So welcome to the first lecture of the first week uhh of the course a functional genomics

So in todays lecture we are have going to look into the growth of a field called genomics

How did really this particular field came into existence and what the main people who

contributed to the growth of this course or whether the field and uhh so this can be bit

history but very important and interesting So I thought I would share with you

If you look into our you know human body then you know that the smallest unit uhh in terms

of functionality you can call it as a cell and cell as all of you know has got chromosomes

which has got DNA and that is what the genetic material which has all the signal as to how

the cell as to function specific to that tissue that it is present in and how that tissue

contributes to the function of the system that it has the skin beat digestive tracked

and then how all the system gets integrated in terms of function to be successful organism

So the basic uhh information that a cell needs or the tissue requires or organism requires

is present in your DNA that is our belief but we do not know really how and what way

the sequence information is understood and the cell is able to perform its function So

one of the uhh major question is that most the scientist have been asking since uhh centuries

back is to understand how the genetic material or what is fundamental you know information

that is present in the cell and how that information is retrieved and uhh executed So that you

can go back in history and we will look into some landmark discovery is as to how we understood

So if you look into the chromosome as shown in the slide you can pull out the DNA from

the chromosome you know there from the top to the bottom what you call the telomeres

the two ends of the chromosome Inner is one double helix run all the way So that is what

you call is a DNA And of course a small segment of the DNA constitutes a functional part of

a gene So this gene has all the sequences that that constitute the the gene in terms

of its function It includes for example the region gives you the uhh signal as to where

the transcription should begin where it should stop and and which sequence the RNA should

be translated meaning copy it for making uhh amino acids to form peptide and so on

But if you look in the history that the first time somebody really talked about that there

are uhh certain factors that are there in your cell that gives you a particular phenotype

When I say phenotype it could be any of the uhh changes that you see in a body for example

whether you are able to roll tongue or you are unable to roll tongue or the way your

hair structure is whether the straight or curly or for example you have free ear lobe

or it is fused sometimes it could be your height and there are many other such phenotypes

that are regulated by your DNA

So what is that in your gene gene genetic material that really regulates This understanding

comes from one of the pioneering studies done by this monk called Gregor Mendel he looked

at plants uhh as most of you would have studied uhh on to some of such contrasting characters

like height of the plant the the color of the flower this the size or the shape of the

seed and so on and try to understand whether whatever factor that determine as to what

should be the phenotype be the height of the plant or color of the flower or the shape

of the seed whether these are transmitted from one generation to the other and how they

are transmitted

He looked at he did some really amazing experiments you have to go back and study the original

literature you can understand how beautifully he selected the plant How beautifully he selected

the phenotype and came up with hypothesis then he called as there are three hypothesis

we talks about segregation dominance and what is called as independent assortment which

we call them as a laws now because every gene obeys whatever hypothesis that he proposed

therefore he call them as laws

So in that was the birth of genetics Generally people consider because that is a one that

really give the fundamental understanding as to how the genes can regulate without you

know Mendel of course did not know that there is a DNA there is a gene but he said these

are some factors and beautifully as shown and still if you look into the human population

or animal or plant and this is what you see They you know all the genes and their phenotype

obey the three hypothesis that Mendel proposed and that is why we call them as laws So that

is the pioneering discovery and that let to a kind of a concept that there is something

there in your cell that is transmitted to the next generation that governs your character

Almost to the same time somewhat overlapping is another person who came called flemming

Flemming again you know he looked at plants but not like Gregor Mendel Mendel looked at

plants as a phenotype; the he looked at how the plants look like what is height What is

a color What is seed and he really did wonderful experiments He crossed them looked at the

second generation generation came up with the last but this gentleman Flemming he did

phenomenal work He looked at the cells of the plants Okay These cells as to how do they

divide So (you) what you see on the right side in the in the power point slide is one

of the drawing that he made after looking at the cells that are dividing So you can

for example those who have done biology in their school you must of used the onion root

tip to look at you know how the cells divide mainly the mitosis

So basically he also did very similar kind of you know he is one proudly started with

such kind of analysis and drew all these different stages and you can see beautifully the chromosome

that are forming in the meta phase and how the cell is about to divide and you have this

uhh cells about to divide and so on and he came up with you know the theory as to we

call them as you know the concept that you are talking about now chromosome and chromatin

meaning you know the chromosome is a distinct entity which is different from the other Chromatin

is you know what you call as a DNA with the protein that forms the compact structure

