Human genetics and genomics
Lecture 1: introduction & basic human genetics – Van Diemen
Computer practicals, paper seminar, assignments & ethics discussion are mandatory. – everything
made in groups of 3-4 students.
What is DNA?
Located in the nucleus, contains the recipe for all proteins in cells. Structured in chromosomes, can
only see them only during division.
How big is our genome?
3 gigabases (9 zeros) (x2 in a cell because chromosomes come in pairs)
How many chromosomes pairs per cells?
23 chromosome pairs. (22 + sex pair)
How to go from DNA to protein?
Signal sent to nucleus that a gene needs to be transcribed – DNA transcribed to pre-mRNA – post-
transcriptional processing to get to mRNA (introns spliced out) – mRNA translated to polypeptide in
ribosomes – polypeptide forms a functional protein after post-translational processing
During all this processes the end result can be altered.
What is a gene?
A functional unit of DNA encoding a protein sequence.
Regulatory sequence = to enhance or diminish gene transcription
Promotor = to start transcription
Start codon = simple 3 letter code
Exons = code for protein
Introns = spliced out, non-coding
Splice sites = sequences that indicate where splicing occurs
Transcription factors bind regulatory sequences and promotors to activate or inhibit gene
expression
How is RNA to protein translation?
One amino acids is decoded by three subsequent nucleotides = codon. A stretch of amino acids forms
a polypeptide.
,What is the reading frame?
How the mRNA is read.
Every 3 NTs forms amino acid. – insertion or deletion can lead to completely different read and thus
different protein.
What is alternative splicing?
RNA can form different functional proteins due to different splicing: exons left out to form protein B
instead of A.
Which percentage of the genome is protein coding?
2%, 25.000 coding genes of the 3.000.000.000.
The more complex the organism is the transcribed non-coding and un-transcribed
regions become bigger.
How are genes on the anti-sense strand?
Different coding sequences on the reverse strand and the verse strand. So for example there is an
intron on the verse strand but that is a coding region on the reverse strand.
Mutation in intron can have diseasing effects on the opposite strand
How are the non-coding regions?
Great variation in length & number of introns. Contain highly conserved areas and highly repetitive
sequence.
Portion still read into functional noncoding RNA molecule: transfer RNA, ribosomal RNA & regulatory
RNA.
ENCODE project found out that 80% of human genome serves purpose, biochemically. – regulator
functions: promotor, enhancers, silencers etc.
How does genetic variation arise?
- Recombination: During meiosis crossing-over occurs between homologous chromosomes ->
genetic recombination = new combinations of genes -> higher variation.
- Occurrence of mutation: high mutation frequency, have good repair mechanism. No repair
during meiosis = new germline mutations. No repair during mitosis = somatic mutations.
,How do mutations occur?
- Spontaneous mutation such as replication errors
- Induced mutation = mutagens
Effects on protein van be very diverse: gain of function or loss of function
Benefits and harms of mutations
What are the 4 types of genetic diseases?
- Chromosomal abnormalities: large chromosomal aberrations.
- Monogenic disorders: rare, caused by 1-2 strong mutations (single point mutations)
- Multifactorial (polygenic) disorders: common, combination of multiple genetics and
environmental causes. Caused by many weak mutations
- Mitochondrial disorders: mitochondria are separate mini genome therefore distinguished.
How are chromosomal abnormalities?
Clinically important as occur in 1-1.5% of all live-born babies.
Loss of chromosome or extra chromosome is often incompatible with life & main cause of
spontaneous abortions (50%)
- Numerical:
aneuploidies: extra or missing chromosome.
Edwards syndrome extra set at 18, compatible with
life but usually do not live very long. Also diseases
associated with 13 & 21 (downs syndrome).
Poly-ploidies: extra complete set of chromosomes
- Structural:
Translocation (most common): one part of
chromosome is put into another chromosome and a
part of the other is put into the first chromosome as
well.
Inversions: swapping of places between two parts
Insertions: one part of chromosome is put into
another chromosome (not vice versa)
Deletions: part is missing
Duplication: two times the same part after each other.
What is Klinefelter?
In 1/1000 males. 47 chromosomes, have XXY (extra X).
More female like phenotype, problems with fertility.
What is Turner?
1/2500 females. 45 chromosomes, have X (miss an X).
More male like phenotype, problem with fertility
, How are trisomy and monosomy caused?
Meiosis 1 nondisjunction get two copies in one cell, none in the
other. Then get two cells with two gametes leading to three
gametes after fertilization.
Meiosis 2 nondisjunction get two gametes in one cell leading to
three gametes after fertilization.
Translocations give rise to partial trisomy and
monosomy. Balanced carrier usually does not give
any problems, however, can pass it on unbalanced to
their children.
What is Robertsonian translocation?
Break occurs at centromere & the long arms are attaching and form one
chromosome. Short arms are usually lost as they do not contain much
essential information. Carriers are often phenotypically normal.
How are single nucleotide variants?
Most frequent occurring variation. In coding and non-coding parts. Non-
coding parts hard to know function.
- Silent mutations: NT change but no change in AA
- Missense mutation: AA change such as Val instead of Asp.
- Nonsense mutation: Stop codon inserted - usually no protein made.
Quite harmful
- Frame-shift mutations: all AA acids changed beyond the point of insertion/deletion. Can also
shift into a premature stop codon = shorter protein
How is the Beckwith-Wiedemann syndrome?
From point mutations in the CDKN1C gene.
Pediatric overgrowth disorder involving a predisposition to tumor development.
How are point mutations in splice site?
