How we became human.
Gene expression.
Heredity.
Life starts with a single fertilised egg.
We can call it as a zygote.
Starting from here, a series of rapid and dramatic changes, takes place,
before the baby is born.
Initially, the cells just replicate themselves, resulting in identical daughter cells.
At some stage, they decide to get more specialised.
Interestingly, the specialisation, happens in stages.
Initially, the cells are directed to be ‘up’ or ‘down’.
It is also directed to be ‘left’ or ‘right’,
and whether it is ‘inside’ or ‘outside’.
This is with reference to the spine of the body.
This forms a basic layout plan, for the human form.
For example, a liver cell is directed to go right.
A heart cell is directed to go left.
That is why, we have our heart, in the left side,
and the liver, on the right side.
This way a cell gets to know, it’s general regional coordinates in the body.
As the cells continue to divide and multiply,
they get more specific specialisation instructions.
A cell that was instructed to go up,
is now instructed to become an ‘eye’ cell.
It is then instructed to be a eye retina cell.
These cells, are capable of recognising light signals,
and sending messages to the brain.
Another cell is destined, to a different fate.
it is instructed to become a neurone cell.
It is then instructed to be part of the brain.
It is then told to recognise signals, from the eye,
and interpret them as light signals.
The genes that direct cell specialisation, are called as homeotic genes.
This is also called as transcription factors.
These genes specify where the organs are located,
what form they take, and what function they should carry out.
During the development of the baby, these transcription factors,
almost magically, are expressed just at the right time.
This is easy to imagine.
The instruction to become an eye type cell, can be expressed,
only when the environment for the eye, is developed.
Nail expression for example, is expressed,
very late in the development of the baby.
In reality, some transcription factors, induce the generation,
of other transcription factors.
A cascade of transcription factors, result in the final cell specialisation.
The orchestration, of this complex series of gene expression,
is initiated when the sperm fertilises the egg.
About 38 weeks later, the grand finale takes place.
”A bundle of joy” is born.
A new life is born.
All the genetic material, as a whole, is referred to as the genome.
All the cells in the body, have the same pair of 23 chromosomes.
The same genes, are present in every cell.
Does this mean, that all the genes, are used by all the cells?
No !
Different cell types use a limited number of genes.
Each type of cell, uses a sub set, of the entire genome.
Different tissues, organs, etc, have different cell types.
A neurone in the brain, has a special cell type.
The eye has a special cell type.
Muscle tissues, have a special cell type.
Bones have a special cell type.
And so on.
Each cell type specialises, in a function.
Each cell type, is said to be differentiated.
This differentiation, happens by selective gene expression.
Only the relevant genes, are expressed, in every type of specialised cell.
Each type of specialised cell, expresses a distinct pattern of genes,
that gives cells, its special properties and functions.
Rhodopsin is a special type of light sensitive protein.
It is present in the retina cells, of the eye.
These cells express the genes, required to synthesise Rhodopsin.
The same genes, are present, in the liver cell.
But, they do not express themselves, in the liver cell,
since the liver cells, do not sense light.
Some genes express themselves, only when induced to do so.
For example, some genes, express themselves only at puberty.
This is induced by certain hormones, produced by the body.
Genes in some skin cells, produce a pigment, called melanin,
when exposed to sunlight.
The ultra violet rays, in sunlight, induce some genes in skin cells,
to produce melanin.
The melanin produced, causes skin, to get a tan.
There are many cases, like these, where genes express themselves,
when induced by a internal or external factor.
The human genome, was mapped quite recently, around 2000 A D.
We now know, almost all the genes present in the human genome.
This was a giant leap forward, in the understanding of science of genetics.
But, mapping of the genome, is only part of the story.
It is like knowing, all the characters, of a novel, like say, a Harry potter novel,
without knowing the story.
How the genes, express themselves, as a whole, is the story,
of the genome.
We are just beginning, to understand this story.
This makes it all the more exciting, because we can expect,
many more exciting discoveries, to follow.
During cell division, identical sets, of the DNA molecules,
passes to each of the daughter cells.
Every somatic cell in the body, contains the same genetic information.
Though the DNA is same, different combination of genes,
express themselves, in different cells.