Now this is what he drew and he called them as chromosome and chromatin The very concept

that you have something like this which becomes compact and when the cell divides they are

sorted as come from this gentleman uhh Flemming So that is his phenomenal contribution uhh

we can see when uhh you know possibly it could have done

And then came another person Boveri You can again phenomenal he basically looked into

the chromosomes and he he looked into what is called as meiosis How cells divide in the

germ cells that makes gametes So he looked into the reductional division whereas Flemming

looked at your mitosis synomal cell division So Boveri really gave a kind of explanation

as to what Mendel has proposed that is that you have different forms of the genes what

you called as a alleles for example a gene could determine your height So you may have

two variants of the gene one that gives you tall phenotype the other one gives you somewhat

short phenotype and these two you know get separated during what is called as gametogenesis

Therefore if you cross a plant that is tall but having one allele that is you know when

giving the phenotype that is note that tall and cross it with another plant which is not

tall then you would expect in the next generation 40 percent of them not being so tall right

So that means that chromosomes you know the two alleles are sorted into two gametes when

the cell undergo meiosis and basically he looked into the meiotic process and he has

shown that you know this chromosomes gets sorted and they become you know kind of reductional

division happens and that is something that his contribution again it is very very major

contribution in terms of understanding how the genetic material then they do not know

that it was genetic material but whatever it is he get sorted in the self

But almost at the same time these all three people Mendel Flemming and the Boveri all

from European origin and they were working from the Europe but at the same time Walter

Sutton he is an American who also was looking at the same phenomenon as to how the chromosomes

are sorted in meiotic cell and what is shown on the right side this is one observation

He basically has shown that a cell which is undergoing meiosis at the end of cell division

the number of chromosomes become half So we can see that what he call as a somatic series

the chromosomes he named by then and then you say somatic series if it is 2 in the reduce

series it will be half of it

So he has basically shown that how the reductional division takes place and then he spoke about

combination in gametes and combination in zygote when you know this uhh 2 gametes the

sperm and worm and when fuse together to form what you call as zygote How they again restored

the original number that was seen there So basically if you know looked at all these

things and that is how we as shown that there is meiotic cells undergo what is called as

reductional division that is an amazing discovery So these all uhh you know independent Boveri

and Sutton have done independent observation that eventually turn out to be the same

What is interesting here is that what kind of organisms they have used to understand

this uhh phenomenon whether it is mitosis or meiosis which pretty much you know universal

So you know whether it is the plant animal human you find the cell divide to grow or

to repair the damaged part by mitosis right So there then you know DNA replicates meaning

makes another copy and then eventually cell divides what is normal number of chromosomes

but it is was very difficult you know note not until 1960s people have not really looked

into the human system because it is very difficult

So they have used a variety of different organisms to understand like for example Flemming I

said he looked into plants and because easily one can do the preparation and see the chromosome

that is why he named it as chromosome and chromatin but Boveri and Sutton they looked

at meiosis which is very difficult So they went and looked at animal system So much of

our understanding in the early years for mitosis have come from plants whereas for meiosis

have come from animals

Although such cell division do happen in the plants as well when they you know make the

sperm Boveri used here worm call Ascaris you know he looked into the looked into that and

then and looked at the meiosis process whereas Sutton looked into Grasshopper a obviously

insect American insect and in these spices you know the tissue that form the gamete the

is this the soft one can dissect and looked at make you know make it uhh thin layer under

a microscope and then we can stay in for the chromosome and look at and that is how they

