Chromosomes and Gametes

Question 1

The defining feature of all evolving living organisms is

Answer 1

the ability to reproduce

Through reproduction we pass on our genes to a new generation

Question 2

A second principle that is fundamental to evolution is

Answer 2

variation

The replicating system must undergo changes
The changes mean that you are better adapted to the environment.
Each new generation either reproduces or dies out – survival of the fittest.

Question 3

Karyotype of Human Chromosomes

Answer 3

Humans can karyotype chromosomes – visualise
This can be exploited in reproductive technologies

Question 4

Karyotype definition

Answer 4

number and appearance of human chromosomes

Question 5

Centromere

Answer 5

Each chromosome has a constriction point called the centromere, which divides the chromosome into 2 sections or “arms” – short (p) and long (q).
The centromere location gives a chromosome the characteristic shape and is used to describe the location of the gene

There are 22 pairs of autosomes (inherit one from each parent.
1 pair of sex chromosomes = total of 46 chromosomes

Question 6

For genes to be functional DNA must be able to

Answer 6

replicate
separate its 2 copies at mitosis
maintain itself between generations

Question 7

DNA requirements for sexual reproduction are different

Answer 7

Each parent passes on one allele (i.e. one version of a particular gene) to each offspring
So if there are any abnormalities in the alleles, it can be passed on, BUT it can also be compensated for depending on what is inherited from each parent.
This is why in consanguineous relationships there is a loss of the ability to filter out common mutations.
Copy number variants (CNV) occur if there are one, three of more copies of alleles
If Alleles are heterozygous the phenotype of the trait can be dominant or recessive.

Question 8

Gene Transcription and Translation

Answer 8

Another way we can induce differences is through the transcription and translation of these genes.

DNA has a promotor and coding sequence that is transcribed into a gene product -> RNA
Introns are then removed from exon by splicing
Exons will come together
mRNA is then exported out of nucleus
It is translated into proteins in ribosomes i.e. complexes of tRNA and proteins
Proteins are then folded into unique 3D structure that determines function

Question 9

Tissue specific control of gene transcription

Answer 9

One gene controlled by different promoters in a tissue specific manor.
The same gene can be tissue specific by having alternative promoters
Eg the gene CYP19A1 codes for aromatase (androgens -> estrogens).
Aromatase is found in the granulosa cells in the ovary
But there is also the gene in breast, placental and adipose tissue.
The aromatase produced in the different tissues is exactly the same, this is because the coding region is the same (2-10)
BUT there is a splice site at the start of exon 2, this leads to different exon 1s being attached.
These different exons will have different promoters.
Eg: Ovary = promoter 2. The difference is that this promoter will respond to different hormones (FSH, insulin). This will then drive the exons 2-10 to make aromatase. SO… the aromatase is the same, but it responds to different hormones.
Breast = promoter 1.4 will respond to different growth factors.
In post menopausal women there is no ovarian function so they are not producing estrogen from their ovary. There is a risk of estrogen dependant breast cancer. This is due to abnormal activation of various promoters in the breast, this can drive the breast to produce estrogen which can drive the cancer. The breast gets androgens to make estrogen from the adrenal gland, and as you have abnormal activation of promoters there is a risk of breast cancer.

Question 10

Gene to protein

Answer 10

One gene giving rise to several products

One gene can give rise to several products by alternative splicing of exons
These products are known as isoforms

A protein can be modified once it has been made by:
Post-translational modification eg phosphorylation,
eg. how are LH and FSH modified?
Glycosylation i.e. adding on carbohydrates to protein, making protein more stable and soluble

Often hormones are secreted as pro-hormones and then they must be enzymatically processed to form the active hormone.
Eg: pre-proGnRH and insulin

Question 11

Describe alternate splicing

Answer 11

DNA is transcribed into RNA
It moves out of the nucleus
There is then splicing -> removal of introns
Depending on how the exons join, this can form a different protein
eg. 3 alternatively spliced variants of human FSHR found in testicular tissue – possible association with spermatogenic defects

Question 12

Glycosylation of FSH and LH

Answer 12

Proteins can further be modified in the endoplasmic reticulum eg with glycosylation.
Adding on of various glycosyl groups
Eg can have tetra, di and tri glycosylated X
Each of these will behave differently
These proportions of glycosylation varies as you age, this can alter fertility.