This gene expression, differentiates the specialised cells,
like nerve cells, muscle cells, skin cells, etc.
The genes that contain the information, for synthesis of muscle cells,
generate the corresponding, messenger RNA, in muscle cells.
The same genes, in the nerve cells, will not do so.
Cell differentiation, is related to regulating protein synthesis.
Certain genes are turned on and off, during cell differentiation.
The fascinating complexity of life, is built from these elemental design principles.
Cell differentiation, can take place, at different stages, of human development.
Most of the basic cell differentiation takes place, during the development,
of the baby in the womb.
Some of this cell differentiation, takes place in adults, for cell replacement.
Many factors influence the behaviour of genes.
They are :
The gene or genes involved.
The order in which genes, are transcribed.
How often the genes are transcribed.
How long, the messenger RNA, endures, once it is produced.
The simultaneous expression, of a network of genes.
The coordinated regulation, of the expression of genes.
These factors determine, how the genes will behave.
We will discuss, some of the basic factors, which determine the gene expression.
The DNA is a long sequence of the basic characters A, T, C, and G.
Some of the sequences, represent a gene.
A gene can have a variable length.
The role played by some of the characters, in the DNA are unknown.
As of now, scientists call them “Junk” DNA.
There are some set of characters, which play a critical role,
in the expression of the gene.
These set of characters are called promoters.
Typically a promoter sequence, is located at the beginning of the gene.
We can think of promoters, like a switch for a gene.
A gene can be switched “off”, or “on” by a promoter.
When the gene, is switched “off”, it will not express itself.
When the gene, is switched “on”, it will express itself.
So, a gene can be present in a cell, but be active or inactive,
depending on whether it is switched “on” or “off”
This is the fundamental way, a cell gets specialised, or differentiated.
A differentiated cell, has only specific, relevant genes, switched on.
When a gene is switched “on”, it will produce only specific messenger RNA.
Specific messenger RNA, will synthesise, only specific proteins.
Specific proteins, will determine specific behaviour, of a cell.
A muscle cell, has genes relevant to the muscle functionality, switched on.
A nerve cell, has genes relevant to the nerve functionality, switched on.
Using this simple, but elegant mechanism, thousands of types, of specialised cells,
is created, each containing the same genome.
This explains the most basic, and simplest mechanism, for cell differentiation.
Now we can look at a more detailed model of gene expression.
The promoter can now, be looked at as a regulator.
A gene can not only be switched “on” or “off”, but can be regulated.
This is something like, a fan regulator, which can be set for different speeds.
For example, the regulator can be set as “high” or “low”.
When it is set to “high”, the gene might produce more RNA, and proteins.
When it is set to “low”, the gene might produce less RNA, and proteins.
There are other ways, that it can be regulated.
For example, it can be set to “fast” or “slow”.
When set to “fast”, the rate of production increases.
When set to “slow”, the rate of production decreases.
Now, we have a even more powerful way, of regulating the genes.
We can now think of even more complex model.
We can think of the promoter, like a combination lock.
This combination lock, has a number of digits.
Each digit, let us say, can be set to 0 or 1.
Let us imagine, that there are 6 digits that can be set.
As an example, it can be set as, 1, 0, 1, 1, 0, 1.
Each digit might represent ‘on’, ‘off’, ‘high’ , ‘low’, ‘slow’, ‘fast’, etc.
This will give a unique way, for the gene to express itself.
This way, the promoter can be used, to express a gene in many possible ways.
There are many more, practical and interesting ways, that a promoter,
can be used to regulate a gene.
This gives life, a tremendous amount of flexibility, in regulating the gene.
Now, we not only have active genes, in a specialised or differentiated cell,
we have a mechanism, for regulating the gene.
We know that cells are not electronic circuits.
They are bio chemical organisms.
The switches themselves, are DNA sequences.
The switches are set by other bio chemical molecules.
Typically, these bio chemical molecules will be proteins.
Each type of protein, will be able to operate a particular switch,
or gene sequence.
These regulatory proteins, are called transcription factors.
The regulatory proteins themselves, are produced by other genes.
So, the genes to regulate the genes, is also present, in the DNA.
This makes DNA an equivalent, fascinating bio chemical computer.
The information, and the instructions, are built into the computer.