have really came up with these discoveries right

So what is generally you know spoken as a descriptive science in biology How come from

such kind of observation that is nothing but looked at in on different snap shots of event

that to plays when you fix a cell and observed them and try to correlate as to what could

possibly the sequence and they came up with the discovery which is amazing So uhh so in

science this is nothing called descriptive or analytical experimental sciences science

that you guys should remember whenever study anything So this is the system like Ascaris

and grasshopper really contributed to the understanding of the concept that even talk

about in the humans today whether it is uhh disorder or reproduction or normal growth

whatever observation they have made in any of the system really really helped us in understanding

what goes on in our body as well

So the fifth person I am going to introduce is a Bateson So he is again the one who made

or term the uhh the field called genetics is one who gave this term and he is one really

understood what Gregor Mendel has done By then until then Mendel’s contribution was

not known He has done that and he recorded and left but nobody really looked into the

implications some of them who looked into felt like what he was done is observed is

not explaining anything it may not be applicable to humans and animals and so on but it was

Bateson who really looked into Mendel’s data and then he develop the field he coined

the field called term called genetics and then he said what Mendel did applicable to

each and every organisms So if pretty much popular as what Mendel has done then people

took note of Mendel’s contribution When Mendel was no longer living So that is a legendary

work that he was done

So then there are people who really try to look into variety of model system to understand

because depending on what question you are asking you need to have appropriate model

system to understand that is when a Morgan came an American uhh geneticist and he started

using the most famous model system that we have on drosophila So he basically went with

what Sutton did using insects as a model but you found drosophila to be much much better

for simple reason one it has a shorter life span so you can cross them to have the next

generation and so on because genetics cannot be you know done without looking into the

generations and two the organism has got fewer number of chromosome

So basically he wanted you know organism that has fewer number of chromosome Therefore in

a wherever character that are linked to the chromosome or fewer therefore will be able

to understand better So what is shown on the top here in the in the slide on your right

side is uhh chromosome schematic of the chromosome from a female and the male uhh drosophila

which you know of course you have this like human you have that are depicted on either

side and then you have the sex chromosome which is XX or XY

So he has used this you know drosophila to understand the chromosomes and he is one who

really established what you call as a genetic linkage meaning there are different segments

of a chromosomes and these segments represent a character like what Mendel’s you know

said it could be a gene that determines your height or it could be a gene that determines

you know your any other phenotype for example in plants it could be the color of the plant

it could be the shape of the seed and so on and he said that they are physically connected

each other and then he also said in though they are physically connected when you have

a pair of chromosome which are homologous meaning identical but about to be separated

during the formation of the gametes each of the homologous could have what is called as

say variant of the gene

The other form of a given gene what you call as allele and there could be shuffling takes

place meaning there could be exchange of DNA material from one homologue to the other and

that we call as crossing over So he hypothesized everything by only looking at the chromosomes

in the fly and then during different (seg) you know generations and then looking at what

(we) how the fly look likes

So like Mendel he also selected uhh flies that have variants in terms of how do we look

like for example it could be the color of the eye it could be the shape of the of the

wing it could be the size of the fly itself their color body color and there are many

different uhh pattern that we will discuss uhh little later So he has used that to show

that all these phenotype just like Mendel did can run through in families meaning different

generations and they are linked to the chromosome uhh some of them the same chromosome Therefore

you can show that more often they are you know transmitted together right

So this is the major difference between Mendel and Morgan because mendel whatever character

he took it so happen or he has selected those character that are present on different chromosome

that is why his law the third law what you called as independent assortment applies because

that law applies to genes who govern you know characters the genes are present in during

chromosome that is why they are sorted independent of each other So this law does not apply two

genes present on the same chromosome There are because they would if they are closer

to each other they going to go together often or separated there may be cross over but it

cannot obey the law that he has given 9 is to 3 is to 3 is to 1 that applies only if

they are present on different chromosomes

So that is where morgan has really contributed to show the linkage and he gave what is called

as a say genetic distance between genes by looking into the recombination frequency and