Question 13

DNA reproduction

Answer 13

DNA needs to be able to be passed through generations
Most cells and many organisms replicate by doubling DNA and dividing to give 2 identical progeny or clones = asexual reproduction
The name given to the duplication of the DNA in this process is: Mitosis

BUT
This is different for sexual reproduction, the DNA requirement is to half the number of the chromosomes.
Need fusion of haploid cells (gametes) to create unique diploid progeny
This uniqueness brought about by crossing over and independent sorting of chromosomes.

Question 14

Somatic cells

Answer 14

Somatic or diploid cells replicate by simple cell division
give identical progeny, usually have limited number of divisions,
eg hepatocytes, pancreas, skin cells

Question 15

Asexual vs Sexual Reproduction

Answer 15

The advantages of sexual reproduction are:
Prevents the accumulation of genetic mutations
Increase in genetic diversity
Maintenance occurs because of the advantage of genetic variability
Variation in off-spring → survival of the fittest? Better able to evolve and adapt to changing environment

Question 16

X and Y chromosomes

Answer 16

Originally there wasn’t X and Y chromosomes.
It is thought to have differentiated from a pair of identical chromosomes (autosomes)..300 million years ago
Ancestral mammal developed a variation which made it male….gradually this chromosome became the Y and the other the X.

With evolution, genes advantageous to either sex became focussed on X or Y and those for ‘maleness’ close to SRY gene.
X chromosome → 1000 working genes
Y chromosome → 86 working genes
Recent comparisons of human and chimpanzee Y chromosomes shown that human Y chromosome has not lost any genes since divergence of human and chimpanzees 6-7 million years ago

Question 17

Gametes

Answer 17

Gametes are haploid cells that are specialised for sexual fusion. They have 23 chromosomes.

Unlike other cells, gametes go through cycles of diploidy and haploidy:

Gametes are formed from germ line cells: primordial germ cells that migrate into the gonad and then differentiate to either male or female gametes
The process producing oocytes – oogenesis (incorporated as part of folliculogenesis)
The process producing sperm - spermatogenesis
Undergo cycles of mitosis to increase numbers
Then undergo meiosis
Then combine at fertilisation

Question 18

Duplication of Chromatids

Answer 18

Chromosomes replicate during S-phase of cell cycle
They remain attached at the centromere
Each copy known as a chromatid → the 2 copies are identical to each other → “sister” chromatids
Exact copy of original chromosomes

Question 19

Mitosis SUMMARY

Answer 19

Mitosis can be broadly divided into 4 stages:
Prophase, metaphase, anaphase and telophase.

Question 20

Interphase

Answer 20

Interphase is where DNA is duplicated to sister chromatids. The centrioles are also duplicated. There is growth in preparation for cell division.
Interphase is the period of the cell cycle between cell divisions.
Interphase is not a “resting period,” as once thought. Instead, interphase is a time when the cell carries out its functions and grows.
If the cell is going to divide, interphase is a time of intense preparation for cell division. During interphase, the DNA and organelles are duplicated. Throughout interphase, the genetic material is in the form of long, thin threads that are often called chromatin. They twist randomly around one another like tangled strands of yarn. In this state, DNA can be synthesized (replicated) and genes can be active. At the start of interphase, during G1, each chromosome consists of a DNA molecule and proteins.

Question 21

Prophase

Answer 21

Prophase Mitosis begins with prophase, a time when changes occur in the nucleus as well as the cytoplasm. In the nucleus, the chromatin condenses and forms chromosomes as DNA wraps around histones. The DNA then loops and twists to form a tightly compacted structure. When DNA is in this condensed state, it cannot be replicated, and gene activity is shut down. In this condensed state, the sister chromatids are easier to separate without breaking. At about this time, the nuclear membrane also begins to break down.

Outside the nucleus, in the cytoplasm, the mitotic spindle forms. The mitotic spindle is made of microtubules associated with the centrioles. During prophase, the centrioles, duplicated during interphase, move away from each other toward opposite ends of the cell.

Question 22

Metaphase

Answer 22

Metaphase During the next stage of mitosis, metaphase, the chromosomes attach to the mitotic spindles, forming a line at what is called the equator (center) of the mitotic spindles. This alignment ensures each daughter cell receives one chromatid from each of the 46 chromosomes when the chromosomes separate at the centromere.

