 to 10-7 per locus per cell division depending on:
o Gene size – more likely with large genes
o Mutation hotspots – methylated CG to TG
o Advanced paternal age – marfan achondroplasia
o A parent of specific sex –
repeat expansion
Mutations in genes can occur because of:
• Deletions
• Insertions
• Duplications
• Substitutions
• Gene fusion
• Amplifications
, Deletions:
• Uncommon, indicated by the absence / altered size of a DNA fragment
• Thalassemia
o Cluster of simiar DNA sequences in close proximity
• Cystic Fibrosis
o Deletion of F508 phenylalanine from CFTR protein
• DMD/DMB
o Deletions of several exons within the gene
o With or without frame shift
• Growth Hormone Deficiency
o Deletion of a cluster of DNA sequences in close proximity
• Familial Hypercholesterolemia
o LDL receptor gene – highly repetitive alu sequences
Duplications:
• Common
• Charcot marie tooth disease
type 1A
• Mispairing between
homologous DNA sequences in
close proximity
Insertions
• Rare
• Hemophilia – insertion of a
LINE in the factor VIII gene
• Neurofibromatosis – insertion
of an Alu (SINE) sequence
• As common as transposition of
DNA
Substitutions
• The most common cause of mutagenesis
• Missense mutations – a single nucleotide substitution
• Sickle cell anemia
• Phenylkentonuria
• Thalassemia
Gene fusion
• Hemoglopin lepore
• Red/green colour blindness
• Unequal crossing over
• The generation of hemoglobin leopre and its anti-lepore counterpart by unequal crossing over.
Amplifications – Expanded repeats
• A recently disovered mutation mechanism
• Fragile X syndrome
• Huntingtons disease
• Muscular dystrophy
• Friedreich ataxia
• Increase in size of repeat DNA sequences normally present within or near certain genes.