so on and this model what he developed become very famous model and most of the genetic

uhh concepts and developmental biology what you call how the genes regulate development

how come from this beautiful in a system that is a contribution of Morgan

So they not only contributed in terms of developing model but they also trained their students

to ask more deeper fundamental questions some of them which they could not test One of his

students Morgan’s students you know later on to look at some other aspect but the concept

the very concept what is called as chromosome theory of inheritance meaning your cells do

have a genetic material which we call as chromosome and these you know chromosomes are transmitted

to the next generation and chromosomes have certain segments which dictate what would

you be your phenotype we call as chromosome theory of in a written and this is called

as theory then because it is purely observational

There is evidence to show indeed that is the case because they did not know what the chromosomes

are made up of and what to really dictates as to which phenotype should be there they

were not you know how clear about that but they made this theory but now you know certainly

the chromosomes are the basic material and these people that that you see in the screen

are the major contributors There are many other who I did not discuss but these people

are the major contributors for our understanding as to how the chromosomes contribute in terms

of you know your phenotype that goes from one generation to the other so that is a major

a contribution

As I told you these contributions are not only in the science but they also trained

the people so that is the that is where uhh Morgan’s legacy even today you see him because

uhh you know he has trained students who took up newer challenges and develop new model

depending on what kind of question they are asking and that let to discovery of genes

and DNA and so on So let us look in here for example what is shown here in the cartoon

is so for we spoke about the chromosome The chromosome theory of when inheritance but

you have pull out the DNA that DNA as I said as we know now has got segments which are

the functional unit what is called as gene say a chromosome could have thousands and

thousands of genes

Now the question is how did we really know that the chromosome is made up of DNA because

whatever uhh the previous section that we have seen whether is Boveri or Sutton or Morgan

They looked at something that are they are inside the cell that gives you particular

straining property which becomes compact you know segregating to the daughters to cell

there are dividing but they name it has chromosome whout knowing what it is it is like you are

seeing something but without knowing what it is Similar way you know really there are

many scientist who looked into what is this chromosome What is a chemical composition

of the chromosome and how uhh that chemical moiety or biomolecule that is present there

really gives the information as to what phenotype you should have

So that has come from again you know several scientist who came after morgan two of them

are uhh these people George wells and Edward Fleury These are the people who gave the theory

called one gene one enzyme hypothesis This you look into the text book even in biochemistry

textbook or genetics this how it will be called and is very very because they said that there

are certain segments in the chromosome that gives an information as to what protein should

be made and so happen here you know obviously that protein in an enzyme that the looked

at

Both of them are students of uhh morgan both of them were trained in drosophila and and

then all the genetics that we discussed uhh sometime back but they felt you know the how

to go deeper deeper than looking into just chromosomes and looking at you know next generation

what is phenotype We have understand how whatever that is there in the chromosome that dictates

as to how the organism the fly for example uhh behave or what phenotype it has So they

found that system the model system is good for genetics meaning looking at the chromosome

on segregation pattern but is not so good in terms of you know understanding what kind

of information that the chromosomes gives So with that available tools that they had

they could number go deeper So they looked at some system where they can go and study

for example you know proteins meaning enzymes their functions and so on

At the same time they use the same technique that Morgan used that is creating you know

mutations What he did was he looked into different flies where in there was natural variation

that variation resulted in different phenotype whether it is eye color or the body structure

or the wing shape and so on So they went for a system which of course can be you know (which

we) which you can create certain changes whatever the genetic material and then look at the

phenotype and then now go at the protein and study the protein So they selected system

called neurospora it is a it is a fungus uhh mold and there are forms what you call as

a uhh applied meaning just like a gamete like just one copy of the genome or deployed which

is two copies of the genome and so on and you can create mutations and then look into

isolate for exam you can grow them and you can extract protein from there and understand

the function of the protein

So they went and looked at the biochemistry enzyme activity and so on combining genetics

with bio-chemistry and they came up with clear understanding that there are certain phenotype

that are caused due to enzyme deficiency and these are linked just it could be one gene

which thus by then they have given this term called gene a segment which possibly gives

information as to what function you should do here it is a protein that as an enzyme

activity So they develop this particular model system to understand the protein So protein

became much easier for people to handle still DNA is for a way

So they started studying protein fat enough we will talking about little later uhh we

were able to sequence the protein uhh much earlier uhh we will that than we could sequence

the DNA So much of our understanding and the protein have come much before the DNA sequence