IMPORTANT: In mitosis, the chromosomes line up on the spindle one after the other.

Question 23

Anaphase

Answer 23

Anaphase Anaphase begins when the sister chromatids of each chromosome begin to separate, splitting at the centromere. Now separate entities, the sister chromatids are considered chromosomes in their own right. The spindle fibers (microtubules condense) pull the chromosomes toward opposite poles of the cell. By the end of anaphase, equivalent collections of chromosomes are located at the two poles of the cell.

Question 24

Telophase

Answer 24

Telophase During telophase, a nuclear envelope forms around each group of chromosomes at each pole, and the mitotic spindle disassembles. The chromosomes also become more threadlike in appearance.

Question 25

Cytokinesis

Answer 25

Cytokinesis—division of the cytoplasm—begins toward the end of mitosis, sometime during telophase. During this period, a band of microfilaments in the area where the chromosomes originally aligned contracts and forms a furrow. The furrow deepens, eventually pinching the cell in two. Thus each daughter cell is a diploid cell that is genetically identical to the parent cell.

Question 26

Meiosis vs Mitosis

Answer 26

The difference in meiosis is that you have two stages: Meiosis 1 and 2.
This allows for crossing over between homologous chromosomes before the first division

Meiosis and mitosis begin the same way. Both are preceded by the same event—the replication of chromosomes. Forming sister chromatids. There is duplication of the centrioles and formation of the spindles.

Unlike mitosis, meiosis involves two divisions.
In the first division, the chromosome number is reduced, because the two homologues of each pair of chromosomes (each replicated into two chromatids attached by a centromere) are separated into two cells so that each cell has one member of each homologous pair of chromosomes.

IMPORTANT: The chromosomes align differently to mitosis. Eg mothers chromosome 1 will be next to fathers chromosome 1. They are adjacent to each other.

In the second division, the replicated chromatids of each chromosome are separated.

We see, then, that meiosis begins with one diploid cell and, two divisions later, produces four haploid cells. The orderly movements of chromosomes during meiosis ensure that each haploid gamete produced contains one member of each homologous pair of chromosomes.

Question 27

2 important sources of genetic variation are:

Answer 27

Recombination due to crossing over in prophase 1 – where parts of non sister chromatids are exchanged
Independent assortment during metaphase 1 – where maternal and paternal members of homologous pairs align randomly at the equator, creating a random assortment of maternal and paternal chromosomes in the daughter cell.

Question 28

Define synapsis- pairing of homologous chromosomes to form a Tetrad in Prophase I

Answer 28

The homologous chromosomes line up on the spindle next to each other.
Due to their close proximity, they have the ability to randomly exchange genetic material
They form chiasmata where material is exchanged
This created 4 unique chromatids, hence increasing overall genetic diversity of all the gametes.

The separation of homologous chromosomes occurs reliably during meiosis I because, during prophase I (the I indicates this phase takes place during meiosis I), members of homologous pairs line up next to one another by a phenomenon called synapsis (“bringing together”).
For example, the chromosome 1 that was originally from your father would line up with the chromosome 1 originally from your mother. Paternal chromosome 2 would pair with maternal chromosome 2, and so on.

Question 29

Meiosis 2

Answer 29

In meiosis 2, there is no interphase or duplication as we still have the duplicated chromatids.
The same process occurs: centrioles duplicate, nuclear membrane breaks down, line up on the spindle…
BUT now they line up exactly like mitosis, one after the other. When they pull apart, the chromatids now split apart from the centromeres.
This creates haploid daughter cells

Meiosis II (better explanation) During the second meiotic division—meiosis II— each chromosome lines up in the centre of the cell independently (as occurs in mitosis), and the sister chromatids (attached replicates) making up each chromosome separate. Separation of the sister chromatids occurs in both daughter cells that were produced in meiosis I.
This event results in four cells, each containing one of each kind of chromosome. The events of meiosis II are similar to those of mitosis, except that only 23 chromosomes are lining up independently in meiosis II compared with the 46 chromosomes aligning independently in mitosis.

