Summary BBS1005 Human genetics, reproduction and prenatal development
Case 1
Mutations
Point mutations
1. Substitution: one base is replaced with another
a. Transition purine with purine (A & G) or pyrimidine with pyrimidine (T & C)
b. Transversion purine with pyrimidine or vice versa
2. Insertion: one or nucleotides is added
3. Deletion: one or more nucleotides is removed
Point mutations can be
Silent: the same protein will be synthesized
Missense: another amino acid will be synthesized
o Conservative: an amino acid with the same properties
o Nonconservative: a very different amino acid
Nonsense: mutation results in the synthesis of a stop codon which will result in a very short
amino acid chain
Chromosomal mutations
1. Inversion: two parts of the chromosome are switched
a. Paracentric centromere not included
b. Pericentric centromere included
2. Insertion: insertion of a larger sequence into a chromosome
3. Deletion: region of the chromosome is lost
a. Terminal deletion in terminal part of chromosome,
leads to an adhesive terminus
b. Intercalary deletion in the interior part
c. Microdeletion small amount (up to 5 Mb = 12 genes)
4. Duplication: region of the chromosome is doubled
a. Tandem duplication
b. Reverse tandem duplication
c. Terminal tandem duplication
5. Translocation: region of one chromosome is attached to another
chromosome
a. Nonreciprocal intrachromosomal movement of a
chromosome segment from one location in the chromosome, to another
b. Nonreciprocal interchromosomal chromosomal segments are exchanged between
two non-homologous chromosomes
c. Reciprocal interchromosomal one-way transfer of a chromosomal segment to
another
DNA repair mechanisms
Mismatch repair
Happens right after the new DNA has been made and its job is to remove and replace mis-
paired bases, which weren’t fixed during proofreading
Steps:
1. Protein complex recognizes and binds to the mis-paired base
2. Second complex cuts the DNA near the mismatch
3. More enzymes chop out the incorrect nucleotide and a surrounding patch of DNA
4. A DNA polymerase replaces the missing section with correct nucleotides
5. DNA ligase seals the gap
, Proteins recognise nicks (single-stranded breaks) to know which of the bases is “wrong”
nicks are only found on newly synthesized DNA
Direct reversal
Fix DNA by reversing the chemical reaction that caused it
Mutations often occur because an extra group of atoms gets attached to DNA
Base excision repair
Group of enzymes (glycosylases): each detects and removes a specific kind of damaged base
E.g. deamination can convert cytosine into uracil, which will then match with adenine
glycosylases detect and remove deaminated cytosine and the gap is filled by other enzymes
Nucleotide excision repair
Remove multiple bases and replace it with the help of DNA polymerase
Detects and corrects types of damage that distort the double helix
Helicase cranks open the DNA to form a bubble and DNA-cutting enzymes chop out the
damaged part of the bubble DNA polymerase replaces the missing DNA and ligase seals
Double stranded break repair
Double stranded break = splitting the chromosome in two
Non-homologous end joining
o The two broken ends are glued back together messy and involves loss or addition
of nucleotides (produces mutation, but this is better than losing the entire part of a
chromosome)
Homologous recombination
o Information from the homologous chromosome that matches the damaged one is
used to repair the break two homologous chromosomes come together and the
undamaged region is used as a template to replace the damaged region of the
broken chromosome
Clearer and doesn’t cause mutations, usually
Only possible when you have the sister strand
End of G2 phase in mitosis
During crossing over in meiosis (prophase I)
Meiosis and mitosis
,Production of gametes
Sperm
Primordial germ cells migrate to the testes: gonocytes develop into spermatogonium
Puberty: spermatogonium will perform meiosis and become a haploid sperm cell
Sperm production in seminiferous tubules: separate from systemic circulation by blood-testis
barrier formed by Sertoli cells, prevents hormones and constituents from affecting the
sperm, and prevents the immune system recognising the sperm as foreign
Primary spermatocytes undergo meiosis, creating first spermatocytes and then spermatids
Spermatids then undergo spermiogenesis and form mature spermatozoa
When the sperm are in the female reproductive tract, capacitation takes place
Oocytes
Primordial germ cells migrate to ovaries: gonocytes develop into oogonium
20 weeks: ~7 million cells before birth: ~2 million primary oocytes due to cell death
puberty: ~40.000 left due to artresia
Clusters of primary oocytes surrounded by epithelial cells: follicular cells and will form
primordial follicles
Three stages of maturation of the primary oocytes
1. Pre-antral stage: oocyte and follicular cells grow and become granulosa cells (= secrete
glycoproteins to form zona pellucida)
Surrounding connective tissue becomes theca
folliculi, LH present: secrete androgens
2. Antral stage: spaces between granulosa cells
combines and forms one fluid filled space = the
antrum. Follicles are secondary follicles and will
develop under influence of FSH, LH and oestrogen
3. Pre-ovulatory stage: meiosis I is complete: 1
secondary oocyte + 3 polar bodies
Ovulation process: LH increases collagenase activity to
weaken the follicular wall, the ovarium wall will have
muscle contractions, and the ovum is released and
taken up into the fallopian tube via fimbriae
Fertilisation: secondary oocyte completes meiosis II
after fertilisation; if fertilisation does not occur, the
oocyte degenerates; if it is fertilised, peristaltic
movements of the fallopian tube move the egg to the
uterus where it implants to the uterine wall
, Case 2
Capacitation of sperm cells
Because of the changes, the sperm cell
can penetrate the zona pellucida
Fertilization
1. Spermatozoon reaches the zona
pellucida, and binds due to interaction
with a glycoprotein sperm receptor
2. The acrosome releases degradative