This exquisite control, of gene expression, allows the development,
of complex life forms.
Human beings are one such example, of such a complex form of life.
There is a underlying elegance and beauty, in all this complexity.
The same regulatory proteins, are used in different specialised cells.
This helps to synchronise, multiple specialised cells, to act in a co-ordinated way.
More interestingly, the same regulatory proteins, are used across many life forms.
Nature has a way, to reuse a design, which it has perfected.
This is the reason, that we share genes, with fireflies, elephants, and chimpanzees.
More than 95% of our genes, are shared with chimpanzees.
If we think about it, it does make a lot of sense.
The basic functionality of the eye, is the same, whether it is a firefly,
or an elephant, or a chimpanzee.
Specific gene expression, results in specialised cells.
Each specialised cell has a set of genes, which are active,
and others, which are inactive.
Much of this specialisation, takes place during the growth of the baby,
in the womb.
The development of a human being,
is a complex preset program, of expression of genes,
starting from a fertilised egg, to the delivery of a breathing, living baby.
Once a cell is fully specialised, it will remain specialised.
Typically the process, is irreversible.
What becomes a muscle cell, will remain as a muscle cell.
What becomes a nerve cell, will remain as a nerve cell.
In this way, the whole human being is synthesised.
Since ancient times, they have always known,
that children have similarities with their parents,
though they did not know how, or why?
Ancient philosophers like Aristotle, proposed that females had containers,
and males provided the design and spark for life.
One early theory included the “homunculus” idea.
According to this, dad’s sperm contained a miniature, perfectly formed human,
called the homunculus.
Mom provided the ideal growing conditions.
Even a modern scientist, like Charles Darwin, thought that the baby,
was a blend of the parents.
People thought that the blood of the male, and the female,
blended to provide the characteristics of the baby.
Even today, we talk about blood line, and blood relatives,
to indicate shared ancestry.
It is only as late as the 19th century, a monk called Mendel,
proved that these assumptions are wrong.
Mendel though a monk, did extensive research on heredity.
At that time, DNA was not discovered.
He used pea plants, for his research.
He experimented with thousands of plants, over many generations.
Some of the basic principles of heredity, that he discovered, still holds good.
Mendel’s work was unrecognised, and he died in obscurity, in the 19th century.
His concepts was rediscovered, in the 20th century.
In fact it makes sense, to start understanding heredity,
using Mendelian genetics.
We can start with one of the simplest, but most profound experiments.
Some pea plants, that he bred, were pure green pod peas.
Some pea plants, that he bred, were pure yellow pod peas.
When he bred pure green pea plants with each other,
he always got green pea pod offspring.
When he bred pure yellow pea plants with each other,
he always got yellow pea pod offspring.
When he interbred, the green and the yellow pea plants,
he got the surprise, and shock of his life.
The resultant pea plant, where all green pod, pea plants.
With centuries of thinking, which revolved over blending,
he was expecting a sort of greenish blue pea pods.
That is, he was expecting the green and blue colours to blend,
in the offspring.
No wonder, he was surprised and shocked.
He cross bred, the resulting pea plants, again.
This gave him a bigger surprise.
Some of the offspring pea plants, had green colour pea pods.
Some of the offspring, had yellow colour pea pods.
None of them, were a blend of green and yellow.
He repeated these experiments, over and over again.
He was amazed to find, that the results were consistent.
To understand these results, first and foremost,
he had to get rid of his mindset of “blending”.
He carefully and consistently observed, that the yellow colour,
always disappeared in the second generation,
and reappeared in the third generation.
Mendel made a profound conceptual breakthrough.
He said, that a trait is passed down, from the first generation,
to the next generation.
We now call this, as genotype.
This trait, he said, does not physically manifest itself, in the second generation.
We now call this phenomena, as phenotype.
Mendel proposed that there were discrete units of heredity.
We now call them “genes”.
Mendel proposed that, there could be different forms, of a gene.
For example, a gene, that determines colour, of the pea pod,
could have two variants.
One variant gives it a green colour.
Another variant gives it a yellow colour.
We now call these variants, of a gene, as alleles.
Dominant and recessive alleles.
The second profound concept, that Mendel discovered was,
the concept of dominant and recessive alleles.