Question 30

Meiosis vs Mitosis

Answer 30

Mitosis: cell divides to produce 2 new ‘daughter’ cells that are identical to the original and diploid

Meiosis: similar to mitosis but more complex → results in production of ‘daughter’ cells that are non-identical and haploid
Meiosis serves two important functions in sexual reproduction:
Meiosis keeps the number of chromosomes in a body cell constant from generation to generation.
Meiosis increases genetic variability in the population
Meiosis is advantageous as there is:
random distribution of male and female homologous chromosomes
chromosomal crossing over occurs

Question 31

How is genetic variability achieved?

Answer 31

Independent assortment
Crossing over/recombination

Question 32

Independent assortment

Answer 32

Independent Assortment
Homologous pairs of chromosomes line up at the equator (midpoint) of the spindle during metaphase I.
However, the orientation of the members of the pair is random with respect to which member is closer to which pole:

Question 33

Crossing over/recombination

Answer 33

Crossing over / recombination
Corresponding pieces of chromatids of maternal and paternal homologues (non-sister chromatids) are exchanged during synapsis when the homologues are aligned side by side.
Each of the affected chromatids has a mixture of maternal and paternal genetic information:

Question 34

Sex chromosomes align but crossing over does not usually occur in X and Y chromosomes.
You can’t have crossing over of the main genes as this will be lethal
Apart from at the pseudoautsomal regions (PAR), which are usually at the ends of the X and Y chromosomes.

why?

Answer 34

They are hemizygous to each other & so recombination proved harmful
PAR allows the X & Y chromosomes to pair and properly segregate during meiosis in males

In females, you inherit 2 X chromosomes, but you do not want to have a duplication of genes and gene products, this can be harmful. So one of the X chromosomes are inactivated:
X-inactivation occurs in which one of the copies of the X-chromosome is silenced to prevent females from having twice as many gene products as males.
Choice of which is inactivated is random in placental mammals like humans.

Question 35

Aneuploidies

Answer 35

A gain or loss of chromosomes from the normal 46 is called aneuploidy, affecting normal development and functioning.

Since each chromosome contains hundreds of genes, the addition or loss of a single chromosome disrupts the existing equilibrium of the cell leading to profound phenotypes.

Question 36

Rate of aneuploidy

Answer 36

Using cytogenetics (assistive reproductive technology) (including karyotyping) - aneuploid gametes produced at surprisingly high rates in humans
The majority occur from an error in maternal meiosis I, because human oocytes are arrested in prophase I for decades
Aneupolidy is present in 6% of sperm from ostensibly normal men and in 20% of oocytes

Majority are lethal
E.g. trisomies (47 chromosomes) account for 35% of spontaneous abortions/miscarriages

Question 37

What is non-disjunction?

Answer 37

is the failure of homologous chromosome to separate during Meiosis I or sister chromatids to separate during Meiosis II, resulting in extra or missing chromosomes
A pair of chromosomes or sister chromatids may adhere so tightly to one another that they do not separate during anaphase. As a result, both go to the same daughter cell, and the other daughter cell receives none of this type of chromosome:

Question 38

Abnormality in Chromosomes and pregnancy

Answer 38

50% of recognized pregnancy loss result from chromosomal abnormality.

Question 39

Most common aneuploidies and viable ones

Answer 39

Most common aneuploidies in humans are trisomies (0.3% of live births).
Viable ones are:
Trisomy 21 (aka Down’s syndrome, 1:750 births)
Trisomy 18 (Edwards syndrome)
Trisomy 13 (Patau syndrome)

Question 40

Abnormal karyotype and amenorrhea

Answer 40

50% of patients with primary amenorrhea as a result of premature ovarian insufficiency (POI) have an abnormal karyotype

Question 41

Sex Chromosome aneuploidy are more viable, usually random, examples include:

Answer 41

Turner syndrome (45, X monosomy) (WOMEN) » caused by complete or partial absence of 2nd sex chromosome (occurrence 1:2000 female births) → phenotype=short stature, primary amenorrhea (classic Turners)

Klinefelter syndrome (47,XXY trisomy) (MEN) » caused by presence of two X and one Y chromosome (occurrence 1:500 male births) → variable phenotype=taller than average, small testes producing reduced testosterone, infertility

Question 42

Effect of Maternal Age and Risk of Trisomy

Answer 42

There is an association between the maternal age and the risk of trisomy.

Multiple mechanism contribute to the maternal age effect :
Recombination failure
Premature homologue separation – separate too early
Premature sister chromatid separation due to loss of cohesion between sister centromeres