DNA structure was not even the RNA years old know structure or if sequence was sort solved

In that way they were pioneering in terms of uhh connecting the protein with a gene

Then we have people uhh again must have studied this in the text book uhh this is Avery MacLeod

and McCarty these three gentle man together in a proven that the DNA is the genetic material

Although the protein uhh uhh Wells and Laurie did say that protein uhh connects to the DNA

or gene without knowing what is the gene is but these are the three gentleman who really

you know established that DNA is a genetic material By then we know that you know all

the living system that as cells have got three major biomolecules the protein nucleic acid

and the lipid and they are able to uhh carbohydrate and so on and there were able to show that

it is not the protein but it is the DNA that gives the phenotypes

So you must have studied about how they have used the microbes that are virulent which

can kill the animal and they are able to separate the protein or labels protein and DNA mixture

them and then able to show uhh that DNA is a one that that that gives the phenotype the

virulence right So you can look into that I am not going to the detail but most of the

textbooks really talk about it

So what you will see now there is a shift So in the in the when the theory was about

the chromosome we looked that there mostly plant and insects being used to understand

how the chromosome functions but now you will find all of a sudden people are going to the

new system because the question that you ask is very very different you find that neurosporal

fungus was used and there you will find again quickly that these are microbes that are coming

in fact from uhh uhh the the concept called as molecular biology where you really look

into the molecule whether it is you know whether it is DNA or RNA or protein all these understanding

are come from microbes because they are much easier to handle and grow them in the culture

and then the complexity is less So you find now that you know really the understanding

of the microbes let to the field what si called as molecular biology that let to the genomic

cell comeback little later

Of course this is considered to be the landmark discovery There are controversies as well

that it is Watson and Crick uhh in 1953 who proposed model for the DNA So although the

Avery MacLeod McCarty they did say the DNA is a genetic material The structure and how

we that particular molecule can function genetic material was not understood until Watson and

Crick solved not solved a propose his model that is what shown here This is on the right

side of the screen what you see is that seminal paper published in nature just page uhh in

a proposed model for the DNA double helix it is model now you know that it is no longer

model that that is indeed the structure and that basically uhh gave an understanding has

to how the DNA has a genetic material can function because it is double helix

It is anti-parallel complement reverse complementarity all these things help the DNA to function

as genetic material because one of the strands can serve as a template to make a new strand

and likewise the new strand can be a DNA or RNA If it is RNA it is perfect copy of what

sequence is there and that can go on give the signal as to what protein it has to make

So in that way it was you know considered to be a land mark discovery and and in all

the textbook describe as to how important that discovery So that is the birth if what

you call as molecular biology So the moment we know that there are four basis and they

complementary to each other and base pair and form a structure like this anti-parallel

and then people just started studying into how the DNA is copied into another copy of

the DNA or to RNA and how really that functions as a biomolecule

So we are going to discuss now is about uhh 40 years of history where what you call as

molecular biology era so that basically plate the foundation for what you call as genomics

now so without this uhh revolution of what is called as molecular biology we would not

have reached uhh what you see as a genomics Let us see how this journey begins It all

started with Kornberg who looked at again this whatever you are talking about from 1946

to 1990 is going to be most of them are studies based on microbes whether it is microbes whether

is a phage bacteria and so on e coli and so on yeast and so on

So Kornberg is a one who really looked into the process of DNA being copied So he looked

at an enzyme which reach one of the strands and then makes a copy of it It is seminal

discovery again you we know because in terms of how the DNA may can be copied because that

is important for the cell to divide The cell has to divided as to make a copy of the entire

genome and then you know put them into two daughter cells that is how we grow So that

is fundamental for any living system whether you are multicellular or unicellular So it

is a seminal discovery that started with that

Then we came uhh Jacob and Monod because there are the people who really you know shown how