Dominant alleles express themselves.
Recessive alleles, do not express themselves,
when a dominant allele is present.
However, if the dominant allele is not present,
the recessive allele, can express itself.
In the experiment we discussed, the colour gene, had two alleles.
A green allele,
and a yellow allele.
The green allele was dominant.
The yellow allele was recessive.
Depending on what alleles are expressed, it is a phenotype.
In the first generation phenotype, the green allele was dominant.
This explains how, in the first generation, all the offspring,
had green pods.
We will now see, how this happens, from a genetic perspective.
We will represent the dominant green allele, as capital ‘G’.
We will represent the recessive yellow allele, as lower case ‘g’.
Dominant genes, by convention, is represented in capital letters.
Recessive genes, by convention, is represented in lower case letters.
We know that chromosomes, come as pairs.
Genes also come as pairs.
The offspring, get one copy of each gene, from each parent.
One randomly chosen copy of each gene, from each parent,
is passed on to the offspring.
This is called as the law of segregation.
Let us start with the pure bred, pea plants that Mendel started with.
The pure green pea plants, had two capital ‘G’ alleles.
We will call them capital ‘GG’ types.
This is also known as the capital ’GG’ genotype.
The pure yellow pea plants, had two lower case ‘g’ alleles.
We will call them lower case, ‘gg’ genotype.
When two alleles, of a gene, are the same we call them homozygotes.
The capital ‘GG’ genotype is a homozygote.
The lower case ‘gg’ genotype is a homozygote.
When a capital ‘GG’ homozygote, is bred, with another capital ‘GG’ homozygote,
the resulting offspring, inherits one capital ‘G’ allele, from each parent.
This results in a offspring, with capital ‘GG’ homozygote.
This results in green pea pod plants.
When a lower case ‘gg’ homozygote, is bred, with another lower case,
‘gg’ homozygote,
the resulting offspring, inherits one lower case ‘g’ allele from each parent.
This results in a offspring, with lower case ‘gg’ homozygote.
This results in yellow pea pod plants.
Now we will see, what will happen, if we inter breed,
a capital ‘GG’ homozygote,
with a lower case ‘gg’ homozygote.
The resulting offspring ,
will inherit one capital ‘G’ allele from one parent,
and one lower case ‘g’ allele from one parent.
This will result in a capital ‘G’, lower case ‘g’ genotype.
What colour will the pea pod be?
This is where Mendel gave us the insight, that we never had before.
It will have the colour, of the dominant allele.
Since the green allele is dominant,
all the offspring, will have green colour pea pod plants.
We can note the fact, that all the four possibilities,
of crossing a capital ‘GG’ homozygote, with a lower case ‘gg’ homozygote,
will be four instances of capital ‘G’, lower case ‘g’ genotype.
In this case, the genotype, has different alleles.
This kind of genotype is called heterozygous.
All the heterozygous possibilities, in this example,
carry a recessive lower case ‘g’ allele.
But, since all of them also carry a dominant, capital ‘G’ allele,
none of the lower case ‘g’ allele, can express themselves.
All the off spring, have green colour, but all of them are carriers,
of the lower case ‘g’ allele.
Mendel, we recollect, again cross bred, the second generation, pea plants.
Let us examine, what would happen, from a genetic view point.
Each of the second generation pea plants, are heterozygous.
We are now crossing, a capital ‘G’, lower case ‘g’,
with a capital ‘G’, lower case ‘g’.
The offspring pea plants, will inherit, one allele from each parent.
There are four possible offsprings.
1. Capital ‘G’, capital ‘G’.
2. Capital ‘G’ , lower case ‘g’.
3. Lower case ‘g’, capital ‘G’.
4. Lower case ‘g’, lower case ‘g’.
How will each of these genotypes, express themselves?
In other words, what will be their phenotype?
Case-1.
Capital ‘G’ capital ‘G’.
Only dominant alleles are present.
It will express itself as green.
Case-2.
Capital ‘G’ , lower case ‘g’.
Dominant ‘G’ is present.
It will express itself as green.
Case-3.
Lower case ‘g’, capital ‘G’
Dominant ‘G’ is present.
It will express itself as green.
Case-4.
Lower case ‘g’, lower case ‘g’.