enzymes sperm can penetrate in the
zona pellucida
Case 1
Mutations
Point mutations
1. Substitution: one base is replaced with another
a. Transition purine with purine (A & G) or pyrimidine with pyrimidine (T & C)
b. Transversion purine with pyrimidine or vice versa
2. Insertion: one or nucleotides is added
3. Deletion: one or more nucleotides is removed
Point mutations can be
Silent: the same protein will be synthesized
Missense: another amino acid will be synthesized
o Conservative: an amino acid with the same properties
o Nonconservative: a very different amino acid
Nonsense: mutation results in the synthesis of a stop codon which will result in a very short
amino acid chain
Chromosomal mutations
1. Inversion: two parts of the chromosome are switched
a. Paracentric centromere not included
b. Pericentric centromere included
2. Insertion: insertion of a larger sequence into a chromosome
3. Deletion: region of the chromosome is lost
a. Terminal deletion in terminal part of chromosome,
leads to an adhesive terminus
b. Intercalary deletion in the interior part
c. Microdeletion small amount (up to 5 Mb = 12 genes)
4. Duplication: region of the chromosome is doubled
a. Tandem duplication
b. Reverse tandem duplication
c. Terminal tandem duplication
5. Translocation: region of one chromosome is attached to another
chromosome
a. Nonreciprocal intrachromosomal movement of a
chromosome segment from one location in the chromosome, to another
b. Nonreciprocal interchromosomal chromosomal segments are exchanged between
two non-homologous chromosomes
c. Reciprocal interchromosomal one-way transfer of a chromosomal segment to
another
DNA repair mechanisms
Mismatch repair
Happens right after the new DNA has been made and its job is to remove and replace mis-
paired bases, which weren’t fixed during proofreading
Steps:
1. Protein complex recognizes and binds to the mis-paired base
2. Second complex cuts the DNA near the mismatch
3. More enzymes chop out the incorrect nucleotide and a surrounding patch of DNA
4. A DNA polymerase replaces the missing section with correct nucleotides
5. DNA ligase seals the gap
, Proteins recognise nicks (single-stranded breaks) to know which of the bases is “wrong”
nicks are only found on newly synthesized DNA
Direct reversal
Fix DNA by reversing the chemical reaction that caused it
Mutations often occur because an extra group of atoms gets attached to DNA
Base excision repair
Group of enzymes (glycosylases): each detects and removes a specific kind of damaged base
E.g. deamination can convert cytosine into uracil, which will then match with adenine
glycosylases detect and remove deaminated cytosine and the gap is filled by other enzymes
Nucleotide excision repair
Remove multiple bases and replace it with the help of DNA polymerase
Detects and corrects types of damage that distort the double helix
Helicase cranks open the DNA to form a bubble and DNA-cutting enzymes chop out the
damaged part of the bubble DNA polymerase replaces the missing DNA and ligase seals
Double stranded break repair
Double stranded break = splitting the chromosome in two
Non-homologous end joining
o The two broken ends are glued back together messy and involves loss or addition
of nucleotides (produces mutation, but this is better than losing the entire part of a
chromosome)
Homologous recombination
o Information from the homologous chromosome that matches the damaged one is
used to repair the break two homologous chromosomes come together and the
undamaged region is used as a template to replace the damaged region of the
broken chromosome
Clearer and doesn’t cause mutations, usually
Only possible when you have the sister strand
End of G2 phase in mitosis
During crossing over in meiosis (prophase I)
Meiosis and mitosis
,Production of gametes
Sperm
Primordial germ cells migrate to the testes: gonocytes develop into spermatogonium
Puberty: spermatogonium will perform meiosis and become a haploid sperm cell
Sperm production in seminiferous tubules: separate from systemic circulation by blood-testis
barrier formed by Sertoli cells, prevents hormones and constituents from affecting the
sperm, and prevents the immune system recognising the sperm as foreign
Primary spermatocytes undergo meiosis, creating first spermatocytes and then spermatids
Spermatids then undergo spermiogenesis and form mature spermatozoa
When the sperm are in the female reproductive tract, capacitation takes place
Oocytes
Primordial germ cells migrate to ovaries: gonocytes develop into oogonium
20 weeks: ~7 million cells before birth: ~2 million primary oocytes due to cell death
puberty: ~40.000 left due to artresia
Clusters of primary oocytes surrounded by epithelial cells: follicular cells and will form
primordial follicles
Three stages of maturation of the primary oocytes
1. Pre-antral stage: oocyte and follicular cells grow and become granulosa cells (= secrete
glycoproteins to form zona pellucida)
Surrounding connective tissue becomes theca
folliculi, LH present: secrete androgens
2. Antral stage: spaces between granulosa cells
combines and forms one fluid filled space = the
antrum. Follicles are secondary follicles and will
develop under influence of FSH, LH and oestrogen
3. Pre-ovulatory stage: meiosis I is complete: 1
secondary oocyte + 3 polar bodies
Ovulation process: LH increases collagenase activity to
weaken the follicular wall, the ovarium wall will have
muscle contractions, and the ovum is released and
taken up into the fallopian tube via fimbriae
Fertilisation: secondary oocyte completes meiosis II
after fertilisation; if fertilisation does not occur, the
oocyte degenerates; if it is fertilised, peristaltic
movements of the fallopian tube move the egg to the
uterus where it implants to the uterine wall
, Case 2
Capacitation of sperm cells
Because of the changes, the sperm cell
can penetrate the zona pellucida
Fertilization
1. Spermatozoon reaches the zona
pellucida, and binds due to interaction
with a glycoprotein sperm receptor
2. The acrosome releases degradative
enzymes sperm can penetrate in the
zona pellucida