Can cause generation of new mRNA product via:
- Exon skipping: exon not read
- Intron retention
- Partial intron retention
Often leads to dysfunctional mRNA and thus altered/no protein
Lecture 1: introduction & basic human genetics – Van Diemen
Computer practicals, paper seminar, assignments & ethics discussion are mandatory. – everything
made in groups of 3-4 students.
What is DNA?
Located in the nucleus, contains the recipe for all proteins in cells. Structured in chromosomes, can
only see them only during division.
How big is our genome?
3 gigabases (9 zeros) (x2 in a cell because chromosomes come in pairs)
How many chromosomes pairs per cells?
23 chromosome pairs. (22 + sex pair)
How to go from DNA to protein?
Signal sent to nucleus that a gene needs to be transcribed – DNA transcribed to pre-mRNA – post-
transcriptional processing to get to mRNA (introns spliced out) – mRNA translated to polypeptide in
ribosomes – polypeptide forms a functional protein after post-translational processing
During all this processes the end result can be altered.
What is a gene?
A functional unit of DNA encoding a protein sequence.
Regulatory sequence = to enhance or diminish gene transcription
Promotor = to start transcription
Start codon = simple 3 letter code
Exons = code for protein
Introns = spliced out, non-coding
Splice sites = sequences that indicate where splicing occurs
Transcription factors bind regulatory sequences and promotors to activate or inhibit gene
expression
How is RNA to protein translation?
One amino acids is decoded by three subsequent nucleotides = codon. A stretch of amino acids forms
a polypeptide.
,What is the reading frame?
How the mRNA is read.
Every 3 NTs forms amino acid. – insertion or deletion can lead to completely different read and thus
different protein.
What is alternative splicing?
RNA can form different functional proteins due to different splicing: exons left out to form protein B
instead of A.
Which percentage of the genome is protein coding?
2%, 25.000 coding genes of the 3.000.000.000.
The more complex the organism is the transcribed non-coding and un-transcribed
regions become bigger.
How are genes on the anti-sense strand?
Different coding sequences on the reverse strand and the verse strand. So for example there is an
intron on the verse strand but that is a coding region on the reverse strand.
Mutation in intron can have diseasing effects on the opposite strand
How are the non-coding regions?
Great variation in length & number of introns. Contain highly conserved areas and highly repetitive
sequence.
Portion still read into functional noncoding RNA molecule: transfer RNA, ribosomal RNA & regulatory
RNA.
ENCODE project found out that 80% of human genome serves purpose, biochemically. – regulator
functions: promotor, enhancers, silencers etc.
How does genetic variation arise?
- Recombination: During meiosis crossing-over occurs between homologous chromosomes ->
genetic recombination = new combinations of genes -> higher variation.
- Occurrence of mutation: high mutation frequency, have good repair mechanism. No repair
during meiosis = new germline mutations. No repair during mitosis = somatic mutations.
,How do mutations occur?
- Spontaneous mutation such as replication errors
- Induced mutation = mutagens
Effects on protein van be very diverse: gain of function or loss of function
Benefits and harms of mutations
What are the 4 types of genetic diseases?
- Chromosomal abnormalities: large chromosomal aberrations.
- Monogenic disorders: rare, caused by 1-2 strong mutations (single point mutations)
- Multifactorial (polygenic) disorders: common, combination of multiple genetics and
environmental causes. Caused by many weak mutations
- Mitochondrial disorders: mitochondria are separate mini genome therefore distinguished.
How are chromosomal abnormalities?
Clinically important as occur in 1-1.5% of all live-born babies.
Loss of chromosome or extra chromosome is often incompatible with life & main cause of
spontaneous abortions (50%)
- Numerical:
aneuploidies: extra or missing chromosome.
Edwards syndrome extra set at 18, compatible with
life but usually do not live very long. Also diseases
associated with 13 & 21 (downs syndrome).
Poly-ploidies: extra complete set of chromosomes
- Structural:
Translocation (most common): one part of
chromosome is put into another chromosome and a
part of the other is put into the first chromosome as
well.
Inversions: swapping of places between two parts
Insertions: one part of chromosome is put into
another chromosome (not vice versa)
Deletions: part is missing
Duplication: two times the same part after each other.
What is Klinefelter?
In 1/1000 males. 47 chromosomes, have XXY (extra X).
More female like phenotype, problems with fertility.
What is Turner?
1/2500 females. 45 chromosomes, have X (miss an X).
More male like phenotype, problem with fertility
, How are trisomy and monosomy caused?
Meiosis 1 nondisjunction get two copies in one cell, none in the
other. Then get two cells with two gametes leading to three
gametes after fertilization.
Meiosis 2 nondisjunction get two gametes in one cell leading to
three gametes after fertilization.
Translocations give rise to partial trisomy and
monosomy. Balanced carrier usually does not give
any problems, however, can pass it on unbalanced to
their children.
What is Robertsonian translocation?
Break occurs at centromere & the long arms are attaching and form one
chromosome. Short arms are usually lost as they do not contain much
essential information. Carriers are often phenotypically normal.
How are single nucleotide variants?
Most frequent occurring variation. In coding and non-coding parts. Non-
coding parts hard to know function.
- Silent mutations: NT change but no change in AA
- Missense mutation: AA change such as Val instead of Asp.
- Nonsense mutation: Stop codon inserted - usually no protein made.
Quite harmful
- Frame-shift mutations: all AA acids changed beyond the point of insertion/deletion. Can also
shift into a premature stop codon = shorter protein
How is the Beckwith-Wiedemann syndrome?
From point mutations in the CDKN1C gene.
Pediatric overgrowth disorder involving a predisposition to tumor development.
How are point mutations in splice site?
Can cause generation of new mRNA product via:
- Exon skipping: exon not read
- Intron retention
- Partial intron retention
Often leads to dysfunctional mRNA and thus altered/no protein