DNA is copied into what is called as messenger RNA or mRNA and what you study in textbook

what is called as Jocob-Monod pathway the Lac operon and so on are the discoveries which

talks about even how the gene is organized What are the different elements that control

the function of the gene and how mRNA is made copied and how the RNA is important for whatever

phenotype you see So that is very seminal discovery that came in 1961

Then we have this gentleman Marshall Nirenberg again uhh an American uhh scientist who desified

the genetic code the triplet the there three basis together gives a code as to what amino

acid should be made when the RNA translated meaning decoded and later of course we have

our uhh scientist of Indian origin uhh Khurana really helped in in a solving all the you

know that different codes code on that you have in the table they are the people who

solved it and but the siminal contribution that that three basis together form a come

from the study of Nirenberg

In 1970 there is a another landmark Here they looked at another enzyme which copies the

RNA into DNA what you called as reverse transcriptase This reverse transcriptase came from the group

Baltimore Delbanco and Temin they contributed in understanding a special polymerase which

you know copies the RNA into DNA that really helped us to understand you know how the virus

functions and how they are able to infect other cells the virus that have only RNA as

a genome and that is the discovery part but that really helped us to uhh make several

tools for example we understand now what are the RNA that we have we convert them into

DNA that is doable only by this particular enzyme called reverse transcriptase in that

way that is seminal

Then came in a 70 uhh Hamilton Smith discovered another enzyme again from microbe These are

called as restriction enzymes you know now that these are the enzyme that can uhh identify

a unique set of sequence in the DNA and make a cut tab and regardless how much enzyme you

add these enzymes would cut only if subsequence is present not otherwise So that really revolutionized

uhh you know the way we understand DNA because the so called recombinant DNA meaning combining

to you know DNA from two different source is possible because of this enzyme because

now we can cut the enzyme and join them sticks them together so that again is a fantastic

achievement and that let to you know for the first time Paul Berg made a DNA from two different

source what you called as rDNA or recombinant DNA that is again a seminal discovery that

you can sticks the DNA together and form a new synthetic DNA having different source

is something amazing because that is what we use every day now in recombinant DNA technology

or molecular biology genomics and so on

In 77 as again a landmark uhh Gilbert and Sanger came together and proposed a method

or a established method to sequence the DNA until then we are talking about DNA as a nucleic

acid without really having no tool to understand what is a sequence much of the protein sequence

are known from protein sequence but these are the people came up with the method that

we call as dideoxy sequencing which is very efficient tool for sequencing the DNA They

proposed and they establish they are shown that can be used and that let to you know

enormous uhh uhh data because then every lab started sequencing DNA and RNA because now

you have reverse transcriptase So we can convert the RNA into DNA and sequence the DNA

So basically you can understand the sequence of RNA from from DNA using the same method

that again is a seminal contribution and last but not the least is the contribution from

Kary Mullis we used all this principle right from the 1956 or Arthur Kornberg principal

that there are enzyme that copy the DNA to the double helix concept and so on What he

came up with his simple approach to make millions of copies of a small segment of the DNA using

an enzyme DNA polymerase and the four basis of the DNA and we can make in a tube quickly

in 5-6 hours in enormous copies that that is these method has really changed the way

you look at the DNA because earlier tube used to put the DNA inside a host for most often

E coli and allow e coli to grow and make copies on its own way so that is you know removed

all this botel naxen and you are able to make millions of copies of a small segment so which

is now being used every day in clinic in labs for diagnosis for any other such kind of approach

So in that way the contribution that we have talked about from 1956 to uhh nearly 1980s

is something which you call as molecular biology era because they are able to understand analyse

and manipulate the DNA and that led to the field what is called as genomics and that

we will see in our next class