Both the alleles are lower case ‘g’.
Both are yellow alleles.
There is no dominant capital ’G’.
It will express itself as yellow.
Three of the pea plants will be green.
One of the pea plant will be yellow.
In other words, green has a 75% probability.
Yellow will have a 25% probability.
In general, a recessive gene, will have lower probability,
of expressing itself.
The principle of Mendelian genetics, is equally applicable to human beings.
In fact it is applicable to most forms of life.
We are aware, that human beings have 23 pairs of chromosomes.
22 of these pairs are homologous.
Homologous have the same genes, in each copy of the pair.
The 23rd sex chromosome could be heterologous.
The 22 homologous chromosomes,
have the same genes in both copies of the chromosomes.
Gametes are responsible for reproduction.
Sperms and ovums, are gamete cells.
They carry only 23 chromosomes.
That is, they do not carry 23 pairs.
We inherit 23 paternal chromosomes,
and 23 maternal chromosomes.
Each of our parents can be carrying alleles of a gene.
We will only inherit one allele from each parent,
just like the pea plant.
What alleles we inherit, determines what genotype we are.
We know that the same gene can have a allele.
For example, we can have a particular ‘eye’ gene,
which determines the ‘eye’ colour, in a chromosome.
The paired chromosome, will also have the same ‘eye colour’ gene.
’Eye colour’ gene can have alleles.
One allele can give, say a blue colour.
Another allele can give, say a black colour.
Just like Mendel’s pea plants,
an individual can carry different combinations of this alleles.
The person can have two black ‘eye colour’ alleles.
The person could have one blue colour, and one black, ‘eye colour’ allele.
The person could have two blue ‘eye colour’ alleles.
If the black colour is expressed, the person will actually have black colour eyes.
The black colour will be his phenotype.
What will happen when a person with a black eye colour,
marries a person with a blue ‘eye colour’?
We should remember, that what we see is the expressed colour.
The eye colour of the person, is the person’s phenotype.
We cannot see the person’s genotype.
The same principles of Mendelian heredity apply.
The eye colour of the offspring, will depend on,
genotype of each parent,
and which eye colour gene is dominant.
We have taken colour, as an example, to explain genetic inheritance principles.
This was done, to make it easy, to understand the principles, of inheritance.
Colour is not a critical trait in our body.
Most of the genes carry other much more important functionality.
Inheritance is much more important in those genes.
But the same principles apply for all the genes.
We can expand our basic understanding, to the full genome.
We have thousands of genes, in our genome.
Each gene can express some specific trait.
Many of these genes, could have alleles.
Some of these alleles will be dominant.
Some of these alleles will be recessive.
Depending on what alleles we are carrying, we are a genotype.
Depending on what alleles we are expressing, we are a phenotype.
We can make out what phenotype we are.
We cannot make out what genotype we are.
We might be carriers of recessive genes, which we do not express.
These alleles might express themselves, in future generations.
Most people have wet ear wax.
Some people have dry ear wax.
We can say that, wet ear wax, is normal,
and dry ear wax, is abnormal.
A type of ear gene, is responsible for this.
We will call the wet ear wax, allele, as capital ‘E’.
Capital ‘E’ allele, is the dominant allele.
We will call the dry ear wax, allele, as lower case ‘e’.
Lower case ‘e’, is the recessive allele.
People carrying the homozygous genotype,
capital ‘E’, capital ‘E’, will have wet ear wax.
People carrying the heterozygous genotype,
capital ‘E’, lowercase ‘e’,
will have wet ear wax.
This is because, capital ‘E’ allele is dominant.
These people are carriers, of the recessive allele, lower case ‘e’.
They carry the allele, but do not express it.
People carrying the homozygous genotype,
lower case ‘e’, lower case ‘e’,
will have abnormal, or dry ear wax.
This is how, we inherit abnormalities.
The alleles of the genes that we carry is inherited from our ancestors.
Knowing the family history, specially a long history, can help understand,
certain traits that we inherited.
This can be of special use, when studying abnormal genes.
Some of these abnormalities, can be more serious, than dry ear wax.
We now know, that many defects and diseases, have a genetic basis.
We hope, that in the future, the science of genetics,
can prevent or alleviate these abnormalities.